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A model to predict the development of mental status changes of unclear cause after liver transplantation
A Model to Predict the Development of Mental Status Changes of Unclear Cause After Liver Transplantation Fasiha Kanwal,* David Chen,‡ Lena Ting,§ Jeffrey Gornbein,§ Sammy Saab,*† Francisco Durazo,*† Hasan Yersiz,† Douglas Farmer,† R. Mark Ghobrial,† Ronald W. Busuttil,† and Steven-Huy Han*† Postoperative mental status changes are common after liver transplantation (LT). A clear cause of these mental status changes cannot be identified in a significant proportion of patients. In adult liver transplant recipients, our goals are to: (1) identify independent predictors for the development of post-LT mental status changes of unclear cause and (2) derive a practical formula to predict the risk for developing this complication by using simple clinical parameters. Eligible patients had documented mental status changes of at least 3 days’ duration, occurring within 1 month of LT. Exclusion criteria were known structural brain disorders, major organ dysfunction, or metabolic causes of altered mentation. Age- and sex-matched controls were liver transplant recipients without post-LT neurological sequelae. Data were collected on preoperative, intraoperative, and postoperative variables. Univariate and multivariate analyses were performed to detect factors predictive of the development of post-LT mental status of unclear cause. There were 40 cases and 40 controls. Independent predictors of mental status changes of unclear cause included alcoholic and metabolic liver diseases; pre-LT mechanical ventilation; Model for End-Stage Liver Disease (MELD) score greater than 15; and nonelective LT. Using these four preoperative factors, a simple predictive rule was developed. Risk for developing altered mental status of unclear cause after LT was 78% to 89% if all four predictors were present versus 0.8% to 2.4% if no predictors were present. In conclusion, alcoholic and metabolic liver diseases, pre-LT mechanical ventilation, MELD score greater than 15, and nonelective LT are independent predictive factors for post-LT altered mental status changes of unclear cause. A simple model can be used to calculate the risk for developing altered mental status post-LT. (Liver Transpl 2003;9:1312-1319.)
From the *Division of Digestive Diseases, †Dumont- University of California at Los Angeles Liver Transplant Center, Pfleger Liver Institute; and Departments of ‡Internal Medicine and §Biomathematics, David Geffen School of Medicine at University of California at Los Angeles, CA. Supported in part by the Talal A. Bakr Fellowship in Hepatology (F.K.) and Schering/American Association for the Study of Liver Diseases Advanced Hepatology Fellowship (F.K.). Address reprint requests to Steven-Huy Han, MD, Dumont-UCLA Liver Transplant Center, Pfleger Liver Institute, 200 Medical Plaza, Ste 214, Los Angeles, CA 90095-7302. Telephone: 310-206-6705; FAX: 310-206-4197; E-mail: [email protected]. Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0912-0011$30.00/0 doi:10.1016/j.lts.2003.09.023
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eurological complications are encountered commonly in patients undergoing liver transplantation (LT), with a reported incidence of 13% to 42%.1-6 These complications are a major cause of morbidity and mortality after LT.7 In addition, post-LT neurological complications increase health care costs (mainly because of prolonged hospitalization) and worsen the health-related quality of life of these patients.8 The most frequent clinical presentations are mental status changes (ranging from delirium to frank coma) with or without seizures.9,10 Causes of mental status changes post-LT are diverse and include factors related to recipient pre-LT status; intraoperative factors; and post-LT factors, including anoxia, cerebrovascular accidents, primary graft nonfunction, renal failure, sepsis, central pontine myelinosis, and medications, specifically immunosuppressive drugs.7 However, in a proportion of post-LT patients, a clear cause for their altered sensorium cannot be identified. In this subset, even with normal blood levels, immunosuppressive medications may be the culprit. However, dose reduction or discontinuation improves symptoms in some, but not all, patients,10 indicating that other factors may have a role, i.e., the cause may be multifactorial. Nevertheless, some liver transplant recipients seem to be more susceptible to developing these mental status changes than others. In addition, these mental status changes often are unpredictable and can be difficult to manage. Aims of this case-control study are to: (1) identify predictors for the development of post-LT mental status changes of unclear cause in adults undergoing LT and (2) derive a practical formula to predict the risk for developing this complication in liver transplant recipients by using simple clinical parameters.
Patients and Methods We retrospectively reviewed medical records of 500 consecutive adults who underwent LT at the Dumont-University of California at Los Angeles Liver Transplant Center between July 1, 1999, and December 31, 2001. Approval to conduct this study was granted by our institutional review board before commencement.
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Study Patients Patients were selected as cases if they had documented mental status changes lasting a minimum of 3 days and occurring within 1 month of LT. This time frame was chosen because the majority of neurological complications after LT have been reported to occur within the first month, and a minimum duration of 3 days was selected to enhance the specificity, as well as clinical significance, of the diagnosis. Patients were excluded if they had undergone a second or third LT or had mental status changes documented in the medical records as attributed to: (1) structural brain disorders, defined as cerebrovascular accidents, tumors, or central pontine myelinosis; (2) major organ dysfunction, including hepatic (e.g., primary graft nonfunction, hepatic artery thrombosis requiring re-LT), cardiac (e.g., recent myocardial infarction resulting in hemodynamic instability, cardiogenic shock), and pulmonary failure (e.g., adult respiratory distress syndrome); patients with renal failure undergoing dialysis and those requiring mechanical ventilation secondary to altered mental status were included in the study; (3) anoxic encephalopathy, defined as a previous significant episode of brain anoxia or radiological evidence of anoxic-ischemic brain damage; (4) septic encephalopathy, defined as mental status changes in critically ill patients with evidence of sepsis; (5) central nervous system infections; and (6) obvious metabolic alteration, defined as abnormalities in serum electrolyte, creatinine, blood urea nitrogen, and ammonia levels at the time of neurological complications. Of the initial 500 patients screened, 40 patients were found to be eligible as cases.
Controls Controls were selected from the initial 500 patients screened. For each case, we selected an age- and sex-matched control patient (1:1 ratio; n ⫽ 40) undergoing primary LT within the study period without documented mental status changes.
Definition of Mental Status Changes Medical records of all patients were reviewed for such key words as “confused,” “disoriented,” “agitated,” “delirious,” and “stuporous.” When these words appeared in the medical records, subsequent progress notes were reviewed to determine the duration and clinical presentation of these mental status changes. Patients were classified as having one of the following clinical presentations: (1) confusion or disorientation, (2) agitation and/or delirium, (3) stupor, or (4) coma. In patients without precise documentation of clinical presentation, we identified the degree of dysfunction by using predefined standardized definitions derived from previously described literature.10,11
Data Collection Clinical data for preoperative, intraoperative, and postoperative variables previously identified as potential predictors of post-LT mental status changes of unclear cause5,10,12-16 were collected for all cases (n ⫽ 40) and controls (n ⫽ 40) and
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entered into an Excel (Microsoft Corp, Redmond, WA) database by two of the authors (F.K. and D.C.).
Clinical Variables Preoperative clinical variables included patient ethnicity, cause of liver disease, biochemical liver and renal function tests obtained within 1 month of LT, Model for End-Stage Liver Disease (MELD) score immediately before LT, presence or absence of previous episodes of hepatic encephalopathy (in the former case, total duration and grade of hepatic encephalopathy immediately before LT according to established criteria),17 presence or absence of a transjugular intrahepatic portosystemic shunt, elective (defined as patients called in from home for LT) versus nonelective LT (defined as those undergoing LT while in the intensive care unit [ICU] or hospital), length of pre-LT ICU stay, presence or absence of renal failure requiring dialysis therapy, presence or absence of mechanical ventilation, presence or absence of variceal bleeding, and presence or absence of significant hypotension requiring pharmacological blood pressure support. In addition, changes in serum sodium concentrations were noted for all patients, when available. Intraoperative variables included cold ischemia time, use of split- or whole-organ allograft, length of surgery, units of blood products transfused, warm ischemia time, and presence or absence of reperfusion syndrome. Postoperative variables included primary immunosuppressive, mean as well as highest trough blood level of immunosuppressive medication, serum cholesterol and magnesium levels, use or nonuse of mycophenolate mofetil (MMF), presence or absence of renal failure, allograft dysfunction, and episodes of acute cellular rejection. Only data predating the onset of mental status changes were recorded for study patients.
Patient Categories Causes of underlying liver disease were grouped into six categories. Categories included chronic viral hepatitis (B and C), alcoholic liver disease, cryptogenic and nonalcoholic fatty liver disease, cholestatic and autoimmune liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis), metabolic liver diseases (hereditary hemochromatosis, Wilson’s disease, ␣1-antitrypsin deficiency), and fulminant hepatic failure. Patients with a diagnosis of both alcoholic liver disease and chronic hepatitis C were analyzed in the category of alcoholic liver disease because it was believed the influence of alcoholism would have a more significant impact on altered mental status than chronic hepatitis C within the first month post-LT.
Statistical Methods SAS (SAS Institute, Cary, NC) software package was used for statistical analysis. Data are expressed as percentages for categorical variables (e.g., ethnicity, cause of liver disease) and medians for continuous variables (e.g., creatinine level,
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MELD score). MELD score was dichotomized at 15 for the multivariate model because a MELD value of 15 best separated controls from cases when using MELD alone. Univariate analyses identified correlates of post-LT mental status changes of unclear cause by using Wilcoxon’s rank-sum test for continuous variables and Chi-squared test for categorical variables. Thereafter, all variables univariately significant at P less than .15 were considered for the multivariate logistic regression analysis to determine independent predictors of mental status changes of unclear cause post-LT. Variables identified to have an independent relationship with post-LT mental status changes of unclear cause were used to construct a clinical prediction rule by dividing each  coefficient ( ⫽ log odds ratio) by the smallest  coefficient, then rounding the value to the nearest integer to give a score to each variable. Adding individual scores resulted in a sum total score for each patient, depending on the number of risk factors present or absent. A predicted risk for developing post-LT mental status changes of unclear cause then was calculated for each individual score. The diagnostic value of the logistic model was assessed by calculating the area under the receiver operating characteristic (ROC) curves. An ROC area of 1.0 is characteristic of an ideal test or model, whereas an area of 0.5 indicates a test or model of no diagnostic value. The ROC analysis also identified the total raw score threshold (cutoff point) with the best diagnostic sensitivity and specificity, which also are reported. Unweighted accuracy also is reported and is defined as accuracy ⫽ (sensitivity ⫹ specificity)/2.
Results Study Population Table 1 lists clinical characteristics and underlying causes of liver disease of patients studied. Mean age of the study population was 54 ⫾ 7.8 (SD) years. There were 31 men (77.5%) and 9 women (22.5%) in both study patients and controls. Ethnic distribution of the two groups was similar. All liver transplant recipients were managed according to standardized protocols at our institution, including immunosuppressive medications and ICU care in the immediate post-LT period, with transfer to a stepdown unit when clinically indicated. The primary immunosuppressive regimen in all patients consisted of tacrolimus and corticosteroids. Description of Mental Status Changes In 40 cases, primary mental status changes manifested as confusion or disorientation (n ⫽ 26), delirium (n ⫽ 8), stupor (n ⫽ 4), coma (n ⫽ 1), and confusion with seizure (n ⫽ 1). Head computed tomography or magnetic resonance imaging was performed in 26 of 40 cases (65%). Findings were reported as normal (n ⫽
10), nonspecific with or without atrophy (n ⫽ 9), old infarct (n ⫽ 3), and white matter changes consistent with calcineurin inhibitor toxicity (n ⫽ 4). Brain imaging was not performed in 14 patients for reasons that could not be completely ascertained on medical record review. However, 8 of these 14 patients had shortlasting (3 to 4 days, n ⫽ 3), mild (n ⫽ 2), intermittent (n ⫽ 2), or fluctuating (n ⫽ 1) mental status changes, and 2 patients responded to low doses of antipsychotic medications. In 9 of 40 patients, primary immunosuppression was changed from tacrolimus to cyclosporine, with noticeable improvement in symptoms in 6 patients. Symptoms lasted for a median of 14 days (interquartile range, 7 to 30 days). Two patients developed permanent neurological symptoms (cortical blindness and dysarthria). Predictors of Mental Status Changes and Estimation of the Model Univariate analyses. Univariate analyses identified significant differences between the two study groups in 10 clinical variables. Table 2 lists results of univariate analyses. All variables except for acute rejection were present pre-LT. There were statistically significant differences in causes of liver disease between study patients and controls. In the control group, chronic viral hepatitis was the most common cause (62.5%), followed by cryptogenic/nonalcoholic fatty liver disease (12.5%) and alcoholic liver disease (12.5%). In study patients, chronic viral hepatitis again was the most common (37.5%) underlying liver disease. However, in contrast to the control group, alcoholic liver disease was more prevalent (30%), followed by metabolic liver diseases (15%) and cryptogenic nonalcoholic fatty liver disease (2.5%). Compared with controls, study patients were more likely to have a greater severity of underlying liver disease, higher grade of hepatic encephalopathy, and greater pre-LT serum creatinine level. Other pre-LT clinical variables identified to be statistically significant (P ⬍ .05) included number of ICU days, presence of significant hypotension, need for dialysis therapy, and mechanical ventilation. There was no difference in the median highest trough blood level of immunosuppressive medication between cases and controls (P ⫽ .07). Multivariate analyses. Seventeen variables were considered in an additive logistic regression model. Preoperative variables were cause of liver disease, serum creatinine level, MELD score, encephalopathy grade and duration, elective versus nonelective LT, presence or absence of renal failure requiring dialysis therapy, mechanical ventilation, hypotension, and variceal
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Table 1. Sample Characteristics
Variable Age (yr) Male gender Mental status changes Confusion/disorientation Delirium Stupor Coma Seizure* Duration of symptoms (d) Ethnicity Caucasian Latino Hispanic African American Asian Others Diagnoses Cryptogenic cirrhosis NAFLD ETOH Hep C ⫹ ETOH FHF Hemochromatosis ␣1-Antitrypsin deficiency Wilson’s disease Chronic hepatitis C Chronic hepatitis B PBC PSC Autoimmune hepatitis Polycystic liver disease
Overall (n ⫽ 80)
Study Patients (n ⫽ 40)
Controls (n ⫽ 40)
P
54 ⫾ 7.8 62 (77.5)
53.4 ⫾ 8.0 31 (77.5)
53.9 ⫾ 7.7 31 (77.5)
.836 1.000
37 (46) 19 (24) 6 (8) 2 (2) 9 (11) 7 (9)
18 (45) 8 (20) 4 (10) 2 (5) 5 (12.5) 3 (7.5)
19 (47.5) 11 (27.5) 2 (5) 0 (0) 4 (10) 4 (10)
5 (6.25) 1 (1.25) 9 (8.75) 8 (10) 3 (3.75) 5 (6.25) 1 (1.25) 1 (1.25) 31 (38.75) 9 (11.25) 3 (3.75) 1 (1.25) 2 (2.5) 1 (1.25)
0 (0) 1 (2.5) 7 (17.5) 5 (12.5) 2 (5) 4 (10) 1 (2.5) 1 (2.5) 12 (30) 3 (7.5) 1 (2.5) 0 (0) 2 (5) 1 (2.5)
5 (12.5) 0 (0) 2 (5) 3 (7.5) 1 (2.5) 1 (2.5) 0 (0) 0 (0) 19 (47.5) 6 (15) 2 (5) 1 (2.5) 0 (0) 0 (0)
26 (65) 8 (20) 4 (10) 1 (2.5) 1 (2.5) 14 (7-30) .694
.027
NOTE. Values expressed as mean ⫾ SD, number (percent), or median (interquartile range). Abbreviations: NAFLD, nonalcoholic fatty liver disease; ETOH, alcohol-induced liver disease; Hep C, hepatitis C; FHF, fulminant hepatic failure; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. *Seizures with mental status change.
bleeding. Intraoperative variables included warm ischemia time and presence or absence of reperfusion syndrome. Postoperative variables were highest trough blood level of immunosuppressive medication, use of MMF, presence and absence of renal failure, allograft dysfunction, and acute cellular rejection. Of these candidate variables, four variables were identified as independent additive predictors of post-LT mental status changes of unclear cause in the multivariate logistic regression analysis (Table 3). These variables were: (1) cause of underlying liver disease, specifically alcoholic and metabolic liver disease diagnosis (odds ratio, 9.89; 95% confidence interval [CI], 2.44 to 40.05; P ⫽ .001); (2) pre-LT mechanical ventilation (odds ratio, 4.5; 95% CI, 1.08 to 18.72; P ⫽
.039); (3) MELD score greater than 15 (odds ratio, 4.15; 95% CI, 0.962 to 17.958; P ⫽ 0.056); and (4) nonelective LT (odds ratio, 2.28; 95% CI, 0.709 to 7.378; P ⫽ 0.16). The raw mental status risk score (logit) based on this model is calculated as follows: Risk score ⫽ ⫺ 2.57 ⫹ 1.50 (mechanical ventilation) ⫹ 2.29 (selected diagnoses) ⫹ 1.42 (MELD ⬎ 15) ⫹ 0.83 (nonelective LT)
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Table 2. Univariate Summary: Risk Factors for Post-LT Mental Status Change Study Patients (n ⫽ 40)
Variables Diagnoses Cryptogenic/NAFLD ETOH/Hep C ⫹ ETOH* FHF Hemochromatosis/A1AT/Wilson*† Chronic hepatitis B or C PBC/PSC/autoimmune Polycystic liver disease MELD score Creatinine (mg/dL) Encephalopathy grade 3-4 Dialysis Ventilation Hypotension Nonelective LT Acute rejection Days in ICU
Controls (n ⫽ 40)
P .027
1 (2.5) 12 (30) 2 (5) 6 (15) 15 (37.5) 3 (7.5) 1 (2.5) 24 (19.7-35) 1.65 (1.1-2.3) 13 (32.5) 12 (30) 17 (42.5) 7 (17.5) 30 (75) 1 (9) 3 (0-8)
5 (12.5) 5 (12.5) 1 (2.5) 1 (2.5) 25 (62.5) 3 (7.5) 0 (0) 17.5 (11-27.5) 1.05 (0.7-1.7) 5 (12.5) 2 (5) 4 (10) 0 (0) 16 (40) 11 (27.5) 0 (0-0)
.004 .009 .0004 .003 .002 .01 .003 .005 .0004
NOTE. Values expressed as number (percent) or median (interquartile range). Abbreviations: NAFLD, nonalcoholic fatty liver disease; ETOH, alcohol-induced liver disease; Hep C, hepatitis C; FHF, fulminant hepatic failure; A1AT, ␣1-antitrypsin deficiency; Wilson, Wilson’s disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; autoimmune, autoimmune hepatitis. *Positive diagnosis in multivariate model. †Four study patients had a diagnosis of hemochromatosis, defined by hepatic iron index greater than 1.9. Wilson’s disease and ␣1-antitrypsin deficiency were the underlying liver diseases in another two study patients. One patient in the control group had hemochromatosis (hepatic iron index ⬎ 1.9).
In this model, mechanical ventilation ⫽ 1 if there was mechanical ventilation pre-LT, and 0 otherwise. Selected diagnoses ⫽1 for alcohol-related liver disease or metabolic liver disease, and 0 otherwise. MELD greater than 15 ⫽ 1 if MELD score was greater than 15, and 0 otherwise. Nonelective LT ⫽ 1 for nonelective LT, and 0 otherwise. The ROC area for this model is 0.826, implying approximately 83% accuracy. Using the optimal raw score of 0.544 as the threshold (cutoff point) for predicting mental status change, model sensitivity is 73% and specificity is 85% in predicting the occurrence of post-LT mental status changes of unclear cause. Unweighted accuracy is 79%. To adapt the model to routine clinical application,
predicted risk for experiencing post-LT mental status changes of unclear cause for an individual patient was calculated based on the presence or absence of these prognostic variables. The reference patient did not have alcoholic or metabolic liver disease, was not on mechanical ventilation at LT, had a MELD score of 15 or less, and underwent an elective LT. Table 4 assigns a score to each of the four variables (see Methods section): alcoholic and metabolic liver diseases ⫽ 3, mechanical ventilation at LT ⫽ 2, MELD score greater than 15 ⫽ 2, and nonelective LT ⫽ 1. The reported incidence of post-LT neurological complications varies from 13.2% to 42% in the literature. To our knowledge, there are no studies reporting
Table 3. Multivariate Logistic Regression Model Summary for Post-LT Mental Status Change Variable Mechanical ventilation pre-LT Selected diagnoses* MELD score ⬎ 15 Nonelective LT
Odds Ratio
95% CI for Odds Ratio
P
4.500 9.895 4.157 2.287
(1.081-18.724) (2.444-40.054) (0.962-17.958) (0.709-7.378)
.039 .001 .056 .16
*Alcohol-related liver disease (including patients with alcohol and chronic hepatitis C infection, see text) and metabolic liver disease.
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Table 4. Mental Status Change Score Assignment Variable
Score
Selected diagnosis* Mechanical ventilation pre-LT MELD score ⬎ 15 Nonelective LT
3 2 2 1
*Alcohol-related liver disease (including patients with alcohol and chronic hepatitis C infection; see text) and metabolic liver disease.
the incidence of post-LT mental status changes of unclear cause; however, extrapolation from published studies suggests an incidence ranging from 10% to 20%.9,10 Applying the lower estimate of this incidence (10%), the predicted risk for experiencing post-LT mental status changes of unclear cause with a score of 1 is 1.9%. This risk increases to 78% with a maximum score of 8. For example, a patient undergoing LT on a nonelective basis has a 2% chance of developing post-LT mental status changes. However, a patient undergoing nonelective LT for alcoholic liver disease with a MELD score greater than 15 and requiring mechanical ventilation pre-LT has a 78% risk for developing these complications. These predicted risks increase to 4% (with a score of 1) and 89% (with a score of 8) if a greater incidence rate (20%) of post-LT mental status changes of unclear cause is applied. Table 5 lists average predicted risks for each individual score across a
Table 5. Predicted Risk for the Development of Post-LT Mental Status Change Average Predicted Risk Total Score 0 1 2 3 4 5 6 7 8
Incidence ⫽ 0.10
Incidence ⫽ 0.15
Incidence ⫽ 0.20
0.008 0.019 0.035 0.075 0.146 0.262 0.449 0.606 0.779
0.013 0.029 0.054 0.114 0.214 0.361 0.564 0.710 0.848
0.018 0.041 0.075 0.154 0.278 0.445 0.647 0.776 0.888
NOTE. Average predicted risk for each individual score across a range of incidence rates of post-LT mental status changes of unclear cause.
Figure 1. Average predicted risk for each individual score across a range of incidence rates of post-LT mental status changes of unclear cause. Risk increases with higher scores. Changes versus scores derived from the model.
range of incidence rates of post-LT mental status changes of unclear cause. Figure 1 shows the distribution of predicted risks at various scores.
Discussion Recipients of liver transplants experience the greatest incidence of post-LT neurological complications compared with recipients of other organ transplants.7 This greater susceptibility may be caused by various preoperative and postoperative factors, including metabolic and circulatory disorders or immunosuppressive agent toxicity.7,10,15 Furthermore, in a significant proportion of patients, a cause for their altered mental status is not clear, especially while being evaluated in real time. The most frequent clinical manifestations are mental status changes,9,10 and these often are unpredictable and difficult to manage. In our study, patients with post-LT mental status changes of unclear cause had a significantly greater degree of liver disease severity and were medically more unstable before LT than controls. These findings are consistent with those of previous studies.5,10,12-16 We identified four variables as independent predictors of post-LT mental status changes of unclear cause. These variables were cause of liver disease (alcoholic liver disease and metabolic liver diseases, specifically), pre-LT mechanical ventilation, MELD score greater than 15, and nonelective LT. The last two of these four variables (MELD score ⬎ 15 and nonelective LT) did not reach statistical significance (P ⫽ .056 and P ⫽ .16, respectively), but were included in the logistic regression model for clinical and practical reasons. Pre-LT liver disease severity, measured by Child-Pugh-Turcott score and United Network for Organ Sharing status, has been
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shown to predict post-LT morbidity,18 including post-LT neurological complications.5 Nonelective LT was included in our model because it correlated strongly with other predictive factors identified in univariate analyses. ROC analysis indicates that our model is valid (pending replication by others), and these four variables predict the development of post-LT mental status changes of unclear cause with approximately 83% accuracy in this study. According to our model, patients with all four risk factors have a score of 8 of 8 and a 78% to 90% risk for developing post-LT mental status changes lasting at least 3 days up to 1 month post-LT. Conversely, patients with no risk factors (score ⫽ 0) have a significantly lower risk (8% to 18%) for this complication. Several of our findings are worthy of further commentary. First, the majority of patients (65%) with mental status changes of unclear cause had confusion or disorientation, with only a few patients experiencing a greater degree of dysfunction. These changes, although reversible in all except two patients, lasted for a median of 2 weeks. This suggests that despite a relatively mild degree of dysfunction in most patients, mental status changes can result in significant comorbidity and may have implications as far as overall resource utilization and cost of care are concerned. Second, alcoholic liver disease was identified as an independent predictor of mental status changes in the post-LT period. This is in agreement with several other studies that reported a greater incidence of post-LT neurological complications, including acute confusional states, in patients undergoing LT for alcoholic liver disease.5,12,19 Interestingly, we also found that a significantly greater number of study subjects underwent LT for underlying metabolic liver disease (hemochromtosis, n ⫽ 4; ␣1-antitrypsin deficiency, n ⫽ 1; and Wilson’s disease, n ⫽ 1) than controls (␣1-antitrypsin deficiency, n ⫽ 1). An association between metabolic liver disease and post-LT neurological complications has not been described previously in the literature. The diagnosis of primary hemochromatosis in our patients was based on a hepatic iron index greater than 1.9. Hereditary hemochromatosis gene mutation testing was not performed. It is possible that increased hepatic iron levels in these individuals resulted from underreported alcohol use in the past or cirrhosis itself.20 We could not confirm the former possibility because of the retrospective nature of the study. Future prospective studies are needed to evaluate this potential association between metabolic liver disease and post-LT neurological complications. The negative impact of pre-LT mechanical ventilation on several post-LT out-
comes, including patient and graft survival, is well described.21,22 We found pre-LT mechanical ventilation to be associated with the development of post-LT altered mental status. None of the intraoperative variables assessed correlated significantly with the development of post-LT altered mental status of unclear cause in our analyses. Of note, tacrolimus blood levels were not identified as significant predictive factors of post-LT altered mental status in both univariate and multivariate analyses. There was no difference in the highest trough blood level of tacrolimus between groups. Despite this, mental status improved in six of the nine patients on change in primary immunosuppression. These findings are corroborated by other investigators,10,23 indicating a greater sensitivity to calcineurin inhibitors and potentially other factors in some liver transplant recipients. The present study is the first in which practical clinical variables are used to identify patients at high risk for developing post-LT mental status changes of unclear cause. Patients with a 50% or greater predicted risk for experiencing post-LT altered mental status identified by our model might be appropriate candidates for interventions designed to prevent or reduce the incidence and impact of these complications. Strategies may include close monitoring of these high-risk patients, correction of concomitant factors (electrolyte imbalance, sepsis), and use of tacrolimus-sparing agents (e.g., MMF) alone or as part of combination immunosuppressive therapy. An open prospective study of 20 liver transplant recipients has shown that MMF appears to be a safe and potentially useful adjuvant immunosuppressive agent for rescue and maintenance therapy that will not increase the risk for neurotoxicity.24 Our study has several limitations. First, cases may not be representative of all liver transplant recipients with mental status changes of otherwise unclear cause because some patients may have been undiagnosed or undocumented. In addition, brain imaging was not obtained in a proportion of our cases (14 of 40 patients), leading to a possibility that we included some patients as cases who otherwise may have had an identifiable cause of altered mental status. However, these patients were included in the analysis as cases because undergoing head computed tomography and/or magnetic resonance imaging was not one of the inclusion criteria for our case selection, and these patients did not have an identifiable cause of altered mental status on review of medical records. Moreover, in the absence of progressive or irreversible neurological signs, major structural damage could be excluded on clinical grounds.
Altered Mental Status Post-Liver Transplant
Our study also was limited by the retrospective nature of data collection. We tried to control for differential measurement bias by standardizing definitions of variables, supplementing key variables with data from several sources, and using data recorded before mental status changes developed in cases. Despite this, we may have misclassified the clinical presentation in some patients. However, we believe this does not change the validity of our results. Despite these limitations, we attempted to identify all patients who were documented to have mental status changes of unclear cause after LT. We selected our controls from the population of liver transplant recipients who were at risk for the outcome, with matching to ensure that cases and controls are similar with respect to major constitutional variables (age, sex, and era of LT). In addition, the present study is the first in which practical clinical variables are incorporated into a simple rule to predict the risk for the development of a common problem after LT: mental status changes. In conclusion, our model can be applied easily to identify patients at high risk for developing mental status changes post-LT. Prospective validation of this rule is still needed. Future studies should address whether early identification of and intervention in patients at high risk for the development of neurological complications post-LT will reduce the morbidity, mortality, and economic costs associated with neurological complications in liver transplant recipients.
8. 9.
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24.
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ME. Neurological complications of orthotopic liver transplantation. Mt Sinai J Med 1994;61:63-69. Bechstein WO. Neurotoxicity of calcineurin inhibitors: Impact and clinical management. Transpl Int 2000;13:313-326. Guarino M, Stracciari A, Pazzaglia P, Sterzi R, Santilli I, Donato F, D’Alessandro R. Neurological complications of liver transplantation. J Neurol 1996;243:137-142. Mueller AR, Platz KP, Bechstein WO, Schattenfroh N, St Tenburg-Didinger G, Blumhardt G, et al. Neurotoxicity after orthotopic liver transplantation. A comparison between cyclosporine and FK506. Transplantation 1994;58:155-169. Bleck TP. Levels of consciousness and attention. In: Goetz CG (ed): Textbook of clinical neurology (ed 1). Philadelphia: Saunders, 1999:2-3. Beltran J, Taura P, Garcia-Valdecasas JC, Navasa M, Zavala E, Anglada T, et al. Neurological disorders and intraoperative factors in liver transplantation. Transplant Proc 1993;25:17491750. Jain A, Brody D, Hamad I, Rishi N, Kanal E, Fung J. Conversion to Neoral for neurotoxicity after primary adult liver transplantation under tacrolimus. Transplantation 2000;69:172-176. de Groen PC, Aksamit AJ, Rakela J, Forbes GS, Krom RA. Central nervous system toxicity after liver transplantation: The role of cyclosporin and cholesterol. N Engl J Med 1987;317: 861-866. Erer B, Polchi P, Lucarelli G, Angelucci E, Baronciani D, Galimberti M, et al. Cyclosporin associated neurotoxicity and ineffective prophylaxis with clonazepam in patients transplanted for thalassemia major: Analysis of risk factors. Bone Marrow Transplant 1996;18:157-162. Berden JH, Hoitsma AJ, Merx JL, Keyser A. Severe central nervous system toxicity associated with cyclosporin. Lancet 1985;1;219-220. Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood transfusion. N Engl J Med 1966;274:473-481. Kim WR, Dickson ER. Timing of liver transplantation. Semin Liver Dis 2000;20:451-464. Buis CI, Wiesner RH, Krom RA, Kremers WK, Wijdicks EF. Acute confusional state following liver transplantation for alcoholic liver disease. Neurology 2002;59; 601-605. Cotler SJ, Bronner MP, Press RD, Carlson TH, Perkins JD, Emond MJ, et al. Endstage liver disease without hemochromatosis associated with elevated hepatic iron index. J Hepatol 1998; 29:257-262. Eckhoff DE, Pirsch JD, D’Alessandro AM, Knechtle SJ, Young CJ, Geffner SR, et al. Pretransplant status and patient survival following liver transplantation. Transplantation 1995;60:920925. Markmann JF, Gornbein J, Markowitz JS, Levy MF, Klintmalm GB, Yersiz H, et al. A simple model to estimate survival after retransplantation of the liver. Transplantation 1999;67:422430. Wijdicks EF, Wiesner RH, Dahlke LJ, Krom RA. FK506 induced neurotoxicity in liver transplantation. Ann Neurol 1994;35:498-501. Klupp J, Bechstein WO, Platz KP, Keck H, Lemmens HP, Knoop M, et al. Mycophenolate mofetil added to immunosuppression after liver transplantation. Transplant Int 1997;10:223238.
From the *Division of Digestive Diseases, †Dumont- University of California at Los Angeles Liver Transplant Center, Pfleger Liver Institute; and Departments of ‡Internal Medicine and §Biomathematics, David Geffen School of Medicine at University of California at Los Angeles, CA. Supported in part by the Talal A. Bakr Fellowship in Hepatology (F.K.) and Schering/American Association for the Study of Liver Diseases Advanced Hepatology Fellowship (F.K.). Address reprint requests to Steven-Huy Han, MD, Dumont-UCLA Liver Transplant Center, Pfleger Liver Institute, 200 Medical Plaza, Ste 214, Los Angeles, CA 90095-7302. Telephone: 310-206-6705; FAX: 310-206-4197; E-mail: [email protected]. Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0912-0011$30.00/0 doi:10.1016/j.lts.2003.09.023
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eurological complications are encountered commonly in patients undergoing liver transplantation (LT), with a reported incidence of 13% to 42%.1-6 These complications are a major cause of morbidity and mortality after LT.7 In addition, post-LT neurological complications increase health care costs (mainly because of prolonged hospitalization) and worsen the health-related quality of life of these patients.8 The most frequent clinical presentations are mental status changes (ranging from delirium to frank coma) with or without seizures.9,10 Causes of mental status changes post-LT are diverse and include factors related to recipient pre-LT status; intraoperative factors; and post-LT factors, including anoxia, cerebrovascular accidents, primary graft nonfunction, renal failure, sepsis, central pontine myelinosis, and medications, specifically immunosuppressive drugs.7 However, in a proportion of post-LT patients, a clear cause for their altered sensorium cannot be identified. In this subset, even with normal blood levels, immunosuppressive medications may be the culprit. However, dose reduction or discontinuation improves symptoms in some, but not all, patients,10 indicating that other factors may have a role, i.e., the cause may be multifactorial. Nevertheless, some liver transplant recipients seem to be more susceptible to developing these mental status changes than others. In addition, these mental status changes often are unpredictable and can be difficult to manage. Aims of this case-control study are to: (1) identify predictors for the development of post-LT mental status changes of unclear cause in adults undergoing LT and (2) derive a practical formula to predict the risk for developing this complication in liver transplant recipients by using simple clinical parameters.
Patients and Methods We retrospectively reviewed medical records of 500 consecutive adults who underwent LT at the Dumont-University of California at Los Angeles Liver Transplant Center between July 1, 1999, and December 31, 2001. Approval to conduct this study was granted by our institutional review board before commencement.
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Study Patients Patients were selected as cases if they had documented mental status changes lasting a minimum of 3 days and occurring within 1 month of LT. This time frame was chosen because the majority of neurological complications after LT have been reported to occur within the first month, and a minimum duration of 3 days was selected to enhance the specificity, as well as clinical significance, of the diagnosis. Patients were excluded if they had undergone a second or third LT or had mental status changes documented in the medical records as attributed to: (1) structural brain disorders, defined as cerebrovascular accidents, tumors, or central pontine myelinosis; (2) major organ dysfunction, including hepatic (e.g., primary graft nonfunction, hepatic artery thrombosis requiring re-LT), cardiac (e.g., recent myocardial infarction resulting in hemodynamic instability, cardiogenic shock), and pulmonary failure (e.g., adult respiratory distress syndrome); patients with renal failure undergoing dialysis and those requiring mechanical ventilation secondary to altered mental status were included in the study; (3) anoxic encephalopathy, defined as a previous significant episode of brain anoxia or radiological evidence of anoxic-ischemic brain damage; (4) septic encephalopathy, defined as mental status changes in critically ill patients with evidence of sepsis; (5) central nervous system infections; and (6) obvious metabolic alteration, defined as abnormalities in serum electrolyte, creatinine, blood urea nitrogen, and ammonia levels at the time of neurological complications. Of the initial 500 patients screened, 40 patients were found to be eligible as cases.
Controls Controls were selected from the initial 500 patients screened. For each case, we selected an age- and sex-matched control patient (1:1 ratio; n ⫽ 40) undergoing primary LT within the study period without documented mental status changes.
Definition of Mental Status Changes Medical records of all patients were reviewed for such key words as “confused,” “disoriented,” “agitated,” “delirious,” and “stuporous.” When these words appeared in the medical records, subsequent progress notes were reviewed to determine the duration and clinical presentation of these mental status changes. Patients were classified as having one of the following clinical presentations: (1) confusion or disorientation, (2) agitation and/or delirium, (3) stupor, or (4) coma. In patients without precise documentation of clinical presentation, we identified the degree of dysfunction by using predefined standardized definitions derived from previously described literature.10,11
Data Collection Clinical data for preoperative, intraoperative, and postoperative variables previously identified as potential predictors of post-LT mental status changes of unclear cause5,10,12-16 were collected for all cases (n ⫽ 40) and controls (n ⫽ 40) and
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entered into an Excel (Microsoft Corp, Redmond, WA) database by two of the authors (F.K. and D.C.).
Clinical Variables Preoperative clinical variables included patient ethnicity, cause of liver disease, biochemical liver and renal function tests obtained within 1 month of LT, Model for End-Stage Liver Disease (MELD) score immediately before LT, presence or absence of previous episodes of hepatic encephalopathy (in the former case, total duration and grade of hepatic encephalopathy immediately before LT according to established criteria),17 presence or absence of a transjugular intrahepatic portosystemic shunt, elective (defined as patients called in from home for LT) versus nonelective LT (defined as those undergoing LT while in the intensive care unit [ICU] or hospital), length of pre-LT ICU stay, presence or absence of renal failure requiring dialysis therapy, presence or absence of mechanical ventilation, presence or absence of variceal bleeding, and presence or absence of significant hypotension requiring pharmacological blood pressure support. In addition, changes in serum sodium concentrations were noted for all patients, when available. Intraoperative variables included cold ischemia time, use of split- or whole-organ allograft, length of surgery, units of blood products transfused, warm ischemia time, and presence or absence of reperfusion syndrome. Postoperative variables included primary immunosuppressive, mean as well as highest trough blood level of immunosuppressive medication, serum cholesterol and magnesium levels, use or nonuse of mycophenolate mofetil (MMF), presence or absence of renal failure, allograft dysfunction, and episodes of acute cellular rejection. Only data predating the onset of mental status changes were recorded for study patients.
Patient Categories Causes of underlying liver disease were grouped into six categories. Categories included chronic viral hepatitis (B and C), alcoholic liver disease, cryptogenic and nonalcoholic fatty liver disease, cholestatic and autoimmune liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis), metabolic liver diseases (hereditary hemochromatosis, Wilson’s disease, ␣1-antitrypsin deficiency), and fulminant hepatic failure. Patients with a diagnosis of both alcoholic liver disease and chronic hepatitis C were analyzed in the category of alcoholic liver disease because it was believed the influence of alcoholism would have a more significant impact on altered mental status than chronic hepatitis C within the first month post-LT.
Statistical Methods SAS (SAS Institute, Cary, NC) software package was used for statistical analysis. Data are expressed as percentages for categorical variables (e.g., ethnicity, cause of liver disease) and medians for continuous variables (e.g., creatinine level,
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MELD score). MELD score was dichotomized at 15 for the multivariate model because a MELD value of 15 best separated controls from cases when using MELD alone. Univariate analyses identified correlates of post-LT mental status changes of unclear cause by using Wilcoxon’s rank-sum test for continuous variables and Chi-squared test for categorical variables. Thereafter, all variables univariately significant at P less than .15 were considered for the multivariate logistic regression analysis to determine independent predictors of mental status changes of unclear cause post-LT. Variables identified to have an independent relationship with post-LT mental status changes of unclear cause were used to construct a clinical prediction rule by dividing each  coefficient ( ⫽ log odds ratio) by the smallest  coefficient, then rounding the value to the nearest integer to give a score to each variable. Adding individual scores resulted in a sum total score for each patient, depending on the number of risk factors present or absent. A predicted risk for developing post-LT mental status changes of unclear cause then was calculated for each individual score. The diagnostic value of the logistic model was assessed by calculating the area under the receiver operating characteristic (ROC) curves. An ROC area of 1.0 is characteristic of an ideal test or model, whereas an area of 0.5 indicates a test or model of no diagnostic value. The ROC analysis also identified the total raw score threshold (cutoff point) with the best diagnostic sensitivity and specificity, which also are reported. Unweighted accuracy also is reported and is defined as accuracy ⫽ (sensitivity ⫹ specificity)/2.
Results Study Population Table 1 lists clinical characteristics and underlying causes of liver disease of patients studied. Mean age of the study population was 54 ⫾ 7.8 (SD) years. There were 31 men (77.5%) and 9 women (22.5%) in both study patients and controls. Ethnic distribution of the two groups was similar. All liver transplant recipients were managed according to standardized protocols at our institution, including immunosuppressive medications and ICU care in the immediate post-LT period, with transfer to a stepdown unit when clinically indicated. The primary immunosuppressive regimen in all patients consisted of tacrolimus and corticosteroids. Description of Mental Status Changes In 40 cases, primary mental status changes manifested as confusion or disorientation (n ⫽ 26), delirium (n ⫽ 8), stupor (n ⫽ 4), coma (n ⫽ 1), and confusion with seizure (n ⫽ 1). Head computed tomography or magnetic resonance imaging was performed in 26 of 40 cases (65%). Findings were reported as normal (n ⫽
10), nonspecific with or without atrophy (n ⫽ 9), old infarct (n ⫽ 3), and white matter changes consistent with calcineurin inhibitor toxicity (n ⫽ 4). Brain imaging was not performed in 14 patients for reasons that could not be completely ascertained on medical record review. However, 8 of these 14 patients had shortlasting (3 to 4 days, n ⫽ 3), mild (n ⫽ 2), intermittent (n ⫽ 2), or fluctuating (n ⫽ 1) mental status changes, and 2 patients responded to low doses of antipsychotic medications. In 9 of 40 patients, primary immunosuppression was changed from tacrolimus to cyclosporine, with noticeable improvement in symptoms in 6 patients. Symptoms lasted for a median of 14 days (interquartile range, 7 to 30 days). Two patients developed permanent neurological symptoms (cortical blindness and dysarthria). Predictors of Mental Status Changes and Estimation of the Model Univariate analyses. Univariate analyses identified significant differences between the two study groups in 10 clinical variables. Table 2 lists results of univariate analyses. All variables except for acute rejection were present pre-LT. There were statistically significant differences in causes of liver disease between study patients and controls. In the control group, chronic viral hepatitis was the most common cause (62.5%), followed by cryptogenic/nonalcoholic fatty liver disease (12.5%) and alcoholic liver disease (12.5%). In study patients, chronic viral hepatitis again was the most common (37.5%) underlying liver disease. However, in contrast to the control group, alcoholic liver disease was more prevalent (30%), followed by metabolic liver diseases (15%) and cryptogenic nonalcoholic fatty liver disease (2.5%). Compared with controls, study patients were more likely to have a greater severity of underlying liver disease, higher grade of hepatic encephalopathy, and greater pre-LT serum creatinine level. Other pre-LT clinical variables identified to be statistically significant (P ⬍ .05) included number of ICU days, presence of significant hypotension, need for dialysis therapy, and mechanical ventilation. There was no difference in the median highest trough blood level of immunosuppressive medication between cases and controls (P ⫽ .07). Multivariate analyses. Seventeen variables were considered in an additive logistic regression model. Preoperative variables were cause of liver disease, serum creatinine level, MELD score, encephalopathy grade and duration, elective versus nonelective LT, presence or absence of renal failure requiring dialysis therapy, mechanical ventilation, hypotension, and variceal
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Table 1. Sample Characteristics
Variable Age (yr) Male gender Mental status changes Confusion/disorientation Delirium Stupor Coma Seizure* Duration of symptoms (d) Ethnicity Caucasian Latino Hispanic African American Asian Others Diagnoses Cryptogenic cirrhosis NAFLD ETOH Hep C ⫹ ETOH FHF Hemochromatosis ␣1-Antitrypsin deficiency Wilson’s disease Chronic hepatitis C Chronic hepatitis B PBC PSC Autoimmune hepatitis Polycystic liver disease
Overall (n ⫽ 80)
Study Patients (n ⫽ 40)
Controls (n ⫽ 40)
P
54 ⫾ 7.8 62 (77.5)
53.4 ⫾ 8.0 31 (77.5)
53.9 ⫾ 7.7 31 (77.5)
.836 1.000
37 (46) 19 (24) 6 (8) 2 (2) 9 (11) 7 (9)
18 (45) 8 (20) 4 (10) 2 (5) 5 (12.5) 3 (7.5)
19 (47.5) 11 (27.5) 2 (5) 0 (0) 4 (10) 4 (10)
5 (6.25) 1 (1.25) 9 (8.75) 8 (10) 3 (3.75) 5 (6.25) 1 (1.25) 1 (1.25) 31 (38.75) 9 (11.25) 3 (3.75) 1 (1.25) 2 (2.5) 1 (1.25)
0 (0) 1 (2.5) 7 (17.5) 5 (12.5) 2 (5) 4 (10) 1 (2.5) 1 (2.5) 12 (30) 3 (7.5) 1 (2.5) 0 (0) 2 (5) 1 (2.5)
5 (12.5) 0 (0) 2 (5) 3 (7.5) 1 (2.5) 1 (2.5) 0 (0) 0 (0) 19 (47.5) 6 (15) 2 (5) 1 (2.5) 0 (0) 0 (0)
26 (65) 8 (20) 4 (10) 1 (2.5) 1 (2.5) 14 (7-30) .694
.027
NOTE. Values expressed as mean ⫾ SD, number (percent), or median (interquartile range). Abbreviations: NAFLD, nonalcoholic fatty liver disease; ETOH, alcohol-induced liver disease; Hep C, hepatitis C; FHF, fulminant hepatic failure; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. *Seizures with mental status change.
bleeding. Intraoperative variables included warm ischemia time and presence or absence of reperfusion syndrome. Postoperative variables were highest trough blood level of immunosuppressive medication, use of MMF, presence and absence of renal failure, allograft dysfunction, and acute cellular rejection. Of these candidate variables, four variables were identified as independent additive predictors of post-LT mental status changes of unclear cause in the multivariate logistic regression analysis (Table 3). These variables were: (1) cause of underlying liver disease, specifically alcoholic and metabolic liver disease diagnosis (odds ratio, 9.89; 95% confidence interval [CI], 2.44 to 40.05; P ⫽ .001); (2) pre-LT mechanical ventilation (odds ratio, 4.5; 95% CI, 1.08 to 18.72; P ⫽
.039); (3) MELD score greater than 15 (odds ratio, 4.15; 95% CI, 0.962 to 17.958; P ⫽ 0.056); and (4) nonelective LT (odds ratio, 2.28; 95% CI, 0.709 to 7.378; P ⫽ 0.16). The raw mental status risk score (logit) based on this model is calculated as follows: Risk score ⫽ ⫺ 2.57 ⫹ 1.50 (mechanical ventilation) ⫹ 2.29 (selected diagnoses) ⫹ 1.42 (MELD ⬎ 15) ⫹ 0.83 (nonelective LT)
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Table 2. Univariate Summary: Risk Factors for Post-LT Mental Status Change Study Patients (n ⫽ 40)
Variables Diagnoses Cryptogenic/NAFLD ETOH/Hep C ⫹ ETOH* FHF Hemochromatosis/A1AT/Wilson*† Chronic hepatitis B or C PBC/PSC/autoimmune Polycystic liver disease MELD score Creatinine (mg/dL) Encephalopathy grade 3-4 Dialysis Ventilation Hypotension Nonelective LT Acute rejection Days in ICU
Controls (n ⫽ 40)
P .027
1 (2.5) 12 (30) 2 (5) 6 (15) 15 (37.5) 3 (7.5) 1 (2.5) 24 (19.7-35) 1.65 (1.1-2.3) 13 (32.5) 12 (30) 17 (42.5) 7 (17.5) 30 (75) 1 (9) 3 (0-8)
5 (12.5) 5 (12.5) 1 (2.5) 1 (2.5) 25 (62.5) 3 (7.5) 0 (0) 17.5 (11-27.5) 1.05 (0.7-1.7) 5 (12.5) 2 (5) 4 (10) 0 (0) 16 (40) 11 (27.5) 0 (0-0)
.004 .009 .0004 .003 .002 .01 .003 .005 .0004
NOTE. Values expressed as number (percent) or median (interquartile range). Abbreviations: NAFLD, nonalcoholic fatty liver disease; ETOH, alcohol-induced liver disease; Hep C, hepatitis C; FHF, fulminant hepatic failure; A1AT, ␣1-antitrypsin deficiency; Wilson, Wilson’s disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; autoimmune, autoimmune hepatitis. *Positive diagnosis in multivariate model. †Four study patients had a diagnosis of hemochromatosis, defined by hepatic iron index greater than 1.9. Wilson’s disease and ␣1-antitrypsin deficiency were the underlying liver diseases in another two study patients. One patient in the control group had hemochromatosis (hepatic iron index ⬎ 1.9).
In this model, mechanical ventilation ⫽ 1 if there was mechanical ventilation pre-LT, and 0 otherwise. Selected diagnoses ⫽1 for alcohol-related liver disease or metabolic liver disease, and 0 otherwise. MELD greater than 15 ⫽ 1 if MELD score was greater than 15, and 0 otherwise. Nonelective LT ⫽ 1 for nonelective LT, and 0 otherwise. The ROC area for this model is 0.826, implying approximately 83% accuracy. Using the optimal raw score of 0.544 as the threshold (cutoff point) for predicting mental status change, model sensitivity is 73% and specificity is 85% in predicting the occurrence of post-LT mental status changes of unclear cause. Unweighted accuracy is 79%. To adapt the model to routine clinical application,
predicted risk for experiencing post-LT mental status changes of unclear cause for an individual patient was calculated based on the presence or absence of these prognostic variables. The reference patient did not have alcoholic or metabolic liver disease, was not on mechanical ventilation at LT, had a MELD score of 15 or less, and underwent an elective LT. Table 4 assigns a score to each of the four variables (see Methods section): alcoholic and metabolic liver diseases ⫽ 3, mechanical ventilation at LT ⫽ 2, MELD score greater than 15 ⫽ 2, and nonelective LT ⫽ 1. The reported incidence of post-LT neurological complications varies from 13.2% to 42% in the literature. To our knowledge, there are no studies reporting
Table 3. Multivariate Logistic Regression Model Summary for Post-LT Mental Status Change Variable Mechanical ventilation pre-LT Selected diagnoses* MELD score ⬎ 15 Nonelective LT
Odds Ratio
95% CI for Odds Ratio
P
4.500 9.895 4.157 2.287
(1.081-18.724) (2.444-40.054) (0.962-17.958) (0.709-7.378)
.039 .001 .056 .16
*Alcohol-related liver disease (including patients with alcohol and chronic hepatitis C infection, see text) and metabolic liver disease.
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Table 4. Mental Status Change Score Assignment Variable
Score
Selected diagnosis* Mechanical ventilation pre-LT MELD score ⬎ 15 Nonelective LT
3 2 2 1
*Alcohol-related liver disease (including patients with alcohol and chronic hepatitis C infection; see text) and metabolic liver disease.
the incidence of post-LT mental status changes of unclear cause; however, extrapolation from published studies suggests an incidence ranging from 10% to 20%.9,10 Applying the lower estimate of this incidence (10%), the predicted risk for experiencing post-LT mental status changes of unclear cause with a score of 1 is 1.9%. This risk increases to 78% with a maximum score of 8. For example, a patient undergoing LT on a nonelective basis has a 2% chance of developing post-LT mental status changes. However, a patient undergoing nonelective LT for alcoholic liver disease with a MELD score greater than 15 and requiring mechanical ventilation pre-LT has a 78% risk for developing these complications. These predicted risks increase to 4% (with a score of 1) and 89% (with a score of 8) if a greater incidence rate (20%) of post-LT mental status changes of unclear cause is applied. Table 5 lists average predicted risks for each individual score across a
Table 5. Predicted Risk for the Development of Post-LT Mental Status Change Average Predicted Risk Total Score 0 1 2 3 4 5 6 7 8
Incidence ⫽ 0.10
Incidence ⫽ 0.15
Incidence ⫽ 0.20
0.008 0.019 0.035 0.075 0.146 0.262 0.449 0.606 0.779
0.013 0.029 0.054 0.114 0.214 0.361 0.564 0.710 0.848
0.018 0.041 0.075 0.154 0.278 0.445 0.647 0.776 0.888
NOTE. Average predicted risk for each individual score across a range of incidence rates of post-LT mental status changes of unclear cause.
Figure 1. Average predicted risk for each individual score across a range of incidence rates of post-LT mental status changes of unclear cause. Risk increases with higher scores. Changes versus scores derived from the model.
range of incidence rates of post-LT mental status changes of unclear cause. Figure 1 shows the distribution of predicted risks at various scores.
Discussion Recipients of liver transplants experience the greatest incidence of post-LT neurological complications compared with recipients of other organ transplants.7 This greater susceptibility may be caused by various preoperative and postoperative factors, including metabolic and circulatory disorders or immunosuppressive agent toxicity.7,10,15 Furthermore, in a significant proportion of patients, a cause for their altered mental status is not clear, especially while being evaluated in real time. The most frequent clinical manifestations are mental status changes,9,10 and these often are unpredictable and difficult to manage. In our study, patients with post-LT mental status changes of unclear cause had a significantly greater degree of liver disease severity and were medically more unstable before LT than controls. These findings are consistent with those of previous studies.5,10,12-16 We identified four variables as independent predictors of post-LT mental status changes of unclear cause. These variables were cause of liver disease (alcoholic liver disease and metabolic liver diseases, specifically), pre-LT mechanical ventilation, MELD score greater than 15, and nonelective LT. The last two of these four variables (MELD score ⬎ 15 and nonelective LT) did not reach statistical significance (P ⫽ .056 and P ⫽ .16, respectively), but were included in the logistic regression model for clinical and practical reasons. Pre-LT liver disease severity, measured by Child-Pugh-Turcott score and United Network for Organ Sharing status, has been
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shown to predict post-LT morbidity,18 including post-LT neurological complications.5 Nonelective LT was included in our model because it correlated strongly with other predictive factors identified in univariate analyses. ROC analysis indicates that our model is valid (pending replication by others), and these four variables predict the development of post-LT mental status changes of unclear cause with approximately 83% accuracy in this study. According to our model, patients with all four risk factors have a score of 8 of 8 and a 78% to 90% risk for developing post-LT mental status changes lasting at least 3 days up to 1 month post-LT. Conversely, patients with no risk factors (score ⫽ 0) have a significantly lower risk (8% to 18%) for this complication. Several of our findings are worthy of further commentary. First, the majority of patients (65%) with mental status changes of unclear cause had confusion or disorientation, with only a few patients experiencing a greater degree of dysfunction. These changes, although reversible in all except two patients, lasted for a median of 2 weeks. This suggests that despite a relatively mild degree of dysfunction in most patients, mental status changes can result in significant comorbidity and may have implications as far as overall resource utilization and cost of care are concerned. Second, alcoholic liver disease was identified as an independent predictor of mental status changes in the post-LT period. This is in agreement with several other studies that reported a greater incidence of post-LT neurological complications, including acute confusional states, in patients undergoing LT for alcoholic liver disease.5,12,19 Interestingly, we also found that a significantly greater number of study subjects underwent LT for underlying metabolic liver disease (hemochromtosis, n ⫽ 4; ␣1-antitrypsin deficiency, n ⫽ 1; and Wilson’s disease, n ⫽ 1) than controls (␣1-antitrypsin deficiency, n ⫽ 1). An association between metabolic liver disease and post-LT neurological complications has not been described previously in the literature. The diagnosis of primary hemochromatosis in our patients was based on a hepatic iron index greater than 1.9. Hereditary hemochromatosis gene mutation testing was not performed. It is possible that increased hepatic iron levels in these individuals resulted from underreported alcohol use in the past or cirrhosis itself.20 We could not confirm the former possibility because of the retrospective nature of the study. Future prospective studies are needed to evaluate this potential association between metabolic liver disease and post-LT neurological complications. The negative impact of pre-LT mechanical ventilation on several post-LT out-
comes, including patient and graft survival, is well described.21,22 We found pre-LT mechanical ventilation to be associated with the development of post-LT altered mental status. None of the intraoperative variables assessed correlated significantly with the development of post-LT altered mental status of unclear cause in our analyses. Of note, tacrolimus blood levels were not identified as significant predictive factors of post-LT altered mental status in both univariate and multivariate analyses. There was no difference in the highest trough blood level of tacrolimus between groups. Despite this, mental status improved in six of the nine patients on change in primary immunosuppression. These findings are corroborated by other investigators,10,23 indicating a greater sensitivity to calcineurin inhibitors and potentially other factors in some liver transplant recipients. The present study is the first in which practical clinical variables are used to identify patients at high risk for developing post-LT mental status changes of unclear cause. Patients with a 50% or greater predicted risk for experiencing post-LT altered mental status identified by our model might be appropriate candidates for interventions designed to prevent or reduce the incidence and impact of these complications. Strategies may include close monitoring of these high-risk patients, correction of concomitant factors (electrolyte imbalance, sepsis), and use of tacrolimus-sparing agents (e.g., MMF) alone or as part of combination immunosuppressive therapy. An open prospective study of 20 liver transplant recipients has shown that MMF appears to be a safe and potentially useful adjuvant immunosuppressive agent for rescue and maintenance therapy that will not increase the risk for neurotoxicity.24 Our study has several limitations. First, cases may not be representative of all liver transplant recipients with mental status changes of otherwise unclear cause because some patients may have been undiagnosed or undocumented. In addition, brain imaging was not obtained in a proportion of our cases (14 of 40 patients), leading to a possibility that we included some patients as cases who otherwise may have had an identifiable cause of altered mental status. However, these patients were included in the analysis as cases because undergoing head computed tomography and/or magnetic resonance imaging was not one of the inclusion criteria for our case selection, and these patients did not have an identifiable cause of altered mental status on review of medical records. Moreover, in the absence of progressive or irreversible neurological signs, major structural damage could be excluded on clinical grounds.
Altered Mental Status Post-Liver Transplant
Our study also was limited by the retrospective nature of data collection. We tried to control for differential measurement bias by standardizing definitions of variables, supplementing key variables with data from several sources, and using data recorded before mental status changes developed in cases. Despite this, we may have misclassified the clinical presentation in some patients. However, we believe this does not change the validity of our results. Despite these limitations, we attempted to identify all patients who were documented to have mental status changes of unclear cause after LT. We selected our controls from the population of liver transplant recipients who were at risk for the outcome, with matching to ensure that cases and controls are similar with respect to major constitutional variables (age, sex, and era of LT). In addition, the present study is the first in which practical clinical variables are incorporated into a simple rule to predict the risk for the development of a common problem after LT: mental status changes. In conclusion, our model can be applied easily to identify patients at high risk for developing mental status changes post-LT. Prospective validation of this rule is still needed. Future studies should address whether early identification of and intervention in patients at high risk for the development of neurological complications post-LT will reduce the morbidity, mortality, and economic costs associated with neurological complications in liver transplant recipients.
8. 9.
10.
11.
12.
13.
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17. 18.
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