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Transfusion support in liver transplantation
Transfus. Sci. 1993; 14:345-352 Printed in Great Britain. All rights reserved
0955-3886/93 $6.00+0.00 Copyright 6~) 1993 Pergamon Press Ltd
Transfusion Support in Liver Transplantation Darrell J. Triulzi, Franklin A. Bontempo, Joseph E. Kiss, Alan Winkelstein,
MD MID MD MD
INTRODUCTION
MASSIVE TRANSFUSION
Allogeneic liver transplantation provides a unique model for assessing several factors involved in optimal transfusion support. It is commonly recognized that the liver serves as the major synthetic source of clotting factors and other essential serum proteins, as a prime regulator of acid-base, electrolyte and glucose homeostasis, and as the major organ for detoxifying potentially harmful compounds. During the three phases of hepatic transplantation, preanhepatic, anhepatic, and posthepatic, these functions are all seriously deranged. These problems are further complicated by the massive bleeding encountered during transplantation. The necessities of large volume transfusion introduces a series of added metabolic effects, several of which must be recognized and controlled. This review will concentrate on three key areas related to successful support of hepatic transplantation; the requirements and consequences of massive transfusions, the effects of the excess citrate administered with the transfusions, and the coagulopathies encountered in these patients.
The evolution of transfusion practice in liver transplantation over the last decade has resulted in a drastic reduction in blood usage. In a study I of 70 liver transplants performed at the University of Pittsburgh in 1981-83, the mean component usage was 43 red cells, 40 fresh frozen plasma, and 21 units of platelets. Eighty-six percent of patients required 10 or more units of red cells. Today, in the same center, the median component usage for an adult primary liver transplant is 16 red cells, 16 fresh frozen plasma, and 11 platelets. Seventyone percent of patients require 10 or more units of red cells. (Triulzi D], unpublished data.) The factors contributing to the reduction in blood usage are multiple and include: improved surgical technique, organ preservation, and anesthetic management, and better intraoperative monitoring of coagulation status and pharmacologic treatment of fibrinolysis3 Despite these changes, the majority of cases still require a large number of transfusions and meet the accepted definition of massive transfusion; one blood volume transfused within a 24-h period. Massive transfusion in the setting of liver transplantation is !mique in that the major metabolic complications of transfusion are exacerbated by underlying liver disease and preexisting metabolic abnormalities. Each of the phases
Central Blood Bank, University of Pittsburgh Medical Center, Pittsburgh, PA 15219, U.S.A. 345
346
Tmnsfus. Sci. Vol. 14, No. 4
of the transplant procedure: preanhepatic, anhepatic, and postanhepatic is associated with characteristic changes in biochemical parameters. We will describe the kinetics of blood replacement, biochemical changes in stored blood, and finally the role of massive transfusion in the observed alterations in pH, electrolytes, and glucose.
100
eo
60
40
KINETICS OF BLOOD REPLACEMENT One can approximate the kinetics of Mood replacement in massive transfusion by using mathematical models constructed for exchange transfusion. 3,4 If one assumes that blood volume is maintained by administering blood at a rate equal to its loss {continuous exchange), and mixing of infused blood is instantaneous, then the fraction of original Mood remaining at any time can be expressed by the formula: X/Xo
= e -b/v
where: X = final concentration; Xo = initial concentration; b = the amount of blood replaced; v = the total blood volume. A more complex formula can be used when blood is lost and replaced in increments {discontinuous exchange}. X/Xo
= (1-[b/vl) n
where: X = final concentration; Xo = original concentration; v = total blood volume; b = volume of each aliquot replaced; n = number of aliquots. There exists little difference in the kinetics between continuous or incremental exchange, as long as the incremental volume is small in relation to the patient's total blood volume (i.e. 500 mL aliquots in an adult with a blood volume of 5000 mL). The formula describing normovolemic continuous replacement is represented graphically
20
1
2
3
4
Number of Blood Volumes Repleoed
Figure 1. Kinetics of euvolemic continuous blood replacement.
in Fig. 1. Thirty-five percent of the ori# h a l blood volume remains after one blood volume replacement (10 red cells and an equal volume of colloid or plasma in a 70 kg adult), 13% after 2 blood volumes, and 5% after 3 blood volumes. The major clinical variable that results in deviation from the above graph is rapid hemorrhage and hypovolemia prior to blood replacement. The result is a downshift of the curve as the patient's ori#nal Mood volume is more quickly depleted and replaced by transfused blood. BIOCHEMICAL AND COAGULATION FACTOR CHANGES IN STORED BLOOD The vast majority of donor units are stored in one of two anticoagulant-preservative solutions: CPDA-1 {citrate, phosphate, dextrose, adenine) or additive solutions (Adsol, Nutricel, Optisol). The additive solutions contain citrate, phosphate, adenine, glucose, and varying concentrations of mannitol. Red cells can be stored at 1-6~ in CPDA-1
Transfusion Support in Liver Transplantation
for 35 days and in one of the additive solutions for 42 days. The biochemical changes in stored blood are a result of metabolism occurring in an anaerobic environment. Glucose is metabolized by the Embden-Meyerhof pathway to lactate and pyruvate with a resultant fall in pH. The increase in hydrogen ions slows glycolysis and decreases the production of adenosine triphosphate IATP). This reversibly disrupts the ATP dependent Na*/K + membrane pump resulting in leakage of potassium out of the cell and the accumulation of intracellular sodium. Accompanying the fall in pH is a rapid decrease in red cell 2,3-diphosphoglycerate [2,3-DPG) levels. Low levels of red cell 2,3-DPG shift the oxygen dissociation curve to the left such that hemoglobin has a greater affinity for oxygen and is less likely to release oxygen to tissues. The biochemical changes in stored blood are summarized in Table 1.s-7 Studies of coagulation factors in the plasma from citrated blood products stored at 1-6~ {liquid state} have shown that levels of all coagulation factors except V and v m are maintained within normal range for up to 35 days.s,9 The most labile component, Factor VIII, falls to about 50% of its initial value in the first 24 h s,9 and is below hemostatic levels after two s to fourteen9days of storage. Factor V is maintained at greater than 50% of normal levels for 2-3 weeks and above hemostatic levels for 35 days.s'9 Levels of both stable and labile
347
coagulation factors are maintained at normal levels in plasma stored in a frozen state [-18~ or colder) and for 6 h after thawing. TRANSFUSION AND THE BIOCHEMICAL CHANGES DURING LIVER TRANSPLANTATION Patients undergoing liver transplantation frequently have preexisting abnormalities in electrolytes prior to surgery thought to be primarily related to hyperaldosteronism. ~~ Glucose intolerance is also common; this is thought to be due to failure to degrade glucagon. Hypokalemia, hyponatremia, and hyperglycemia each occur in about 50% of patients, n The contribution of transfusion to the observed electrolyte disturbances is difficult to ascertain in the setring of bleeding, hypotension, and massive crystalloid infusion during surgery. To some extent, there are predictable biochemical changes related to the phase of surgery. The preanhepatic phase is characterized by rapid blood loss and intravascular volume depletion. A rapid infusion system was developed to transfuse a mixture of blood products and crystalloid {300 mL red cells: 250 mL fresh frozen plasma: 250 mL PlasmalyteR) at a rate up to 2000 mL/min, n This minimizes the extent and duration of hypotension, restores electrolytes, and does not appear to be associated with arrhythmias or adverse clinical manifestations. In patients with
TaMe 1. Biochemical Changes in Stored Blood Parameter Days of storage
pH Glucose tmmol/LI ATP (% initial) 2,3-DPG {% initial) Plasma K+ {mmol/LI
CPDAol Whole Blood
0 7.60 24 100 100 4.2
35 6.98 16 56 <10 27.3
Data compiledfrom Refs 5-7. "K+ appearshigherdue to total plasma content of only 70 mL. $49 daysof storage,based on manufacturer'sdata submitted to FDA.
Additive System Red Cells Red Cells
0 7.55
35 6.71
42 6.5
22
5
28
100 100 5.1
45 <10 78.5"
58 <10 6.5t
348 Trans[us. Sci. Vol. 14, No. 4
preexisting renal failure, normal saline instead of Plasmalyte R has been used to reduce exogenous potassium, n Some patients requiring rapid massive transfusion will have acute increases in potassium levels. Potassium levels should be kept below 5.0 mmol/L using insulin and glucose. Patients with hyperkalemia unresponsive to this therapy may benefit from intraoperative washing of red cells using a Cell Saver [Haemonetics, Braintree, Mass.I. The anhepatic phase begins when the major vessels to and from the liver are cross clamped, and ends when the new liver is revascularized. This phase has a mean duration of approximately 90 min. Hypoglycemia and profound metabolic acidosis have been described during this period) 4 A study of 28 consecutive adult patients undergoing liver transplantation at the University of Pittsburgh found no significant change in glucose levels during the an_hepatic phase with a mean value of 169 + 52 mg/dL. ~sInfusion of dextrose containing blood products probably contributed to the prevention of hypoglycemia. Metabolic acidosis is a particular problem in the anhepatic phase due to the lack of hepatic clearance of organic acids. Approximately half of all patients require exogenous bicarbonate therapy for treatment of metabolic acidosis. Generally, metabolic acidosis may be improved by transfusions which replete volume and result in more rapid peripheral clearance of acids. When massive rapid transfusions are required however, the acid load in the blood may overwhelm the metabolic ability of peripheral tissues, resulting in a lowering of the blood pH to a level approximating that of stored blood. The requirement for bicarbonate therapy is increased in this setting. Potassium levels are generally stable during the anhepatic period. 13 Recommendations for the treatment of hyperkalemia are similar to those described in the preanhepatic period. The postanhepatic phase begins following revascularization and is initially probably the most unstable period. Clin-
ically, the patients exhibit hemodynamic instability and arrhythmias. Typical biochemical abnormalities include hyperglycemia, is hyperkalemia, ~6 and acidosis. 16 These changes are felt to be due to washout of accumulated hepatocellular metabolic byproducts or residual preservative solution and not to infused blood products. Treatment with bicarbonate therapy prior to revascularization can moderate the degree of acidosis) 6 Potassium levels should be maintained less than 5 mmol/L as noted previously. These data suggest that there are minimal adverse biochemical effects associated with the volume of transfused blood required for most liver transplant procedures. In those patients who require massive rapid transfusion as a lifesaving measure, the acute biochemical effects of hyperkalemia and/or acidosis generally can be successfully treated. CITRATE TOXICITY A transfusion-associated metabolic disturbance that assumes special importance in liver transplantation surgery is citrate toxicity, which can result in profound hypocalcemia and depressed hemodynamic function. A comprehensive review of this problem in the setting of massive transfusion has recently been published, lz During liver transplant surgery, excessive chelation of ionized calcium occurs due to the rapid infusion of large amounts of citrated blood components together with severely reduced metabolic clearance of citrate. Additional factors affecting the clearance of this organic compound include the presence of hypotension with inadequate hepatic blood flow, hypothermia, acidbase status, and the operative stage of hepatic transplantation itself, is Serum citrate levels begin to rise during the preanhepatic period, reaching peak levels when the major vessels are crossclamped and the recipient liver is removed (the anhepatic period). The changes in citrate levels are inversely
