Author Affiliations: Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China (Li X, Wen DX, Zhao YH and Hang YN), Department of Anesthesiology, Shuguang Hospital, Shanghai University of TCM, Shanghai 201203, China (Li X), Department of Anesthesiology, University of Colorado Health Science Center Denver, Aurora, Colorado, USA (Mandell MS)

Corresponding Author: Da-Xiang Wen, MD, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China (Tel/Fax: 86-21-63842916; Email: wdxrwj@126.com)

 

© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60058-2

 

Contributors: WDX, HYN and MMS designed the study. LX and ZYH performed research. LX collected and analyzed the data. MMS wrote the final manuscript. All authors contributed to the design and interpretation of the study. WDX is the guarantor.

Funding: None.

Ethical approval: This study was approved by Ethics Committee of the Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Postoperative cognitive dysfunction (POCD) is an adverse condition characterized by declined cognitive functions following surgeries and anesthesia. POCD has been associated with increased hospital stay and mortality. There are histological similarities to Alzheimer's disease. Most early studies were conducted in patients receiving cardiac surgery. Since there is no information about POCD in liver transplant recipients, we measured the incidence of POCD in patients after liver transplantation and examined the correlation between neurological dysfunction and biological markers of dementia-based diseases.

 

METHODS: We studied 25 patients who had a liver transplan-tation between July 2008 and February 2009. Patients with prior encephalopathy or risk factors associated with the development of POCD were excluded from the study. Five validated neuropsychiatric tests were used for diagnosis. The diagnosis was based on one standard deviation decline in two of the five neuropsychiatric tests. The correlation between patient variables and the development of POCD was examined. Serum levels of beta-amyloid and C-reactive protein were measured by standard ELISA and compared between patients with and without POCD.

 

RESULTS: POCD was present in 11 (44%) of the 25 patients. Patients with POCD had significantly higher MELD scores, were more often Child-Pugh class C and received more blood transfusion during surgery. The serum beta-amyloid protein and C-reactive protein concentrations were significantly increased at 24 hours after surgery in the POCD group.

 

CONCLUSIONS: The incidence of POCD in our group of liver transplant patients was greater than that reported in other surgical patients. The increase in the serum biomarkers of dementia in the POCD patients supports the hypothesis that chronic cognitive defects are due to a process similar to that seen in Alzheimer's disease.

 

(Hepatobiliary Pancreat Dis Int 2013;12:370-376)

 

KEY WORDS: dementia; neuropsychiatric tests; Alzheimer's disease; biological markers; neurological injury

Postoperative cognitive dysfunction (POCD) is diagnosed when the ability of a patient to learn and reason becomes impaired after surgery.^[1] Defects are observed in diverse cognitive abilities including functions such as memory, perception, verbal articulation, attention and abstract thinking.^[2] Investigators^[3] observed that the clinical symptoms of POCD are similar to those of the patients who have other acute and chronic cognitive disorders.

 

Two distinct proteins have been validated as biological markers that cause cognitive defects. β-amyloid protein (β-Ap) is the principal component of senile plaques in Alzheimer's disease (AD) and other forms of dementia.^[4] Evidence from experimental animals also suggests that the level of serum C-reactive protein (CRP) is increased in cognitive diseases.^[5] Studies^{[6, 7]} have shown that the serum levels of CRP and β-Ap correlate with the severity of cognitive impairment in AD and other cognitive diseases. The increase in both biological markers in more than one disease has led to the conclusion that there is a common pathway of neuro-inflammation in dementia-type diseases.^[7]

 

Studies in liver transplant recipients with encephalo-pathy have shown that successful transplantation does not always improve cognitive function.^[8] Rather, some patients may have a significant decline in cognitive function after surgery. The specific defects vary, but some patients appear to exhibit a rapid aging in brain function that is similar to AD.^[9] Possibly, events associated with the surgical procedure itself may initiate or facilitate the development of POCD.

 

To date, there is no information about POCD in liver transplant recipients. The incidence is unknown. Further, there is no data that examines the relationship between patient characteristics and the risk of developing POCD. We reason that the incidence of POCD is greater in liver transplant recipients compared to other surgical populations. Our hypothesis is supported by evidence suggesting the presence of a common neuro-inflammatory pathway in diverse dementia-like diseases.^{[10, 11]} We suggest that anesthesia and surgery in liver transplant patients initiates or exacerbates a generalized inflammatory process. This finding is supported by observations in other surgical patients including those receiving cardiac surgery, who have a clear association between generalized inflammation and neurocognitive disorders.^[12]

 

Liver transplant recipients have a pattern of biological serum markers similar to patients with AD if there is a common pathway of neuro-inflammation. We therefore suggest that the plasma markers of AD will acutely increase in liver transplant recipients who develop POCD. The current study therefore is undertaken to measure the incidence of POCD in a cohort of liver transplant recipients and examine the association between POCD and specific patient variables.

 

 

This study was approved by the Ethics Committee of Renji Hospital, Shanghai Jiaotong University School of Medicine (Shanghai, China). The study included 25 patients who had a liver transplant between July 2008 and February 2009. The time of the study was limited to minimize the effects of changes in clinical management on patient outcome. We excluded patients with inde-pendent risk factors associated with the development of POCD.^[12] These factors included age older than 65 years, preoperative hypertension and/or cardiovascular disease, preoperative cognitive dysfunction identified by the mini-mental state examination (MMSE) score less than 20, a history of neurological or psychiatric diseases, a history of alcohol or drug abuse and medical conditions that would interfere with neurocognitive testing (e.g. visual or hearing impairment).^{[13, 14]} We therefore excluded patients with a history of grade 2 or greater hepatic encephalopathy.

 

Anesthesia was induced with midazolam 0.08-0.1 mg/kg, propofol 1-2 mg/kg, sufentanil 0.8-1 mcg/kg, and cis-atracurium 0.1-0.15 mg/kg. Then it was maintained with inhaled sevoflurane 0.5%-1.5%, propofol 2-5 mg/kg per hour, sufentanil 0.005-0.007 mcg/kg per minute, and cis-atracurium 0.002-0.004 mg/kg per minute. PaCO₂ was maintained between 35-45 mmHg by mechanical ventilation, and body temperature was kept between 36.5-37.5 �� using warming blankets. Ulinastatin of one million unit was given intravenously after induction of anesthesia. Methylprednisolone (0.5 g) was administered in an anhepatic phase. We maintained a tight control of blood pressure and kept the mean arterial pressure within 10% of the preoperative value by the administration of bolus doses of phenylephrine (50-200 µg or epinephrine 10-50 µg). The electrolyte and acid-base balance were kept within normal range during surgery. After the surgery, all patients were admitted to a transplant intensive care unit (ICU). The patients were rapidly weaned using a standard fast track protocol and extubated within 8 hours of arrival at the intensive care unit.^[15]

 

Neuropsychological tests were conducted by a single professionally trained psychiatrist. Each patient underwent five separate tests during a single session before surgery. The same tests were then performed on the seventh day after surgery. The neuropsychological tests included MMSE, verbal fluency test (VFT), digits span tests (DSTs) that were conducted forwards and backwards, item memory (IM), and source memory (SM). MMSE includes questions examining orientation, arithmetics, and memory. VFT tests subject's language capabilities. DST examines attention span and short-term memory. Each of these tests has been validated in human subjects and is designed to identify cognition defects that are not apparent during a routine clinical examination. In this study each test was performed 4 times in a random order to minimize a potential learning effect and increase the sensitivity to identify cognitive dysfunction without increasing the possibility of false positive results. The mean and median values of each test were then calculated.

 

A standard deviation (SD) was calculated for each test score. The SD was used to measure changes in cognitive function during the time interval between the day of surgery and postoperative day 7. We used standard diagnostic criteria to identify significant findings that subsequent test results were greater than or equal to the SD. A diagnosis of POCD was made when there were significant findings in two or more postoperative neurocognitive tests.^[16]

 

Venous blood (5 mL) was collected from a right internal jugular catheter and placed into vacuum tubes containing sodium heparin. The blood samples were collected at four time points: just prior to induction of general anesthesia, 30 minutes after the start of the anhepatic phase, 3 hours after reperfusion of the new liver, and at 24 hours after surgery. The samples were quick frozen, batched and kept at -60 �� until analysis. For analysis, the blood samples were centrifuged at 4 �� for 10 minutes at 3000 rpm. Molecular analysis was conducted using a commercial beta-amyloid 42 ELISA kit (Biosource™, Tokyo, Japan) and Human C-Reactive Protein ELISA kit (USA R&D Systems Inc., Minnesota USA). ELISA was performed with a standard protocol and used chromogenic reporters in a quantitative format to measure β-Ap and CRP specific activity. We used the Shanghai Zhili Biological Technology Company (Shanghai, China) to construct reaction standard curves. The protein level was calculated while comparing the optical density value of samples and the standard curve.

 

The data were analyzed using SPSS version 15.0. All measurement data were tested for equal variances, expressed as either mean±SD or median (inter-quartile range). They were expressed as percentages. The independent samples t test and the Mann-Whitney U test were used to compare data among the groups. The Chi-square test and Fisher's exact test were used to compare numeration data among the groups. A P value of less than 0.05 was considered statistically significant.

 

 

The postoperative course of the 25 patients in our study was not complicated. None of the patients were readmitted to the intensive care unit, and nor had clinical evidence of donor liver graft failure or rejection. The majority (80%) of the patients were male (Table 1) and their mean age was 44.96±8.92 years. Of the 25 patients, 10 received a right lobe from a living donor and the remaining 15 received whole cadaveric donor grafts. The mean MELD score for the study group was 20.24±7.06, whereas 56% of the patients were classified as Child-Pugh C. Patients with chronic viral hepatitis associated with or without hepatocellular carcinoma accounted for 64% of all patients in the study. Five patients (20%) had hepatocellular carcinoma.

 

There was no difference in the incidence of POCD between the patients who received a cadaveric liver graft and those who received a living donor liver graft (Table 1). Patients who developed POCD had higher MELD scores (25.36±7.03 vs 16.21±3.77, P=0.000). A significant number of patients with POCD also had Child-Pugh C scores (71.4%, P=0.007). Other variables that signi-ficantly differentiated the patients who developed POCD were the etiology of liver disease (P=0.003) and the amount of blood infused during surgery (P=0.012). More patients with POCD had cirrhosis due to viral hepatitis while those without POCD more commonly had a diagnosis of hepatocellular carcinoma with or without cirrhosis.

 

There were no significant differences in the surgical parameters of patients with or without POCD. These patients had an average anhepatic time of 73.24±31.67 minutes. The serum levels of AST were higher in the patients without POCD than that in those with POCD on postoperative day 7. There was no significant difference in age, gender, weight, height, and a history of diabetes (Table 1) and nor difference in ICU or hospital stay between the two groups. The one-year survival rate of the patients was 76%, and there was no significant difference between the two groups.

 

High school education of the patients did not affect the outcome of neurocognitive testing. MMSE and SE showed a significant decline in cognitive function (Table 2). The postoperative MMSE score was significantly lower than the preoperative score (28±1.66 vs 25.84±2.53, P<0.01) in patients undergoing liver transplantation. The SM postoperative score was also lower (1.51±0.18 vs 1.36±0.26, P<0.05). The other test scores were not significantly different.

 

Serum assays were performed at four timepoints: preoperation, anhepatic stage, 3 hours after reperfusion, and 24 hours after surgery. There were significant differences in the serum concentrations of CRP and β-Ap in patients with POCD compared with those without POCD (Fig.). CRP and β-Ap demonstrated a spike in serum concentration at 24 hours after surgery in contrast to the preoperative value (CRP: 276.1±109.45 vs 159.94±53.79 ng/mL, P<0.01) (β-Ap: 164.96±70 vs 74.9±15.13 pg/mL, P<0.01). Obviously, no significant differences were observed during the two time points during surgery. CRP and β-Ap tended to increase at 3 hours after reperfusion in POCD patients, but this was not statistically significant. In patients without POCD, however, no significant differences in CRP and β-AP were seen at the time points.

 

 

In the present study, POCD was common in liver transplant recipients. Defects in cognitive function compatible with a diagnosis of POCD occurred in 11 (44%) of the 25 patients. Patients with POCD had a greater severity of the illness before liver transplantation. They also had a more complicated surgical course, reflected by a large amount of blood transfused. After surgery, the patients with POCD had a significant increase in the biomarkers of neuro-degenerative disease, β-Ap and CRP, but those without POCD did not exhibit this change. We agreed with other investigators that POCD may share a common molecular pathway with AD.^[17]

 

The incidence of POCD in elective and critical surgical patients is not clear because POCD could not be confirmed unless pre- or postoperative neuropsychological test is performed.^[18] Preoperative neuropsychiatric test is rarely indicated in surgical patients, but the incidence of POCD was estimated as high as 25% in elderly patients, and the disease eventually resolved one year after surgery.^[19] Despite the gradual resolution of cognitive dysfunction, patients with symptoms compatible with a diagnosis of POCD have a higher postoperative mortality.^[17]

 

One of the objectives of this study was to determine the incidence of POCD in liver transplant recipients. To ensure the reliability, we selected strict exclusion criteria for the study cohort, which are those likely affect or interfere with the diagnosis of POCD. Specific methods were used for cognitive test, and one uniform set of criteria was selected for the diagnosis. We therefore excluded all patients with a prior history of alcohol and drug abuse, for such patients may have symptoms interfering with the diagnosis of POCD. We did not exclude patients with diabetes since this has not been identified as an independent risk factor.^[20] We also excluded patients who were receiving treatment for or who had cognitive defects that were due to encephalopathy. This narrowed our study cohort to a group of patients who were not representative of most patients waiting for liver transplantation. This step, however, was necessary to meet the aims of our study for two reasons. First, there is no accepted method for the assessment of POCD in patients who already suffer from neurocognitive defects. Second, we are interested in identifying the potential role that the surgical procedure may play in the development of POCD. The inclusion of patients with encephalopathy would interfere with our diagnosis of POCD and confound the correlation between liver transplant surgery and POCD.

 

We compared pre- and postoperative neuropsycho-logical tests for each patient. This enabled us to exclude patients with preoperative cognitive defects and to calculate the degree of change in cognitive performance of each patient. This was done to prevent average disparate findings in the cohort, which could mask the diagnosis of POCD.^[2] Several methods could determine a significant decrease in cognitive function. We used a single well accepted method, where patients have more than one standard deviation decline in two separate tests.^[21]

 

With this experimental design, we estimated an incidence of 44% for POCD in liver transplant patients without encephalopathy. We anticipate that the incidence would be significantly greater than that of cognitive decline in an unselected group of liver transplant recipients. This hypothesis is supported by a recent study^[22] showing that a pre-existing cognitive defect increases the risk of developing POCD. Therefore, we suggest that an incidence of 44% represents the minimum number in a range that would include all potential liver transplant patients. This is significantly greater than the incidence of POCD reported in carefully controlled studies of high risk patients (>70 years) undergoing elective surgery.^[20] A large multi-center study reported that the incidence of POCD in a general surgical population was 25% at 2-10 days after surgery.^[20] Patients with POCD in this study had a decrease in their quality of life and were more likely to die within three months of surgery.

 

The increased incidence of POCD in liver transplant recipients suggests they are more vulnerable to neurological injury than other surgical patients. This conclusion is supported by the overall higher rate of neurological complications in patients after liver transplantation.^[23] Some of these complications are due to the chronic use of immunosuppressive agents or to the presence of preoperative encephalopathy.^[24] Our data suggest, however, that at least 44% of the patients may suffer from additional neurological injury due to the events that occur during surgery alone.

 

Demographic features associated with developing POCD in other patients include age, lower educational level and a prior cerebrovascular accident with no residual impairment.^[25] A study^[26] has identified 60 and 70 years of age as two threshold values where the risk of POCD increases significantly. Because our patients were younger, we were unable to assess age in our study. We also did not find the correlation between educational level and the incidence of POCD.

 

The severity of illness prior to transplantation was correlated best with POCD in our study. Both preoperative MELD score and Child-Pugh score were significant predictors of POCD. Similar findings have been reported for the recurrence of encephalopathy after liver transplantation and for a decline in cognitive function at one month following the transplantation.^[27] The amount of blood transfused and a diagnosis of viral cirrhosis also correlated with the occurrence of POCD. We did not have enough data to conduct a multivariate analysis in order to determine if the latter two variables were independent predictors in our study. Another study however, has shown a close relationship between an increased MELD score and the amount of blood given during surgery.^[28] Both variables require further test to determine their predictive value.

 

We used a battery of standard neuropsychological tests to determine cognitive function in our study. However, there are no standard tests specifically designed to diagnose POCD. We used a wide battery of five tests but were only able to find defects in the MMSE and SM. While the MMSE measures global function, the SM test measures the recall for details of the relationship between events and the judgment about the source of information.^[29] This function is primarily located in the medial temporal lobe (hippocampal formation) and frontal lobe.^{[30, 31]} A previous study of long-term outcome in liver transplant recipients has shown that global defects in cognition are not uncommon.^[21] However, our findings add to the current knowledge by identifying specific anatomic defects. The hippocampal formation and frontal lobe may be sensitive neurological regions that are prone to injury during transplantation. Further study is needed to test this hypothesis.

 

The proteins β-Ap and CRP were significantly increased at 24 hours after surgery in the study patients with POCD. Other investigations^{[32, 33]} suggested a common neuropathogenic link between POCD and AD, and found that metabolic insults induced POCD by initiating AD-like neuropathogensis.^[32] Two principle defects in AD are β-Ap processing and apoptosis. There is an accumulation of β-Ap leading to the deposition of neuronal plaques and a loss of neurons.

 

A recent study^[34] suggested that inhaled anesthetics such as isoflurane can induce neuronal apoptosis and enhance β-Ap oligomerization. Kalenka et al^[35] identified changes in the enzymes responsible for post translational modification of the β-Ap precursors. However, the specific genotypes in the apolipoprotein E family associated with the development of dementias have not been observed in patients with POCD.^[36] These findings suggest that POCD may have unique characteristics from AD.

 

Elevated CRP in patients with POCD,^[37] suggested the role of inflammation in the development of POCD, similar to other types of cognitive disorders including AD. Although most investigations have not identified a specific role of CRP in cognitive disease, it is considered a biomarker or participant in the neuro-inflammation pathway.

 

The limitation of this study is the small sample size. Since no recognized standard is available for the diagnosis of POCD, further studies can be directed toward a double-blinded, randomized prospective study. Large sample size would probably provide a more realistic incidence of POCD in post-liver transplant patients. Better exclusion criteria for patients are needed and patients should be evaluated for baseline of dementia, psychosis or anxiety/depressive disorders. Preoperative base levels of β-Ap and CRP should also be measured in all subjects. Lastly, a series of measurements of β-Ap and CRP in the post-liver transplant period would provide better understanding of time course of the aforementioned biological markers and their temporal correlation to the onset of POCD.

 

In summary, this study shows that patients who undergo liver transplantation are at increased risk of developing POCD, which decreases the quality of life and increases the risk of mortality. The data of the study have shown that patients at risk of developing POCD have a greater severity of illness, a more complicated intra-operative course, and some POCD-related risk factors after liver transplantation. Larger studies are required to validate which patient variables independently increase the risk of POCD. The postoperative increase in β-Ap and CRP in transplant patients supports the hypothesis that POCD in liver transplant recipients shares metabolic similarities with AD-like disease.

 

 

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