Expert consensus on perioperative management of liver transplantation in adults with acute-on-chronic liver failure☆,☆☆,☆☆☆

Transplantation Immunology Committee of Branch of Organ Transplantation Physician of Chinese Medical Doctor Association;Enhanced Recovery of Liver Transplantation Group of Enhanced Recovery after Surgery Committee of Chinese Research Hospital Society

Keywords:Acute-on-chronic liver failure Chronic liver disease Infection prevention and control Liver transplantation Nutritional support Organ protection Rehabilitation exercise Surgery timing

ABSTRACT Acute-on-chronic liver failure (ACLF) is a syndrome in which acute liver failure with extrahepatic organ failure occurs on chronic liver disease.Recently,liver transplantation is the only effective treatment for ACLF.There is still room for discussion on the optimal surgery timing for ACLF,perioperative infection prevention and control,and maintenance of nutrition and organ function.The Transplantation Immunology Committee of Branch of Organ Transplantation Physician of Chinese Medical Doctor Association and Enhanced Recovery of Liver Transplantation Group of Enhanced Recovery after Surgery Committee of Chinese Research Hospital Association invited relevant experts to discuss the perioperative management of ACLF liver transplantation in areas including surgery timing,organ protection,nutritional support,infection prevention and control,rehabilitation exercises,regulation of the internal environment,etc.An expert consensus was developed as reference for clinicians.

1.Introduction

Acute-on-chronic liver failure (ACLF) is a syndrome in which acute liver failure and single or multiple extrahepatic organ failure occur on chronic liver disease.Its 90-day mortality rate is 60-70%.Recently,liver transplantation is the only effective treatment for ACLF.Liver failure patients often have comorbid malnutrition,infection,disturbances of the internal environment,coagulation dysfunction,respiratory failure,cerebral edema,hepatorenal syndrome (HRS),and other multiorgan impairments.These complications will further increase the risk of liver transplantation.Concurrently,the high incidence and mortality rate of post-liver transplantation complications are also challenges in liver transplantation in ACLF patients.There are many problems and room for discussion for ACLF liver transplantation timing selection,perioperative infection control,nutrition,and maintenance of organ function.Therefore,experts from the Transplantation Immunology Committee of Branch of Organ Transplantation Physician of Chinese Medical Doctor Association and Enhanced Recovery of Liver Transplantation Group of Enhanced Recovery after Surgery Committee of Chinese Research Hospital Association conducted a discussion on the surgery timing,organ protection,nutritional support,infection prevention and control,rehabilitation exercises,and regulation of the internal environment.This expert consensus was written according to the principles of evidence-based medicine as a reference for clinicians.

2.Timing of ACLF liver transplantation

2.1.Surgery timing

For acute or subacute liver failure and chronic liver failure patients,the model for end-stage liver disease (MELD) score is the primary reference marker in evaluating the severity of their condition.1The Chronic Liver Failure Consortium ACLF (CLIF-C ACLF)score is better than the MELD score in predicting the ACLF mortality rate.2The 28-day and 180-day survival rates of grades 2-3 CLIF-C ACLF (2 or more extrahepatic organ failure) patients who underwent liver transplantation 3-7 days after ACLF diagnosis were 95.2% and 80.9%,respectively,while the survival rates of patients who did not undergo liver transplantation at the corresponding time points were 23.3% and 10.0%,respectively.3

The Asian Pacific Association for the Study of the Liver ACLF Research Consortium(AARC)score is also suitable in evaluating the severity and prognosis of ACLF.4

ACLF is classified as grade 3 based on the following AARC score:Grade I is 5-7 points,grade II is 8-10 points,and grade III is 11-15 points.The 28-day postoperative mortality rates are 12.7%,44.5%,85.9%,respectively.5

Recommendation 1:Priority should be given to grades 2-3 CLIF-C ACLF patients for liver transplantation 3-7 days after ACLF diagnosis.With regard to AARC scores,grades I-II ACLF patients whose scores do not decrease within 1 week and grade III AARC ACLF patients should be given priority for liver transplantation.

2.2.Surgery contraindications

With the development of liver transplantation techniques,contraindications for liver transplantation are also continuously changing.Except for the absolute contraindications for liver transplantation,the transplantation center should consider relative contraindications based on the actual situation of each unit and the disease severity of ACLF patients.