Transfusion Support in Liver Transplantation 349
correlated wih serum ionized calcium levelsJ 9 Upon revascularization and return of function of the donor liver, citrate levels decline gradually to normal. Recognition that citrate-induced ionic hypocalcemia could lead to clinically significant cardiovascular depression during liver transplant surgery came from several studies performed in the 1980s. Gray e t al. 2~ reported cardiac decompensation with arterial hypotension in 2 of 11 patients despite adequate cardiac filling pressures. In one patient this occurred at a nadir ionic calcium level of 0.57 mmol/L (normal 1.18-1.29 mmol/L}. The hypotension responded rapidly to bolus CaC12 in_fusion, which raised the ionic calcium level to 0.81 m m o l / L . In the second patient, a similar occurrence was noted after a fall in calcium level to 0.79 mmol/L In the face of co-existing hyperkalemia. Marquez e t al. 21 studied cardiovascular function with respect to citrate and ionic calcium levels in a group of 9 patients who received a mean of 39 units of red cells and 33 units of fresh frozen plasma during hepatic transplantation. They found that a decrease in ionic calcium into the range of 0.56 mmol/L was associated with decreased cardiac index, stroke index, and left ventricular stroke work index despite adequate pulmonary artery wedge pressure and unchanged systemic vascular resistance index. The depressed cardiac indices were rapidly corrected with aggressive calcium supplementation. Although the presence of hypothermia {nadir temperature 33.6~ in their patients might also have contributed to the cardiac effects, cardiovascular improvement occurred despite persisting hypothermia. This points to the hypocalcemia itself as the primary determinant impairing cardiac performance. In a subsequent group of patients, aggressive prevention of hypocalcemia with calcium monitoring and replacement appeared to obviate the cardiovascular depression due to citrate toxicity.IS This preventive approach required nearly three times more CaC12, averIS 14:4-r
aging 1 g for every 6 units of citrated blood components (RBC and FFP). Frequent monitoring and correction of the ionic calcium level, based on the rate of blood infusion and the operative stage of the procedure, is considered essential in the management of these patients. 21'22 The difficulty in optimally managing calcium requirements during liver transplant surgery is underscored by a recent report of serious complications due to iatrogenic hypercalcemia in this setting. ~7 COAGULATION CHANGES D U R I N G LIVER
TRANSPLANTATION Because the liver plays a central role in the synthesis of clotting factors and the regulation of hemostasis, significant coagulation abnormalities requiring coagulation factor replacement are encountered during liver transplantation. In the preanhepatic phase of liver transplantation, the degree of coagulation abnormality is largely related to the underlying hepatic disease with disorders associated with greater parenchymal damage usually causing more severe coagulation defects. ~'23 Most patients will have abnormal prothrombin times (PT}, partial thromboplastin times {PTT} and platelet counts; however, fibrinogen, possibly because it has a long halflife and is an acute phase reactant, will rarely be abnormally low. 1 Increased fibrinolytic activity may be seen in 1020% of patients prior to transplantation ''~ but this is not usually clinically sigmificant in the preanhepatic period. Blood loss in this phase is more likely to be related to the number of collateral vessels that must be transected and the time required for the dissection of the native liver. In order to avoid dilutional coagulopathy or thrombocytopenia as a result of large volume transfusion, replacement of clotting factors and platelets in this part of the procedure is usually by standard methods. Red cells and plasma are r~placed on a unit for
350
Traasfus. Sci,
V o l . 14, N o . 4
unit basis, usually via a rapid infusion device. In the anhepatic period, changes in coagulation become significant and progressive as decreases in levels of most clotting factors, especially factor I (fibrinogen), factor V and factor VIII, occur. 24 In addition, elevated levels of tissue plasminogen activator (t-PA)2s and shortening of the euglobulin lysis time (ELT)24 are seen, indicating activation of fibrinolysis. This is apparently due to the inability of the native liver, damped during the anhepatic phase, to inactivate the plasminogen activators released from the vascular endothelium during this phase of the liver transplant procedure. Evidence supporting this concept is provided by reports of normal levels of t-PA in auxiliary liver transplantation where the native liver remains in place while a donor liver is transplanted in a heterotopic position allowing hepatic clearance throughout the procedure.~s Antithrombin III levels do not decrease significantly during orthotopic transplantation 2z'2a which is evidence against the possibility that active DIC is the cause of the anhepatic coagulopathy or that antithrombin III concentrates would be beneficial. Because of the sometimes exaggerated fibrinolytic response seen in some patients in the anhepatic period of orthotopic transplantation, antifibrinolytic agents such as e-aminocaproic acid and thrombelastographic monitoring of the coagulation status of the patient are sometimes recommended.2 However, no standard approach to monitoring and treatment of this coagulopathy has been determined as yet. In the postanhepatic period the severe coagulopathy generally resolves as liver function returns, t-PA levels normalize, and clotting factor levels rise. Factor V levels tend to stay low longer than other factors, but even ff graft function is optimal, 10-14 days may be necessary until a normal coagulation pattern is found in the transplanted patient (Bontempo FA, unpub-
lished data). Plots of changes in coagulation during the three stages of transplantation are shown in Figures 2-5. SUMMARY
Massive transfusion is required in the majority of adult patients undergoing liver transplantation. The metabolic and biochemical changes in a typical case are largely the result of preexisting liver disease, surgical factors, and to a lesser extent blood transfusion. When rapid massive transfusion is required, hyperk-
0.7
1 L
FI
0.6-'1 F'n"
o.4J
~=
""
,
,
""
--~
0"3 1 0.2 0.1
,
STAGE
Figure 2. Coagulation changes in factors II, V, VII, and X during liver transplantation. Stage I--preanhepatic, Stage II--anhepatic, Stage m-postanhepatic.
o.s] 0.7
F ~
_j 0.6 0.5
~
04 0.3 0.2
,
"IT STAGE
l'l-f
Figure 3. Coagulation changes in fibrinogen and factors IX, XI, and XII during liver transplantaion. Stage I-preanhepatic, Stage I I anhepatic, Stage llI-postanhepatic.
Transfusion Support in Liver Transplantation 351 TIME 160' 80"
140' 70" 1
L2o'6o" A~"ELY
9r;
8o'40" t
7=
60' 30"
40'20"
o 20' I0" I
P't '
o ~
a," ~
~'r
'
'
STAGE
Figure 4. Changes in euglobulin lysis time {ELT), prothrombin time (PTI, and activated partial thromboplastin time (APTT) during liver transplantation. Stage I--preanhepatic, Stage II-anhepatic, Stage HI--postanhepatic. I.S 1.6
:7
D 1.0 0.8 0.6 0.4
i
•
'
STAGE
Figure 5. Changes in factor VIII levels during liver transplantation. Stage I--preamhepatic, Stage II-- anhepatic, Stage m-postanhepatic.
alemia, acidosis, and citrate related hypocalcemia m a y be acutely exacerbated. For these reasons, intraoperative monitoring of these parameters and appropriate therapy are central to patient management. Coagulation factor changes during liver transplantation are well defined although there is no agreement on standard monitoring techniques and treatment. Use of a rapid infusion device with equal volume red cell and plasma infusion provides adequate replacement
in the preanhepatic period. The unpredictability of fibrinolysis in the anhepatic phase requires monitoring of coagulation parameters and appropriate replacement therapy. The postanhepatic period is characterized by improved coagulation status as liver function returns. Aggressive transfusion support continues to be critical to successful liver transplantation. The deleterious metabolic effects of rapid massive transfusion are generally manageable with careful monitoring and treatment.
REFERENCES 1. Bontempo FA, Lewis JI-I, Van Thiel DH, Spero JA, Ragni MV, Butler P, Israel L, Starzl TE: The relation of preoperative coagulation findings to diagnosis, blood usage, and survival in adult liver transplantation. Transplantation 1985; 39: 532-536. 2. Kang Y, Lewis JH, Navalgund A, Russell MW, Bontempo FA, Niren LS, Starzl TE: e-aminocaproic acid for treatment of fibrinolysis during liver transplantation. Anesthesiology 1987; 66:766-773. 3. Collins JA: Problems associated with the massive transfusion of stored blood. Surgery 1974; 75:274-295. 4. McCullough J, Chopek M: Therapeutic plasma exchange. Lab ivied 1981; 12: 745-753. 5. Latham JT, Bove JR, Weirich FL: Chemical and hematologic changes in stored CPDA-1 blood. Transfusion 1982; 22: 158-159. 6. Moore GL, Peck CC, Sohmer PR, Zuck TF: Some properties of blood stored in anticoagulant CPDA-1 solution. A brief summary. Transfusion 1981; 21:135137. 7. Simon TL, Marcus CS, Myhre BA, Nelson EJ: Effects of AS-3 nutrientadditive solution on 42 and 49 days of storage of red cells. Transfusion 1987; 27:178-182. 8. Counts RB, Haisch C, Simon TL, Maxwell NG, Heimbach DM, Carrico CI: Hemostasis in massively transfused trauma patients. Ann Surg 1979; 190:9199. 9. Nilsson L, Hedner U, Nilsson IM, Robertson B: Shelf-life of bank blood and stored plasma with special reference to
352 Transfus. Sci. Vol. 14, No. 4 coagulation factors. Transfusion 1983; 23:377-381. 10. Rosoff L, Zia P, Reynolds TB, Horton R: Studies of renin and aldosterone in cirrhotic patients with ascites. Gastroenterology 1975; 69:698. 11. Martin D: Fluid and electrolyte balance, in Winter PM, Kang YG (eds): Hepatic Transplantation: Anesthetic and Perioperative Management. New York, Praeger 1986, pp. 33-43. 12. Sassano lJ: The rapid infusion system, in Winter PM, Kang YG (eds): Hepatic Transplantation: Anesthetic and Perioperative Management. New York, Praeger, 1986, pp. 120-134. 13. Carmichael FJ, Lindop MJ, Farman JV: Anesthesia for hepatic transplantation: cardiovascular and metabolic alterations and their management. Anesth Analg 1985; 64:108-116. 14. Aldrete JA, Goldman E, de Campo T: Anesthetic implications in hepatic transplantation, in Brown B. {edl: Anesthesia and the Patient with Liver Disease. Contemporary Anesthesia Practice. Philadelphia, Davis, 1981. 15. Mallett SV, Kang Y, Freeman JA, Aggarwal S, Gasion T, Fortunato FL: Prognostic significance of reperfusion hyperglycemia during liver transplantation. Anesth Analg 1989; 68:182-185. 16. Martin DJ, Marquez JM, Kang YG, Shaw BW Jr: Liver transplantation: hemodynamic and electrolyte changes seen immediately following revascularization. Anesth Analg 1984; 63:175-246. 17. Dzik WH, Kirkley SA: Citrate toxicity during massive blood transfusion. Trans[us Med Rev 1988; 2:76-94. 18. Marquez JM: Citrate intoxication during hepatic transplantation, in Winter PM, Kang YG (eds): Hepatic Transplantation. New York, Praeger, 1986, pp 110-119. 19. Gray TA, Buckley BM, Sealey M, et al.: Is calcium important for hemodynamic
20.
21.
22.
23. 24.
25.
26.
27.
28.
stability during liver transplantation? Transplant Proc 1985; 17:290-292. Gray TA, Buckley BM, Sealey MM, et a/.: Plasma ionized calcium monitoring during liver transplantation. Transplantation 1986; 41:335-339. Marquez J, Martin D, Virji MA, et al.: Cardiovascular depression secondary to ionic hypocalcemia during hepatic transplantation in humans. Anesthesiology 1986; 65:457--461. 22. Wu AHB, Bracey A, Bryan-Brown CW: Ionized calcium monitoring during liver transplantation. Arch Pathol Lab Med 1987; 111:935-938. Porte RJ, Knot EAR, Bontempo FA: Hemostasis in liver transplantation. Gastroenterology 1989; 97:488-501. Lewis JH, Bontempo FA, Awad SA, Kang YG, Kiss JE, Ragni MV, Spero JA, Starzl TE: Liver transplantation: intraoperative changes in coagulation factors in 100 first transplants. Hepatology 1989; 9:710-714. Dzik WH, Arkin CF, Jenkins RL, Stump DC: Fibrinolysis during liver transplantation in humans: role of tissue-type plasminogen activator. Blood 1988; 71: 1090-1095. Bakker CM, Metselaar HJ, Groenland TN, Gomes JM, Knot EAR, Hesselink EJ, Schalm SW, Stibbe J, Terpstra OT: Increased tissue-type plasminogen activator activity in orthotopic but not heterotopic liver transplantation: the role of the anhepatic period. Hepatology 1992; 16:40 A. A.08. Lewis JH, Bontempo FA, Ragni MV, Starzl TE: Antithrombin III levels during liver transplantation. Transplant Proc 1989; 21:3543-3544. Sato M, Nashan B, Ringe B, Grosse H, Barthels M, Pichylmayr R: Coagulation disorder during liver transplantation. Blood Coag Fibrinolysis 1991; 2:225-31.
0955-3886/93 $6.00+0.00 Copyright 6~) 1993 Pergamon Press Ltd
Transfusion Support in Liver Transplantation Darrell J. Triulzi, Franklin A. Bontempo, Joseph E. Kiss, Alan Winkelstein,
MD MID MD MD
INTRODUCTION
MASSIVE TRANSFUSION
Allogeneic liver transplantation provides a unique model for assessing several factors involved in optimal transfusion support. It is commonly recognized that the liver serves as the major synthetic source of clotting factors and other essential serum proteins, as a prime regulator of acid-base, electrolyte and glucose homeostasis, and as the major organ for detoxifying potentially harmful compounds. During the three phases of hepatic transplantation, preanhepatic, anhepatic, and posthepatic, these functions are all seriously deranged. These problems are further complicated by the massive bleeding encountered during transplantation. The necessities of large volume transfusion introduces a series of added metabolic effects, several of which must be recognized and controlled. This review will concentrate on three key areas related to successful support of hepatic transplantation; the requirements and consequences of massive transfusions, the effects of the excess citrate administered with the transfusions, and the coagulopathies encountered in these patients.
The evolution of transfusion practice in liver transplantation over the last decade has resulted in a drastic reduction in blood usage. In a study I of 70 liver transplants performed at the University of Pittsburgh in 1981-83, the mean component usage was 43 red cells, 40 fresh frozen plasma, and 21 units of platelets. Eighty-six percent of patients required 10 or more units of red cells. Today, in the same center, the median component usage for an adult primary liver transplant is 16 red cells, 16 fresh frozen plasma, and 11 platelets. Seventyone percent of patients require 10 or more units of red cells. (Triulzi D], unpublished data.) The factors contributing to the reduction in blood usage are multiple and include: improved surgical technique, organ preservation, and anesthetic management, and better intraoperative monitoring of coagulation status and pharmacologic treatment of fibrinolysis3 Despite these changes, the majority of cases still require a large number of transfusions and meet the accepted definition of massive transfusion; one blood volume transfused within a 24-h period. Massive transfusion in the setting of liver transplantation is !mique in that the major metabolic complications of transfusion are exacerbated by underlying liver disease and preexisting metabolic abnormalities. Each of the phases
Central Blood Bank, University of Pittsburgh Medical Center, Pittsburgh, PA 15219, U.S.A. 345
346
Tmnsfus. Sci. Vol. 14, No. 4
of the transplant procedure: preanhepatic, anhepatic, and postanhepatic is associated with characteristic changes in biochemical parameters. We will describe the kinetics of blood replacement, biochemical changes in stored blood, and finally the role of massive transfusion in the observed alterations in pH, electrolytes, and glucose.
