Indocyanine green retention is a potential prognostic indicator after splenectomy and pericardial devascularization for cirrhotic patients

Yuan-Biao Zhang， Yi Lu， Wei-Ding Wu， Cheng-Wu Zhang， Guo-Liang Shen and De-Fei HongHangzhou， China

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Indocyanine green retention is a potential prognostic indicator after splenectomy and pericardial devascularization for cirrhotic patients

Yuan-Biao Zhang， Yi Lu， Wei-Ding Wu， Cheng-Wu Zhang， Guo-Liang Shen and De-Fei Hong
Hangzhou， China

BACKGROUND： Splenectomy and pericardial devascularization （SPD） is an effective treatment of upper gastrointestinal bleeding and hypersplenism in cirrhotic patients with portal hypertension. Indocyanine green retention at 15 minutes （ICGR15） was reported to offer better sensitivity and specificity than the Child-Pugh classification in hepatectomy， but few reports describe ICGR15 in SPD. The present study was to evaluate the prognostic value of ICGR15 for cirrhotic patients with portal hypertension who underwent SPD.

METHODS： From January 2012 to January 2015， 43 patients with portal hypertension and hypersplenism caused by liver cirrhosis were admitted in our center and received SPD. The ICGR15， Child-Pugh classification， model for end-stage liver disease （MELD） score， and perioperative characteristics were analyzed retrospectively.

RESULTS： Preoperative liver function assessment revealed that 34 patients were Child-Pugh class A with ICGR15 of 13.6%-43.0% and MELD score of 7-20； 8 patients were class B with ICGR15 of 22.8%-40.7% and MELD score of 7-17； 1 patient was class C with ICGR15 of 39.7% and MELD score of 22. The optimal ICGR15 threshold for liver function compensation was 31.2%， which offered a sensitivity of 68.4% and a specificity of 70.8%. Univariate analysis showed preoperative ICGR15， MELD score， surgical procedure， intraoperative blood loss， and autologous blood transfusion were significantly different between postoperative liver function compensated and decompensated groups. Multivariate regression analysis revealed that ICGR15 was an independent risk factor of postoperative liver function recovery （P=0.020）.

CONCLUSIONS： ICGR15 has outperformed the Child-Pugh classification for assessing liver function in cirrhotic patients with portal hypertension. ICGR15 may be a suitable prognostic indicator for cirrhotic patients after SPD.

（Hepatobiliary Pancreat Dis Int 2016；15：386-390）

indocyanine green；

liver function test；

liver cirrhosis；

splenectomy；

pericardial devascularization

Introduction

I n China， portal hypertensio n due to liver cirrhosis can cause a lethal esophageal variceal rupture and hepatic encephalopathy with an estimated incidence of 30% and a 30-day mortality of 20%.［1］About 10%-30% patients died after the initial onset of gastrointestinal bleeding， so splenectomy and pericardial devascularization （SPD） are universally used to prevent bleeding as well as to support surgical procedures.［2］

Complications subsequent to impaired liver function usually occur after cirrhosis. Though Child-Pugh classification is typically used to estimate surgical safety for treating portal hypertension in cirrhotic patients， postoperative ascites， hepatic encephalopathy and liver failure can occur after SPD in patients with preoperatively normal Child-Pugh classification. This indicates that this technique is not optimal for identifying liver functional reserve，［3］especially for a surgical procedure.

The model for end-stage liver disease （MELD） score has been accepted as a useful tool for estimating mortality in patients awaiting liver transplantation. It has been also applied to predict the postoperative mortality of patients receiving hepatectomy. But the total bilirubin，creatinine and international normalized ratio （INR） in MELD system could easily be affected by generation rate，organ perfusion and bile duct disease. Indocyanine green（ICG） clearance is the most commonly used quantitative assessment of liver function， and ICG retention at 15 minutes （ICGR15） has been reported to be closely associated with hepatectomy outcomes，［4］its utility for predicting cirrhotic liver transplantation succeeded.［5， 6］However， few studies have used ICGR15 for SPD prognosis. Thus， we analyzed the relationship between ICGR15 and perioperative liver function and SPD outcomes and described the prognostic value of ICGR15 for SPD.

