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- Patients and Methods
The interaction of systemic hemodynamics with hepatic flows at the time of liver transplantation (LT) has not been studied in a prospective uniform way for different types of grafts. We prospectively evaluated intraoperative hemodynamics of 103 whole and partial LT. Liver graft hemodynamics were measured using the ultrasound transit time method to obtain portal (PVF) and arterial (HAF) hepatic flow. Measurements were recorded on the native liver, the portocaval shunt, following reperfusion and after biliary anastomosis. After LT HAF and PVF do not immediately return to normal values. Increased PVF was observed after graft implantation. Living donor LT showed the highest compliance to portal hyperperfusion. The amount of liver perfusion seemed to be related to the quality of the graft. A positive correlation for HAF, PVF and total hepatic blood flow with cardiac output was found (p = 0.001). Portal hypertension, macrosteatosis >30%, warm ischemia time and cardiac output, independently influence the hepatic flows. These results highlight the role of systemic hemodynamic management in LT to optimize hepatic perfusion, particularly in LDLT and split LT, where the highest flows were registered.
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- Patients and Methods
The systemic hemodynamics in patients undergoing liver transplantation (LT) is abnormal (1–3). As well as a high resistance from the cirrhotic liver, the augmented splanchnic volume increases portal pressure progressively with the development of collateral circulation, diverting splanchnic blood to the systemic circulation. Initial systemic vasodilatation is followed by a decrease in central volume causing relative hypovolemia, which leads to sodium retention and plasma volume expansion, resulting in increased cardiac output (CO) (4–7). High CO together with decreased peripheral vascular resistance and arterial pressure characterize this hyperdynamic circulation, worsening the initial endothelial stress and closing the circuit. LT replaces the cirrhotic liver with a normal liver, relieving the mechanical component of portal hypertension but without immediately restoring the systemic or the splanchnic circulation to normal (8–11). At the same time, the relative central hypovolemia accentuates the influence of vasoactive drug administration and adequate volume management during LT, because tissue hypoperfusion during surgery has been shown to be a cause of poor outcome (2,12,13). The normal liver has no active role in the physiological regulation of hepatic inflow. Hence, the liver is a passive recipient of fluctuating amounts of blood flow, which can encompass a wide range of flow (7,14). Moreover, the newly grafted liver has to comply with the high splanchnic volume of the recipient. The presence of a hepatic arterial buffer response (HABR) operates to compensate for portal vein flow (PVF) changes (15–17). Indeed, the extreme increase of PVF observed after living donor LT (LDLT) together with the HABR are responsible for the reduced hepatic artery flow (HAF) usually encountered in this setting (18,19). Exposition of grafts (mainly partial grafts, but not exclusively) to excessive portal perfusion could determine specific problems such as prolonged cholestasis, ascites and increased vascular thrombosis rates, events characterizing the small-for-size syndrome (SFSS) and potentially leading to graft loss (20–22). To overcome the SFSS and to reduce postreperfusion graft flow imbalance, the concept of graft inflow modulation (GIM) has been proposed with beneficial influence in optimization of HAF and improved outcome in LDLT (23–25).
To our knowledge, no prospective evaluation on direct liver flow measurement in different types and qualities of grafts is currently available. To fill this gap, we designed a prospective protocol for intraoperative hepatic hemodynamic data collection to evaluate systemic and regional hemodynamics of LT with different graft types, measuring intraoperative HAF and PVF. The aim of this report is to explore the influence of hyperdynamic flows in different graft types and assess variables that could potentially influence hepatic hemodynamics.
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- Patients and Methods
Interpretation of normal liver flows during LT is complex and is influenced by several factors such as the quality of the organ, ischemia–reperfusion damage, clinical status of the recipient, systemic hemodynamics and anesthesiology management. The heterogeneity of methods used in literature, type of patients and reporting of flows or perfusions add further complexity to the interpretation of an adequate inflow (Table 1). In these exploratory analyses, we present a prospective data collection with uniform methods in over 100 liver transplants.
Table 1. Intraoperative direct measurement of hepatic flow
|Author||Year||Graft type||n||Type||HAF||PVF||TBF||P/A ratio|
|Paulsen (8)||1992||FS||282||Electromagnetic||32.5 (571.8)||137.2 (2348.3)||169.9 (2920.3)|| 4.1|
|Henderson (9)||1992||FS||34||TTFM||(268)||(1808)||(2091)|| 6.7|
|Margarit (44)||1999||FS||45||TTFM||(184)||(1590)||(1744)|| 8.6|
|García-Valdecasas(66)||2003||LDLT||22||TTFM||16 (121)3||243 (1970)3||259 (2091)3||15.2|
|Troisi (54)||2003||LDLT4||24||TTFM||12.8 (104)||318 (2100)||330.8 (2155)||24.8|
|Gontarczyk (67)||2007||FS||15||TTFM||16.2 (158)1||127 (1700)1||143.2 (2180)1|| 7.8|
|Hashimoto (68)||2010||FS||234||TTFM||17||115||1321|| 6.7|
|Present series||2010||All types5||103||TTFM||14.5 (198)3||121.5 (1618)3||130.9 (1837)3|| 7.9|
Native flows through the cirrhotic liver are characterized by low PVF and concomitant increase of HAF (8,43,44), which is confirmed by the results of our study (Table 5; Figure 1). After transplantation PVF increases to double the flows observed in healthy subjects (43,45,46). In half of the patients, PVF accounted for 93% of total liver flow after reperfusion. Portal vein perfusion values were higher in all graft types, the HAF values were inferior and the P/A ratio at least doubled by comparison to the reference flows from healthy live donors, suggesting a still functioning hepatic artery buffer response (Figure 2). In contrast, the native liver had a low portal to arterial ratio confirming a chronically active HABR with increased HAF in response to the reduced PVF, registering an inferior range as low as 0.03 (19).
WIT intensifies the ischemia–reperfusion damage of the hepatic sinusoids causing structural alterations and impaired microcirculation, and has been identified as an independent risk factor for graft failure (47). An association between the severity of steatosis and the degree of microvascular impairment has been previously shown (48–51). In our study, a negative trend for PVF and a positive trend for HAF did not reach significance. When grouped, macrosteatosis >30%, present in 5% of grafts, showed a reduced HAF in multivariate linear regression model, even though confidence intervals are wide.
As expected, graft weight (GW) and graft-to-recipient weight ratio (GRWR) of LDLT and SLT groups were smaller than FS and DCD groups. The use of perfusion values (mL/min/100 g LW), as presented, allows for a better understanding of the stress that an augmented portal flow poses on the liver graft by correcting the measured flows for the amount of liver that has to accommodate it, and minimizes the influence of GW on the measured flows. Indeed, the median GW of the SLT doubled the weight of the LDLT group but the flows were comparable (Figure 2). In clinical practice, the ‘ideal’ target PVF for LDLT has been regarded as twice the perfusion observed in the FS graft (250 mL/min/100 g LW) (8,52,53), or as twice the flows observed in the healthy donor (180 mL/min/100 g LW) (25). In LDLT, in spite of the smaller GW, and consequently reduced hepatic vascular bed, the highest recorded PVF were observed (Figure 2), doubling the reference values measured in living donors. We could hypothesize that, granted a good hepatic outflow as described in our technique, the optimal quality of the organ allows for a higher compliance of the portal hyperperfusion when safe GRWR and PVF are respected (24,25,52,54). The opposite may hold true for DCD grafts, where we observed the highest GW and GRWR and still, the TBF was low after reperfusion consistent with reports of edema and decreased compliance after cold preservation and warm ischemia (Tables 4 and 6; Figure 2) (55–58).
This study also suggests a direct effect of hyperdynamic systemic circulation on hepatic hemodynamics during LT. The greater the CO the higher the hepatic flows (Figure 3). Total hepatic blood flow after reperfusion represented in median 23% of CO. As previously described (9,16,19,59), our results seem to confirm the presence of an active intrahepatic buffer response, while both HAF and PVF are influenced by systemic hemodynamics. According to multivariate analysis, the effect on hepatic flows of CO seems to affect to a greater extent the HAF (Table 8).
An increase of HAF and PVF with a concomitant CO increase has been previously described when comparing hemodynamic patterns in the same patients before and after LT (8). Previous experience has shown single correlation of CO with PVF and a negative trend with HAF (9), while our prospective study indicates a correlation with HAF, PVF and TBF. The elevated TBF probably represents a significant contribution to the elevated CO observed after reperfusion (Table 5; Figure 1), which in turn increases the hepatic flows (Figure 3). Indeed, persisting portosystemic collateral circulation has been described up to 23 months after transplantation (10,11). Surprisingly, PVF registered through the temporary porto-caval shunt showed inferior flows and perfusions compared to reperfusion values. Besides a possible technical factor regarding torsion of the portal vein or anastomotic stricture of the temporary PCS, the increased flow after reperfusion observed could be a direct effect of increased CO. Indeed, another possible explanation relates to the intraoperative management of fluid and drug administration in different phases of LT. Prior to the reperfusion phase, the hemodynamic status is optimized and as a result CO may increase.
Our study presents some limitations, from data collection to data analysis. Concerning the latter, it could be fittingly underlined that our analyses are mainly exploratory, because reaching an adequate sample size for this type of hypotheses is not feasible in any clinical setting. With regards to the former, because we did not collect prospectively data regarding volume filling during transplantation we cannot ascertain the effect of fluid load and vasopressor use. We assumed that patients that did not need vasoactive therapy while maintaining a diuresis above 1 mL/kg/h after reperfusion, were normovolemic. Our results highlight the crucial role of an adequate hemodynamic management during, and immediately after, LT to optimize hepatic hemodynamics, particularly in LDLT and SLT, where the highest flows were registered.
In spite of a higher PVF, type 3 (hyperdynamic patients alone) showed the highest HAF of all four types, and significantly higher than type 2 patients (PHT alone). This result is in line with the correlation found between CO and HAF. Type 4 patients showed the influence of combining PHT and hyperdynamic status on the hepatic flows, a significantly higher PVF compared to type 2, where a reduced flow can be expected. Furthermore, type 4 showed an independent association with increased hepatic flows, stressing the need for flow measurement in this type of patients (Tables 7 and 9).
With the use of flow measurement we were able to identify 7 patients (6.9%) with abnormal average flows requiring correction, an incidence congruent with previous experiences (59). Two of these patients with normal pulsatility at palpation presented altered flow measurements, allowing us to identify and correct technical failures that otherwise could have compromised outcome (59,60). The low rate of HAT (1.9%) compares favorably with available reports (61,62). It is well known that causes of thrombosis are always multifactorial (61–63). However, we might speculate an effect of the systematic graft flow measurement directing inflow modulation or correction of vascular anastomosis on this low incidence. GIM is applied only in case of transplantation with small-for-size grafts (64,65). A different situation is represented by the need of GIM in FS grafts. In a previous publication, hyperperfusion was defined as flow values four times above the reference values observed in living donors (≥360 mL/min/100 g LW). FS grafts transplanted into hyperdynamic patients with hyperperfusion flow measurements presented similar histological changes as those observed in small-for-size grafts with inferior graft survival (22). In the absence of sound evidence in either direction, we choose to improve the chance of recovery of all grafts in case of manifest hyperperfusion. On the contrary, patients with low PVF can present with spontaneous porto-systemic shunts (SPSS). In such case, a clamp test can be performed and, if PVF improve, the SPSS should be ligated.
We have described the evolution of hepatic flows according to donor factors such as macrosteatosis superior to 30% and technical factors such as WIT that showed a significant association with inferior hepatic flows. Other factors of suboptimal quality of grafts potentially influencing graft perfusion, either individually (donor age, CIT, DRI, steatosis), or when grouped (ECD), did not show an association with hepatic flows in this exploratory study. The question of whether attributing abnormal flows to the graft quality in marginal grafts remains open. The analysis of associations between systemic and regional hemodynamics showed a significant relationship between CO and HAF, PVF and TBF. Although an association between CO and HAF is intuitive, the association found between CO and PVF (PVF representing in median 93% of TBF), is a more complex one in need of further investigation.
In conclusion, hemodynamics of LT show a significant increase of PVF during the different phases when compared to native liver and reference flows recorded in living donors. LDLT and SLT showed a higher capability to comply with a superior hemodynamic stress. This higher perfusion must be anticipated and GIM considered, also in FS grafts. The association between systemic and hepatic hemodynamics was prospectively confirmed. Portal hypertension, macrosteatosis >30%, WIT, CO and type 4 recipients were identified as independent variables influencing hepatic hemodynamics. Notwithstanding the multiplicity of factors modifying hepatic hemodynamics, which hinder an identification of the ideal inflow, this experience adds a piece to the puzzle of liver hemodynamics during LT with an insight into different graft type perfusions.