- Email: [email protected]
Splanchnic and systemic circulation cross talks: Implications for hemodynamic management of liver transplant recipients
Journal Pre-proof Splanchnic and systemic circulation cross talks: Implication for hemodynamic management of liver transplant recipient Ahmed Mukhtar, MD, Ahmed Lotfy, MD, Amr Hussein, MD, Eman Fouad, MD
PII:
S1521-6896(19)30099-0
DOI:
https://doi.org/10.1016/j.bpa.2019.12.003
Reference:
YBEAN 1057
To appear in:
Best Practice & Research Clinical Anaesthesiology
Received Date: 1 December 2019 Accepted Date: 11 December 2019
Please cite this article as: Mukhtar A, Lotfy A, Hussein A, Fouad E, Splanchnic and systemic circulation cross talks: Implication for hemodynamic management of liver transplant recipient, Best Practice & Research Clinical Anaesthesiology, https://doi.org/10.1016/j.bpa.2019.12.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Ltd. All rights reserved.
Splanchnic and systemic circulation cross talks: Implication for hemodynamic management of liver transplant recipient Ahmed Mukhtar, MDa, Ahmed Lotfy, MDa, Amr Hussein, MDa , Eman Fouad, MDa a
Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of
Medicine, Cairo University, Egypt. Ahmed Mukhtar. (Corresponding author) Email: [email protected] Tel: +20 111 420 8444 Address: Address: 1 Alsaray st, Almanial, Cairo. Egypt. Ahmed Lotfy: Email: [email protected] Tel: +20 1000608905 Address: 1 Alsaray st, Almanial, Cairo. Egypt. Amr Hussein: Email: [email protected] Tel: +20 1069338998 Address: 1 Alsaray st, Almanial, Cairo. Egypt. Eman Fouad Email: [email protected]
Tele: +20 223215368
1
Abstract The interaction between splanchnic and systemic circulation has many hemodynamic and renal consequences during liver transplant. In patient with liver cirrhosis, splanchnic vasodilatation causes arterial steal from systemic circulation into splanchnic bed which decreases effective blood volume. Moreover, rapid volume loading in these patients has little impact on cardiac output because higher proportion of infused fluid is shifted to splanchnic area. Thus, in dissection phase the traditional approach of volume loading to maintain intraoperative hemodynamic stability seems not only ineffective but also may aggravate surgical bleeding. Two approaches of volume therapy have been mentioned to maintain hemodynamic stability during liver transplantation: splanchnic volume reduction by volume restriction with or without and splanchnic decongestion by using splanchnic vasoconstrictors. After reperfusion, increase in central blood volume was thought to have deleterious effect on the new graft function, however, the precise central venous pressure value that causes hepatic congestion after reperfusion is unknown Key words: Splanchnic circulation, Liver transplantation, Splanchnic vasoconstrictors, Renal dysfunction
2
Pathophysiological changes in patients with liver cirrhosis I. Splanchnic and systemic vasodilatation in patients with liver cirrhosis Portal hypertension (PH) is defined as increase the gradient between portal venous pressure (PVP) and hepatic venous pressure above 5 mmHg. The pathophysiology of PH is started by increase in intrahepatic vascular resistance (IHVR). The IHVR increases with progression of chronic liver disease because of architecture disruption, endothelial dysfunction of liver parenchyma and intrahepatic microthrombi(1)(2)(3). The increase in IHVR impairs the portal venous flow (PVF) with pooling of the blood into the splanchnic circulation (4). With more advanced degree of liver cirrhosis, there is marked impairment of PVF with compensatory splanchnic vasodilatation in attempt to increase hepatic blood flow. However, instead of increasing hepatic perfusion, the PVP markedly increases and the associated hyperemia in splanchnic vasculatures creates shunts between portal and systemic circulation via portosystemic collaterals (4). The concomitant increase in porto-systemic collaterals and shunting of blood away from the liver increases the systemic circulation of vasodilators such as nitric oxide and calcitonin gene related peptides which augments both systemic and splanchnic vasodilatation.(5) II. Splanchnic steal and blood volume in patients with liver cirrhosis Splanchnic vasodilatation causes arterial steal from systemic circulation into splanchnic bed which decreases effective blood volume.(6) The reduction in effective blood volume activates neurohumoral reflexes to increase salt and water retention and increases total plasma and blood volume (7). The aforementioned pathophysiological changes induce two important differences between healthy individual and patients with end-stage liver disease (ESLD). First, patients with 3
ESLD have a substantial increase in their total blood volume, more than 37% of their total blood volume located in the abdomen, which is significantly higher when compared to healthy subjects, in whom abdominal organs contain <30% of the total blood volume. Second, there is blunted response of patients with ESLD to blood volume expansion. In healthy individuals, the value for total vascular compliance is 0.5~1 mL/mmHg/kg body weight (8). Thus each 500 cc of fluid loading produces a 5 mmHg increase in blood pressure (Figure 1). However, total vascular compliance is significantly increased (values of 1.5~2.5 mL/mmHg/kg body weight (9) in patients with liver cirrhosis which renders the response of CO to volume expansion is poor in these patients (Figure 2) (10). Recently, we investigated the validity of mini-fluid challenge in predicting fluid responsiveness in patients with ESLD after liver transplantation (11). We found that that a mini-fluid challenge (150 ml of albumin 5%) is sufficient to assess fluid responsiveness in patients with Child A cirrhosis but not Child B or C cirrhosis (11). The reason of our finding was that patients with Child A have less severe alteration in vasomotor and venous capacitance compared to Child B and C. Thus, mini fluid bolus (150 mL) could increase the mean systemic filling pressure in patients with Child A but not in patients with Child B or C. III. Effect of excessive volume loading on splanchnic circulation Extensive fluid loading may result in increased blood loss due to aggravation of portal hyperemia and increased splanchnic venous congestion (12). In randomized controlled trial (RCT) performed in the setting of acute gastrointestinal bleeding, patients were randomized to receive either a “liberal” RBC transfusion threshold of 90 g/L or “restrictive” of 70 g/L (13). Portal pressure gradient increased significantly in patients assigned to liberal transfusion group but not
4
on those assigned to restrictive strategy. Moreover, bleeding was significantly higher in liberalstrategy group compared to restrictive group. Interaction between splanchnic and central circulation during dissection phase Because of splanchnic steal and interaction between systemic and splanchnic circulation, the traditional approach of volume loading to maintain intraoperative hemodynamic stability seems not only ineffective but also may aggravate surgical bleeding. Two approaches have been suggested to manage volume therapy during liver transplantation: The first approach is by using central and splanchnic volume reduction by volume restriction with or without phlebotomy to maintain low CVP and refill the circulation after reperfusion. The second approach is splanchnic decongestion by using splanchnic vasoconstrictors. (Figure 3) I. Approach #1: Restricted volume therapy with or without phlebotomy to target low central and splanchnic blood volume The theory behind the first approach is that, if we can lower the total blood volume, the central and splanchnic blood volumes will decrease, and this may decrease surgical bleeding. Several observational and randomized controlled studies had tested this approach (14) (15) (16)(17). All these studies agreed that surgical bleeding and blood transfusion decreased when targeting central venous pressure (CVP) below 5 mmHg, which reflects the strong correlation between the level of CVP and portal hypertension (18). Although, restricted volume therapy seems to be an appealing approach, there are several questions that need to be answered. First, to what extent should we lower CVP during operation? The first published retrospective study showed that patients undergoing liver transplant whose central venous pressure was 5
maintained below 5 mmHg during the pre-anhepatic were transfused less than patients whose central venous pressure was maintained at normal levels (14). A few year later, similar results were produced but when targeting 40% decrease in baseline central venous pressure. So, it is not clearly known what is the ideal CVP that should be maintained during operation to decrease blood loss. Second, which intervention is most effective? Several approaches have been used to lower the CVP during liver transplant which include fluid restriction, no routine correction of coagulation defect, use of diuretics, and reverse Trendelenburg position. (16)(17) The addition of phlebotomy to fluid restriction was mentioned in one center and was consistently associated with lower blood loss (15) (19). Lastly, what is the safety of restricted volume therapy in relation to kidney function? The data in this area yielding conflicting results. Although the two RCTs that reported no effect on acute kidney injury (AKI) used an intraoperative low-CVP management (16)(20), one observational study suggested an increased risk of AKI with low-CVP management. More recently, Carrier et al conducted systematic review to evaluate the effect of perioperative restrictive fluid strategy in liver transplant on kidney function. Although they did not find any association between restrictive fluid management strategies and acute kidney injury, the quality of evidence is very low, because of small number of RCTs. II. Approach #2: Squeezing the blood in the splanchnic area to decongest the splanchnic circulation and refill the central circulation. The theory behind the second approach is that if we can squeeze the blood in the splanchnic area, we can decongest the splanchnic circulation and refill the central circulation.
6
Effect of different types of vasopressors on blood shift from splanchnic to central circulation Normally in healthy subjects, the blood moves from splanchnic circulation through liver to systemic circulation. A stimulation of prehepatic vascular resistance induces splanchnic venoconstriction which expels blood from splanchnic to systemic circulation (21), while an increase in intrahepatic vascular resistance can cause blood to pool within the splanchnic area and worsen any pre-existing systemic hypovolemia (22). Thus, Intrahepatic vascular resistance can affect the volume of the splanchnic blood reservoir. By decreasing or increasing this resistance, vasopressor may either facilitate or impede the shift of blood from splanchnic capacitance vessels to the systemic circulation (23). The pre-portal (intestinal capacitance) and portal veins contain α–adrenergic, but not β2-adrenergic receptors (24). Capacitance vessels located inside the liver contain only α–adrenergic receptors, while the hepatic veins contain both α- and β2-adrenergic receptors. Thus, in healthy subject, the effect of any vasopressor agent on shift of blood from splanchnic to systemic circulation depends on effect of the vasopressor agent on various subtypes of receptors and the volume of blood within the splanchnic circulatory system (21). A pure α- adrenergic receptor agonist such as phenylephrine might fail to create a gradient sufficient to shift blood from splanchnic to systemic circulation because of stimulation of the alpha receptors in pre- and post-portal capacitance vessels (21). On the other hand, agent like epinephrine has both α1 and β2 effect and can increase venous return, entirely by increasing splanchnic blood flow and decreasing splanchnic venous resistance (21). One study used Doppler ultrasound to examine the effect of low-dose epinephrine infusion on spleen size and hepatic vein blood velocity in healthy volunteers (25). Those results showed that spleen volume began to decrease following an epinephrine infusion, and this decrease was accompanied by an 7
increase in hepatic blood flow, which was primarily due to activation of β2-adrenergic receptors and decreased vascular resistance (25). However, in patients with ESLD because of high and fixed intrahepatic vascular resistance, most of blood shift occurs mainly through port-systemic shunt. Because of these pathophysiological changes in cirrhotic patients, the effect of any vasopressor agent on distribution of blood volume between splanchnic and systemic circulation during liver transplantation depends on two factors: (1) blood volume in splanchnic vasculature; (2) the presence of portosystemic shunts. There is a few studies examined the effect of vasopressors on splanchnic circulation during liver resection and liver transplant surgeries (15) (26) (27) (28) . I. Effect of catecholamines on shift of blood volume from splanchnic to systemic circulation The data examined the effect of catecholamines on splanchnic circulation are scarce. Only one study tested the effect of phenylephrine on portal venous pressure and intravascular blood volume in patients undergoing orthotopic liver transplantation (15). Intravascular blood volumes were assessed by measuring early peak velocities of transmitral flow, pulmonary artery occlusion pressure, and cardiac output. The results showed that phlebotomy decreased both portal venous pressure and intravascular blood volume, and an infusion of phenylephrine following phlebotomy failed to restore the previous intravascular blood volume. Moreover, an infusion of phenylephrine did not further reduce portal venous pressure. No other data are available regarding the effect of other catecholamines on splanchnic circulation during a liver transplant.
8
II. Effect of vasopressin receptor agonist on shift of blood volume from splanchnic to systemic circulation There are two main types of vasopressin receptor agonist agent: arginine-vasopressin (AVP) and triglycyl lysine vasopressin (terlipressin). arginine-vasopressin is a non-peptide molecule that acts by stimulating V1 and V2 receptors and has a short duration of action (half-life ~ 6 minutes) (29). Terlipressin is a synthetic analogue of arginine vasopressin, and has a half-life of ~ 6 h (30). Terlipressin has a similar pharmacodynamic profile but displays different pharmacokinetic properties compared to its parent molecule. Terlipressin is rapidly metabolized by endopeptidases to form vasoactive lysine vasopressin, which is characterized by its greater selectivity for V1 vs. V2 receptors (2.2:1 compared to 1:1 for arginine vasopressin) (30). Several reports have described the effect of AVP on splanchnic vasculature in animal models of portal hypertension (31) (32). In those studies, AVP was shown to be a powerful splanchnic vasoconstrictive agent capable of reducing portosystemic collateral blood flow. In another study, AVP displayed this same effect in cirrhotic patients without variceal bleeding (33). However, in that study, AVP increased intrahepatic vascular resistance and decreased hepatic blood flow by 30%. Terlipressin has demonstrated splanchnic and systemic hemodynamic effects similar to those produced by AVP when examined in animal models (34), and also patients with liver cirrhosis (35). However, terlipressin and AVP showed different effects on intrahepatic hemodynamics. Terlipressin reduced intrahepatic vascular resistance, resulting in a concomitant increase in hepatic arterial blood flow (35) . Kiszka-Kanowitz et al(36) reported that when administered to cirrhotic patients, terlipressin increased the volumes of blood in the liver and
9
thoracic regions by 12% and 6%, respectively, resulting in an increase in mean arterial pressure and reduction in hyperdynamic circulation. In liver transplant patient, Wagener et al (26) infused vasopressin into 16 patients undergoing liver transplantation at a mean dose of 3.8 (1.1) units/hour and found that although vasopressin significantly decreased portal vein pressure and flow of native liver blood, there was no change in either CVP and cardiac output (CO). More recently, Bown et al (27) investigated the effect of two doses of AVP: 2.4 and 4.8 units/hour in 12 patients undergoing liver resections. Although both doses decreased the portal venous pressure, only the higher dose (4.8 Unit/hour) was able to centralize the blood volume and increased both CVP and CO. Our group investigated the effect of intraoperative terlipressin infusion at a dose of 2 µg/kg/hour on splanchnic and systemic hemodynamics in patients undergoing a living donor liver transplant (LDLT) (28). We found that patients received terlipressin had higher CVP and required a lower volume of fluid therapy compared to control group. Thus, terlipressin might benefit central blood volume by increasing effective blood volume via stimulating arteriolar vasoconstriction in the splanchnic area, and redistributing blood into systemic circulation. Interaction between splanchnic and central circulation during reperfusion phase The goal during reperfusion phase is to maintain adequate graft perfusion by maintaining the delicate balance between PVF and hepatic venous drainage. Several studies demonstrated that excessive PVF may be associated with graft dysfunction by reducing hepatic artery flow through hepatic arterial buffer response. On the other hand, high venous pressure may impede blood flow out of transplanted liver and jeopardize graft function. Although, there are some evidence that maintaining low CVP below 5 mmHg in pre-anhepatic phase might be beneficial in term of 10
reducing surgical bleeding, the precise CVP value that causes hepatic congestion after reperfusion is unknown. Saner et al investigated the effect of PEEP on hepatic outflow using Doppler ultrasound (37). They found that increasing PEEP up to 10 cm H2O has no negative impact on flow velocity in either hepatic vein or portal vein despite the increase of CVP up to 10 cm H2O. In more recent retrospective study, Cywinski et al confirmed these results and showed no significant difference in overall patient survival, graft survival or length of intensive care unit and hospital stay between two groups whose central venous pressures were maintained either below 10 mmHg or above 10 mmHg during the neohepatic phase (38). To understand the negative findings of the previous two studies, we need to fully comprehend the mechanisms involved in the complex physiology of liver perfusion, and this could be better clarified by Ohm’s law which states that the current equals the voltage difference divided by the resistance. In this model,the current is the PVF, the voltage difference is the pressure difference between PVP and hepatic venous pressure and the resistance is the resistance to flow offered by the blood vessel