100
eo
60
40
KINETICS OF BLOOD REPLACEMENT One can approximate the kinetics of Mood replacement in massive transfusion by using mathematical models constructed for exchange transfusion. 3,4 If one assumes that blood volume is maintained by administering blood at a rate equal to its loss {continuous exchange), and mixing of infused blood is instantaneous, then the fraction of original Mood remaining at any time can be expressed by the formula: X/Xo
= e -b/v
where: X = final concentration; Xo = initial concentration; b = the amount of blood replaced; v = the total blood volume. A more complex formula can be used when blood is lost and replaced in increments {discontinuous exchange}. X/Xo
= (1-[b/vl) n
where: X = final concentration; Xo = original concentration; v = total blood volume; b = volume of each aliquot replaced; n = number of aliquots. There exists little difference in the kinetics between continuous or incremental exchange, as long as the incremental volume is small in relation to the patient's total blood volume (i.e. 500 mL aliquots in an adult with a blood volume of 5000 mL). The formula describing normovolemic continuous replacement is represented graphically
20
1
2
3
4
Number of Blood Volumes Repleoed
Figure 1. Kinetics of euvolemic continuous blood replacement.
in Fig. 1. Thirty-five percent of the ori# h a l blood volume remains after one blood volume replacement (10 red cells and an equal volume of colloid or plasma in a 70 kg adult), 13% after 2 blood volumes, and 5% after 3 blood volumes. The major clinical variable that results in deviation from the above graph is rapid hemorrhage and hypovolemia prior to blood replacement. The result is a downshift of the curve as the patient's ori#nal Mood volume is more quickly depleted and replaced by transfused blood. BIOCHEMICAL AND COAGULATION FACTOR CHANGES IN STORED BLOOD The vast majority of donor units are stored in one of two anticoagulant-preservative solutions: CPDA-1 {citrate, phosphate, dextrose, adenine) or additive solutions (Adsol, Nutricel, Optisol). The additive solutions contain citrate, phosphate, adenine, glucose, and varying concentrations of mannitol. Red cells can be stored at 1-6~ in CPDA-1
Transfusion Support in Liver Transplantation
for 35 days and in one of the additive solutions for 42 days. The biochemical changes in stored blood are a result of metabolism occurring in an anaerobic environment. Glucose is metabolized by the Embden-Meyerhof pathway to lactate and pyruvate with a resultant fall in pH. The increase in hydrogen ions slows glycolysis and decreases the production of adenosine triphosphate IATP). This reversibly disrupts the ATP dependent Na*/K + membrane pump resulting in leakage of potassium out of the cell and the accumulation of intracellular sodium. Accompanying the fall in pH is a rapid decrease in red cell 2,3-diphosphoglycerate [2,3-DPG) levels. Low levels of red cell 2,3-DPG shift the oxygen dissociation curve to the left such that hemoglobin has a greater affinity for oxygen and is less likely to release oxygen to tissues. The biochemical changes in stored blood are summarized in Table 1.s-7 Studies of coagulation factors in the plasma from citrated blood products stored at 1-6~ {liquid state} have shown that levels of all coagulation factors except V and v m are maintained within normal range for up to 35 days.s,9 The most labile component, Factor VIII, falls to about 50% of its initial value in the first 24 h s,9 and is below hemostatic levels after two s to fourteen9days of storage. Factor V is maintained at greater than 50% of normal levels for 2-3 weeks and above hemostatic levels for 35 days.s'9 Levels of both stable and labile
347
coagulation factors are maintained at normal levels in plasma stored in a frozen state [-18~ or colder) and for 6 h after thawing. TRANSFUSION AND THE BIOCHEMICAL CHANGES DURING LIVER TRANSPLANTATION Patients undergoing liver transplantation frequently have preexisting abnormalities in electrolytes prior to surgery thought to be primarily related to hyperaldosteronism. ~~ Glucose intolerance is also common; this is thought to be due to failure to degrade glucagon. Hypokalemia, hyponatremia, and hyperglycemia each occur in about 50% of patients, n The contribution of transfusion to the observed electrolyte disturbances is difficult to ascertain in the setring of bleeding, hypotension, and massive crystalloid infusion during surgery. To some extent, there are predictable biochemical changes related to the phase of surgery. The preanhepatic phase is characterized by rapid blood loss and intravascular volume depletion. A rapid infusion system was developed to transfuse a mixture of blood products and crystalloid {300 mL red cells: 250 mL fresh frozen plasma: 250 mL PlasmalyteR) at a rate up to 2000 mL/min, n This minimizes the extent and duration of hypotension, restores electrolytes, and does not appear to be associated with arrhythmias or adverse clinical manifestations. In patients with
TaMe 1. Biochemical Changes in Stored Blood Parameter Days of storage
pH Glucose tmmol/LI ATP (% initial) 2,3-DPG {% initial) Plasma K+ {mmol/LI
CPDAol Whole Blood
0 7.60 24 100 100 4.2
35 6.98 16 56 <10 27.3
Data compiledfrom Refs 5-7. "K+ appearshigherdue to total plasma content of only 70 mL. $49 daysof storage,based on manufacturer'sdata submitted to FDA.
Additive System Red Cells Red Cells
0 7.55
35 6.71
42 6.5
22
5
28
100 100 5.1
45 <10 78.5"
58 <10 6.5t
348 Trans[us. Sci. Vol. 14, No. 4
preexisting renal failure, normal saline instead of Plasmalyte R has been used to reduce exogenous potassium, n Some patients requiring rapid massive transfusion will have acute increases in potassium levels. Potassium levels should be kept below 5.0 mmol/L using insulin and glucose. Patients with hyperkalemia unresponsive to this therapy may benefit from intraoperative washing of red cells using a Cell Saver [Haemonetics, Braintree, Mass.I. The anhepatic phase begins when the major vessels to and from the liver are cross clamped, and ends when the new liver is revascularized. This phase has a mean duration of approximately 90 min. Hypoglycemia and profound metabolic acidosis have been described during this period) 4 A study of 28 consecutive adult patients undergoing liver transplantation at the University of Pittsburgh found no significant change in glucose levels during the an_hepatic phase with a mean value of 169 + 52 mg/dL. ~sInfusion of dextrose containing blood products probably contributed to the prevention of hypoglycemia. Metabolic acidosis is a particular problem in the anhepatic phase due to the lack of hepatic clearance of organic acids. Approximately half of all patients require exogenous bicarbonate therapy for treatment of metabolic acidosis. Generally, metabolic acidosis may be improved by transfusions which replete volume and result in more rapid peripheral clearance of acids. When massive rapid transfusions are required however, the acid load in the blood may overwhelm the metabolic ability of peripheral tissues, resulting in a lowering of the blood pH to a level approximating that of stored blood. The requirement for bicarbonate therapy is increased in this setting. Potassium levels are generally stable during the anhepatic period. 13 Recommendations for the treatment of hyperkalemia are similar to those described in the preanhepatic period. The postanhepatic phase begins following revascularization and is initially probably the most unstable period. Clin-
ically, the patients exhibit hemodynamic instability and arrhythmias. Typical biochemical abnormalities include hyperglycemia, is hyperkalemia, ~6 and acidosis. 16 These changes are felt to be due to washout of accumulated hepatocellular metabolic byproducts or residual preservative solution and not to infused blood products. Treatment with bicarbonate therapy prior to revascularization can moderate the degree of acidosis) 6 Potassium levels should be maintained less than 5 mmol/L as noted previously. These data suggest that there are minimal adverse biochemical effects associated with the volume of transfused blood required for most liver transplant procedures. In those patients who require massive rapid transfusion as a lifesaving measure, the acute biochemical effects of hyperkalemia and/or acidosis generally can be successfully treated. CITRATE TOXICITY A transfusion-associated metabolic disturbance that assumes special importance in liver transplantation surgery is citrate toxicity, which can result in profound hypocalcemia and depressed hemodynamic function. A comprehensive review of this problem in the setting of massive transfusion has recently been published, lz During liver transplant surgery, excessive chelation of ionized calcium occurs due to the rapid infusion of large amounts of citrated blood components together with severely reduced metabolic clearance of citrate. Additional factors affecting the clearance of this organic compound include the presence of hypotension with inadequate hepatic blood flow, hypothermia, acidbase status, and the operative stage of hepatic transplantation itself, is Serum citrate levels begin to rise during the preanhepatic period, reaching peak levels when the major vessels are crossclamped and the recipient liver is removed (the anhepatic period). The changes in citrate levels are inversely
Transfusion Support in Liver Transplantation 349
correlated wih serum ionized calcium levelsJ 9 Upon revascularization and return of function of the donor liver, citrate levels decline gradually to normal. Recognition that citrate-induced ionic hypocalcemia could lead to clinically significant cardiovascular depression during liver transplant surgery came from several studies performed in the 1980s. Gray e t al. 2~ reported cardiac decompensation with arterial hypotension in 2 of 11 patients despite adequate cardiac filling pressures. In one patient this occurred at a nadir ionic calcium level of 0.57 mmol/L (normal 1.18-1.29 mmol/L}. The hypotension responded rapidly to bolus CaC12 in_fusion, which raised the ionic calcium level to 0.81 m m o l / L . In the second patient, a similar occurrence was noted after a fall in calcium level to 0.79 mmol/L In the face of co-existing hyperkalemia. Marquez e t al. 21 studied cardiovascular function with respect to citrate and ionic calcium levels in a group of 9 patients who received a mean of 39 units of red cells and 33 units of fresh frozen plasma during hepatic transplantation. They found that a decrease in ionic calcium into the range of 0.56 mmol/L was associated with decreased cardiac index, stroke index, and left ventricular stroke work index despite adequate pulmonary artery wedge pressure and unchanged systemic vascular resistance index. The depressed cardiac indices were rapidly corrected with aggressive calcium supplementation. Although the presence of hypothermia {nadir temperature 33.6~ in their patients might also have contributed to the cardiac effects, cardiovascular improvement occurred despite persisting hypothermia. This points to the hypocalcemia itself as the primary determinant impairing cardiac performance. In a subsequent group of patients, aggressive prevention of hypocalcemia with calcium monitoring and replacement appeared to obviate the cardiovascular depression due to citrate toxicity.IS This preventive approach required nearly three times more CaC12, averIS 14:4-r
aging 1 g for every 6 units of citrated blood components (RBC and FFP). Frequent monitoring and correction of the ionic calcium level, based on the rate of blood infusion and the operative stage of the procedure, is considered essential in the management of these patients. 21'22 The difficulty in optimally managing calcium requirements during liver transplant surgery is underscored by a recent report of serious complications due to iatrogenic hypercalcemia in this setting. ~7 COAGULATION CHANGES D U R I N G LIVER
TRANSPLANTATION Because the liver plays a central role in the synthesis of clotting factors and the regulation of hemostasis, significant coagulation abnormalities requiring coagulation factor replacement are encountered during liver transplantation. In the preanhepatic phase of liver transplantation, the degree of coagulation abnormality is largely related to the underlying hepatic disease with disorders associated with greater parenchymal damage usually causing more severe coagulation defects. ~'23 Most patients will have abnormal prothrombin times (PT}, partial thromboplastin times {PTT} and platelet counts; however, fibrinogen, possibly because it has a long halflife and is an acute phase reactant, will rarely be abnormally low. 1 Increased fibrinolytic activity may be seen in 1020% of patients prior to transplantation ''~ but this is not usually clinically sigmificant in the preanhepatic period. Blood loss in this phase is more likely to be related to the number of collateral vessels that must be transected and the time required for the dissection of the native liver. In order to avoid dilutional coagulopathy or thrombocytopenia as a result of large volume transfusion, replacement of clotting factors and platelets in this part of the procedure is usually by standard methods. Red cells and plasma are r~placed on a unit for
350
Traasfus. Sci,
V o l . 14, N o . 4
unit basis, usually via a rapid infusion device. In the anhepatic period, changes in coagulation become significant and progressive as decreases in levels of most clotting factors, especially factor I (fibrinogen), factor V and factor VIII, occur. 24 In addition, elevated levels of tissue plasminogen activator (t-PA)2s and shortening of the euglobulin lysis time (ELT)24 are seen, indicating activation of fibrinolysis. This is apparently due to the inability of the native liver, damped during the anhepatic phase, to inactivate the plasminogen activators released from the vascular endothelium during this phase of the liver transplant procedure. Evidence supporting this concept is provided by reports of normal levels of t-PA in auxiliary liver transplantation where the native liver remains in place while a donor liver is transplanted in a heterotopic position allowing hepatic clearance throughout the procedure.~s Antithrombin III levels do not decrease significantly during orthotopic transplantation 2z'2a which is evidence against the possibility that active DIC is the cause of the anhepatic coagulopathy or that antithrombin III concentrates would be beneficial. Because of the sometimes exaggerated fibrinolytic response seen in some patients in the anhepatic period of orthotopic transplantation, antifibrinolytic agents such as e-aminocaproic acid and thrombelastographic monitoring of the coagulation status of the patient are sometimes recommended.2 However, no standard approach to monitoring and treatment of this coagulopathy has been determined as yet. In the postanhepatic period the severe coagulopathy generally resolves as liver function returns, t-PA levels normalize, and clotting factor levels rise. Factor V levels tend to stay low longer than other factors, but even ff graft function is optimal, 10-14 days may be necessary until a normal coagulation pattern is found in the transplanted patient (Bontempo FA, unpub-
lished data). Plots of changes in coagulation during the three stages of transplantation are shown in Figures 2-5. SUMMARY
Massive transfusion is required in the majority of adult patients undergoing liver transplantation. The metabolic and biochemical changes in a typical case are largely the result of preexisting liver disease, surgical factors, and to a lesser extent blood transfusion. When rapid massive transfusion is required, hyperk-
0.7
1 L
FI
0.6-'1 F'n"
o.4J
~=
""
,
,
""
--~
0"3 1 0.2 0.1
,
STAGE
Figure 2. Coagulation changes in factors II, V, VII, and X during liver transplantation. Stage I--preanhepatic, Stage II--anhepatic, Stage m-postanhepatic.
o.s] 0.7
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_j 0.6 0.5
~
04 0.3 0.2
,
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l'l-f
Figure 3. Coagulation changes in fibrinogen and factors IX, XI, and XII during liver transplantaion. Stage I-preanhepatic, Stage I I anhepatic, Stage llI-postanhepatic.
Transfusion Support in Liver Transplantation 351 TIME 160' 80"
140' 70" 1
L2o'6o" A~"ELY
9r;
8o'40" t
7=
60' 30"
40'20"
o 20' I0" I
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o ~
a," ~
~'r
'
'
STAGE
Figure 4. Changes in euglobulin lysis time {ELT), prothrombin time (PTI, and activated partial thromboplastin time (APTT) during liver transplantation. Stage I--preanhepatic, Stage II-anhepatic, Stage HI--postanhepatic. I.S 1.6
:7
D 1.0 0.8 0.6 0.4
i
•
'
STAGE
Figure 5. Changes in factor VIII levels during liver transplantation. Stage I--preamhepatic, Stage II-- anhepatic, Stage m-postanhepatic.
alemia, acidosis, and citrate related hypocalcemia m a y be acutely exacerbated. For these reasons, intraoperative monitoring of these parameters and appropriate therapy are central to patient management. Coagulation factor changes during liver transplantation are well defined although there is no agreement on standard monitoring techniques and treatment. Use of a rapid infusion device with equal volume red cell and plasma infusion provides adequate replacement
in the preanhepatic period. The unpredictability of fibrinolysis in the anhepatic phase requires monitoring of coagulation parameters and appropriate replacement therapy. The postanhepatic period is characterized by improved coagulation status as liver function returns. Aggressive transfusion support continues to be critical to successful liver transplantation. The deleterious metabolic effects of rapid massive transfusion are generally manageable with careful monitoring and treatment.
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352 Transfus. Sci. Vol. 14, No. 4 coagulation factors. Transfusion 1983; 23:377-381. 10. Rosoff L, Zia P, Reynolds TB, Horton R: Studies of renin and aldosterone in cirrhotic patients with ascites. Gastroenterology 1975; 69:698. 11. Martin D: Fluid and electrolyte balance, in Winter PM, Kang YG (eds): Hepatic Transplantation: Anesthetic and Perioperative Management. New York, Praeger 1986, pp. 33-43. 12. Sassano lJ: The rapid infusion system, in Winter PM, Kang YG (eds): Hepatic Transplantation: Anesthetic and Perioperative Management. New York, Praeger, 1986, pp. 120-134. 13. Carmichael FJ, Lindop MJ, Farman JV: Anesthesia for hepatic transplantation: cardiovascular and metabolic alterations and their management. Anesth Analg 1985; 64:108-116. 14. Aldrete JA, Goldman E, de Campo T: Anesthetic implications in hepatic transplantation, in Brown B. {edl: Anesthesia and the Patient with Liver Disease. Contemporary Anesthesia Practice. Philadelphia, Davis, 1981. 15. Mallett SV, Kang Y, Freeman JA, Aggarwal S, Gasion T, Fortunato FL: Prognostic significance of reperfusion hyperglycemia during liver transplantation. Anesth Analg 1989; 68:182-185. 16. Martin DJ, