Neurocrit Care (2008) 8:253–258 DOI 10.1007/s12028-007-9020-4 ORIGINAL RESEARCH Perioperative Neurological Complications After Liver Transplantation are Best Predicted by Pre-transplant Hepatic Encephalopathy Rajat Dhar Æ G. Bryan Young Æ Paul Marotta Published online: 10 October 2007 Ó Humana Press Inc. 2007 Abstract Introduction Liver transplant (LT) recipients are at significant risk for the development of neurological complications, such as altered mental status and seizures, in the postoperative period. Identifying accurate predictors of these events may allow optimal selection and preparation of candidates, and minimize risk after transplantation. Methods One hundred and one consecutive adult LT recipients were evaluated retrospectively for neurological morbidity occurring in the first 30 days postoperatively. These events were analyzed in relation to specific predictive variables including preoperative complications of liver failure, such as hepatic encephalopathy (HE). Results Median age was 50 years, 63% were male and hepatitis C was the most common indication for LT (n = 36). Median Child-Pugh score was 9 with 45% being Class C. Over half (n = 52) had experienced clinical HE prior to LT, while one quarter (n = 26) were encephalopathic at the time of LT. Neurological complications occurred in 31 patients in the postoperative period, with encephalopathy occurring in 28 and seizures occurring in 4; drug toxicity was responsible for neurological morbidity in 12 patients (39%). Length of hospital stay was R. Dhar (&) Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8111, Saint Louis, MO 63110, USA e-mail: [email protected] G. B. Young Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada P. Marotta Multi-Organ Transplant Unit, London Health Sciences Centre, London, ON, Canada significantly prolonged (median 19 vs. 12 days, P = 0.005) and all mortality (n = 3) occurred in those with neurological complications. There was no association between etiology of liver failure and complications; logistic regression identified active preoperative HE as the strongest predictor of postoperative morbidity (OR 10.7 95% CI 3.8–29.9). Conclusion Neurological events, manifesting most often as encephalopathy, occurred in almost one-third of patients after LT. Those suffering from HE at the time of LT may be more vulnerable to the metabolic stresses of surgery and the neurotoxicity of the drugs used, and were at highest risk for such complications. Keywords Liver transplantation Hepatic encephalopathy Complications Postoperative Seizures Drug toxicity Introduction Although liver transplantation (LT) extends survival and improves quality of life for patients suffering complications of severe hepatic dysfunction [1], postoperative complications remain a significant source of morbidity and mortality [2]. The brain, functionally and structurally altered in patients with liver disease [3, 4], may be preferentially vulnerable to perioperative insults and the toxicity of the immunosuppressive regimens utilized. Adverse neurological events are known to complicate 10% or more of LT procedures [5–8], with the majority occurring in the first month postoperatively [9, 10]. Common complications include postoperative delirium, encephalopathy, and seizures; drug-related neurotoxicity from calcineurin inhibitors (cyclosporine or tacrolimus) plays a 254 role in a significant proportion of these events, with a greater risk after LT than after other transplants [11]. Few clinical studies have both accurately assessed the frequency of neurological complications in this high-risk population as well as tried to identify factors that may predict these adverse events [12]. Knowledge of these factors may help optimize selection and preparation of candidates for LT, in order to minimize the risks for those undergoing this procedure. In this study, we assessed the incidence, severity, and implications of neurological complications in the immediate postoperative period after LT. We then analyzed the relationship of these events to important preoperative variables, including history of hepatic encephalopathy (HE), to identify factors that place recipients at higher risk for postoperative neurological dysfunction. Methods Patients One hundred and one consecutive adult recipients from our regional transplant center who underwent liver transplantation over an 18-month period between September 2000 and March 2002. Approval for this study was obtained from our institution’s Research Ethics Board. Neurocrit Care (2008) 8:253–258 considered present if the measured value rose by 10 mmol/l or more in the perioperative period. The immunosuppressive regimen used was recorded. Outcome Measures The primary outcome was the development of any neurological dysfunction in the 30-days after LT. This duration of follow-up was selected because it encompassed the majority of complications in a number of previous studies [9, 10], and comparable