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

Table 2 Studies included for study of plasmapheresis in acute liver failure in adults

Ref.	Type of study/No. of patients recruited	Study group(s)	Plasma exchange regime	Etiology of liver failure	Results/outcome(s) of interest
Larsen et al[3]	Open randomized control trial;	PE + SMT vs SMT	Plasma exchange volume: Volume of plasma exchange was 15% of ideal body weight (representing 8-12 L per day per procedure); patient plasma was removed at a rate of 1-2 L per hour with replacement with fresh frozen plasma in equivalent volume	Predominantly paracetamol (59%), followed by unknown etiology, toxic hepatitis, viral hepatitis, acute Budd Chiari syndrome	HVP increases transplant free survival after 3 mo, and maximal effect of HVP was achieved in patients who did not undergo emergency transplantation
	n = 182 (Plasma exchange + SMT 92, SMT 90)
					Overall hospital survival was 58.7% for patients treated with high volume plasma exchange vs 47.8% for control group HR: 0.56 (95%CI: 0.36-0.86), P < 0.01
					However, HVP prior to transplantation did not improve survival compared with patients who received SMT alone P = 0.75
			HVP procedure was undertaken on three consecutive days but with no fixed time interval between each treatment
					Bilirubin, INR, ALT and ammonia concentration decreased significantly during the first 7 d compared to SMT
			Mean number of HVP = 2.4 ± 0.8
			Plasma exchange with donor plasma
Nakae et al[10]	Prospective cohort study; n = 13	PE vs PE + CHDF	Plasma exchange volume: 3.6 to 4.0 L of plasma was exchanged for the same volume of normal FFP, interval between sessions was 48h or more for both treatment methods	7 post surgery, 4 fulminant hepatitis, 4 sepsis	Total bilirubin levels were significantly lower after treatment in both arms: Both P < 0.01 in both groups
					No outcomes available on mortality
					Of note, decreased increase in citrate in patients with PE CHDF compared to PE alone
			Plasma exchange with FFP
Hung et al[5]	Retrospective cohort study; n = 62 (Control 32, PE 30)	PE vs control	Average plasma exchange volume: 2916 mL (range, 1875-3750 mL), plasma exchange occurred over 2 h	46.7% HBV, 33.3% Drug induced, 6.7% unknown, 33.3% cirrhosis.	At the end of the first week (week 1), the level of total bilirubin and grading of hepatic encephalopathy in the PE group were significantly lower than those in the control group. At the end of the second week (week 2), there were no differences in the level of total bilirubin and grading of hepatic encephalopathy between the two groups of patients
					Difference in survival rate was not significant 66.7% in PE group vs 59.4% in control group
				No significant differences in etiology of liver failure between treatment and control groups
			Average of 6 rounds of exchange per patient (range, 2-15 rounds)
					Difference in survival days were significant, with 17.63 ± 1.86 in PE group vs 8.69 ± 0.86 in control group. P = 0.01
			Plasma exchange with FFP
Li et al[4]	Retrospective cohort study; n = 61	PE + HP + CVVHDF, PE + CVVHDF and HP + CVVHDF	Plasma exchange volume: 2000-3000 mL of fresh per session. Flow rate was 80-120 mL/min, the plasma separation rate was 25-30 mL/min, the replacement time was 2.0-3.0 h	3/61 acute viral hepatitis, 17/61 chronic toxic acute liver failure. 41 cases of non-viral induced liver injury: 5 after cardiac surgery, 7 with drug poisoning, 13 cases after pregnancy childbirth, 1 case mushroom poisoning, 10 cases with severe infection, 5 others	Treatment of the 61 patients using the artificial liver support system yielded a survival rate of 62.3% (38/61), and a viral survival rate of 35.0% (7/20); with the non-viral survival rate being 75.6% (31/41) Biochemically PE + HP + CVVHDF and PE + CVVHDF groups saw improvement in total bilirubin, ALT, PT, Albumin and HP+CVVHDF saw improvement in total and ALT (P < 0.05)
			In the PE + HP + CVVHDF group: After completion of a single plasma exchange, the HP was carried out. After HP, the CVVHDF is carried out
			Total of 171 exchanges were done
Nakamura et al[11]	Retrospective case series n = 49; Fulminant hepatitis 15; Severe acute hepatitis 14; Healthy controls 20	No comparative arm	Plasma exchange volume: Approximately 2000–4000 mL of fresh-frozen plasma was substituted during each exchange	No mention	10/15 fulminant hepatitis and all severe acute hepatitis survived
					Significant decreases in circulating TNF-a, IL-6, and TGF-ß levels in patients with fulminant hepatitis after a single plasma exchange
			Plasma exchange with FFP
Akdogan et al[9]	Retrospective case series; n = 39 (fulminant hepatic failure)	PE, No comparative arm	Plasma exchange volume: Total plasma volume approximately 1	Predominantly undetermined (41%), paracetamol (28.5%), acute hepatitis B, autoimmune liver disease, vascular tumor, acute hepatitis A (in presence of cirrhosis)	Improved biochemically (coagulopathy hyperbilirubinemia, AST, Ammonia, Factor V levels): P < 0.05
			Plasma exchange continued on a daily basis till clinical response (subjective by ICU team) or patient expired, or transplanted		31% underwent liver transplant, 92% of which survived at 1 year
					Overall survival 54% (21/39 patients), 37% (10/27) of non-transplanted patients survived
			No need for calcium replacement or magnesium replacement
			Plasma exchange with low volume citrate plasma
Kondrup et al[6]	Case series; n = 11	PE, No comparative arm	Plasma exchange volume: 20% body weight plasma exchange intended on three consecutive days, obtained a mean 2.6 exchanges and mean volume 16% body weight	6 acetaminophen, 2 non-A/B hepatitis, Halothane, disulfurum toxicity and hepatitis B	5/11 survivors were all acetaminophen toxicity induced ALF
					All had improved bilirubin after treatment
					All 4 Grade IV encephalopathy patients all did not survive
			Plasma exchange with donor plasma.		Those that survived had Grade III encephalopathy or lesser
					Those that did not survive had a longer duration of coma before initiation of PE (3.5 vs 1.8 d)
Freeman et al[13]	Case series	PE, No comparative arm	Plasma exchange volume: 3 L of plasma exchange was performed daily until conscious level improved or patient died Plasma exchange fluid: Equal volume of compatible fresh frozen plasma and plasma protein fraction (PPF) usually in the proportion of 2 units FFP:1 PPF	4 acetaminophen, 2 nonA/B hepatitis, 1 hepatitis A, 1 mixed drug overdose, 1 ETOH in 2	7/9 showed improvement in coma grades, 5 achieved normal mental state, 5 were able to discharge from hospital. Of which 3 were paracetamol induced liver failure, 1 was monoamine oxidase/ tricyclic acid induced, 1 was alcohol. Survival 55%
	n = 9
					Improved biochemistry, bilirubin, coagulation (P < 0.01) 1 died of retroperitoneal bleeding
Buckner et al[7]	Case series	PE, No comparative arm	Plasma exchange volume: Initial 10 L/day plasma exchange with FFP or fresh/outdated plasma	1 Acute viral hepatitis (pediatric), 2 halothane, 1 hepatitis B viral hepatitis	1 died (pediatric)
					1 patient took 37 d to awake from coma
	n = 4 (1 pediatric)
					3/4 of patients survived
Liu et al[31]	Case series	PE, No comparative arm	Plasma exchange volume: Each treatment lasted for 4-6 h, and the total volume exchanged was approximately 7000 mL (1.5-2x TPV)	DILI	The two patients with DILI ALF were treated with PE without need for transplant
	n = 2
					Biochemically improved after PE (AST ALT Bilirubin)
			Plasma exchange fluid: Maximally, 4700 mL of FFP was exchanged in each session, and the rest comprised plasma substitute consisting of 25% human albumin, pentastarch, 0.9% saline, and Ringer's solution. In each session, the plasma substitute was exchanged initially, and FFP was exchanged at the end
			Duration of PE was based on clinical improvement, both patients had intermittent PE, total 3 sessions
Bilgir et al[15]	Case report	PE, No comparative arm	Plasma exchange volume: Each session consists of 15 units of FFP, total 4 sessions	L-asparaginase induced ALF	Patient recovered from ALF: However, no biopsy done
			Plasma exchange fluid: FFP
Aydemir et al[14]	Case report	PE, No comparative arm	Plasma exchange volume: 2500 mL plasma volume removed during each PE session	PTU induced ALF	Patient recovered from ALF: however, no biopsy done
			Plasma exchange fluid: Fresh frozen plasma
Riveiro-Barciela et al[28]	Letter to editor, case report (Ipilimumab)	PE, No comparative arm	Plasma exchange volume: 1500 mL of 5% albumin plus 4 units of plasma as replacement fluid, carried out every other day for total 5 treatments	Immunotherapy induced ALF	Patient improved. Liver tests within normal values within one month
			Plasma exchange fluid: FFP and 5% albumin
Damsgaard et al[8]	Case report (ALF in WD)	PE, No comparative arm	Plasma exchange volume: 8-9 L of plasma, total 12 HVP	Fulminant Wilson’s disease ALF	Even though WD ALF score was 16, patient survived without need for OLT
			Plasma exchange fluid: Fresh frozen plasma as replacement fluid 1:1
Göpel et al[33]	Case report (Letter to editor)	PE, No comparative arm	Plasma exchange treatment was performed for three consecutive days	Peg-asparaginase induced ALF	Patient improved. Continuous stabilization of fibrinogen and antithrombin 3, an increase of cholinesterase, and a decrease of bilirubin. Clinical signs and symptoms such as jaundice and ascites did also rapidly improve
			No mention of volume or type of exchange fluid
Lin et al[16]	Case report	PE, no comparative arm	Plasma exchange was performed 2 times per week, and 2000 to 2500 mL frozen plasma was used each time	HLH	Patient’s condition deteriorated, and he died of multi-organ failure during the 6th week of hospitalization. Autopsy was declined
Chen et al[29]	Case report	PE, No comparative arm	Plasma exchange volume: Estimated two times the plasma volume of the patient was exchanged. At most, 40 units of FFP were exchanged, with the remainder of the infused volume consisting of plasma substitutes. The plasma substitutes consisted of 25% human albumin, pentastarch, normal saline, and Ringer’s solution	Heat stroke	On day 4 after the admission, the patient received high-volume PE (two plasma volumes exchanged). His consciousness was improved a day after PE The patient was discharged on day 16 after admission without sequelae
Holt et al[17]	Case report	PE, No comparative arm	Plasma exchange on post-partum days 3-5. Volume: Average of 3.2 L (1.6 estimated plasma volumes) of FFP replaced per session, followed by a tapering course of prednisone	AFLP vs HSV hepatitis associated ALF	After 3 d of TPE the patient’s mental status had returned to normal
					Treatment with TPE was followed by biochemical and clinical improvement but during her recovery herpes simplex virus type 2 (HSV‐2) infection was diagnosed serologically and confirmed histologically
Shen et al[18]	Case report	PE, No comparative arm	Plasma exchange: performed on days 1, 3, and 5, with 3000 mL of plasma exchanged during each session	Occupational Exposure to Tetrachloroethylene	Bilirubin, ammonia, and prothrombin time improved before hospital discharge and patients mental status gradually became normal discharged on day 26 of hospital admission
Pashaei et al[30]	Case report	PE, No comparative arm	Plasma exchange volume 2.5L	Wilson’s disease	36 h after initiation of PE, encephalopathy recovered and there was no renal impairment. Copper, LDH total bilirubin decreased after the treatment
			Plasma exchange fluid: FFP

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.