Several studies confirmed that CVP could be used as a surrogate of HVP and the equation could be written as follow
11
The difference between PVP and CVP refers to hepatic venous pressure gradient (HVPG). Thus, at any given PVF, the HVPG is modulated by intrahepatic vascular resistance. When the quality of the graft is good, the resistance within the graft is low and increase in the inflow (high PVF) or reduction in the outflow (high central venous pressure) could be accommodated by distensibility of low resistive liver tissue. Once the resistance within the graft increases, HVPG increases and high CVP may further compromise graft function. The effect of graft resistance on HVPG was previously described by Sainz-Barriga et al who demonstrated that donor risk index (DRI) which is a measure of graft quality is significantly correlated with HVPG. (39) Interaction between splanchnic and central circulation and perioperative renal function Acute kidney injury (AKI) is a frequent complication post liver transplant with an estimated incidence between 8 to 78% depending on the definition of AKI. Despite the advances in modalities of renal replacement therapy, AKI remains an independent risk factor for mortality post-liver transplant. The reason why AKI is highly prevalent in liver transplant is most probably because of the presence of either preoperative hepatorenal syndrome or as a result of intraoperative renal hypoperfusion. Splanchnic and central circulation and Perioperative renal function. I. Before liver transplantation The classic theory behind hepatorenal syndrome is reduction of effective central blood volume because of splanchnic steal phenomenon which triggers cascade of neurohormonal pathway that eventually leads to profound cortical renal vasoconstriction and development of hepatorenal syndrome (HRS). In early phase portal hypertension, normal or near normal renal perfusion is maintained as a result of vasodilatory systems antagonizing the renal effects of vasoconstrictor 12
systems (40). However, as liver disease progresses in severity, a critical level of vascular underfilling is finally reached. When this occurs, renal vasodilatory systems can no longer counteract the effects produced by fully activated endogenous vasoconstrictors and/or intrarenal vasoconstrictors; resulting in uncontrolled renal vasoconstriction (40). Splanchnic steal phenomenon is not the only mechanism of renal hypoperfusion in patients with ESLD. There is a growing body of evidence that cardiac dysfunction with varying degree of severity is also present in patients who developed HRS and may contribute to the deterioration of kidney function. Cardiac dysfunction in patient with liver cirrhosis may be in the form of diastolic or systolic dysfunction. Prevalence of left ventricular diastolic dysfunction was found to be as high as 58% of cirrhotics. However, the deterioration in the systolic function is commonly latent and is typically diagnosed in the face of blunted responsiveness to hemodynamic or pharmacologic stress. Although, the ideal therapy of HRS is liver transplant, preoperative use of splanchnic vasoconstrictors was also found to be effective in reverse acute kidney injury in patient while awaiting liver transplantation. Several vasoconstrictors have been tried in patients with HRS and shown
to
be
effective
such
as
terlipressin,
norepinephrine,
and
midodrine
plus
octreotide.(41)(42)(43) II. During and after liver transplantation Postoperative AKI is related to either intraoperative renal hypoperfusion or small for size graft. Intraoperative renal hypoperfusion may be due to hypovolemia, hypotension, cardiac dysfunction or caval clamping for >70 minutes (44). On the hand, persistent portal hyperperfusion and a hyperdynamic state in patients with a small-for-size graft impairs the balance between 13
vasodilatory and vasoconstrictive factors, and thereby causes renal injury (45). Intraoperative use of splanchnic vasoconstrictors was found to be effective to improve renal function in patients undergoing liver transplant. Terlipressin is the most commonly studied drug during liver transplantation and found to have some protection against AKI in patients undergoing liver transplantation via two mechanisms. First, terlipressin increases both effective central blood volume and mean arterial blood pressure by selectively stimulating V1 receptor (46). Fayed et el (47) recently reported the effect of intraoperative terlipressin administration on kidney function in patients with chronic liver disease who had undergone LDLT. In their study, 80 recipients were randomly selected to receive either saline alone or terlipressin at an initial dose of 3 µg/kg/h, which was later reduced to 1.5 µg/kg/h after reperfusion, and then continued for three postoperative days. Their results showed that renal function in the group receiving saline alone was significantly worse than in the group receiving terlipressin. Second, it minimizes portal pressure and hyperdynamic state; this is especially important in patients with a small-for-size graft. We recently reported a significantly lower incidence of AKI among patients given terlipressin when compared to patients in a control group (48). This result occurred despite the fact that more patients in the terlipressin group received a small-for-size graft. Conclusion Understanding the interaction between splanchnic and central circulation has important implications on hemodynamic management during different phases of liver transplant surgery. These implications include maintaining adequate central blood volume, avoiding splanchnic congestion during dissection phase and minimizing graft dysfunction and renal perfusion during reperfusion phase and after surgery. 14
Practice point •
The response of patient with ESLD to volume therapy is different than healthy subject
•
Aggressive volume loading during liver transplantation should be avoided to minimize surgical bleeding
•
Restrictive fluid therapy, splanchnic vasoconstrictors seem to be beneficial in these patients to maintain hemodynamic instability and renal perfusion
•
After reperfusion, there is no exact CVP value that may worsen graft function
Research agenda •
Further work is needed to determine what is the best approach of hemodynamic management during dissection phase of liver transplant
•
We need an evidence to compare the efficacy of different vasopressor on splanchnic circulation
•
There is urgent need to conduct well-designed trials on the safety of splanchnic vasoconstrictor on graft function
Conflict of interest None
15
References 1.
Deleve LD. Liver Sinusoidal Endothelial Cells in Hepatic Fibrosis. Hepatology. 2016;61:1740–6.
2.
Upta TAKG, Oruner MUT, Hung MOONKC. Endothelial Dysfunction and Decreased Production of Nitric Oxide in the Intrahepatic Microcirculation of Cirrhotic Rats. Hepatology. 1998; 28:926–31.
3.
Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365:147–56.
4.
Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions. J Hepatol. 2014;61:912–24.
5.
Kimer N, Goetze JP, Bendtsen F, Møller S. New vasoactive peptides in cirrhosis : organ extraction and relation to the vasodilatory state.2014; 44:441–52.
6.
Newby DE, Hayes PC, Infirmary R. QJM Hyperdynamic circulation in liver cirrhosis : not peripheral vasodilatation but ‘ splanchnic steal .’ 2002; 95:827–30.
7.
Paternostro R, Reiberger T, Mandorfer M, Schwarzer R, Schwabl P, Bota S, et al. Plasma renin concentration represents an independent risk factor for mortality and is associated with liver dysfunction in patients with cirrhosis. 2017;32:184–90.
8.
Henriksen JH. Volume adaptation in chronic liver disease: on the static and dynamic location of water, salt, protein and red cells in cirrhosis. Scand J Clin Lab Invest. 2004;64:523–33. 16
9.
Hadengue A, Moreau R, Gaudin C, Bacq Y, Champigneulle B, Lebrec D. Total effective vascular compliance in patients with cirrhosis: a study of the response to acute blood volume expansion. Hepatology. 1992;15:809–15.
10.
Kiszka-Kanowitz M, Henriksen JH, Moller S, Bendtsen F. Blood volume distribution in patients with cirrhosis: Aspects of the dual-head gamma-camera technique. J Hepatol. 2001;35:605–12.
11.
Mukhtar A, Awad M, Elayashy M, Hussein A, Obayah G, Adawy A El, et al. Validity of mini-fluid challenge for predicting fluid responsiveness following liver transplantation. 2019;19: 56.
12.
Cleland S, Corredor C, Ye JJ, Srinivas C, Mccluskey SA, Cleland S, et al. Massive haemorrhage in liver transplantation: Consequences, prediction and management. World J Transpl 2016;6:291–306.
13.
Hernandez-gea V, Aracil C, Graupera I, Poca M, Alvarez-urturi C, Gordillo J, et al. Transfusion Strategies for Acute Upper Gastrointestinal Bleeding. N Engl J Med. 2013;368:11–21.
