Plasma exchange in patients with acute and acute-on-chronic liver failure: A systematic review

Table 4 Studies included for study of plasmapheresis in acute-on-chronic liver failure

Ref.	Type of study/Number of patients recruited	Study group(s)	Characteristics of study population	Plasma exchange regime	Etiology	Results
Meng et al[39]	Retrospective cohort study, single center; n = 158; PE group: 38; SMT group: 120	PE vs SMT	PE group: Higher MELD score	Performed twice a week until patients’ condition was stable, additional weekly or biweekly visits were instituted if patients felt deterioration of their condition. Total duration of therapy 2-8 wk	Hepatitis B	24/38 (63%) death in the PE group and 82% in SMT group died within 4 wks. By week 12, 71% in PE group and 86% in SMT group died
			Baseline characteristics both groups had 26%-28% of patients with hepatic encephalopathy
			ACLF definition: ACLF was defined as serum bilirubin ≥ 5 mg/dL and an INR 1.5 or prothrombin activity (PTA) 40 %, complicated within 4 wk by ascites and/or encephalopathy in patients with previously diagnosed or undiagnosed chronic liver diseases			18% vs 14% transplant free survival in 3 mo comparing PE vs SMT (P < 0.01)
				Plasma exchange volume not mentioned
						Biochemically, there is decreased bilirubin in PE arm cf SMT (P < 0.01)
Mao et al[38]	Retrospective cohort study, single center	PE vs SMT	ACLF definition: Acute decompensation of liver function in patients with chronic preexisting liver diseases. ACLF is defined as a syndrome with severe jaundice (total bilirubin: 171 mmol/L), coagulopathy (prolonged prothrombin time, prothrombin activity 40%), or hepatic encephalopathy (above grade II)	Plasma exchange volume: 3500 mL at 25-30 mL/min. A total of 3000–4500 mL of fresh frozen plasma (40-60 mL/kg) and 20-40 g of human albumin were supplied	Hepatitis B. Drug hepatitis, Wilson disease, alcoholic liver disease, autoimmune hepatitis excluded	26 survivors and 36 non-survivors were in the PE group, whereas 33 survivors and 98 non-survivors were in the control group after 30 d treatment. Their survival rates were 41.9% and 25.2% for PE and medical therapy, respectively (P < 0.05)
		Baseline characteristics 74%-77% had HE at baseline
	PE group: 62
	SMT group 131
						No mention re: Biochemical improvement
				Flow rate of blood was adjusted to 60–130 mL/min
	Not randomised
				PE was carried out 2-3 times per week for the first two weeks, then weekly, then stopped based on clinical results
Chen et al[42]	Retrospective cohort study multicentre (10)	PE, no comparative arm	ACLF definition: Guidelines for Diagnosis and Treatment of Liver Failure in China (2006): Early stage is defined as a progressively deepening jaundice (Bilirubin level ≥ 171 μmol/L or a daily increase of ≥ 17.1 μmol/L), PTA > 30% but ≤ 40%, and no HE or other complications. Middle-stage disease represents progression of the symptoms of the early stage, including one of the following symptoms: Grades I/II HE, ascites, or a PTA of > 20% but ≤ 30%. In the end-stage disease, the condition deteriorates further with a PTA of ≤ 20% and includes one of the following symptoms: Hepatic-renal syndrome, severe upper gastrointestinal bleeding, serious infection, and grades III/IV HE	Plasma exchange volume: 2500-3500 mL, and the PE rate was 20-25 mL/min	Hepatitis B	Forty-two of the 52 (80.8%) patients in the early stage, seventy-five of the 99 (75.8%) patients in the middle stage and thirty-seven of the 99 (37.4%) patients in the end stage survived for one month after diagnosis
	n = 250 patients
				Dexamethasone (5 mg) and heparin (2500 U) were injected routinely before PE
						Authors concluded that late stage ACLF might benefit from PE as a bridge to definitive treatment-liver transplant
				PE was repeated every 2-4 d
Zhou et al[45]	Retrospective, cohort	PBA + PE vs PE	ACLF was defined as acute liver injury emerging as jaundice and coagulopathy, complicated by ascites and/or encephalopathy within 4 wk in a patient with known or unknown chronic liver disease. The definition of liver failure in ACLF was as follows: Severe jaundice (total serum bilirubin ≥ 5 mg/dL) and coagulopathy (INR ≥ 1.5 or prothrombin activity < 40%) and ascites and/or encephalopathy.	Plasma exchange volume: Approximately 3000 mL of plasma was exchanged per time at a blood flow rate of 20 to 25 mL/min	HBV 56.6%, HBV+HEV 31.9% Others 11.5%	The mean overall survival for the derivation cohort was 441 d (95%CI: 379-504), and the 90- and 270-d survival probabilities were 70.3% and 58.3%, respectively
	Derivation cohort 113
	Validation cohort 68					The mean survival times of patients treated with PBA plus PE and patients treated with PE were 531 days (95%CI: 455-605) and 343 d (95%CI: 254-432), respectively (P = 0.012)
	From the derivation cohort: PE, n = 54; PE+PA, n = 59
