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

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.