14.
Schroeder RA, Collins BH, Tuttle-Newhall E, Robertson K, Plotkin J, Johnson LB, et al. Intraoperative fluid management during orthotopic liver transplantation. J Cardiothorac Vasc Anesth. 2004;18:438–41.
15.
Massicotte L, Lenis S, Thibeault L, Sassine MP, Seal RF, Roy A. Effect of low central venous pressure and phlebotomy on blood product transfusion requirements during liver 17
transplantations. Liver Transplant. 2006;12:117–23. 16.
Xiao ZF, Zhu XS. Effects of Low Central Venous Pressure During Preanhepatic Phase on Blood Loss and Liver and Renal Function in Liver Transplantation. 2010;34:1864–73.
17.
Wang B, Bo HH. Effect of low central venous pressure on postoperative pulmonary complications in patients undergoing liver transplantation. 2013;43:777–81.
18.
Massicotte L, Carrier FM, Denault AY, Karakiewicz P, Hevesi Z, McCormack M, Thibeault L, Nozza A, Tian Z, Dagenais RA. Development of a predictive model for blood transfusions and bleeding during liver transplantation. J Cardiothorac Vasc Anesth 2018;32:1722–30.
19.
Massicotte L, Thibeault L, Roy A. Classical Notions of Coagulation Revisited in Relation with Blood Losses , Transfusion Rate for 700 Consecutive Liver Transplantations. 2015;1:538–46.
20.
Surgery LT. Restricted Crystalloid Fluid Therapy during Orthotopic Liver Transplant Surgery and its Effect on Respiratory and Renal Insufficiency in the Early Post-operative Period: A Randomized Clinical Trial. Int J Organ Transpl Med. 2014;5:113–9.
21.
Weiskopf RB. Catecholamine-induced Changes in the Splanchnic Circulation Affecting Systemic Hemodynamics. 2004;(2):434–9.
22.
Bennett TD, MacAnespie CL, Rothe CF. Active hepatic capacitance responses to neural and humoral stimuli in dogs. Am J Physiol. 1982;242:H1000–9.
23.
Rutlen DL, Supple EW, Powell WJ. Adrenergic regulation of total systemic distensibility. 18
Venous distensibility effects of norepinephrine and isoproterenol before and after selective adrenergic blockade. Am J Cardiol. 1981; 47:579-88 24.
Richardson PD. Physiological regulation of the hepatic circulation. Fed Proc. 1982;41:2111–6.
25.
Bakovic D, Pivac N, Eterovic D, Breskovic T, Zubin P, Obad A, et al. The effects of lowdose epinephrine infusion on spleen size, central and hepatic circulation and circulating platelets. Clin Physiol Funct Imaging. 2013;33(1):30–7.
26.
Wagener G, Gubitosa G, Renz J, Kinkhabwala M, Brentjens T, Guarrera J V, et al. Vasopressin decreases portal vein pressure and flow in the native liver during liver transplantation. Liver Transpl. 2008;14:1664–70.
27.
Rizell M, Lundin S. Vasopressin-induced changes in splanchnic blood flow and hepatic and portal venous pressures in liver resection. 2016;60:607–15.
28.
Mukhtar A, Salah M, Aboulfetouh F, Obayah G, Samy M, Hassanien A, et al. The use of terlipressin during living donor liver transplantation: Effects on systemic and splanchnic hemodynamics and renal function. Crit Care Med. 2011;39:1329–34.
29.
Barrett LK, Singer M, Clapp LH. Vasopressin: mechanisms of action on the vasculature in health and in septic shock. Crit Care Med. 2007;35:33–40.
30.
Nilsson G, Lindblom P, Ohlin M, Berling R, Vernersson E. Pharmacokinetics of terlipressin after single i.v. doses to healthy volunteers. Drugs Exp Clin Res. 1990;16:307–14. 19
31.
Moreau R, Cailmail S, Lebrec D. Effects of vasopressin on haemodynamics in portal hypertensive rats receiving clonidine. Liver. 1994;14:45–9.
32.
Huang HC, Wang SS, Lee FY, Chang CC, Chang FY, Lin HC, et al. Vasopressin response and shunting modulation in cirrhotic rats by chronic nitric oxide inhibition. J Gastroenterol Hepatol. 2008;23:e265-9
33.
Iwao T, Toyonaga A, Oho K, Shigemori H, Sakai T, Tayama C, et al. Effect of vasopressin on esophageal varices blood flow in patients with cirrhosis: comparisons with the effects on portal vein and superior mesenteric artery blood flow. 1996;25:491-7.
34.
Oberti F, Veal N, Kaassis M, Pilette C, Rifflet H, Trouvé R, et al. Hemodynamic effects of terlipressin and octreotide administration alone or in combination in portal hypertensive rats. J Hepatol. 1998;29:103–11.
35.
Freeman JG, Cobden I, Lishman AH, Record CO. Controlled trial of terlipressin ('Glypressin’) versus vasopressin in the early treatment of oesophageal varices. Vol. 2, Lancet. 1982. 2L66-8
36.
Kiszka‐Kanowitz M, Henriksen JH, Hansen EF, Møller S, Bendtsen F. Effect of terlipressin on blood volume distribution in patients with cirrhosis. Scand J Gastroenterol . 2004;39:486–92
37.
Saner FH, Olde Damink SWM, Pavlaković G, Van Den Broek MAJ, Sotiropoulos GC, Radtke A, et al. Positive end-expiratory pressure induces liver congestion in living donor liver transplant patients: Myth or fact. Transplantation. 2008;85:1863–6. 20
38.
Cywinski JB, Mascha E, You J, Argalious M, Kapural L, Christiansen E, et al. Central venous pressure during the post-anhepatic phase is not associated with early postoperative outcomes following orthotopic liver transplantation. Minerva Anestesiol. 2010;76:795– 804.
39.
Sainz-barriga M, Scudeller L, Costa MG, Hemptinne B De, Troisi RI. Lack of a Correlation Between Portal Vein Flow and Pressure : Toward a Shared Interpretation of Hemodynamic
Stress
Governing Inflow
Modulation
in
Liver
Transplantation.
2011;17:836–48. 40.
Angeli P, Merkel C. Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis. Vol. 48, Journal of Hepatology. 2008;48:S93-103
41.
Rajekar H, Chawla Y. Terlipressin in hepatorenal syndrome: Evidence for present indications. J Gastroenterol Hepatol. 2011;26L109–14.
42.
Singh V, Ghosh S, Singh B, Kumar P, Sharma N, Bhalla A, et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: A randomized study. J Hepatol. 2012; 56:1293-8
43.
Kalambokis G, Economou M, Fotopoulos A, Al Bokharhii J, Pappas C, Katsaraki A, et al. The effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics and function in nonazotemic cirrhotic patients with ascites. Am J Gastroenterol. 2005; l100::879-85.
44.
Yamamoto S, Sato Y, Ichida T, Kurosaki I, Nakatsuka H, Hatakeyama K.. Acute renal 21
failure during the early postoperative period in adult living-related donor liver transplantation. Vol. 51, Hepato-Gastroenterology. 2004;51:1815-9 45.
Kiuchi T, Kasahara M, Uryuhara K, Inomata Y, Uemoto S, Asonuma K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation. 1999;67:321–7.
46.
Kam PCA, Williams S, Yoong FFY. Vasopressin and terlipressin: Pharmacology and its clinical relevance. Anaesthesia. 2004 ;59:993-1001
47.
Fayed N, Refaat EK, Yassein TE, Alwaraqy M. Effect of perioperative terlipressin infusion on systemic, hepatic, and renal hemodynamics during living donor liver transplantation. J Crit Care. 2013;28:775–82.
48.
Intraoperative Terlipressin Therapy Reduces the Incidence of Postoperative Acute Kidney Injury After Living Donor Liver Transplantation. J Cardiothorac Vasc Anesth. 2015;29:678-83
22
Figure 1: Fluid loading in normal subject with normal vascular compliance. More blood will be distributed to central circulation than splanchnic circulation
Figure 2: Fluid loading in patient with end stage liver disease with high vascular compliance. More blood will be distributed into splanchnic circulation with little effect on central circulation.