				Each patient in the derivation cohort received PE 1 to 4 times
						Predictors of survival: Age, MELD, Complication, type of ALSS No mention re: Baseline characteristics of PE vs PBA
			Baseline population in this study is 51% cirrhotic
Wan et al[44]	Prospective cohort study	PE vs DPMAS	ACLF was defined as serum bilirubin 5 mg/dL and INR > 1.5 or PTA < 40%, complicated within 4 wk by ascites and/or HE in patients with previously diagnosed or undiagnosed chronic liver diseases	Plasma exchange volume: About 3000 mL of plasma exchanged at an exchange rate of 20-30 mL/min at each session.	HBV	During the study, a total of 42 patients died, with 24 in TPE group and 18 in DPMAS group. The median survival times were 12 wk in TPE group and 11 wk in DPMAS group
	n = 60
	TPE 33			PE was performed 2-3 times/week, lasting 2-3 h every session		The 4-wk and 12-wk survival rates in TPE group and DPMAS group were 87.9% and 88.9%, 34.6% and 33.3%, respectively. There was no marked difference in survival between the two groups
	DPMAS 27		Baseline eAg positive greater in TPE group (18% vs 7.4%)
						Bilirubin removal in TPE more efficient compared to DPMAS
Qin et al[37]	Open label randomized controlled parallel group single-center study	PE centered ALSS vs SMT	Definition of ACLF was according to the Chinese guidelines, Bilirubin ≥ 10 mg/dL, PTA ≤ 40% and cirrhosis and multiorgan failure were not taken as mandatory criteria, according to the Chinese guidelines	PE volume: 3500 mL (40–60 mL/kg) FFP, at 25-30 mL/min	HBV	Survival rates after 90 d were 60% (62/104) in ALSS-treated patients and 47% (61/130) in the control group. (P < 0.05). The 5-year cumulative survival rates of the ALSS and control groups were 43% (45/104) and 31% (40/130), respectively (P < 0.05)
				ALSS schedule: 3 routine treatments were performed in the first 10 d after inclusion in the study (once per 3–4 d); extra treatments were offered according to the improvement of the patients. The methods of PE-centered ALSS were chosen based on clinical conditions. For patients with coagulopathy, PE was applied; for patients with encephalopathy, PE plus hemoperfusion or continuous hemodiafiltration was used; for patients complicated with HRS or imbalance of water or electrolytes, PE plus continuous hemodiafiltration was used
	n = 234
						No mention of biochemical improvement
Xia et al[40]	Retrospective cohort study	NBAL (all had PE) vs SMT	ACLF definition:	All of the patients were treated with PE, and most were treated with one or more additional methods, including 13/26 (50.00%) ALF patients, 16/27 (59.26%) Subacute ALF patients, and 228/407 (56.02%) ACLF patients	For ACLF: 91.24% chronic hepatitis B, 3.69% alcohol abuse, 1.01% autoimmune, 1.01% cholestasis, 3.05% other causes	Clinical outcomes were improved after NBAL treatment. The 30-d survival rates of subacute liver failure (SALF) patients were 63% among those who received NBALs and 21% among those who did not receive NBALs (P < 0.01)
			1 Acute deterioration of pre-existing chronic liver disease
	n = 882
	460 NBAL 422 control		2 Extreme fatigue with severe digestive symptoms, such as obvious anorexia, abdominal distension or nausea and vomiting
						The 30-day survival rate of acute-on-chronic liver failure (ACLF) patients who received NBALs was 47%, significantly higher than that of the non-NBAL patients (P < 0.05)
	Of which 49 ALF, 46 SALF and 787 ACLF
			3 Progressively worsening jaundice within a short period (serum total bilirubin ≥ 10 mg/dL or a daily elevation ≥ 1 mg/dL)
				The choice of therapy was based on each patient’s condition: PE in combination with PP for HE was administered in 12.24% (6/49) of ALF patients, 10.77% (7/65) of SALF patients, and 7.41% (80/1079) of ACLF patients. In patients with HRS, we administered PE with CHDF in 32.65% (16/49) of ALF patients, 23.08% (15/65) sessions of SALF patients and 28.17% (304/1079) sessions of ACLF patients
						Reported to be effective in biochemical improvement
			4 Obvious hemorrhagic tendency with PTA ≤ 40% (PT ≥ 18.3 s or INR > 1.50)
			The absence of any of the above four criteria precluded a diagnosis of ACLF
				Pts underwent 1-4 times of NBAL each
Li et al[49]	Prospective cohort Study	PE vs PE + UCMSCs	ACLF was defined as serum bilirubin ≥ 5 mg/dL and INR ≥ 1.5 or PTA < 40%, complicated within 4 wk by ascites and/or encephalopathy in patients with previously diagnosed or undiagnosed chronic liver disease	PE volume: About 3000 mL, and the exchange rate of plasma was 20–30 mL/min. Heparin was used as anticoagulant during PE	HBV	The cumulative survival rates at 3 mo in group A and group B were 54.5 % and 29.4 %, respectively (P = 0.015 by log rank test)
	PE: 34
						INR was prominently lower in PE + UCMSCs group than in PE group (P < 0.05). At 12 mo, patients in PE+UCMSCs group showed lower levels of AST than patients in PE group (P < 0.05).
	PE+UCMSCs: 11
	n = 45
			In PE group: MELD score: 22.5 +/- 1.4, 61.8% cirrhotic			At 24 mo, patients in PE+UCMSCs group had significantly improved levels of albumin, PT and INR than patients in PE group (P < 0.05). However, ALT, Total bilirubin, Direct bilirubin, creatinine, white blood cell, Hemoglobin, Platelet and ascites were comparable at each follow-up
Xu et al[43]	Retrospective cohort study	PE	Definition of ACLF: Acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 wk by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease	Total volume exchanged 3300 mL	HBV	1-yr and 5-yr survival rates in the ALSS-LT group and LT group were 79.2% and 83%, 69.7% and 78.6%
	n = 171
				Patients with coagulopathy were indicated for PE, when the patient had HE, PE + hemodiafiltration was used. For patient with hepatorenal syndrome or imbalance of water or electrolytes, PE + continuous hemodiafiltration or MARS was used
	PE before LTx: 115
	Emergent LTx: 56
			PE group: MELD score 31+/-6
Yao et al[41]	Retrospective cohort study	PE vs DPMAS + PE	Definition of ACLF: Acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 wk by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease	PE volume: Fresh frozen plasma was 2200 to 2400 mL per treatment. Duration of single treatment was about 2 h	HBV	The total bilirubin levels immediately after treatment at 24 and 72 h after treatment were markedly decreased in DPMAS + PE group compared to that in PE group (52.3 ± 9.4% vs 42.3 ± 7.2%, P < 0.05; 24.2 ± 10.0% vs 13.5 ± 13.0%, P < 0.05; 24.8 ± 13.1% vs 14.9 ± 14.9%, P < 0.05; respectively).
	n = 131
	PE group (n = 77)			Patients underwent 1-4 times of PE / PE + DPMAS
	DPMAS + PE group (n = 54)		Baseline characteristics were similar in both groups
						The 28- d survival rates was 62.3% and 72.2% in PE and DPMAS + PE groups (P = 0.146).
						28- d survival rates were significantly higher in DPMAS + PE group than that in PE group (57.4% vs 41.7%, P = 0.043) in the intermediate-advanced stage patients
Cheng et al[12]	Retrospective, cohort study single tertiary centre	PE, no comparative arm	ACLF definition: acute hepatic insult that manifests as jaundice (serum bilirubin ≥ 5 mg/dL and coagulopathy (INR ≥ 1.5), which is complicated within 4 wk by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease or cirrhosis	The processed plasma volume was approximately 3000 mL for each session (1-1.5 total plasma volume); the blood flow rate was 100 mL/min; and the PE rate was 25–30 mL/min, with an equivalent volume of replacement fluid using fresh frozen plasma	Hepatitis B (75%) in ACLF group, 6% alcohol, others: HCV, AIH	Biochemical improvements seen after PE: AST/ALT/Bil/INR
						Average 4-5 sessions of PE in ACLF group, 3-5 sessions in ALF
	n = 55; 10 ALF, 45 ACLF
						Initial diagnosis to PE is longer in non-survivors in ACLF and ALF though not significant
						Survival based on etiology of ACLF: 24% HBV, 67% ETOH, 0% HBV + alcohol, 0% HCV 0% HCV + alcohol, 0% AIH
			79% of patients with ACLF have cirrhosis, 55% have grades III-IV HE	PE occurred daily or every other day till sustained clinical improvement, liver transplantation or no clinical response/death

PE: Plasma exchange; SMT: Standard medical treatment; ALF: Acute liver failure; HLH: Hemophagocytic lymphohistiocytosis; FFP: Fresh frozen plasma; INR: International normalised ratio; ALT: Alanine aminotransferase; CVVHDF: Continuous venous-venous hemodiafiltration; CHDF: Continuous hemodiafiltration; HBV: Hepatitis B virus; HSV: Herpes simplex virus; LDH: Lactate dehydrogenase; DILI: Drug induced liver injury; AFLP: Acute fatty liver of pregnancy; DILI: Drug induced liver injury; TPE: Therapeutic plasma exchange; DPMAS: Double plasma molecular adsorption system; AOCLF: Acute on chronic liver failure; PTA: Prothrombin activity; PBA: Plasma bilirubin adsorption; HE: Hepatic encephalopathy; DPMAS: Double plasma adsorption system; ALSS: Artificial liver support system; NBAL: Non-bioartifical liver support; SALF: Subacute liver failure; PP: Plasma perfusion; HRS: Hepatorenal syndrome; PT: Prothrombin time; UCMSCs: Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation.