Post reperfusion syndrome during liver transplantation: From pathophysiology to therapy and preventive strategies

Table 1 Incidence, risk factors and graft effects

Ref.	Title	Type of study	No. subjects	Definition of PRS	PRS pretreatment	Incidence	Risk factors	Graft and recipient effects	Jadad score
Garutti Martinez et al[14]	Response to clamping of the inferior vena cava as a factor for predicting postreperfusion syndrome during liver transplantation	Retrospective	94	30% drop in MAP within 5' lasting for 1'	Fluid challenge to achieve PCWP at least 12 mmHg before clamping the IVC	28.7%	A low increase in SVRI after clamping of IVC is predictive of PRS, this could be correlated to the sensitivity of baroreflexes and hence a more responsive cardiovascular system in those patients who did not develop PRS	N/A	1
Chui et al[5]	Postreperfusion syndrome in orthotopic liver transplantation	Retrospective	321	MAP < 60 mmHg together with classical hemodynamic disturbance (?)	?	12.8%	↑ CIT, ↑ potassium and ↓ bT after reperfusion	-	1
Nanashima et al[8]	Analysis of postrevascularization syndrome after orthotopic liver transplantation: the experience of an Australian liver transplantation center	Retrospective	100	30% drop in MAP within 5' lasting for 1'	?	29%	older donor age	↑ post reperfusion lactate and transaminase; ↑ creatinine on POD 7	1
Ayanoglu et al[13]	Causes of postreperfusion syndrome in living or cadaveric donor liver transplantations	Retrospective	145	30% drop in MAP within 5' lasting for 1'	20% mannitol + Ca gluconate 1-2 g + 30-50 mEq NaHCO3	48.9%	Shorter duration of anhepatic phase, ↑ calcium requirements, ↑ HR pre-post reperfusion, ↓ CVP during the dissection period	-	1
Hilmi et al[2]	The impact of postreperfusion syndrome on short-term patient and liver allograft outcome in patients undergoing orthotopic liver transplantation	Retrospective	338	Hilmi definition	?	55% (significant PRS)	↑ WIT, older recipient age	↑ days on ventilator, ICU stay, hospital stay, need for retransplantation, RBC, FFP, CRYO tansfusions and fibrynolisis, no differences in recipient survival	1
Paugam-Burtz et al[10]	Postreperfusion syndrome during liver transplantation for cirrhosis: outcome and predictors	Prospective	75	30% drop in MAP within 5' lasting for 1'	Colloids, 500 mL	25%	↑ CIT, absence of porto-caval shunt	↑ severe acute renal failure, ↑ 15 d mortality	1
Cordoví de Armas et al[15]	Rapid and homogeneous reperfusion as a risk factor for postreperfusion syndrome during orthotopic liver transplantation	Prospective	94	30% drop in MAP within 5' lasting for 1'	None	32.90%	SQR (reperfusion's speed-quality) can be considered an unambiguous predictor of PRS	N/A	1
Siniscalchi et al[12]	Hyperdinamic circulation in acute liver failure: reperfusion syndrome and outcome following liver transplantation	Retrospective	58	30% drop in MAP within 5' lasting for 1'	N/A	41%	↑ MELD, creatinine, FHF	↑ hospital mortality, ↓ survival rates at 3, 6, 12 mo	0
Khosravi et al[17]	Postreperfusion syndrome and outcome variables after orthotopic liver transplantation	Retrospective	184	Hilmi definition	?	17.4% (significant PRS)	-	↑ post reperfusion blood loss and need for RBC, FFP, PLT. ↑ hospital stay	1
Bukowicka et al[4]	The occurrence of postreperfusion syndrome in orthotopic liver transplantation and its significance in terms of complications and short-term survival	Retrospective	340	30% drop in MAP within 5' lasting for 1'	?	12.10%	↑ CIT, classical technique with VVB, higher HR at the beginning of operation, no correlation with donor' age, and recipient' age or sex	↑ intraoperative RBC and FFP requirements, ↑ early postoperative complications	1
Fukazawa et al[7]	Body surface area index predicts outcome in orthotopic liver transplantation	Retrospective	1228 (3 groups: small for size; controls; large for size)	30% drop in MAP within 5' lasting for 1'	N/A	49% control group, 51% large for size	Lower BSAi is associated with ↓ incidence in PRS, while older donor age ↑ PRS. Note: lower BSAi group had significantly lower age and significantly higher CIT. Low BSAi significantly ↑ arterial hepatic artery thrombosis risk; both low and high BSAi ↓ graft survival	N/A	0
Chung et al[11]	Incidence and predictors of postreperfusion syndrome in living donor liver transplantation	Retrospective	152	30% drop in MAP within 5' lasting for 1'	None	34.2%	Macrovescicular graft steatosis, ↑ recipient MELD score, ↑ preoperative HR, INR, bilirubin and creatinine; lower preoperative haemoglobin, ↑ prereperfusion RBC requirements, lower prereperfusion urine output	↑ Bilirubin peak in the first five POD	0
Xu et al[9]	Postreperfusion syndrome during orthotopic liver transplantation: a single-center experience	Retrospective	330	30% drop in MAP within 5' lasting for 1'	100 mcg phenylephrine, or 10 mcg epinephrine if SBP < 90 mmHg, graft flushed with 500 mL of 5% albumin before reperfusion	17%	Preoperative LVDD, ↑ CIT	↑ Intraoperative mortality, postoperative renal failure, hospital mortality	1
Kim et al[16]	Sympathetic withdrawal is associated with hypotension after hepatic reperfusion	Retrospective	218	30% drop in MAP within 5' lasting for 1'	-	35% (77 PRS vs 141 No-PRS)	Low LF/HF and SBP measured before hepatic graft reperfusion were significantly correlated with subsequent PRS occurrence, suggesting that sympathovagal imbalance and depressed SBP may be key factors predisposing to reperfusion-related severe hypotension in liver transplant recipients	N/A	1
Fukazawa et al[3]	Hemodynamic recovery following postreperfusion syndrome in liver transplantation	Retrospective	715	30% drop in MAP within 5' lasting for 1'	?	31.6%	↑ donor age, DRI, CVP before reperfusion	No effects on graft survival or early graft dysfunction	1

PRS: Post reperfusion syndrome; MAP: Mean arterial pressure; PCWP: Pulmonary capillary wedge pressure; IVC: Inferior vena cava; SVRI: Systemic vascular resistance index; CIT: Cold ischemia time; bT: Body temperature; POD: Post operative day; HR: Heart rate; CVP: Central venous press; FFP: Fresh frozen plasma; CRYO: Cryoprecipitate; SQR: Reperfusion speed-quality; MELD: Model For end-stage liver disease; FHF: Fulminant hepatic failure; PLT: Platelets; VVB: Veno-venous bypass; BSAi: Body surface Area index; SBP: Systolic arterial blood pressure; LVDD: Left ventricular diastolic disease; LF: Low frequency power; HF: High frequency power; DRI: Donor risk index.

Table 2 Pathophysiology

Year	Ref.	Title	Type of study	No. subjects	Findings	Jadad score
1993	De Wolf et al[22]	Right ventricular function during orthotopic liver transplantation	Prospective	20	RVEF maintained throughout the OLT procedure	1
1994	Ronholm et al[36]	Complement system activation during orthotopic liver transplantation in man	Prospective	16	The complement cascade activation demonstrated during OLT is located in the gut and triggered by hypoperfusion of the gut due to clamping of the portal and caval veins. There was a significant correlation between activation of complement with high concentration of C3a anaphylatoxin and development of PRS	1
1995	Blanot et al[41]	Circulating endotoxins and postreperfusion syndrome during orthotopic liver transplantation	Prospective	15	No correlation between plasma endotoxins detectable with the LAL (limulus amoebocyte lysate) test and PRS. However the endotoxenemia is still an important risk factor	1
1995	Scholz et al[38]	Activation of the plasma contact system and hemodynamic changes after graft revascularization in liver transplantation	Prospective	17 (19 OLT procedures)	Liver graft reperfusion was associated with a significant increase in Kallikrein activity with a concomitant drop in antiprotease activity and high molecular weight kininogen. Hemodynamic changes correlated with the plasmatic concentrations	0
1997	Bellamy et al[33]	Changes in inflammatory mediators during orthotopic liver transplantation	Prospective	10	After reperfusion SVRI decreased and CI increased; these were accompanied by increases in TNF-α , TNF-α-R, IL-1β, IL-1 receptor antagonist, IL-6, IL-8; no changes in PAF and Thromboxane B2; Leukotriene C4, D4, E4 decreased	1
1999	Acosta et al[21]	Effect of reperfusion on right ventriculoarterial coupling in liver transplantation	Prospective	52	Similar ↑ in CI, RVEDVI, RVSWI in both PRS and non PRS patients, better ventriculo-arterial coupling in non PRS patients due to a decrease in pulmonary vascular elastance	1
1999	Acosta et al[31]	Changes in serum potassium during reperfusion in liver transplantation	Retrospective	106	No correlation between changes in serum potassium and PRS	1
2004	Bellamy et al[37]	Complement membrane attack complex and hemodynamic changes during human orthotopic liver transplantation	Prospective	40	The formation of MAC complex and degradation of C3,C4 increased markedly at the time of liver graft reperfusion. Concomitantly SVRI decreased and CI increased, with changes correlated to the activation of the MAC	1
2008	Ripoll et al[25]	Cardiac dysfunction during liver transplantation: incidence and preoperative predictors	Retrospective	209	22.5% abnormal cardiac response to reperfusion, predictive factors: hyponatremia, lower PAP and lower CVP and PCWP, at the beginning of the intervention. Preoperative echocardiography couldn't predict abnormal response	1
2011	Bezinover et al[34]	Release of cytokines and hemodynamic instability during the reperfusion of a liver graft	Prospective	17	The concentration of TNF-α correlated directly with the amount of catecholamines used to treat hemodynamic instability. No correlation between any cytokine levels and the duration of CIT, the surgical technique, and the quality of the liver graft	1
2012	Xu et al[23]	Evaluation of the right ventricular ejection fraction during classic orthotopic liver transplantation without venovenous bypass	Prospective	30	RV function is impaired during the anhepatic and early reperfusion stages, particularly in the high MELD score patients	1
2013	Siniscalchi et al[18]	Hyperdynamic circulation in cirrhosis: predictive factors and outcome following liver transplantation	Retrospective	242	Hyperdynamic circulation is associated to ↓ MAP, SVI and ↑ PCWP and PVRI 10 min after reperfusion	1
2013	Escobar et al[26]	Stroke volume response to liver graft reperfusion stress in cirrhotic patients	Prospective	271	Non-responder patients (35.7%) had higher MELD score, left atrial diameter and low SVRI at the beginning of the intervention. These patients experienced more early cardiovascular events and ICU stay	1
2014	Tsai et al[35]	Ischemic reperfusion injury-induced oxidative stress and pro-inflammatory mediators in liver transplantation recipients	Prospective	14	Malondialdehyde (MDA) is one of the intermediate metabolites from lipid peroxidation and representing a indirectly measure of oxidative stress-induced liver injury. Recipients with higher values of preoperative bilirubin, AST, ALT, MELD score, INR, and blood loss tended to have significantly higher levels of MDA and may suffer more injury from this insult	1

RVEF: Right ventricular ejection fraction; OLT: Orthotopic liver transplantation; C3a: Complement anaphylatoxin 3a; PRS: Post reperfusion syndrome; SVRI: Systemic vascular resistance index; CI: Cardiac index; TNF: Tumor necrosis factor; IL: Interleukin; PAF: Platelet activating factor; RVEDVI: Right Ventricular end-diastolic volume index; RVSWI: Right ventricular stroke work index; MAC: Complement membrane attack; PAP: Pulmonary arterial pressure; CVP: Central venous pressure; PCWP: Pulmonary capillary wedge pressure; CIT: Cold ischemia time; RV: Right ventricular; MELD: Model for end-stage liver disease; MAP: Mean arterial pressure; SVI: Stroke volume index; PVRI: Pulmonary vascular resistance index; SVRI: Systemic vascular resistance index; ICU: Intensive care unit.

Table 3 Surgical prevention/treatment strategies

Year	Ref.	Title	Type of study	Rationale	No. subjects	Definition of PRS	Effects	Jadad score
1992	Jugan et al[50]	The failure of venovenous bypass to prevent graft liver postreperfusion syndrome	Prospective interventional	VVBP should grant a better hemodynamic stability during reperfusion	58 (29 VVBP vs 29 NBP)	30% drop in MAP within 5' lasting for 1'	No differences in PRS incidence	1
1997	Millis et al[54]	Randomized controlled trial to evaluate flush and reperfusion techniques in liver transplantation	Randomized Controlled Trial	The techniques used to flush and reperfuse the graft could have an impact on PRS	88 (4 groups: hepatic arterial or portal vein flush with or without vena caval venting)	Three criteria: MAP < 60 mmHg at 1'; MAP < 60 mmHg at 5'; and a decrease of 30% or more for the MAP percent area under the curve (%AUC) during the first 5'	↓ PRS incidence in patients transplanted with a portal vein flush without vena caval venting versus arterial flush with/without vena caval venting	5
1999	Acosta et al[49]	Influence of surgical technique on postreperfusion syndrome during liver transplantation	Prospective interventional	The stability granted by the piggy-back (PGB) technique during the anhepatic phase without the need for VVBP could be extended to the initial minutes of reperfusion	71 (8 VVBP vs 43 NBP vs 20 PGB)	30% drop in MAP within 5' lasting for 1'	The greatest percent decrease in SVRI, and incidence of PRS, occurred in the VVBP group	1
2000	Durcef et al[52]	Hemodynamic profiles during piggyback liver grafts using arterial or portal revascularization	Prospective, randomized	The techniques used to flush and reperfuse the graft could have an impact on PRS	59 (29 HA vs 30 PV)	20% drop in MAP within the first 10' lasting for 5'	Initial arterial revascularization of the liver graft leads to a more stable hemodynamic profile. The time lag between arterial revascularization and the following portal anastomosis allows venous mesenteric pressure release	3
2006	Moreno et al[53]	Hemodynamic profile and tissular oxygenation in orthotopic liver transplantation: Influence of hepatic artery or portal vein revascularization of the graft	Randomized Controlled Trial	Simultaneous arterial and portal anastomosisis feasible due to the hemodynamic improvement offered by the piggy-back technique with temporary portacaval shunt	60 (30 IAR vs 30 IPR)	30% drop in MAP within 5' lasting for 1'	IPR leads to ↑ values of preload parameters, ↑ CO and MAP values than IAR. This increase in pulmonary pressure was lower in the artery group so that IAR of the graft may be indicated in case of poor pulmonary and cardiac reserve	3
2006	Gruttadauria et al[55]	Comparison of two different techniques of reperfusion in adult orthotopic liver transplantation	Retrospective	Better hemodynamic stability of caval venting than flushing with cold Ringer Lactate solution	50 (25 portal vein flush, no caval venting vs 25 caval venting, no portal vein flush)	30% drop in MAP within 5' lasting for 1'	↑ hemodynamic and metabolic stability in the group with portal vein flush	1
2008	Ko et al[46]	Greater hemodynamic instability with histidine-tryptophan-ketoglutarate solution than University of Wisconsin solution during the reperfusion period in living donor liver transplantation	Retrospective	Different vasoactive substances concentration in the two solutions	87 (28 UW vs 59 HTK)	30% drop in MAP within 5' lasting for at least 1' and up to more than 1 h	↑ PRS incidence in non flushed HTK group, flushing the solution ↓ PRS incidence similar to UW	1
2010	Ghafaripour et al[47]	Hypotension after reperfusion in liver transplantation: histidine-tryptophan-ketoglutarate versus University of Wisconsin solution	Randomized Controlled Trial	Different vasoactive substances concentration in the two solutions	89	30% drop in MAP within 5' lasting for at least 1' and up to more than 1 h	↑ PRS incidence in both flushed and non flushed HTK groups, flushing the solution ↓ PRS incidence	3
2011	Garcìa-Gil et al[48]	Celsior versus University of Wisconsin preserving solutions for liver transplantation: postreperfusion syndrome and outcome of a 5-year prospective randomized controlled study	Randomized Controlled Trial	Different potassium concentrations in the two solutions may imply different PRS outcomes as the outcome is closely related to hyperkalemia	102 (51 CS vs 51 UW)	30% drop in MAP within 5' lasting for 1'	Significant ↓ of PRS incidence in CS group; greater control over magnesium, potassium and glucose levels, no differences in long term outcomes	4
2012	Hong et al[56]	Regulated hepatic reperfusion mitigates ischemia-reperfusion injury and improves survival after prolonged liver warm ischemia: a pilot study on a novel concept of organ resuscitation in a large animal model	A pilot study in a animal model	The modification of reperfusion perfusate and cellular environment after warm ischemia would reverse the metabolic deficit and facilitate recovery of organ function	12 (6 RHR vs 6 control)	30% drop in MAP within 5' lasting for 1'	Regulated hepatic reperfusion (RHR) by using an energetic substrate-enriched, oxygen-saturated, and leukocyte-depleted perfusate delivered under regulated reperfusion pressure, temperature, and pH mitigates ischemia-reperfusio injury, facilitates liver function recovery, and improves survival after prolonged WI	1
2013	Fukazawa et al[51]	Crystalloid flush with backward unclamping may decrease postreperfusion cardiac arrest and improve short-term graft function when compared to portal blood flush with forward unclamping during liver transplantation	Retrospective	CB flush grants a lower blood loss during reperfusion, a gradual rewarming wich could foster systemic hemodynamics and graft survival	478 (313 CB vs 165 PF)	30% drop in MAP within 5' lasting for 1'	No differences in PRS incidence, ↓ PNF and cardiac arrest incidence; ↑ 30-d graft survival in CB group	1

PRS: Post reperfusion syndrome; VVBP: Veno-venous bypass; NBP: Without veno-venous bypass; MAP: Mean arterial pressure; PGB: Piggy-back; SVRI: Systemic vascular resistance index; HA: Hepatic artery revascularization; PV: Portal vein revascularization; IAR: Initial arterial revascularization; IPR: Initial portal revascularization; CO: Cardiac output; UW: University of wisconsin solution; HTK: Histidine-tryptophan-ketoglutarate solution; CS: Celsior solution; RHR: Regulated hepatic reperfusion; WI: Warm ischemia; CB: Crystalloid flush with backward unclamping; PF: Portal blood flush with forward unclamping; PNF: Primary non function.

Table 4 Pharmacological prevention/treatment strategies

Year	Authors	Title	Type of study	Rationale	No. subjects	Definition of PRS	Effects	Jadad score
1995	Bromley et al[57]	Effects of intraoperative N-acetylcysteine in orthotopic liver transplantation	Prospective	NAC could be beneficial in blunting the reperfusion effects of OLT	50 (25 NAC vs 25 glucose)	-	NAC ↑ DO2 and CI; ↓ MAP and SVRI, no difference in reperfusion events or postoperative outcome	3
1995	Milroy SJ et al[61]	Improved haemodynamic stability with administration of aprotinin during orthotopic liver transplantation	Randomized Controlled Trial	Aprotinin ↓ fibrinolysis and inflammatory response	55 (3 drop outs, 26 placebo, 26 aprotinin)	-	Aprotinin ↑ SVRI and ↓ CI in aprotinin group, no differences in vasopressors need	5
1999	Acosta et al[66]	Atropine prophylaxis of the postreperfusion syndrome in liver transplantation	Prospective	Pretreatment with atropine could partially prevent the developing of PRS	41 (11 PRS vs 30 NPRS)	30% drop in MAP within 5' lasting for at least 1' and up to more than 1 h	No significant changes in HR occurred, bradycardia was prevented. No change in MAP was recorded	1
2001	Molenaar et al[19]	Reduced need for vasopressors in patients receiving aprotinin during orthotopic liver transplantation	Randomized Controlled Trial	Aprotinin ↓ fibrinolysis and inflammatory response	67 (24 high-dose aprotinin vs 21 regular-dose aprotinin vs 22 placebo)	Syndrome characterized by a decrease in MAP and SVRI and an increase in CI and mean pulmonary artery pressure	Aprotinin ↓ need for vasopressors during OLT, especially during the early postreperfusion period	3
2002	Koelzow et al[58]	The effect of methylene blue on the hemodynamic changes during ischemia reperfusion injury in orthotopic liver transplantation	Randomized Controlled Trial	Methylene blue (MB) is an inhibitor of inducible NO synthase and an NO scavenger	36 (18 MB 1.5 mg/kg vs 18 placebo )	30% drop in MAP within 5' lasting for at least 1' and up to more than 1 h	MB ↑ MAP and CI, ↓ epinephrine requirement, SVR did not change significantly, ↓ lactate levels	1
2003	Findlay et al[62]	Aprotinin reduces vasoactive medication use during adult liver transplantation	Data obtained from patients enrolled in a previously completed, prospective, randomized, double-blind study	Aprotinin ↓ fibrinolysis and inflammatory response	63 (33 aprotinin vs 30 placebo)	-	↓ use of vasoactive infusions in the aprotinin group	3
2011	Fukazawa et al[59]	The effect of methylene blue during orthotopic liver transplantation on post reperfusion syndrome and postoperative graft function	Retrospective	Methylene blue (MB) is an inhibitor of inducible NO synthase and an NO scavenger	715 (105 MB bolus dose vs 610 control)	30% drop in MAP within 5' lasting for at least 1' and up to more than 1 h	No differences in PRS incidence, post reperfusion MAP, need for vasopressors or transfusions and secondary outcomes	1
2011	Ryu et al[63]	Nafamostat Mesylate attenuates post reperfusion syndrome	Randomized Controlled Trial	Aprotinin has been proven effective in preventing PRS but it has been withdrawn from the market, Nafamostat is a protease inhibitor that acts similarly and could prove useful	61 (31 treated vs 31 placebo, 42 excluded)	30% drop in MAP within 5' lasting for at least 1' and up to more than 1 h	Nafamostat ↓ PRS incidence, hastened post reperfusion MAP recovery to normal values and ↓ need for early and late postreperfusion vasopressors	5
2012	Ryu et al[6]	Epinephrine and phenylephrine pretreatments for preventing postreperfusion syndrome during adult liver transplantation	Randomized Controlled Trial	Pretreatment with a vasopressor should reduce PRS incidence and need for continous vasopressor support in late postreperfusion period	96 (32 normal saline vs 33 epinephrine vs 31 phenylephrine)	30% drop in MAP within 5' lasting for 1'	↓ PRS incidence and ↓ need for vasopressors in late postreperfusion period in both pretreatment groups. Overshoot MAP in 6% of patients in both pretreatment groups. No differences in perioperative laboratory data and mortality	5
2013	Kong et al[64]	Epsilon-aminocaproic acid improves postrecirculation hemodynamics by reducing intraliver activated protein C consumption in orthotopic liver transplantation	Randomized Controlled Trial	APC has a role in coagulation and inflammation and could influence the levels of cytokines involved in the developement of PRS after reperfusion	59 (31 EACA vs 28 controls)	30% drop in MAP within 5' lasting for at least 1' and up to more than 1 h	↓ PRS incidence, ↑ MAP, ↓ need for vasopressors, blood transfusion and FFP in EACA group	5
2013	Chung et al[68]	Effects of magnesium pretreatment on the levels of T helper cytokines and on the severity of reperfusion syndrome in patients undergoing living donor liver transplantation	Randomized Controlled Trial	Magnesium has a protective role over ischemia-reperfusion injury	40 (20 mg pretreatment vs 20 controls)	30% drop in MAP within 5' lasting for at least 1' and up to more than 1 h	↓ PRS incidence	5
2014	Fayed et al[67]	Goal directed preemptive ephedrine attenuates the reperfusion syndrome during adult living donor liver transplantation	Randomized Controlled Trial	Preemptive ephedrine administration prereperfusion targeting a rational level of MAP may reduce the incidence of PRS	100 (50 control vs 50 ephedrine)	30% drop in MAP within 5' lasting for 1'	↓ PRS incidence, need for postreperfusion vasoconstrictor support without over shooting of hemodynamic indices. ↓ need for postoperative mechanical ventilation	5

PRS: Post reperfusion syndrome; NAC: N-acetylcysteine; OLT: Orthotopic liver transplantation; DO2: Oxygen delivery; CI: Cardiac index; MAP: Mean arterial pressure; SVRI: Systemic vascular resistance index; NPRS: Without post reperfusion syndrome; HR: Heart rate; MB: Methylene blue; NO: Nitric oxide; SVR: Systemic vascular resistance; CIT: Cold ischemia time; APC: Activated protein C; EACA: Epsilon-aminocaproic acid; FFP: Fresh frozen plasma.