Figure 3: Two approaches of hemodynamic management during liver transplant
23
PII:
S1521-6896(19)30099-0
DOI:
https://doi.org/10.1016/j.bpa.2019.12.003
Reference:
YBEAN 1057
To appear in:
Best Practice & Research Clinical Anaesthesiology
Received Date: 1 December 2019 Accepted Date: 11 December 2019
Please cite this article as: Mukhtar A, Lotfy A, Hussein A, Fouad E, Splanchnic and systemic circulation cross talks: Implication for hemodynamic management of liver transplant recipient, Best Practice & Research Clinical Anaesthesiology, https://doi.org/10.1016/j.bpa.2019.12.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Ltd. All rights reserved.
Splanchnic and systemic circulation cross talks: Implication for hemodynamic management of liver transplant recipient Ahmed Mukhtar, MDa, Ahmed Lotfy, MDa, Amr Hussein, MDa , Eman Fouad, MDa a
Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of
Medicine, Cairo University, Egypt. Ahmed Mukhtar. (Corresponding author) Email: [email protected] Tel: +20 111 420 8444 Address: Address: 1 Alsaray st, Almanial, Cairo. Egypt. Ahmed Lotfy: Email: [email protected] Tel: +20 1000608905 Address: 1 Alsaray st, Almanial, Cairo. Egypt. Amr Hussein: Email: [email protected] Tel: +20 1069338998 Address: 1 Alsaray st, Almanial, Cairo. Egypt. Eman Fouad Email: [email protected]
Tele: +20 223215368
1
Abstract The interaction between splanchnic and systemic circulation has many hemodynamic and renal consequences during liver transplant. In patient with liver cirrhosis, splanchnic vasodilatation causes arterial steal from systemic circulation into splanchnic bed which decreases effective blood volume. Moreover, rapid volume loading in these patients has little impact on cardiac output because higher proportion of infused fluid is shifted to splanchnic area. Thus, in dissection phase the traditional approach of volume loading to maintain intraoperative hemodynamic stability seems not only ineffective but also may aggravate surgical bleeding. Two approaches of volume therapy have been mentioned to maintain hemodynamic stability during liver transplantation: splanchnic volume reduction by volume restriction with or without and splanchnic decongestion by using splanchnic vasoconstrictors. After reperfusion, increase in central blood volume was thought to have deleterious effect on the new graft function, however, the precise central venous pressure value that causes hepatic congestion after reperfusion is unknown Key words: Splanchnic circulation, Liver transplantation, Splanchnic vasoconstrictors, Renal dysfunction
2
Pathophysiological changes in patients with liver cirrhosis I. Splanchnic and systemic vasodilatation in patients with liver cirrhosis Portal hypertension (PH) is defined as increase the gradient between portal venous pressure (PVP) and hepatic venous pressure above 5 mmHg. The pathophysiology of PH is started by increase in intrahepatic vascular resistance (IHVR). The IHVR increases with progression of chronic liver disease because of architecture disruption, endothelial dysfunction of liver parenchyma and intrahepatic microthrombi(1)(2)(3). The increase in IHVR impairs the portal venous flow (PVF) with pooling of the blood into the splanchnic circulation (4). With more advanced degree of liver cirrhosis, there is marked impairment of PVF with compensatory splanchnic vasodilatation in attempt to increase hepatic blood flow. However, instead of increasing hepatic perfusion, the PVP markedly increases and the associated hyperemia in splanchnic vasculatures creates shunts between portal and systemic circulation via portosystemic collaterals (4). The concomitant increase in porto-systemic collaterals and shunting of blood away from the liver increases the systemic circulation of vasodilators such as nitric oxide and calcitonin gene related peptides which augments both systemic and splanchnic vasodilatation.(5) II. Splanchnic steal and blood volume in patients with liver cirrhosis Splanchnic vasodilatation causes arterial steal from systemic circulation into splanchnic bed which decreases effective blood volume.(6) The reduction in effective blood volume activates neurohumoral reflexes to increase salt and water retention and increases total plasma and blood volume (7). The aforementioned pathophysiological changes induce two important differences between healthy individual and patients with end-stage liver disease (ESLD). First, patients with 3
ESLD have a substantial increase in their total blood volume, more than 37% of their total blood volume located in the abdomen, which is significantly higher when compared to healthy subjects, in whom abdominal organs contain <30% of the total blood volume. Second, there is blunted response of patients with ESLD to blood volume expansion. In healthy individuals, the value for total vascular compliance is 0.5~1 mL/mmHg/kg body weight (8). Thus each 500 cc of fluid loading produces a 5 mmHg increase in blood pressure (Figure 1). However, total vascular compliance is significantly increased (values of 1.5~2.5 mL/mmHg/kg body weight (9) in patients with liver cirrhosis which renders the response of CO to volume expansion is poor in these patients (Figure 2) (10). Recently, we investigated the validity of mini-fluid challenge in predicting fluid responsiveness in patients with ESLD after liver transplantation (11). We found that that a mini-fluid challenge (150 ml of albumin 5%) is sufficient to assess fluid responsiveness in patients with Child A cirrhosis but not Child B or C cirrhosis (11). The reason of our finding was that patients with Child A have less severe alteration in vasomotor and venous capacitance compared to Child B and C. Thus, mini fluid bolus (150 mL) could increase the mean systemic filling pressure in patients with Child A but not in patients with Child B or C. III. Effect of excessive volume loading on splanchnic circulation Extensive fluid loading may result in increased blood loss due to aggravation of portal hyperemia and increased splanchnic venous congestion (12). In randomized controlled trial (RCT) performed in the setting of acute gastrointestinal bleeding, patients were randomized to receive either a “liberal” RBC transfusion threshold of 90 g/L or “restrictive” of 70 g/L (13). Portal pressure gradient increased significantly in patients assigned to liberal transfusion group but not
4
on those assigned to restrictive strategy. Moreover, bleeding was significantly higher in liberalstrategy group compared to restrictive group. Interaction between splanchnic and central circulation during dissection phase Because of splanchnic steal and interaction between systemic and splanchnic circulation, the traditional approach of volume loading to maintain intraoperative hemodynamic stability seems not only ineffective but also may aggravate surgical bleeding. Two approaches have been suggested to manage volume therapy during liver transplantation: The first approach is by using central and splanchnic volume reduction by volume restriction with or without phlebotomy to maintain low CVP and refill the circulation after reperfusion. The second approach is splanchnic decongestion by using splanchnic vasoconstrictors. (Figure 3) I. Approach #1: Restricted volume therapy with or without phlebotomy to target low central and splanchnic blood volume The theory behind the first approach is that, if we can lower the total blood volume, the central and splanchnic blood volumes will decrease, and this may decrease surgical bleeding. Several observational and randomized controlled studies had tested this approach (14) (15) (16)(17). All these studies agreed that surgical bleeding and blood transfusion decreased when targeting central venous pressure (CVP) below 5 mmHg, which reflects the strong correlation between the level of CVP and portal hypertension (18). Although, restricted volume therapy seems to be an appealing approach, there are several questions that need to be answered. First, to what extent should we lower CVP during operation? The first published retrospective study showed that patients undergoing liver transplant whose central venous pressure was 5
maintained below 5 mmHg during the pre-anhepatic were transfused less than patients whose central venous pressure was maintained at normal levels (14). A few year later, similar results were produced but when targeting 40% decrease in baseline central venous pressure. So, it is not clearly known what is the ideal CVP that should be maintained during operation to decrease blood loss. Second, which intervention is most effective? Several approaches have been used to lower the CVP during liver transplant which include fluid restriction, no routine correction of coagulation defect, use of diuretics, and reverse Trendelenburg position. (16)(17) The addition of phlebotomy to fluid restriction was mentioned in one center and was consistently associated with lower blood loss (15) (19). Lastly, what is the safety of restricted volume therapy in relation to kidney function? The data in this area yielding conflicting results. Although the two RCTs that reported no effect on acute kidney injury (AKI) used an intraoperative low-CVP management (16)(20), one observational study suggested an increased risk of AKI with low-CVP management. More recently, Carrier et al conducted systematic review to evaluate the effect of perioperative restrictive fluid strategy in liver transplant on kidney function. Although they did not find any association between restrictive fluid management strategies and acute kidney injury, the quality of evidence is very low, because of small number of RCTs. II. Approach #2: Squeezing the blood in the splanchnic area to decongest the splanchnic circulation and refill the central circulation. The theory behind the second approach is that if we can squeeze the blood in the splanchnic area, we can decongest the splanchnic circulation and refill the central circulation.
6
Effect of different types of vasopressors on blood shift from splanchnic to central circulation Normally in healthy subjects, the blood moves from splanchnic circulation through liver to systemic circulation. A stimulation of prehepatic vascular resistance induces splanchnic venoconstriction which expels blood from splanchnic to systemic circulation (21), while an increase in intrahepatic vascular resistance can cause blood to pool within the splanchnic area and worsen any pre-existing systemic hypovolemia (22). Thus, Intrahepatic vascular resistance can affect the volume of the splanchnic blood reservoir. By decreasing or increasing this resistance, vasopressor may either facilitate or impede the shift of blood from splanchnic capacitance vessels to the systemic circulation (23). The pre-portal (intestinal capacitance) and portal veins contain α–adrenergic, but not β2-adrenergic receptors (24). Capacitance vessels located inside the liver contain only α–adrenergic receptors, while the hepatic veins contain both α- and β2-adrenergic receptors. Thus, in healthy subject, the effect of any vasopressor agent on shift of blood from splanchnic to systemic circulation depends on effect of the vasopressor agent on various subtypes of receptors and the volume of blood within the splanchnic circulatory system (21). A pure α- adrenergic receptor agonist such as phenylephrine might fail to create a gradient sufficient to shift blood from splanchnic to systemic circulation because of stimulation of the alpha receptors in pre- and post-portal capacitance vessels (21). On the other hand, agent like epinephrine has both α1 and β2 effect and can increase venous return, entirely by increasing splanchnic blood flow and decreasing splanchnic venous resistance (21). One study used Doppler ultrasound to examine the effect of low-dose epinephrine infusion on spleen size and hepatic vein blood velocity in healthy volunteers (25). Those results showed that spleen volume began to decrease following an epinephrine infusion, and this decrease was accompanied by an 7
increase in hepatic blood flow, which was primarily due to activation of β2-adrenergic receptors and decreased vascular resistance (25). However, in patients with ESLD because of high and fixed intrahepatic vascular resistance, most of blood shift occurs mainly through port-systemic shunt. Because of these pathophysiological changes in cirrhotic patients, the effect of any vasopressor agent on distribution of blood volume between splanchnic and systemic circulation during liver transplantation depends on two factors: (1) blood volume in splanchnic vasculature; (2) the presence of portosystemic shunts. There is a few studies examined the effect of vasopressors on splanchnic circulation during liver resection and liver transplant surgeries (15) (26) (27) (28) . I. Effect of catecholamines on shift of blood volume from splanchnic to systemic circulation The data examined the effect of catecholamines on splanchnic circulation are scarce. Only one study tested the effect of phenylephrine on portal venous pressure and intravascular blood volume in patients undergoing orthotopic liver transplantation (15). Intravascular blood volumes were assessed by measuring early peak velocities of transmitral flow, pulmonary artery occlusion pressure, and cardiac output. The results showed that phlebotomy decreased both portal venous pressure and intravascular blood volume, and an infusion of phenylephrine following phlebotomy failed to restore the previous intravascular blood volume. Moreover, an infusion of phenylephrine did not further reduce portal venous pressure. No other data are available regarding the effect of other catecholamines on splanchnic circulation during a liver transplant.
8
II. Effect of vasopressin receptor agonist on shift of blood volume from splanchnic to systemic circulation There are two main types of vasopressin receptor agonist agent: arginine-vasopressin (AVP) and triglycyl lysine vasopressin (terlipressin). arginine-vasopressin is a non-peptide molecule that acts by stimulating V1 and V2 receptors and has a short duration of action (half-life ~ 6 minutes) (29). Terlipressin is a synthetic analogue of arginine vasopressin, and has a half-life of ~ 6 h (30). Terlipressin has a similar pharmacodynamic profile but displays different pharmacokinetic properties compared to its parent molecule. Terlipressin is rapidly metabolized by endopeptidases to form vasoactive lysine vasopressin, which is characterized by its greater selectivity for V1 vs. V2 receptors (2.2:1 compared to 1:1 for arginine vasopressin) (30). Several reports have described the effect of AVP on splanchnic vasculature in animal models of portal hypertension (31) (32). In those studies, AVP was shown to be a powerful splanchnic vasoconstrictive agent capable of reducing portosystemic collateral blood flow. In another study, AVP displayed this same effect in cirrhotic patients without variceal bleeding (33). However, in that study, AVP increased intrahepatic vascular resistance and decreased hepatic blood flow by 30%. Terlipressin has demonstrated splanchnic and systemic hemodynamic effects similar to those produced by AVP when examined in animal models (34), and also patients with liver cirrhosis (35). However, terlipressin and AVP showed different effects on intrahepatic hemodynamics. Terlipressin reduced intrahepatic vascular resistance, resulting in a concomitant increase in hepatic arterial blood flow (35) . Kiszka-Kanowitz et al(36) reported that when administered to cirrhotic patients, terlipressin increased the volumes of blood in the liver and
9
thoracic regions by 12% and 6%, respectively, resulting in an increase in mean arterial pressure and reduction in hyperdynamic circulation. In liver transplant patient, Wagener et al (26) infused vasopressin into 16 patients undergoing liver transplantation at a mean dose of 3.8 (1.1) units/hour and found that although vasopressin significantly decreased portal vein pressure and flow of native liver blood, there was no change in either CVP and cardiac output (CO). More recently, Bown et al (27) investigated the effect of two doses of AVP: 2.4 and 4.8 units/hour in 12 patients undergoing liver resections. Although both doses decreased the portal venous pressure, only the higher dose (4.8 Unit/hour) was able to centralize the blood volume and increased both CVP and CO. Our group investigated the effect of intraoperative terlipressin infusion at a dose of 2 µg/kg/hour on splanchnic and systemic hemodynamics in patients undergoing a living donor liver transplant (LDLT) (28). We found that patients received terlipressin had higher CVP and required a lower volume of fluid therapy compared to control group. Thus, terlipressin might benefit central blood volume by increasing effective blood volume via stimulating arteriolar vasoconstriction in the splanchnic area, and redistributing blood into systemic circulation. Interaction between splanchnic and central circulation during reperfusion phase The goal during reperfusion phase is to maintain adequate graft perfusion by maintaining the delicate balance between PVF and hepatic venous drainage. Several studies demonstrated that excessive PVF may be associated with graft dysfunction by reducing hepatic artery flow through hepatic arterial buffer response. On the other hand, high venous pressure may impede blood flow out of transplanted liver and jeopardize graft function. Although, there are some evidence that maintaining low CVP below 5 mmHg in pre-anhepatic phase might be beneficial in term of 10
reducing surgical bleeding, the precise CVP value that causes hepatic congestion after reperfusion is unknown. Saner et al investigated the effect of PEEP on hepatic outflow using Doppler ultrasound (37). They found that increasing PEEP up to 10 cm H2O has no negative impact on flow velocity in either hepatic vein or portal vein despite the increase of CVP up to 10 cm H2O. In more recent retrospective study, Cywinski et al confirmed these results and showed no significant difference in overall patient survival, graft survival or length of intensive care unit and hospital stay between two groups whose central venous pressures were maintained either below 10 mmHg or above 10 mmHg during the neohepatic phase (38). To understand the negative findings of the previous two studies, we need to fully comprehend the mechanisms involved in the complex physiology of liver perfusion, and this could be better clarified by Ohm’s law which states that the current equals the voltage difference divided by the resistance. In this model,the current is the PVF, the voltage difference is the pressure difference between PVP and hepatic venous pressure and the resistance is the resistance to flow offered by the blood vessel
Several studies confirmed that CVP could be used as a surrogate of HVP and the equation could be written as follow
11
The difference between PVP and CVP refers to hepatic venous pressure gradient (HVPG). Thus, at any given PVF, the HVPG is modulated by intrahepatic vascular resistance. When the quality of the graft is good, the resistance within the graft is low and increase in the inflow (high PVF) or reduction in the outflow (high central venous pressure) could be accommodated by distensibility of low resistive liver tissue. Once the resistance within the graft increases, HVPG increases and high CVP may further compromise graft function. The effect of graft resistance on HVPG was previously described by Sainz-Barriga et al who demonstrated that donor risk index (DRI) which is a measure of graft quality is significantly correlated with HVPG. (39) Interaction between splanchnic and central circulation and perioperative renal function Acute kidney injury (AKI) is a frequent complication post liver transplant with an estimated incidence between 8 to 78% depending on the definition of AKI. Despite the advances in modalities of renal replacement therapy, AKI remains an independent risk factor for mortality post-liver transplant. The reason why AKI is highly prevalent in liver transplant is most probably because of the presence of either preoperative hepatorenal syndrome or as a result of intraoperative renal hypoperfusion. Splanchnic and central circulation and Perioperative renal function. I. Before liver transplantation The classic theory behind hepatorenal syndrome is reduction of effective central blood volume because of splanchnic steal phenomenon which triggers cascade of neurohormonal pathway that eventually leads to profound cortical renal vasoconstriction and development of hepatorenal syndrome (HRS). In early phase portal hypertension, normal or near normal renal perfusion is maintained as a result of vasodilatory systems antagonizing the renal effects of vasoconstrictor 12
systems (40). However, as liver disease progresses in severity, a critical level of vascular underfilling is finally reached. When this occurs, renal vasodilatory systems can no longer counteract the effects produced by fully activated endogenous vasoconstrictors and/or intrarenal vasoconstrictors; resulting in uncontrolled renal vasoconstriction (40). Splanchnic steal phenomenon is not the only mechanism of renal hypoperfusion in patients with ESLD. There is a growing body of evidence that cardiac dysfunction with varying degree of severity is also present in patients who developed HRS and may contribute to the deterioration of kidney function. Cardiac dysfunction in patient with liver cirrhosis may be in the form of diastolic or systolic dysfunction. Prevalence of left ventricular diastolic dysfunction was found to be as high as 58% of cirrhotics. However, the deterioration in the systolic function is commonly latent and is typically diagnosed in the face of blunted responsiveness to hemodynamic or pharmacologic stress. Although, the ideal therapy of HRS is liver transplant, preoperative use of splanchnic vasoconstrictors was also found to be effective in reverse acute kidney injury in patient while awaiting liver transplantation. Several vasoconstrictors have been tried in patients with HRS and shown
to
be
effective
such
as
terlipressin,
norepinephrine,
and
midodrine
plus
octreotide.(41)(42)(43) II. During and after liver transplantation Postoperative AKI is related to either intraoperative renal hypoperfusion or small for size graft. Intraoperative renal hypoperfusion may be due to hypovolemia, hypotension, cardiac dysfunction or caval clamping for >70 minutes (44). On the hand, persistent portal hyperperfusion and a hyperdynamic state in patients with a small-for-size graft impairs the balance between 13
vasodilatory and vasoconstrictive factors, and thereby causes renal injury (45). Intraoperative use of splanchnic vasoconstrictors was found to be effective to improve renal function in patients undergoing liver transplant. Terlipressin is the most commonly studied drug during liver transplantation and found to have some protection against AKI in patients undergoing liver transplantation via two mechanisms. First, terlipressin increases both effective central blood volume and mean arterial blood pressure by selectively stimulating V1 receptor (46). Fayed et el (47) recently reported the effect of intraoperative terlipressin administration on kidney function in patients with chronic liver disease who had undergone LDLT. In their study, 80 recipients were randomly selected to receive either saline alone or terlipressin at an initial dose of 3 µg/kg/h, which was later reduced to 1.5 µg/kg/h after reperfusion, and then continued for three postoperative days. Their results showed that renal function in the group receiving saline alone was significantly worse than in the group receiving terlipressin. Second, it minimizes portal pressure and hyperdynamic state; this is especially important in patients with a small-for-size graft. We recently reported a significantly lower incidence of AKI among patients given terlipressin when compared to patients in a control group (48). This result occurred despite the fact that more patients in the terlipressin group received a small-for-size graft. Conclusion Understanding the interaction between splanchnic and central circulation has important implications on hemodynamic management during different phases of liver transplant surgery. These implications include maintaining adequate central blood volume, avoiding splanchnic congestion during dissection phase and minimizing graft dysfunction and renal perfusion during reperfusion phase and after surgery. 14
Practice point •
The response of patient with ESLD to volume therapy is different than healthy subject
•
Aggressive volume loading during liver transplantation should be avoided to minimize surgical bleeding
•
Restrictive fluid therapy, splanchnic vasoconstrictors seem to be beneficial in these patients to maintain hemodynamic instability and renal perfusion
•
After reperfusion, there is no exact CVP value that may worsen graft function
Research agenda •
Further work is needed to determine what is the best approach of hemodynamic management during dissection phase of liver transplant
•
We need an evidence to compare the efficacy of different vasopressor on splanchnic circulation
•
There is urgent need to conduct well-designed trials on the safety of splanchnic vasoconstrictor on graft function
Conflict of interest None
15
References 1.
Deleve LD. Liver Sinusoidal Endothelial Cells in Hepatic Fibrosis. Hepatology. 2016;61:1740–6.
2.
Upta TAKG, Oruner MUT, Hung MOONKC. Endothelial Dysfunction and Decreased Production of Nitric Oxide in the Intrahepatic Microcirculation of Cirrhotic Rats. Hepatology. 1998; 28:926–31.
3.
Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365:147–56.
4.
Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions. J Hepatol. 2014;61:912–24.
5.
Kimer N, Goetze JP, Bendtsen F, Møller S. New vasoactive peptides in cirrhosis : organ extraction and relation to the vasodilatory state.2014; 44:441–52.
6.
Newby DE, Hayes PC, Infirmary R. QJM Hyperdynamic circulation in liver cirrhosis : not peripheral vasodilatation but ‘ splanchnic steal .’ 2002; 95:827–30.
7.
Paternostro R, Reiberger T, Mandorfer M, Schwarzer R, Schwabl P, Bota S, et al. Plasma renin concentration represents an independent risk factor for mortality and is associated with liver dysfunction in patients with cirrhosis. 2017;32:184–90.
8.
Henriksen JH. Volume adaptation in chronic liver disease: on the static and dynamic location of water, salt, protein and red cells in cirrhosis. Scand J Clin Lab Invest. 2004;64:523–33. 16
9.
Hadengue A, Moreau R, Gaudin C, Bacq Y, Champigneulle B, Lebrec D. Total effective vascular compliance in patients with cirrhosis: a study of the response to acute blood volume expansion. Hepatology. 1992;15:809–15.
10.
Kiszka-Kanowitz M, Henriksen JH, Moller S, Bendtsen F. Blood volume distribution in patients with cirrhosis: Aspects of the dual-head gamma-camera technique. J Hepatol. 2001;35:605–12.
11.
Mukhtar A, Awad M, Elayashy M, Hussein A, Obayah G, Adawy A El, et al. Validity of mini-fluid challenge for predicting fluid responsiveness following liver transplantation. 2019;19: 56.
12.
Cleland S, Corredor C, Ye JJ, Srinivas C, Mccluskey SA, Cleland S, et al. Massive haemorrhage in liver transplantation: Consequences, prediction and management. World J Transpl 2016;6:291–306.
13.
Hernandez-gea V, Aracil C, Graupera I, Poca M, Alvarez-urturi C, Gordillo J, et al. Transfusion Strategies for Acute Upper Gastrointestinal Bleeding. N Engl J Med. 2013;368:11–21.
14.
Schroeder RA, Collins BH, Tuttle-Newhall E, Robertson K, Plotkin J, Johnson LB, et al. Intraoperative fluid management during orthotopic liver transplantation. J Cardiothorac Vasc Anesth. 2004;18:438–41.
15.
Massicotte L, Lenis S, Thibeault L, Sassine MP, Seal RF, Roy A. Effect of low central venous pressure and phlebotomy on blood product transfusion requirements during liver 17
transplantations. Liver Transplant. 2006;12:117–23. 16.
Xiao ZF, Zhu XS. Effects of Low Central Venous Pressure During Preanhepatic Phase on Blood Loss and Liver and Renal Function in Liver Transplantation. 2010;34:1864–73.
17.
Wang B, Bo HH. Effect of low central venous pressure on postoperative pulmonary complications in patients undergoing liver transplantation. 2013;43:777–81.
18.
Massicotte L, Carrier FM, Denault AY, Karakiewicz P, Hevesi Z, McCormack M, Thibeault L, Nozza A, Tian Z, Dagenais RA. Development of a predictive model for blood transfusions and bleeding during liver transplantation. J Cardiothorac Vasc Anesth 2018;32:1722–30.
19.
Massicotte L, Thibeault L, Roy A. Classical Notions of Coagulation Revisited in Relation with Blood Losses , Transfusion Rate for 700 Consecutive Liver Transplantations. 2015;1:538–46.
20.
Surgery LT. Restricted Crystalloid Fluid Therapy during Orthotopic Liver Transplant Surgery and its Effect on Respiratory and Renal Insufficiency in the Early Post-operative Period: A Randomized Clinical Trial. Int J Organ Transpl Med. 2014;5:113–9.
21.
Weiskopf RB. Catecholamine-induced Changes in the Splanchnic Circulation Affecting Systemic Hemodynamics. 2004;(2):434–9.
22.
Bennett TD, MacAnespie CL, Rothe CF. Active hepatic capacitance responses to neural and humoral stimuli in dogs. Am J Physiol. 1982;242:H1000–9.
23.
Rutlen DL, Supple EW, Powell WJ. Adrenergic regulation of total systemic distensibility. 18
Venous distensibility effects of norepinephrine and isoproterenol before and after selective adrenergic blockade. Am J Cardiol. 1981; 47:579-88 24.
Richardson PD. Physiological regulation of the hepatic circulation. Fed Proc. 1982;41:2111–6.
25.
Bakovic D, Pivac N, Eterovic D, Breskovic T, Zubin P, Obad A, et al. The effects of lowdose epinephrine infusion on spleen size, central and hepatic circulation and circulating platelets. Clin Physiol Funct Imaging. 2013;33(1):30–7.
26.
Wagener G, Gubitosa G, Renz J, Kinkhabwala M, Brentjens T, Guarrera J V, et al. Vasopressin decreases portal vein pressure and flow in the native liver during liver transplantation. Liver Transpl. 2008;14:1664–70.
27.
Rizell M, Lundin S. Vasopressin-induced changes in splanchnic blood flow and hepatic and portal venous pressures in liver resection. 2016;60:607–15.
28.
Mukhtar A, Salah M, Aboulfetouh F, Obayah G, Samy M, Hassanien A, et al. The use of terlipressin during living donor liver transplantation: Effects on systemic and splanchnic hemodynamics and renal function. Crit Care Med. 2011;39:1329–34.
29.
Barrett LK, Singer M, Clapp LH. Vasopressin: mechanisms of action on the vasculature in health and in septic shock. Crit Care Med. 2007;35:33–40.
30.
Nilsson G, Lindblom P, Ohlin M, Berling R, Vernersson E. Pharmacokinetics of terlipressin after single i.v. doses to healthy volunteers. Drugs Exp Clin Res. 1990;16:307–14. 19
31.
Moreau R, Cailmail S, Lebrec D. Effects of vasopressin on haemodynamics in portal hypertensive rats receiving clonidine. Liver. 1994;14:45–9.
32.
Huang HC, Wang SS, Lee FY, Chang CC, Chang FY, Lin HC, et al. Vasopressin response and shunting modulation in cirrhotic rats by chronic nitric oxide inhibition. J Gastroenterol Hepatol. 2008;23:e265-9
33.
Iwao T, Toyonaga A, Oho K, Shigemori H, Sakai T, Tayama C, et al. Effect of vasopressin on esophageal varices blood flow in patients with cirrhosis: comparisons with the effects on portal vein and superior mesenteric artery blood flow. 1996;25:491-7.
34.
Oberti F, Veal N, Kaassis M, Pilette C, Rifflet H, Trouvé R, et al. Hemodynamic effects of terlipressin and octreotide administration alone or in combination in portal hypertensive rats. J Hepatol. 1998;29:103–11.
35.
Freeman JG, Cobden I, Lishman AH, Record CO. Controlled trial of terlipressin ('Glypressin’) versus vasopressin in the early treatment of oesophageal varices. Vol. 2, Lancet. 1982. 2L66-8
36.
Kiszka‐Kanowitz M, Henriksen JH, Hansen EF, Møller S, Bendtsen F. Effect of terlipressin on blood volume distribution in patients with cirrhosis. Scand J Gastroenterol . 2004;39:486–92
37.
Saner FH, Olde Damink SWM, Pavlaković G, Van Den Broek MAJ, Sotiropoulos GC, Radtke A, et al. Positive end-expiratory pressure induces liver congestion in living donor liver transplant patients: Myth or fact. Transplantation. 2008;85:1863–6. 20
38.
Cywinski JB, Mascha E, You J, Argalious M, Kapural L, Christiansen E, et al. Central venous pressure during the post-anhepatic phase is not associated with early postoperative outcomes following orthotopic liver transplantation. Minerva Anestesiol. 2010;76:795– 804.
39.
Sainz-barriga M, Scudeller L, Costa MG, Hemptinne B De, Troisi RI. Lack of a Correlation Between Portal Vein Flow and Pressure : Toward a Shared Interpretation of Hemodynamic
Stress
Governing Inflow
Modulation
in
Liver
Transplantation.
2011;17:836–48. 40.
Angeli P, Merkel C. Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis. Vol. 48, Journal of Hepatology. 2008;48:S93-103
41.
Rajekar H, Chawla Y. Terlipressin in hepatorenal syndrome: Evidence for present indications. J Gastroenterol Hepatol. 2011;26L109–14.
42.
Singh V, Ghosh S, Singh B, Kumar P, Sharma N, Bhalla A, et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: A randomized study. J Hepatol. 2012; 56:1293-8
43.
Kalambokis G, Economou M, Fotopoulos A, Al Bokharhii J, Pappas C, Katsaraki A, et al. The effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics and function in nonazotemic cirrhotic patients with ascites. Am J Gastroenterol. 2005; l100::879-85.
44.
Yamamoto S, Sato Y, Ichida T, Kurosaki I, Nakatsuka H, Hatakeyama K.. Acute renal 21
failure during the early postoperative period in adult living-related donor liver transplantation. Vol. 51, Hepato-Gastroenterology. 2004;51:1815-9 45.
Kiuchi T, Kasahara M, Uryuhara K, Inomata Y, Uemoto S, Asonuma K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation. 1999;67:321–7.
46.
Kam PCA, Williams S, Yoong FFY. Vasopressin and terlipressin: Pharmacology and its clinical relevance. Anaesthesia. 2004 ;59:993-1001
47.
Fayed N, Refaat EK, Yassein TE, Alwaraqy M. Effect of perioperative terlipressin infusion on systemic, hepatic, and renal hemodynamics during living donor liver transplantation. J Crit Care. 2013;28:775–82.
48.
Intraoperative Terlipressin Therapy Reduces the Incidence of Postoperative Acute Kidney Injury After Living Donor Liver Transplantation. J Cardiothorac Vasc Anesth. 2015;29:678-83
22
Figure 1: Fluid loading in normal subject with normal vascular compliance. More blood will be distributed to central circulation than splanchnic circulation
Figure 2: Fluid loading in patient with end stage liver disease with high vascular compliance. More blood will be distributed into splanchnic circulation with little effect on central circulation.
Figure 3: Two approaches of hemodynamic management during liver transplant
23