Methods

Patients

A total of 43 patients with portal hypertension and hypersplenism caused by liver cirrhosis who underwent SPD in our center from January 2012 to January 2015 were analyzed retrospectively. Diagnosis of cirrhosis was based on clinical symptoms， biochemical data， upper gastrointestinal radiology， and endoscopic findings，and all patients had a history of hematemesis or melena. Upper gastrointestinal endoscopy was performed to diagnose esophageal and gastric varices. Clinical examinations included laboratory data with hemograms， serum electrolytes， liver function tests， and a complete coagulogram. Patients with regional portal hypertension caused by portal vein thrombosis or splenic vein drainage reflux were excluded.

Surgical procedures

The open or laparoscopic procedure was chosen depending on the patient's will， history of left upper abdominal surgery and preoperative assessment of abdominal space according to CT scan. The traditional open procedure was performed using Hassab's operation as previously described by Yang and Qiu.［7］The laparoscopic procedure was performed as described by Hong et al.［8］In brief， the abdomen was insufflated with carbon dioxide， 4 or 5 operative ports were used， and the placement of the trocars depended on the volume of the spleen. After the stomach was suspended to the abdominal wall with an 8# urine catheter， splenic artery was exposed and occluded by Hem-o-Lock. Once the splenogastric and lienorenal ligament were dissected by LigaSure? Vessel Sealing System （LVSS， Covidien， USA）， a posterior hilum tunnel was made meticulously from the low to the upper edge of the spleen by a blunt dissection. Then the splenic pedicle was transected en bloc with the application of linear laparoscopic vascular stapler （Endo GIA?， Covidien，USA）. The gastric coronary vein， branches toward the proximal stomach and esophagus were cut by LVSS or blocked by Hem-o-Lock. At least 6 cm of the distal paraesophageal venous collaterals was dissected.

ICG test

The ICG test was performed as described by Sakka.［9］A solution of 50 mg ICG （Dandong Yichuang Pharmaceutical Co.， Ltd， Dandong， China） in 10 mL of sterilized water （5 mg/mL） was injected （0.2 mg/kg） through the median cubital vein within 5-10 seconds， and blood ICG concentrations were monitored using a dilator naris optical probe （DDG-3300K， Nihon Kohden， Tokyo， Japan）. ICGR15 was calculated automatically.

Subgroup

Clinical data and perioperative characteristics were recorded and analyzed， and postoperative liver function was classified as compensated group with no ascites， no or mild jaundice （total bilirubin ＜51.3 μmol/L）， no hepatic encephalopathy or normal liver function within one week and decompensated group with ascites， moderate or severe jaundice （total bilirubin ≥?51.3 μmol/L） for one week， or death from liver failure. The receiver operating characteristic （ROC） curve for postoperative liver function was used to establish a threshold for ICGR15， and high and low ICGR15 groups were formed.

Statistical analysis

Data were analyzed using IBM SPSS version 19 （IBM Co.， Armonk， NY， USA）. Data were analyzed with a Student's t test or a Chi-square test. Relationships were assessed with multivariate regression analysis. Thresholds were established using the highest Youden index retrieved from ROC curves. A P value ＜0.05 was considered statistically significant.

Results

Patients characteristics

Demographic data and clinical characteristics of patients are shown in Table 1. According to the postoperative liver function， the area under the ROC curve for ICGR15 was 0.724 （Fig.）， and the optimal ICGR15 threshold for liver function compensation was 31.2%， with a sensitivity of 68.4% and a specificity of 70.8%.