2.2.1.Nervous system

Head CT and MRI can be used to assess cerebral edema in patients.Patients who are comatose or have diffuse cerebral edema,decerebrate rigidity,no motor response to stimuli,and disappearance of pupillary light reflex and corneal reflex have poor prognosis after liver transplantation.6,7

Recommendation 2:Liver transplantation is not recommended for patients with irreversible brain damage,coma due to diffuse cerebral edema,and brain stem involvement.

2.2.2.Respiratory system

Liver transplantation is recommended to be delayed for patients with partial arterial pressure of oxygen (PaO2)/fraction of inspiration oxygen (FiO2) of <150 mmHg,and uncontrollable lung infection is a contraindication for liver transplantation.8,9The risk of liver transplantation is significantly increased in comorbid portopulmonary hypertension (POPH) patients with mean pulmonary artery pressure (mPAP) of≥35 mmHg or increased pulmonary vascular resistance (PVR).Few patients with mPAP of>50 mmHg can survive after liver transplantation without concomitant pulmonary hypertension targeted therapy.Therefore,mPAP >50 mmHg is an absolute contraindication for liver transplantation.In most centers,comorbid hepatopulmonary syndrome(HPS) patients with pretransplantation PaO2of <50 mmHg developed severe hypoxia after transplantation,and the incidence of postoperative complications and mortality rate are increased.Only a few studies reported good post-liver transplantation outcomes in HPS patients with pretransplantation PaO2of<50 mmHg.10

Recommendation 3:Uncontrolled severe lung infection and mPAP >50 mmHg are contraindications for liver transplantation.The risk of liver transplantation is high in HPS patients with PaO2of<50 mmHg.The transplantation center can comprehensively evaluate surgery risk by combining with the actual condition.

2.2.3.Circulatory system

ACLF patients often have varying degrees of unstable hemodynamics or even circulatory failure.Although the survival rate of ACLF patients with comorbid circulatory failure after liver transplantation is higher than those who do not undergo liver transplantation,liver transplantation should be delayed in patients with persistent hypotension after large doses of vasopressors(1 μg/kg/min norepinephrine or equivalent doses of other vasoactive drugs).11

Recommendation 4:Liver transplantation is contraindicated in grade 3 ACLF patients who require large doses of vasopressors but are unable to maintain normal blood pressure.

3.Perioperative organ protection in ACLF liver transplantation recipients

3.1.Pulmonary protection

Acute lung injury and acute respiratory distress syndrome are extremely common in ACLF patients.Preoperative lung function training can aid in the clearance of airway secretions,improvement of oxygenation,and decrease postoperative lung complications.Transfusion of large amounts of blood products and fluid within a short period should be avoided during the perioperative phase.12-14For patients with comorbid POPH,pulmonary hypertension-targeted therapy should be continuously given,and right heart function should be continuously monitored during surgery.Prostacyclin drugs,phosphodiesterase-5 inhibitors,and endothelin receptor antagonists can decrease pulmonary artery pressure.Extracorporeal membrane oxygenation (ECMO) can be considered when acute mPAP elevation occurs during reperfusion or right cardiac insufficiency occurs.Saturation of arterial oxygen(SaO2)should be maintained as much as possible in comorbid HPS patients.If SaO2is <65% after intraoperative hepatic blood flow occlusion and other procedures and drug interventions fail,ECMO can be considered.10

Endotracheal intubation should be removed as soon as possible after anesthesia recovery to prevent ventilator-associated pneumonia.High-flow oxygen or noninvasive ventilation continuous oxygen therapy should be given to maintain SaO2≥85%.Inhalation of pulmonary vasodilators can increase blood oxygen levels 1 surgery.ECMO can be used as transition for patients with poor oxygenation to decrease mechanical ventilation needs in severe HPS patients.Appropriate analgesia should be given to prevent inhibition of the cough reflex due to wound pain.Tracheotomy should be performed early for patients who require long-term respiratory support.15

Recommendation 5:Fluid restriction management policy should be implemented during perioperative phase.Routine lung function evaluation and guided training are carried out before surgery.After surgery,ventilator weaning should be achieved as early as possible,sufficient sedation should be given,and patients should be encouraged to undergo cough training.Continuous targeted drug therapy should be carried out in POPH patients to maintain mPAP <35 mmHg.ECMO can be carried out when necessary for acute mPAP elevation during surgery or right heart failure.SaO2≥85%must be maintained in HPS patients and ECMO can be performed when necessary.

3.2.Renal protection

ACLF patients often have comorbid HRS and non-HRS acute kidney injury (AKI).Visceral vasodilation is the most important factor causing HRS.Compared with albumin alone or placebo,vasopressor combined with albumin shows significant efficacy in reversing HRS.16-18For patients with secondary renal impairment,ensuring effective renal blood perfusion is key to maintaining renal function.For AKI caused by infection,aggressive infection control is key to improving renal function.19For ACLF patients with renal impairment,continuous renal replacement therapy (CRRT) and plasma exchange can improve their outcomes.20

Recommendation 6:Sufficient renal perfusion and aggressive infection control should be ensured.Vasopressor combined with albumin can improve renal perfusion and can be used as first-line treatment for HRS.Plasma exchange combined with CRRT can be used early for oliguric and anuric patients to reduce renal burden.

3.3.Gastrointestinal protection

Neuroendocrine disorder,large doses of antibiotics,vasoactive drugs,and ischemia-reperfusion injury are main factors resulting in gastrointestinal damage in ACLF patients during the perioperative phase of liver transplantation.Animal experiments proved that ischemia preconditioning can aid in alleviating intestinal ischemiareperfusion injury and trophic enteral nutrition (10-20 mL/h or 10-20 kcal/h (1 kcal=4.184 J)) can prevent mucosal atrophy in low-moderate-risk patients and maintain intestine integrity and aid in maintaining commensal gut microbiota homeostasis.21-23

Recommendation 7:Use antibiotic rationally and enteral nutrition should be maintained.Optimize fluid management,maintain stable vital signs,and improve intestinal mucosal perfusion.

3.4.Cardiac protection

During liver transplantation,the reopening of the portal vein and hepatic artery will result in large hemodynamic changes.24This requires the patient to have good basic cardiac function.Therefore,stringent cardiac evaluation is an important content in preoperative assessment.A history of atrial fibrillation before liver transplantation is a predictor for postoperative atrial fibrillation and atrial flutter.A history of coronary artery disease before surgery,abnormal cardiac pressure markers,and coronary artery disease in echocardiography are also risk factors for cardiovascular accidents after liver transplantation.No adverse effects occur in the transplanted liver when amiodarone is used in patients with postoperative atrial fibrillation and atrial flutter.25,26

Recommendation 8:Cardiac function should be stringently assessed before surgery,and “quadruple assessment” is recommended.This includes medical history,physical examination,and electrocardiography,transthoracic echocardiography,functional tests,and direct coronary artery angiography under suitable circumstances.Short-term amiodarone can be used in patients with arrhythmia,such as atrial fibrillation.

3.5.Cerebral protection

Hepatic encephalopathy is the most common neurological complication in ACLF patients.Hepatic encephalopathy >5 days and type C hepatic encephalopathy are independent factors for delayed recovery after liver transplantation.The disappearance of cerebral sulci and gyri in cranial CT and MRI is a characteristic radiological presentation of cerebral edema.27Rapid intravenous infusion of mannitol or hypertonic saline can be administered to patients when cerebral edema is found in CT scans.Removal and reducing the production of blood ammonia are mainstay measures for preventing and treating hepatic encephalopathy.Lactulose combined with rifaximin can decrease the risk of hepatic encephalopathy-related hospitalization;28,29plasma exchange and CRRT can also effectively decrease blood ammonia levels,improve cerebral edema,and decrease mortality rate.30,31For respiratory dysfunction patients on mechanical ventilation,short-acting sedatives can improve synchrony between the patient and the ventilator.32

At the awakening phase after liver transplantation,a significant correlation is found between the bispectral index (BIS) and Glasgow coma scale (GCS).When BIS is >50,the eye-opening time response to a call is 12.7 ± 8.3 h.As the patient awakens,BIS increase occurs earlier than GCS increase and is more sensitive than GCS changes.33,34

Recommendation 9:Dynamic evaluation of neurological status in hepatic encephalopathy patients should be conducted,and aggressively treat or eliminate causes of hepatic encephalopathy.Mannitol or hypertonic saline can be used to reduce cerebral edema and decrease intracranial pressure.Aggressive plasma exchange and CRRT can also help to improve the internal environment and alleviate cerebral edema.BIS can be used to evaluate the status of consciousness in perioperative patients.

4.Nutritional support in ACLF liver transplant recipients

Malnutrition is a common problem in end-stage liver disease patients and would significantly increase the risk of liver transplantation and incidence of postoperative complications.Therefore,formulating a complete nutritional intervention plan after liver transplantation is especially important.35

4.1.Evaluation of baseline nutritional status

The nutritional risk screening 2002 (NRS2002) score is widely used in inpatients,while nutrition risk in the critically ill(NUTRIC)is mainly designed for critically ill patients.Malnutrition is present when NRS2002 score is>3 or NUTRIC score is≥5,and nutritional intervention is required.Subjective global assessment (SGA) combined with anthropometric methods which based on weight,diet,muscle consumption,and triceps skinfold thickness can further evaluate malnutrition status for grading.36-38

Recommendation 10:Malnutrition is considered present when NRS2002 score is >3 or NUTRIC score is≥5.SGA and anthropometry can be used to assess and grade the nutritional status of subjects.

4.2.Timing and dose for enteral nutrition

Randomized controlled clinical studies found that compared with delayed (>48 h) enteral nutrition,early (<48 h) enteral nutrition and providing more than 80% of the estimated or calculated target energy in 48-72 h can significantly decrease the mortality rate,incidence of infection,and length of hospitalization.39,40

A prospective nonrandomized study found that compared with insufficient treatment,the incidence of nosocomial infection and overall complications significantly decreased in patients with a NRS2002 score of≥5 who received sufficient nutrition treatment(>10 kcal/kg/d continuously for 7 days)before surgery.41For highrisk patients a with NRS2002 score of≥6,increasing the ratio of target energy transport is significantly correlated with reduction in mortality rate.A mixed prospective observation study found that 28-day mortality rate gradually decreases as protein supply increases.42

Recommendation 11:After excluding post-liver transplantation contraindications,early enteral nutrition can be started when hemodynamics are stable.The total energy supply can be determined based on the weight prediction formula (25-30 kcal/kg/d).The recommended protein energy is 1.2-2.0 kcal/kg/d.

4.3.Enteral nutrition method and formula

Early enteral nutrition after liver transplantation through a nasogastric tube is safe.Distal anastomotic feeding can be carried out using a nasojejunal tube for patients with digestive tract anastomosis.Trophic enteral nutrition can be given at the early stage,and target energy should be achieved as soon as possible within 48 h.Efforts should be made to achieve 80% of the target energy and protein energy within 72 h.Simultaneously,residual gastric volume should be monitored,and the risk of aspiration pneumonia should be assessed.Prokinetic drugs (metoclopramide or erythromycin)can be used for patients at high risk for reflux to maintain a residual gastric volume of<500 mL/d.A jejunal feeding tube can be used for post-pyloric feeding in patients with gastric retention.After enteral nutrition is tolerated,the patient should be switched to oral nutrition as soon as possible.Enteral nutrition should not be stopped before oral nutrition achieves nutritional requirements.If diarrhea occurs,enteral nutrition should not be interrupted when assessing for the cause of diarrhea to determine a suitable treatment.43Recently,differences exist in osmolality,energy density,protein content,electrolytes,vitamins,and trace elements,protein supply method (whole protein or pre-digested protein),presence/absence of fiber,and presence/absence of nutrients required for certain diseases between enteral nutrition products.However,most formulas can ensure that the daily recommended amount of vitamins and trace elements can be met when patients’ daily energy intake is≥1000 kcal.42

Recommendation 12:Enteral nutrition speed is gradually increased from 10 mL/h to 20 mL/h,and 80% enteral nutrition should be achieved within 2-3 days.Residual gastric volume should be monitored,and the risk of aspiration pneumonia should be assessed.Prokinetic drugs or post-pyloric feeding can be used for patients at high risk for reflux.A personalized nutrition regimen should be used to more effectively achieve nutritional goals.

5.Prevention and control of infection in ACLF liver transplantation recipients

5.1.Prevention and control of donor-derived infection

Gastrointestinal perforation during multi-organ harvesting and organ harvesting is the main cause of donor organ contamination.44,45A study found that insufficient attention to multidrugresistant bacteria in the donor and lack of effective communication between the donor institute and the transplantation institute are the causes of donor-derived infections in recipients after surgery.46

Recommendation 13:Donor's specific inflammatory markers should be monitored,and microbial culture or sequencing should be carried out in donor's body fluids.During organ harvesting,processing suspected contaminated sites such as the intestine and bile duct should be handled carefully.Concurrently,microbial culture should be performed on organ preservation solution.The organ donation institute should promptly share donor pathogen test results with the organ transplantation institute.If there is any suspected infection,targeted antibiotic therapy should be carried out at the early stage.

5.2.Prevention and control of multidrug-resistant bacteria

5.2.1.Screening

Mathematical models showed that the transmission of multidrug-resistant bacteria can be reduced by 39%if the intensive care unit (ICU) carry out active surveillance culture alone and by 65% if combined with initial isolation.47

Studies found that screening of high-risk patients,particularly rectal colonization sample testing,can increase the detection rate of multidrug-resistant bacteria by 6.1 times.Implementation of contact protective measures and active surveillance decreased the transmission rate of multidrug-resistant bacteria within 12 months.48

Recommendation 14:Routine surveillance of infection rates,composition of infection sites,and pathogens in transplantation patients in the ICU should be conducted,and nosocomial infection surveillance-related information should be recorded.Rectal swabs,perirectal swabs,or stool samples are recommended to be collected for testing in patients at high-risk for infection.

5.2.2.Isolation

The implementation of isolation measures on top of standard prevention in patients with confirmed or highly suspected multidrug-resistant bacteria infection or colonization can prevent the transmission of multidrug-resistant bacteria.49Suspected positive patients should be isolated in single rooms as much as possible,and bedside isolation is implemented when single room isolation is not available.Dedicated medical equipment,tools,and materials that directly contact the patient should be used,and disinfection should be carried out promptly.Public medical facilities should be disinfected after every use.Medical procedures for such patients in nonemergency situations should be scheduled at the end.Complete protective equipment should be worn when contacting patients with multidrug-resistant bacteria infection or colonization.These equipment should be changed after diagnosis and treatment procedures are completed,and handwashing should be carried out.50,51

Recommendation 15:Strict isolation measures must be implemented for patients with confirmed or highly suspected multidrug-resistant bacteria infection or colonization.Simultaneously,procedures and treatment for such patients should be carried out last.

5.2.3.Cluster management of medical behavior-related infection prevention and control

Indwelling device-related infection is the most common infection in the ICU.In addition to reducing the use of invasive devices as much as possible,indwelling device placement and maintenance strategies can decrease 66%of infection risk.52Cluster management can aid in standardizing operation details and reduce iatrogenic transmission of drug-resistant bacteria.53Study data showed that catheter cluster management significantly decreased the incidence of catheter-associated bloodstream infection and mean length of hospitalization in patients.Cluster management for the prevention of ventilator-associated pneumonia significantly decreased the duration of ventilation,length of ICU stay,and hospitalization costs.Many prospective randomized controlled studies showed that cluster management could decrease the incidence of catheterassociated urinary tract infections.54-59

Recommendation 16:Cluster management for catheterassociated urinary tract infection,ventilator-associated pneumonia,and catheter-associated bloodstream infection should be promoted in the ICU.

6.Rehabilitation training for ACLF liver transplantation recipients

6.1.Rehabilitation during the waiting period for liver transplantation

A study showed that long-term or short-term high-intensity aerobic exercise could decrease the severity of steatosis in nonalcoholic fatty liver disease patients.60Studies on patients awaiting liver transplantation found that integrated exercise training before surgery could increase the peak oxygen consumption in patients,decrease the 90-day readmission rate,and shorten the length of hospitalization.61,62

Recommendation 17:Conscious ACLF patients should be guided to perform aerobic exercises or a combination of aerobic exercises and resistance training before surgery.

6.2.Rehabilitation after liver transplantation

Early rehabilitation exercises are safe and feasible in liver transplantation recipients after surgery.A prospective randomized control study showed that the incidence of adverse events in the post-liver transplantation early rehabilitation exercise group was not higher than the usual treatment group and patients could sit/stand on their beds sooner,and length of ICU stay was decreased.63

Recently,a Meta-analysis on early rehabilitation in critically ill(including after liver transplantation) patients found that rehabilitation intervention did not decrease mortality rate but significantly decreased the duration of ICU ventilation and length of ICU stay.More significant benefits were seen in noncritically ill patients and patients with extended mechanical ventilation duration.64

Recommendation 18:Early rehabilitation exercises are safe and feasible in ACLF patients after liver transplantation.In particular,early and active rehabilitation intervention should be carried out in patients with extended mechanical ventilation duration.

7.Internal environment regulation of ACLF liver transplantation recipients

More and more studies show that fluid overload during the perioperative phase of liver transplantation results in poor graft and recipient outcomes.65,66Appropriate negative fluid balance can significantly decrease mechanical ventilation duration and does not increase the risk of AKI.14Short-term negative fluid balance during the perioperative phase causes electrolyte fluctuations and negative nitrogen balance,which results in drastic changes in osmotic pressure.Especially for ACLF patients with preoperative comorbid hyponatremia,changes in osmotic pressure is an important cause of nerve demyelination after liver transplantation.67Several retrospective studies and one prospective randomized controlled study showed that CRRT during liver transplantation was safe and feasible in critically ill (MELD score≥25) or comorbid severe AKI patients.68-71Additionally,intraoperative CRRT has significant effects in maintaining hemodynamic stability and fluid and electrolyte balance.72A study showed that early CRRT after liver transplantation in critically ill ACLF patients with comorbid hepatic encephalopathy could improve the short-term graft and recipient outcomes.73As regards treatment of sepsis,CRRT significantly decreases all-cause mortality and 28-day mortality rate,shortened the duration of ICU stay,and decreased the mortality rate in patients with sepsis accompanied by AKI.The pathophysiology of AKI after liver transplantation is similar to sepsis.74However,a recent Meta-analysis and randomized controlled study showed that CRRT did not result in significant benefits for early AKI (Kidney Disease:Improving Global Outcome (KDIGO) grades 2-3,within 12 h of diagnosis) and could increase the risk of potential adverse events.75,76Therefore,further study on whether early CRRT should be carried out after liver transplantation in ACLF patients is required.

Recommendation 19:Appropriate negative fluid balance should be maintained during and at the early stage after liver transplantation,electrolyte and osmotic pressure should be closely monitored,and fluctuations should be stabilized.Intraoperative CRRT can be used to maintain hemodynamic and internal environment stability in end-stage liver disease or comorbid moderate to severe AKI patients.

Authors’ contributions

Guihua Chen (chgh1955@263.net) and Yang Yang(yysysu@163.com) were as the corresponding authors.Huimin Yi,Jianrong Liu,Pinglan Lu,Lijuan Li,Mingming Fan,Xiaomeng Yi,Haijin Lv and Xuxia Wei (Department of Hepatic Surgery,Liver Transplantation Center,Intensive Care Unit of Organ Transplantation,The Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,China)were the writing authors of the manuscript.All experts read and approved the final manuscript.

List of experts

Yuling An (The Third Affiliated Hospital of Sun Yat-sen University),Xueli Bai(The Second Affiliated Hospital,Zhejiang University School of Medicine),Jinglin Cao (The Third Hospital of Hebei Medical University),Bicheng Chen (The First Affiliated Hospital of Wenzhou Medical University),Guihua Chen (The Third Affiliated Hospital of Sun Yat-sen University),Hao Chen(Lanzhou University Second Hospital),Ming Chen (Zhongda Hospital,Southeast University),Wei Chen (The Second Affiliated Hospital,Zhejiang University School of Medicine),Xiaoping Chen (General Hospital of Southern Theater Command of PLA),Zhonglin Cui (Nanfang Hospital of Southern Medical University),Feiwen Deng (Foshan No.1 People's Hospital),Guosheng Du (The 8th Medical Center of Chinese PLA General Hospital),Juanming Du (Xinhua Hospital,Shanghai Jiao Tong University School of Medicine),Lang Feng(Beijing Friendship Hospital,Capital Medical University),Binsheng Fu (The Third Affiliated Hospital of Sun Yat-sen University),Dazhi Fu (The First Hospital of China Medical University),Xinpu Gao(China Organ Donation Administrative Center),Jun He (The First Affiliated Hospital of Soochow University),Qiang He (Beijing Chaoyang Hospital,Capital Medical University),Xin He (The Third Affiliated Hospital of Sun Yat-sen University),Ziqing Hei(The Third Affiliated Hospital of Sun Yat-sen University),Xiquan Hu(The Third Affiliated Hospital of Sun Yat-sen University),Zemin Hu (Zhongshan People's Hospital),Lei Huang (Peking University People's Hospital),Xiaowu Huang (Zhongshan Hospital,Fudan University),Ruipeng Jia (Nanjing First Hospital,Nanjing Medical University),Wentao Jiang (Tianjin First Central Hospital),Jianhui Li (The First Affiliated Hospital,College of Medicine,Zhejiang University),Jianjun Li(The Second Affiliated Hospital of University of South China),Jian Li(452 Hospital of PLA),Hua Li(The Third Affiliated Hospital of Sun Yat-sen University),Tao Li(Ruijin Hospital,Shanghai Jiao Tong University School of Medicine),Xianliang Li (Beijing Chaoyang Hospital,Capital Medical University),Xiao Li (Xijing Hospital,Air Force Medical University),Yang Li (The Third Affiliated Hospital of Sun Yat-sen University),Guangming Li (Beijing Youan Hospital,Capital Medical University),Fang Liu(Changzheng Hospital,Second Military Medical University),Yong Liu(Shanghai General Hospital),Yu Liu (Third Medical Center of Chinese PLA General Hospital),Gangjian Luo (The Third Affiliated Hospital of Sun Yat-sen University),Hui Luo (The Third Affiliated Hospital of Sun Yat-sen University),Guoyue Lv(The First Hospital of Jilin University),Ling Lv(First Affiliated Hospital of Nanjing Medical University),Wei Meng (The Third Affiliated Hospital of Sun Yat-sen University),Yanwen Peng(The Third Affiliated Hospital of Sun Yat-sen University),Haizhi Qi(The Second Xiangya Hospital of Central South University),Yongbing Qian (Renji Hospital,Shanghai Jiao Tong University School of Medicine),Yan Qin (The Second Hospital of Shanxi Medical University),Jianghua Ran (The First People's Hospital of Kunming),Fangfei Ren(The Third Affiliated Hospital of Sun Yat-sen University),Jie Ren (The Third Affiliated Hospital of Sun Yat-sen University),Conghuan Shen (Renji Hospital,Shanghai Jiao Tong University School of Medicine),Wei Shi (Huashan Hospital,Fudan University),Yinghong Shi (Zhongshan Hospital,Fudan University),Xiaomin Shi(The First Affiliated Hospital of Sun Yat-sen University),Liying Sun(Beijing Friendship Hospital,Capital Medical University),Qiquan Sun (The Third Affiliated Hospital of Sun Yat-sen University),Qipeng Sun (The Third Affiliated Hospital of Sun Yat-sen University),Xiaodong Sun (The First Hospital of Jilin University),Kaishan Tao (Xijing Hospital,Air Force Medical University),Tuerganaili Aji (The First Affiliated Hospital of Xinjiang Medical University),Chidan Wan (Union Hospital,Tongji Medical College,Huazhong University of Science and Technology),Genshu Wang(The Third Affiliated Hospital of Sun Yat-sen University),Guoying Wang (The Third Affiliated Hospital of Sun Yat-sen University),Shaoping Wang(General Hospital of Southern Theater Command of PLA),Jiandong Wang (Xinhua Hospital,Shanghai Jiao Tong University School of Medicine),Lin Wang (Xijing Hospital,Air Force Medical University),Shengjun Wang (The Affiliated People's Hospital of Jiangsu University),Yuantao Wang (The First Hospital of Jilin University),Zhengxin Wang (Huashan Hospital,Fudan University),Zhihui Wang (The First Affiliated Hospital of Zhengzhou University),Zhang Wen (The First Affiliated Hospital of Guangxi Medical University),Zhongjun Wu (The First Affiliated Hospital of Chongqing Medical University),Qiang Xia(Renji Hospital,Shanghai Jiao Tong University School of Medicine),Qinfen Xie (Shulan(Hangzhou) Hospital),Jun Xiong (Union Hospital,Tongji Medical College,Huazhong University of Science and Technology),Yan Xiong(Zhongnan Hospital of Wuhan University),Chi Xu(The Third Affiliated Hospital of Sun Yat-sen University),Leibo Xu(The Second Affiliated Hospital of Sun Yat-Sen University),Haiyan Yang (The First Affiliated Hospital of Harbin Medical University),Jiaying Yang(West China Hospital of Sichuan University),Jun Yang (Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology),Qing Yang (The Third Affiliated Hospital of Sun Yat-sen University),Yang Yang(The Third Affiliated Hospital of Sun Yat-sen University),Zhaoxu Yang(Xijing Hospital,Air Force Medical University),Jia Yao (The Third Affiliated Hospital of Sun Yat-sen University),Junsheng Ye (Nanfang Hospital of Southern Medical University),Huanfa Yi (Jilin University),Huimin Yi (The Third Affiliated Hospital of Sun Yat-sen University),Shuhong Yi (The Third Affiliated Hospital of Sun Yat-sen University),Ming Yuan(The 8th Medical Center of Chinese PLA General Hospital),Xun Zeng(Zhejiang University),Feng Zhang(The First Affiliated Hospital with Nanjing Medical University),Jian Zhang (The Third Affiliated Hospital of Sun Yat-sen University),Leida Zhang (The First Affiliated Hospital of Third Military Medical University),Ming Zhang (Renji Hospital,Shanghai Jiao Tong University School of Medicine),Tong Zhang (The Third Affiliated Hospital of Sun Yat-sen University),Xufeng Zhang (The First Affiliated Hospital of Xi'an Jiaotong University),Yingcai Zhang(The Third Affiliated Hospital of Sun Yat-sen University),Xianling Zhang (The Third Affiliated Hospital of Sun Yat-sen University),Hui Zhao (The Third Affiliated Hospital of Sun Yat-sen University),Lei Zhao (Peking University Third Hospital),Hongchuan Zhao (The First Affiliated Hospital of Anhui Medical University),Yong Zhao (Institute of Zoology,Chinese Academy of Sciences),Haiqing Zheng (The Third Affiliated Hospital of Sun Yatsen University),Lin Zhong(Shanghai General Hospital),Guangwen Zhou (Shanghai Jiao Tong University Affiliated Sixth People's Hospital),Lin Zhou (The First Affiliated Hospital,College of Medicine,Zhejiang University),Peijun Zhou (Ruijin Hospital,Shanghai Jiao Tong University School of Medicine),Xiaodan Zhu (The Affiliated Hospital of Qingdao University),Zhijun Zhu (Beijing Friendship Hospital,Capital Medical University),Li Zhuang (Shulan(Hangzhou)Hospital),Jinfeng Zhuo(The Third Affiliated Hospital of Sun Yat-sen University),Yizhou Zou (Xiangya School of Medicine,Central South University).

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

We would like to thank Professor Yingbin Liu(Xinhua Hospital),Professor Wei Gao (Tianjin First Central Hospital),Professor Wei Zhang(The First Affiliated Hospital of College of Medicine,Zhejiang University),Professor Ting Wang (Zhongshan Hospital),Professor Lai Wei(Tongji Hospital,Tongji Medical College of HUST),Associate Professor Xin Wang (Beijing Youan Hospital,Capital Medical University),and Associate Professor Haixia Liu(Beijing Youan Hospital,Capital Medical University) for their contribution in the revision and completion of the consensus.This work was supported by National 13th Five-Year Science and Technology Plan Major Projects of China (2017ZX10203205-006-001);National Key Research and Development Program of China (2017YFA0104304),National Natural Science Foundation of China (81770648,81972286);Natural Science Foundation of Guangdong Province,China(2015A030312013,2018A0303130305);Science and Technology Program of Guangdong Province,China (2017B020209004,20169013,2020B1212060019);Guangzhou Science and Technology Project,China (201400000001-3).