reliable data were available for all transplant recipients over this well-defined period. The complications ascertained included: (1) Encephalopathy: including delirium, psychosis, or diminished level or consciousness, not necessarily related to hepatic dysfunction; (2) Seizures; (3) Drug neurotoxcity: specifically that ascribed to use of calcineurin inhibitors or corticosteroids; (4) Vascular insults including ischemic or hemorrhagic stroke, and hypoxic brain injury; (5) CNS infections; (6) Central pontine myelinolysis (CPM). Complications were also qualitatively graded as being either mild (if isolated and short-lasting, requiring minimal intervention) or severe (morbidity that was persistent or required active intervention, such as recurrent seizures or significantly reduced level of consciousness). Other outcomes evaluated included time to extubation, length of stay in the hospital after LT, and mortality prior to hospital discharge. Data Collection Pre-specified data were abstracted from hospital records and a transplantation database. This included patient demographics, etiology of liver failure, urgency status and time on the wait list, preoperative metabolic status, including calculation of Child-Pugh score (based on assessment of preoperative liver function, ascites, and HE) [13]. Complications of liver failure, including ascites, variceal bleeding, HE, and hepatorenal syndrome were categorized as either absent, mild if well-controlled, or severe when persistent and/or prominent (for example requiring repeat hospital admissions). The occurrence of active HE at the time of LT was specifically noted. Operative variables included length of procedure, blood transfusion requirements, significant intraoperative hypotension (systolic blood pressure <80 mm Hg for 10 min or more) or the occurrence of the reperfusion syndrome [14]. Postoperative medical complications were recorded including renal failure (threefold rise in serum creatinine or requiring renal replacement therapy), pneumonia, myocardial infarction (MI), sepsis (systemic inflammatory response with hypotension or positive cultures), and graft dysfunction (encompassing primary non-function, acute rejection, and portal vein thrombosis). A major rise in serum sodium was Statistical Analysis Descriptive statistics were used to present baseline and operative variables, along with specific complications. Subjects were divided into those experiencing postoperative neurological complications and those not, and these groups were compared using the v?-statistic (for categorical variables) and the student’s two-tailed t-test (for continuous variables). Significant pre- and postoperative variables are presented in tabular format showing univariate odds ratio for complications, with 95% confidence intervals. All preoperative variables associated at P < 0.010 with major outcomes were entered into a backward stepwise logistic regression model with significance set at P < 0.05 (corrected for multiple analyses using the Bonferroni correction). Analyses were performed using SPSS for Windows (version 11.5; SPSS, Chicago, IL, USA). Results Descriptive features of the 101 patients comprising the study population as well as operative variables are outlined in Table 1. The majority of LT recipients had at least one Neurocrit Care (2008) 8:253–258 255 Table 1 Patient characteristics Variables Table 2 Complications pre- and post-transplantation Frequency (n = 101) Complication Age, years (median, range) 50 (17–72) Preoperative complications Sex (male/female) 64/37 Hepatic encephalopathy 52 (28/24) Preoperative encephalopathy 26 (11/15)a Status at time of transplant Frequency (mild/severe) Status 1–2 84 Ascites 69 (28/41) Status 3–4 17 Variceal bleeding 36 (12/24) Waiting time, d (median, range) 146 (1–1212) Hepatorenal syndrome 13 (5/8) Etiology of liver failure Postoperative complications Hepatitis Ca 36 Primary biliary cirrhosis 13 Encephalopathy Alcoholic cirrhosis 10 Seizures Primary sclerosing cholangitis Autoimmune hepatitis 9 7 Neurological complications Drug toxicity Medical complications Fulminant hepatic failure 6 Renal failure NASH 6 Pneumonia b 28 (17/11) 4 (3/1) 12 (10/2) 23 7 14 Myocardial infarction 5 Child-Pugh score (median, range) 9 (5–14) Sepsis 4 Class A (score 5–6) 17 Graft dysfunction 6 Class B (score 7–9) 39 Class C (score 10–15) 45 Others a Eight patients had HE only in the immediate preoperative period without any prior history Operative variables (median, range) Duration of surgery (minutes) 395 (260–850) RBC transfusions intraoperative 4 (0–18) FFP transfusions intraoperative 8 (0–24) Intraoperative hypotension 21 Reperfusion syndrome 2 a Alcohol was implicated as an additional contributing factor in 8 of these b Other causes incl. cryptogenic, Budd-Chiari, alpha1-antitrypsin deficiency NASH = non-alcoholic steatohepatitis preoperative complication of liver failure (Table 2). Notably, just over half had a history of HE and 26 were encephalopathic at the time of the LT (including seven in hepatic coma). Major shifts in perioperative sodium levels were noted in 26 patients (with a maximal rise of 0.5– 1.0 mmol/l per hour in most cases). Outcomes Time to extubation in the ICU was a median 22 h (range 12–468). Length of hospital stay was a median 12 days (range 6–101). The vast majority (87%) were discharged within a month of LT. Overall, 31 patients suffered at least one neurological complication after LT. The most frequent are shown in Table 2. One encephalopathic patient suffered a hypoxic–ischemic brain injury prior to death from sepsis. There were no confirmed cases of stroke, hemorrhage, CNS infection, or CPM. There was significant overlap between confusional states and drug neurotoxicity, with 11 of the 12 patients felt to have drug-related morbidity presenting with altered mental status. Conversely, seizures were not commonly associated with drug toxicity (one of four patients) or even persistent mental status changes. Length of stay was significantly longer in those with postoperative neurological events (median 19 vs. 12 days, P = 0.005). The three patients who died prior to discharge all experienced postoperative encephalopathy. Mortality was also strongly associated with postoperative sepsis, renal failure, graft dysfunction, as well as intraoperative hypotension. Variables associated with Neurological Complications Factors associated with neurological complications are shown in Table 3. Although a history of HE was strongly associated with morbidity, on further analysis, it was only the group with episodes of severe HE that had a higher risk of complications (13 of 22 vs. 7 of 28 if only mild HE). There was no association between etiology of liver failure or status on the transplant list and occurrence of neurological morbidity. Those with alcoholic cirrhosis did not have a higher rate of postoperative confusion (3/10) than those with other causes for cirrhosis (11/36 in those with hepatitis C). All four patients with sepsis experienced postoperative encephalopathy, associated with a seizure in one. 256 Table 3 Factors associated with neurological complications Neurocrit Care (2008) 8:253–258 Variable, n (%) Complications (n = 31) No complications (n = 70) P value Age (mean ± SD) 52.4 ± 9.9 48.8 ± 12.6 0.16 Child-Pugh Class C 21 (68) 24 (34) 0.002* Univariate OR (95% CI) Preoperative factors * 4.0 (1.6–9.9) Hx of HE 21 (68) 31 (44) 0.03 2.6 (1.1–6.4) Preoperative HE 18 (58) 8 (11) <0.001* 4.1 (1.7–9.8) 8 (26) 5 (7) 0.02* 4.5 (1.3–15.2) 11 (36) 12 (17) 0.04 Hepatorenal syndrome Postoperative factors Renal failure *Variables entered into the multivariate analysis Sepsis 4 (13) 0 0.002 Pneumonia 5 (31) 2 (3) 0.015 In multivariate analysis of the four preoperative variables associated with postoperative neurological complications, only HE in the immediate preoperative period (adjusted OR 10.7, 95% CI 3.8–29.9) remained significantly associated (P < 0.0125). Patients with FHF, many of whom (four of six) were in hepatic coma prior to surgery, did not suffer an excess rate of complications including encephalopathy (2/6 vs. 29/94, P = 1.00) and they all survived to discharge. Excluding this low-risk group, the rate of postoperative neurological complications was 16 out of 21 amongst those with active preoperative HE. No specific variables were associated with postoperative seizures, likely as too few events occurred to discriminate. There was an equivalent rate of drug-induced neurotoxicity distributed between Tacrolimus (11/86, 13%) and Cyclosporine (1/10, 10%, P = NS); the only factor associated with drug toxicity was postoperative pneumonia (OR 6.1, 95% CI 1.1–33.1). Discussion In this study of 101 consecutive patients undergoing LT, neurological complications occurred in almost one-third in the immediate postoperative period. This rate is concordant with a number of previous reports, highlighting the considerable frequency at which neurological morbidity occurs in this setting [7, 10]. The burden associated with these events is also significant; we found an almost doubling in hospital stay after transplant surgery in those suffering such complications. All deaths occurred in those with nervous system dysfunction, likely related to their strong association with sepsis and graft failure, which both induce metabolic encephalopathy. In fact, encephalopathy, the most common neurological complication in our and most other series [6, 15], is usually multifactorial, related to metabolic derangements, organ failure, and drug toxicity. The latter, largely caused by calcineurin inhibitors, occurred in almost one in eight patients after LT and accounted for almost 40% of complications. Alterations in the blood–brain barrier due to preexisting HE may make these patients more vulnerable to neurotoxicity than in other transplant settings [11]. The incidence of seizures appears to have fallen in this and other contemporary series [6, 16, 17], perhaps with closer monitoring of drug levels and cautious dose initiation and adjustment. We found only a single case of a seizure attributable to drug toxicity in our series, compared to a 25% rate of seizures after LT in an older series, where most were related to cyclosporine neurotoxicity [5]. We also did not find any difference in rates of toxicity between cyclosporine and tacrolimus. Intrinsic brain processes, such as vascular insults and CNS infections did not contribute to postoperative neurological dysfunction in this series. Despite sodium shifts being relatively frequent, CPM was not diagnosed in any of our patients. With a documented rate of 1% in a number of studies [7, 10, 18], this may not be surprising for a study of this size. There was no increased rate of confusional episodes in patients transplanted for alcoholic cirrhosis compared to those with hepatitis C. This contrasts with a previous study that showed an eightfold higher rate of encephalopathy in the group with alcoholic cirrhosis [19]. In that report a much higher rate of preoperative HE was present in the alcoholic cirrhosis group; furthermore, those with acute confusional states had higher preoperative ammonia levels. It is more likely that it is not the precise etiology of liver failure that contributes to postoperative confusion, but how vulnerable the brain is prior to LT. Alcoholics with prior episodes of HE, high levels of ammonia, and additional neurotoxicity from their alcohol exposure, may simply have more preexisting brain injury placing them at higher risk for complications. This is supported by the major finding of our analysis, that the strongest predictor of postoperative neurological morbidity was the presence of active HE at the time of Neurocrit Care (2008) 8:253–258 transplantation. This association has been suggested in a prior report: a prospective study of 84 patients seen by a neurologist before and serially after LT found that an abnormal neurological examination prior to LT was the strongest predictor of postoperative neurological complications [12]. There is a strong and coherent rationale for why those with active HE would be at particularly high risk for postoperative encephalopathy. It is now clear that liver failure with even subtle or subclinical HE induces significant changes in cerebral function and morphology, primarily affecting astrocytes [20]. As the site of ammonia detoxification, astrocytes accumulate the osmotically active metabolite glutamine in the setting of liver failure. This promotes intracellular swelling with depletion of the compensatory organic osmolyte, myo-inositol serving as a marker, as measured by magnetic resonance spectroscopy (MRS) studies [21]. Increased astrocyte water content can disrupt cellular function including maintenance of the blood–brain barrier and neurotransmitter clearance. As important constituents of the glio-neuronal network, changes in astrocyte activity can induce widespread neuronal dysfunction. Increased GABA-ergic tone is also found in HE, likely mediated through increased production of neurosteroids as a consequence of astrocyte swelling. Elevations of extracellular glutamate, which accumulates in this setting, can activate NMDA receptors and induce nitric oxide synthesis, cerebral vasodilatation, as well as seizures [22]. There is also a correlation between grade of HE and MRI abnormalities before transplantation, with evidence of subtle brain edema manifested in increased ADC values even in those with subclinical HE [3]. Elevation in ADC correlated with venous ammonia levels, while more overt T2-abnormalities were only seen in those with grade 2 or greater HE. Even though liver transplantation ultimately improves the selective cognitive deficits seen in mild HE [23], the stress of the procedure itself can trigger worsening cerebral dysfunction. Administration of benzodiazepines, shifts in osmolality, and cytokine release known to occur after major surgery, are all well known triggers of HE; their contributions to postoperative encephalopathy may be explained by their modulation of astrocyte swelling. Patients with limited reserves of organic osmolytes, depleted in attempting to compensate for active preoperative HE, are unable to counteract the increased swelling precipitated by these additional perioperative stressors and so are at greater risk for cerebral dysfunction after LT. Limitations of this study include its retrospective nature. Extraction of relevant complications depended on adequate recognition and documentation by the transplant and intensive care services looking after the patients. However, these patients are followed very closely in the post-transplant 257 period by a dedicated and trained team; most persistent and significant changes in neurological status were likely noticed while subtle symptoms may have been missed. 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