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

doi: 10.1016/S1499-3872(13)60093-4

 

 

Contributors: GN, GA and AM proposed the study. GN and AM performed research and wrote the first draft. UO, GA, YO, DM, and SM collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. TY is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: The authors do not choose to declare any conflict of interest related directly or indirectly to the subject of this article.

 

 

 

 

 

 

(Hepatobiliary Pancreat Dis Int 2013;12:589-593)

 

KEY WORDS: liver transplantation|acute liver failure|APACHE-II|waiting time|Glasgow coma scale

Acute fulminant liver failure has a vicious progress and the earliest liver transplantation improves the results of the patients,^[1-7] especially in those with stage 3 or 4 encephalopathy. If liver transplantation is not performed, the spontaneous recovery is less than 20%.^[3-7] Liver transplantation increases the survival of the patients with acute liver failure (ALF) and plays a major role in the management of ALF.

 

The selection of optimal treatment modality is the main challenge in patients with ALF. A variety of selection criteria, such as King's College criteria, Clichy criteria and MELD score, have been used. APACHE-II score, first developed in 1981 by Knaus et al,^[8] is the most commonly used survival estimate model in intensive care units worldwide. APACHE-II score is based on 12 routinely measured physiological parameters together with age and premorbid health status and is to evaluate disease severity. The parameters used to calculate APACHE-II score are collected within 24 hours after the admission. The highest possible APACHE-II score is 71, and the scores have a significant positive correlation with mortality.^{[8, 9]} Compared with APACHE-II score, Glasgow coma scale (GCS) is a simple but useful evaluation method for unconscious patients, the parameters of GCS including eye movements, verbal responses and motor responses. The range of GCS is from 3 to 15, more than 13 is considered as mild coma, 9-12 as moderate and 6 or lower as severe. The lower the GCS, the higher the mortality patients have.

 

The most common cause of death in ALF is brain edema complicated by herniation.^{[1-7, 10-13]} The current criteria for the decision of emergency liver transplantation in fulminant liver failure are King's College and Clichy-Villejuif criteria. APACHE-II score has been validated in cirrhotic patients and acute-on-chronic liver failures. Furthermore, APACHE-II score has been studied in patients with ALF and found that APACHE-II score predicted the outcome of ALF patients whose clinical data were not enough to calculate with the King's College criteria. However, there are paucity data on the impact of GCS and APACHE-II scores on liver transplantation outcomes in patients with ALF. In the present study, we retrospectively analyzed the factors influencing mortality after liver transplantation in patients with ALF and the impact of GCS and APACHE-II scores on the outcome of patients with ALF who had emergency liver transplantation.

 

 

The study covered the period from January 1999 to March 2012. A total of 1305 patients underwent liver transplantation at both the Hepatobiliary Surgery and Organ Transplantation Center of both Sisli Florence Nightingale Hospital and Ege University Medical School. Among them, 25 patients (1.9%) who had emergency liver transplantation due to fulminant liver failure were analyzed. Patients who had acute episodes on a chronic setting were excluded from the study. Twelve adult patients received right lobe from live donors, 1 adult received left lobe from a live donor, 5 pediatric patients received left lateral segment from live donors and 7 adult patients had cadaveric liver transplants. The definition of perioperative period covered the duration of the operation and the first three months thereafter. Evaluated were factors influencing perioperative mortality such as age, MELD score, GCS, APACHE-II score, serum sodium levels, the waiting time before liver transplantation, etiology, the type of the operation and the postoperative complications.

 

All fulminant liver failure patients were evaluated by a team of physicians consisting of liver transplant surgeons, adult and pediatric gastroenterologists, intensive care unit doctors, psychiatrists and neurologists. Fifteen patients had grade 4 and 10 had grade 3 encephalopathy. Patients with grade 4 encephalopathy underwent comprehensive neurological examination and radiological tests, afterwards all of these patients had endotracheal intubations to prevent complications like aspiration pneumonia. Decisions about liver transplants were based on King's College criteria and upon their admissions to our hospitals, a call was made for emergency cadaveric transplants.

 

After arriving at the decision of emergency liver transplantation, the family of the patient was informed about the necessity of this operation together with options of live donor or cadaveric transplants. In the event that cadaveric organs were not accessible, the planned liver transplant from live donor and the risks for the donor, the benefits for the patient and the possible complications for the patient were covered in detail. The candidates for live donor transplants were informed in details. The donor candidates were chosen from the family members who did not have any health concern after related examinations. All donors had blood group typing, hemograms, detailed biochemical analyses, urinalyses, coagulation tests, serological tests including HBV, HCV, HIV, HSV, CMV and EBV, rectal, nasal and urinary cultures, VDRL tests, tests for prothrombin gene and factor 5 Leiden mutations. Female donors had beta-HCG tests performed. During the preoperative period, each donor was subjected to lung X-rays, electrocardiography and echocardiography. Pulmonary and cardiology consultations were requested and female donors had detailed gynecological examinations. CT was used to evaluate the volumetric and vascular structures of the liver. In right lobe donors, remnant liver had to be at least 30% and the ratio of the estimated weight of the right lobe graft to the weight of the liver of the patient had to be at least 0.8. Percutaneous liver biopsy was not performed routinely. Hyperlipidemia, hepatosteatosis, high body mass index and positivity of hepatitis B core antigen were criteria for percutaneous liver biopsy. Individuals with more than 10% of hepatosteatosis were excluded from donor candidates.

 

For all the live donors, preparations were completed within 24-48 hours before the transplantation, all patients with fulminant liver failure were reevaluated for possible contraindications for the operation by the same team of doctors and Doppler ultrasound, cranial MRI and CT were performed before surgery.

 

The data were input into SPSS 14.0. The Chi-square test was used for the analysis of qualitative data and Student's t test was used for the analysis of quantitative data. The Kaplan-Meier test was used to determine the survival of the patients. Multivariable logistic regression analysis and receiver operating characteristic (ROC) curve tests were performed. A P value of <0.05 was considered statistically significant.

 

 

In this series, 20 patients were adult and 5 children. Eighteen of the patients were female. The mean age of the patients was 29.60±16.23 years (3-56), mean MELD score was 34.72±7.17 (23-55), mean GCS was 8.88±2.43 (4-12), mean APACHE-II score was 19.48±2.48 (16-24), mean serum sodium level was 138.41±6.28 mmol/L (128-150), and mean waiting time before the operation was 7.08±4.14 days (2-17). The etiology of the patients was as follows: 8 patients with idiopathic hepatitis, 5 with hepatitis B, 4 with acute hepatitis A, 2 with mushroom intoxication, 4 with autoimmune liver disease, 1 with iatrogenic cause (total cut of the hepatoduodenal ligament during emergency surgery for sigmoid volvulus) and 1 with drug intoxication (piroxicam).

 

There were 12 male and 6 female live donors. Their mean age was 30.2 years (24-36). There was no mortality in live donors. The mean duration of hospital stay after the operation was 9.2 days (7-12). Five donors developed pleural effusion and 1 developed pneumonia. All live donors were discharged without any complication after surgery and returned to their normal lives.

 

One patient complicated with bile leakage, and two patients developed bile obstruction. All of these complications happened at the site of bile anastomosis. ERCP was done on the 17th postoperative day for the patient with bile leakage and a biliary stent was placed to the anastomosis line. Biliary stent was also placed for the other two patients with bile obstruction under ERCP in the 6th and 10th postoperative month respectively. One patient developed hepatic artery thrombosis on the 5th postoperative day and splenic artery reanastomosis was performed. One patient complicated with upper gastrointestinal system bleeding on the second postoperative day. The bleeding was treated with endoscopic sclerotherapy. This patient developed spontaneous jejunum perforation on the 13th postoperative day. The perforation was repaired. One patient had primary repair due to duodenal ulcer perforation on the 25th postoperative day. Two patients died.

 

The mean duration of follow-up after liver transplantation was 39.86±40.23 months (0.5-134). In 7 patients died within the perioperative period (three months), 5 were due to sepsis and multi-organ failure and 2 were due to brain death. Of the perioperative deaths, 5 were female and 2 were male (pediatric). One patient died of ischemic cholangitis at 48 months. One patient died from chronic rejection at 48 months. Kaplan-Meier survival analysis identified that the 1-, 3-, and 5-year survival rates were 72%, 72%, and 60%, respectively (Fig. 1).

 

The parameters evaluated for the perioperative deaths were as follows: mean age of the patients was 33.71±20.39 years, MELD score was 40.00±8.22, GCS was 5.57±1.61, APACHE-II score was 23.00±1.15, serum sodium level was 138.57±5.88 mmol/L, and mean waiting time before the operation was 12.00±4.76 days. On the other hand, the mean values for 18 patients who did not develop perioperative mortalities were as follows: mean age was 28.00±14.67 years, MELD score was 32.66±5.72, GCS was 10.16±1.10, APACHE-II scores were 18.11±1.07, serum sodium level was 138.44±6.59 mmol/L, and mean waiting time before the operation was 5.16±1.54 days. Low GCS (P<0.01), high APACHE-II score (P<0.01), and longer waiting periods before the operation (P<0.01) were found to be statistically significant factors for perioperative mortality (Table, Fig. 2).

 

Since the number of the patients was not sufficient and confidence interval was too large, multivariable logistic regression analysis was impossible. However, there were negative correlation between GCS and APACHE-II (r=-0.423, P=0.035) and positive correlation between the waiting time and APACHE-II (r=0.549, P=0.004). In addition, ROC curve test revealed that if the cut off value for APACHE-II was 21.5, the specificity was 100%, and the sensitivity 85.7%. If the cut off value for waiting time was 6.5 days, the specificity was 89% and the sensitivity 85.7%. Unfortunately, the cut off value for GCS could not be calculated since the area under curve was very low.

 

 

Acute fulminant liver failure is a vicious progressing process and the patients progress to coma and even death within a couple of days if liver transplantation is not performed.^[1-7] All patients with stage 3 or 4 encephalopathy are candidates for liver transplantation. Before transplantation, they should be examined to rule out any irreversible complications. Abnormal pupilla and brain stem reflexes, de-cerebration, sepsis, and serum sodium levels of less than 125 mmol/L are contraindications for liver transplants.^{[5, 12-14]} Especially in patients with stage 3 or 4 encephalopathy, spontaneous recovery without liver transplantation is less than 20%.^[1-7] Although King's College criteria were generally accepted in ALF, it is not optimal because of low sensitivity and limited ability to predict the patients outcomes. Therefore, it is necessary to explore the more accurate markers and selection criteria to foresee the outcome of patients with ALF. In the present study, we investigated the predictive value of GCS and APACHE-II scores on the outcome of liver transplantation in patients with ALF. Our results showed that patients with ALF who had lower GCS, higher APACHE-II scores and longer waiting time had lower survival after liver transplantation.

 

In fulminant liver failure patients, the disease progression is vicious and therefore, it is crucial to perform liver transplantation at the earliest time to avoid developing irreversible cerebral damage. Ostapowicz et al^[13] investigated 135 patients with fulminant liver failure and found that, although the mean waiting time was 3.5 days, 22% died while they were waiting for liver transplantation. In our study, the mean preoperative waiting time was 7.08 days. Before the operation, the patients treated in our clinic for an average of 1.3 days and 18 patients whose general condition deteriorated progressively underwent live donor transplantation under emergency conditions becasue cadaveric transplants were not available. The mean waiting time for 7 patients who died during the early postoperative period was 12.00±4.76 days, the waiting time for our survivors was 5.16±1.54 days, significantly shorter than their counterparts.

 

GCS is a simple method for unconscious patients and it was primarily used for the evaluation of trauma patients. Bastos et al^[15] proposed that it is capable of detecting the mortality in all patients in ICU. Those who have disturbed consciousness may increase the mortality rate.^[14-16] Lehner et al^[14] reported that GCS predicted the mortality in patients with acute or chronic liver failure. Similarly, Karvellas et al^[17] found that lower GCS was an independent predictor of mortality in critically ill patients with acute-on-chronic liver failure. To date no data are available on the effect of GCS on liver transplantation outcome in patients with ALF. The present study showed that lower GCS indicates a lower survival rate after liver transplantation and reflects higher perioperative mortality.

 

APACHE-II score is a commonly used survival estimate model in intensive care units worldwide. High scores have a very good correlation with mortality. Karvellas et al^[18] studied the predictors of mortality in patients with ALF and showed that APACHE-II score was an independent predictor of mortality on admission. Furthermore, a study of 184 patients with acute-on-chronic liver failure showed that bacteremia, higher MELD score, and higher APACHE-II score were independent factors of mortality.^[17] Our present study showed that the mean APACHE-II score (23.00±1.15) was significantly higher in patients who died in a perioperative period compared with that of survivors (18.11±1.07). In conclusion, patients with ALF should be referred to liver transplantation centers as soon as possible. Furthermore, lower GCS and higher APACHE-II scores are identified as negative prognostic factors for the early perioperative mortality after liver transplantation.

 

 

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