**2. Diagnosis**

The post-reperfusion syndrome (PRS) which occurs during liver transplantation was first diagnosed by Aggarwal et al in 1987 and described as cardiovascular collapse following revascularization of the liver graft. They defined PRS as severe hemodynamic instability, persistent hypotension (a greater than 30% drop below the anhepatic mean arterial blood pressure (MAP) within 5 minutes of reperfusion and sustained for at least 1 minute), accompanied by asystole, or significant arrhythmias as well as development of significant, fibrinolysis requiring treatment. Up until now this definition remains the same with some modifications. Hilmi et al defined *mild* PRS as a drop in MAP to less than 30% of mean baseline MAP observed during the anhepatic stage associated with bradycardia and sustained for less than 5 minutes, and requiring calcium or epinephrine boluses, but without the need for continuous vasopressor infusion. *Severe* PRS was defined as persistent severe hypotension with a greater than 30% reduction in MAP from mean baseline MAP during the anhepatic stage, associated with asystole, significant arrhythmias, and requiring prolonged vasopressor infusion (until end of surgery) and fibrinolysis. Other reports have used only persistent hypotension as the defining endpoint for PRS. Therefore, inconsistency of definitions makes it difficult to draw conclusions concerning the precise incidence of PRS, its clinical presentation and causes.

These definitions rely on the value of the percent change in MAP from the mean baseline MAP observed during the anhepatic stage. It so happens that the anhepatic stage is fraught with hemodynamic fluctuations related to manipulation of the inferior vena cava (IVC), blood loss, veno-venous bypass, hypothermia, metabolic acidosis, etc., which are common during the an-hepatic phase. These multi-factorial hemodynamic perturbations call into


Table 1. Definition of Post-Reperfusion Syndrome (PRS) *Abbreviations: MAP: Mean Arterial Blood Pressure*

question the reliability and accuracy of PRS incidence and severity based on one parameter namely, % change in MAP. Moreover, pre-treatment with bolus doses of vasopressors, including calcium chloride, vasopressin or methylene blue immediately prior to reperfusion of the portal vein, intended to preempt severe hypotension post-reperfusion also introduce errors into the calculation of % changes in MAP, before and after reperfusion. More importantly, in some instances there may be a complete absence of hemodynamic instability even in the presence of severe graft dysfunction following reperfusion when portal vein flow is inadequate. This is called the no-reflow phenomenon. No-reflow is associated with high vascular resistance in the microcirculation of the graft secondary to multiple factors, such as: tissue edema, leukocyte plugging and the accumulation of pro-inflammatory factors and cellular debris; vasoconstriction of the tissues due to cold preservation, portal vein thrombosis, or presence of large collateral veins (porto-systemic shunts). In those cases, there is a gradual resolution of no-reflow and hemodynamic fluctuations may be delayed beyond the immediate portal vein or even hepatic artery reperfusion periods when the organ is better perfused. For these reasons, PRS incidence may not be accurately ascertained when a narrow window of MAP readings is used in its determination. Likewise, major changes in MAP in the immediate post-reperfusion period may or may not be associated with graft quality. Although cardiovascular collapse following reperfusion is common in liver transplant practice, it is essential to elucidate the underlying mechanisms of PRS, and to determine more accurately the relationship between PRS and graft quality. Is PRS a cause of poor graft quality or is it a consequence? The definitive answer to this question can only be found in the conduct of a blinded controlled prospective study with well-defined end points in a large cohort of patients. The results of such a study would help to broaden the scope of what constitutes the diagnosis of PRS.

#### **3. Incidence of PRS and confounding factors**

To date, there is wide variation in the reported incidence of PRS (5.9-61.3%). There are several factors attributable to these wide variations, among these are: differences in surgical technique, intraoperative hemodynamic management, as well as chronological and geographical factors. Piggyback technique is used for implantation of the liver graft without interrupting IVC flow. It was first introduced into human liver transplantation in the late 1980's. Veno-venous bypass (VVB) was also introduced in the 1980's. Those techniques were developed to enable more stable hemodynamics upon manipulation of the IVC during orthotopic liver transplantation. Because volume status of the recipient before reperfusion can be an important risk factor for PRS, more stable hemodynamics before reperfusion may decrease its incidence, although the impact of surgical technique between conventional or


Table 2. (continues on next page) Reported Incidence of PRS \*Transplant technique: conventional inferior vena cava anastomosis versus piggyback anastomosis\*\*Sequence of reperfusion: initial hepatic artery revascularization versus initial portal vein revascularization. *Abbreviations: CVP: central venous pressure, HTK: histidine-triptophanketoglutarate solution, ICU: intensive care unit, IVC: inferior vena cava, MELD: models for end stage liver disease, UW: University of Wisconsin solution, VVB: veno-venous bypass*

386 Liver Transplantation – Basic Issues

Geater than 30% of the anhepatic MAP within 5 minutes sustained for at least 1 minute

Table 1. Definition of Post-Reperfusion Syndrome (PRS) *Abbreviations: MAP: Mean Arterial* 

question the reliability and accuracy of PRS incidence and severity based on one parameter namely, % change in MAP. Moreover, pre-treatment with bolus doses of vasopressors, including calcium chloride, vasopressin or methylene blue immediately prior to reperfusion of the portal vein, intended to preempt severe hypotension post-reperfusion also introduce errors into the calculation of % changes in MAP, before and after reperfusion. More importantly, in some instances there may be a complete absence of hemodynamic instability even in the presence of severe graft dysfunction following reperfusion when portal vein flow is inadequate. This is called the no-reflow phenomenon. No-reflow is associated with high vascular resistance in the microcirculation of the graft secondary to multiple factors, such as: tissue edema, leukocyte plugging and the accumulation of pro-inflammatory factors and cellular debris; vasoconstriction of the tissues due to cold preservation, portal vein thrombosis, or presence of large collateral veins (porto-systemic shunts). In those cases, there is a gradual resolution of no-reflow and hemodynamic fluctuations may be delayed beyond the immediate portal vein or even hepatic artery reperfusion periods when the organ is better perfused. For these reasons, PRS incidence may not be accurately ascertained when a narrow window of MAP readings is used in its determination. Likewise, major changes in MAP in the immediate post-reperfusion period may or may not be associated with graft quality. Although cardiovascular collapse following reperfusion is common in liver transplant practice, it is essential to elucidate the underlying mechanisms of PRS, and to determine more accurately the relationship between PRS and graft quality. Is PRS a cause of poor graft quality or is it a consequence? The definitive answer to this question can only be found in the conduct of a blinded controlled prospective study with well-defined end points in a large cohort of patients. The results of such a study would help to broaden the

To date, there is wide variation in the reported incidence of PRS (5.9-61.3%). There are several factors attributable to these wide variations, among these are: differences in surgical technique, intraoperative hemodynamic management, as well as chronological and geographical factors. Piggyback technique is used for implantation of the liver graft without interrupting IVC flow. It was first introduced into human liver transplantation in the late 1980's. Veno-venous bypass (VVB) was also introduced in the 1980's. Those techniques were developed to enable more stable hemodynamics upon manipulation of the IVC during orthotopic liver transplantation. Because volume status of the recipient before reperfusion can be an important risk factor for PRS, more stable hemodynamics before reperfusion may decrease its incidence, although the impact of surgical technique between conventional or

Severe hemodynamic instability

Development of significant fibrinolysis

Persistent hypotension

Significant arrhythmias

Asystole

scope of what constitutes the diagnosis of PRS.

**3. Incidence of PRS and confounding factors** 

*Blood Pressure*


Table 2. (continued) Reported Incidence of PRS \*Transplant technique: conventional inferior vena cava anastomosis versus piggyback anastomosis\*\*Sequence of reperfusion: initial hepatic artery revascularization versus initial portal vein revascularization. *Abbreviations: CVP: central venous pressure, HTK: histidine-triptophan-ketoglutarate solution, ICU: intensive care unit, IVC: inferior vena cava, MELD: models for end stage liver disease, UW: university of Wisconsin solution, VVB: veno-venous bypass*

piggy-back techniques on PRS is still in debate. In addition, VVB reduces small bowel edema, which has been suggested as a primary site for the production and release of potent vasoactive inflammatory mediators. With the improvement of transplant outcomes and recognition of risk factors for graft survival, expanded criteria donors (ECD) have been more frequently used due to severe shortages of organ donors. More frequent usage of ECD as well as the introduction of new surgical techniques may affect the incidence of PRS, depending on the era, a chronological factor. Also, geographical areas with low organ donor conversion rates and acute shortage of organs for transplantation will invariably result in higher usage rates of ECD, as well as sicker recipients due to longer waiting times. Therefore, the incidence of PRS will vary with geographical area. The interpretation of those results also needs to take chronological and geographical factors into account as confounding factors.