Univariate and multivariate analysis

Preoperative liver function assessment revealed that 34 patients were Child-Pugh class A with ICGR15 of 13.6%-43.0% and MELD score of 7-20； 8 patients were class B with ICGR15 of 22.8%-40.7% and MELD score of 7-17； 1 patient was class C with ICGR15 of 39.7% and MELD score of 22. Univariate analysis revealed there was no difference in age， gender， admission status， Child-Pugh classification， operation time， or postoperative plasmause between compensated and decompensated groups，but preoperative ICGR15， MELD score， surgical procedure， intraoperative blood loss， and autologous blood transfusion were significantly different （Table 2）. Multivariate regression analysis revealed that ICGR15 was an independent risk factor of postoperative liver function recovery （P=0.020） （Table 3）.

ICGR15 subgroups

There was no difference in Child-Pugh classification and intraoperative blood loss between high and low ICGR15 groups， but postoperative liver function， complications， and postoperative hospital stay were significantly different between groups （Table 4）.

Fig. The area under the ROC curve of ICGR15 for postoperative liver function.

Table 1. Demographic data and clinical characteristics of patients

Table 2. Risk factors for liver function compensation by univariate analysis

Table 3. Risk factors for liver function compensation by multivariate analysis

Table 4. High and low ICGR15 groups outcomes

Postoperative complications

Postoperative complications included portal thrombi（n=2）， ascites （n=8）， wound （n=2）， intraperitoneal （n=1）and enteric infections （n=1）， fever （n=2）， and heart （n=1）and liver failure （n=1） in 16 patients. Fourteen patients were successfully treated. Two patients died postoperatively， one of liver failure after an emergent operation and the other of enteric infection due to methicillinresistant Staphylococcus aureus.

Discussion

SPD is used to treat cirrhotic patients with variceal bleeding caused by portal hypertension，［10］but many complications such as postoperative moderate/severe ascites， hepatic encephalopathy， and liver failure after SPD occur. For cirrhotic patients， liver function reserve estimations are important for selecting appropriate patients for liver surgery and various methods have been advocated before operation. The Child-Pugh classification was initially developed to evaluate surgical risk of portal hypertension in cirrhotic patients， and it remains the most used liver function assessment for hepatectomy and radiofrequency ablation.

An intrinsic disadvantage of Child-Pugh classification is that ascites and hepatic encephalopathy are subjective parameters， which diminishes its accuracy， and the Child-Pugh classification system is said to be unable to predict surgical suitability.［11］We found that there was no difference between class A compensated and class B decompensated subjects （P=0.650）， suggesting a disadvantage in using Child-Pugh classification for identifying liver functional reserve， these data agree with a report by Jalan and Hayes.［3］

The MELD model was initially developed as a model for predicting poor survival in patients after transjugular intrahepatic portosystemic shunt （TIPS）.［12］Then a modified MELD score was developed to predict mortality in cirrhotic patients and severe liver disease.［13］Delis et al［14］reported that a MELD score ≥9 independently predicted mortality after HCC resection. Cucchetti et al［15］showed that a MELD score ≥11 may have a high risk of postoperative liver failure in cirrhotic patients. Our analysis showed that with the deterioration of liver function，MELD score also increased as well as ICGR15. Although the MELD score includes objective parameters （bilirubin，creatinine and INR） and avoids many drawbacks of the Child-Pugh classification， it has been criticized for several reasons.［11］Many patients undergoing hepatectomy had normal serum creatinine concentrations， resulting in a low MELD score. Marked variations could be observed in serum creatinine measurement with different laboratory methodologies.［16］What's more， the accuracy of the MELD score can easily be affected by creatinine after treatments like diuretic measurement. INR may not reflect the severity of liver disease. A previous study showed that the selection of laboratory methodologies may have a significant impact on MELD score.［17］

Thus， we need a more reliable and sensitive predictor for post-SPD decompensation or complications. ICG is a synthetic dye that is eliminated by the liver without extrahepatic metabolism and excretion. ICG tests reflect uptake， processing， and excretion of ICG and can accurately estimate functioning hepatocytes. ICG is simple，real-time， and minimally invasive and may be a more reliable liver function assessment.［18］ICG has been used to measure liver function to assess graft and donor function for liver transplantation. It was reported to be a good predictor of survival in cirrhotic patients and is routinely used in many centers. Patients using the ICG test have less mortality， and in some centers， mortality is zero.［19］

A previous report indicated that ICGR15 can differentiate between patients with possible hospital mortality，and thresholds for a safe major and minor hepatectomy are 14% and 22%， respectively.［20］In SPD， hepatectomy is not performed， and splenectomy is shown to provide improvements in liver function.［21， 22］Threshold for a SPD is thought to be higher， but no data are available to offer a threshold for ICGR15 that distinguishes SPD outcomes. Our study indicates that the threshold for SPD is 31.2%，and patients with low ICGR15 had better postoperative recovery， better liver function compensation， less incidence of complications， and a shorter hospital stay. For patients with high ICGR15， majority were discharged with good outcomes after treatment of symptoms. Imura' s report of 18 patients who underwent splenectomy confirmed that ICGR15 ranged from 19.9%-60.7% （mean 38.5%）， and postoperative complications were 33%， but all complications were not critical.［23］ICGR15 for the deceased patient was 41.7%， and the cause of death may be emergent surgery with a class C liver function. Our study was limited by fewer C class patients and the small samples size， so we observed fewer adverse events.

Laparoscopic splenectomy （LS） has been reported to be the golden de facto standard for removing normally to moderately enlarged spleens， resulting in minor complications， minor liver function impairment and shorter hospital stay compared with open splenectomy （OS）. Zhu and coworkers revealed the increase of alanine aminotransferase， glutamic oxalacetic transaminase， total bilirubin， and direct bilirubin were significantly different between LS and OS.［24］But Watanabe's data did not show the effect of splenectomy on liver function.［25］Our univariate analysis showed that LS was better to reserve liver function than OS （P=0.013）. However， this difference was not verified with our multivariate regression analysis （P=0.097）.

Intraoperative autologous blood transfusion （cellsalvage） increases postoperative hemoglobin and reduces the need for allogeneic blood transfusion. A report showed that the postoperative liver function was not significantly different between patients who received intraoperative cell salvage and those who did not.［26］But our study indicated a better outcome in liver compensation for those who received intraoperative cell salvage （P=0.029）.

In conclusion， ICGR15 is a potential valuable prognostic indicator after SPD for patients with cirrhosis and portal hypertension， and it offers greater sensitivity and specificity than Child-Pugh classification. More prospective studies are needed to confirm the value of ICGR15 as a single predictor in the assessment of postoperative function.

Contributors： ZYB and HDF conceived this study. ZYB and LY collected and analyzed the data. ZYB wrote and revised the manuscript. All authors contributed to the design and interpretation of the study and to further drafts. HDF is the guarantor.

Funding： This study was supported by grants from the Health and Family Planning Commission of Zhejiang Province （2015KYB042）and the Administration of Traditional Chinese Medicine of Zhejiang Province （2015ZA012）.

Ethical approval： This study was approved by Institutional Ethics Committee of Zhejiang Provincial People's Hospital.

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.

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Accepted after revision May 23， 2016

Author Affiliations： Department of Hepatopancreaticobiliary Surgery & Laparoscopic Minimally Invasive Surgery， Zhejiang Provincial People's Hospital， Hangzhou 310014， China （Zhang YB， Lu Y， Wu WD， Zhang CW，Shen GL and Hong DF）

De-Fei Hong， MD， FACS， Department of Hepatopancreaticobiliary Surgery & Laparoscopic Minimally Invasive Surgery，Zhejiang Provincial People's Hospital， Hangzhou 310014， China （Tel：+86-571-85893396； Email： hongdefi@163.com）
? 2016， Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872（16）60114-5
Published online July 13， 2016.

Feburary 3， 2016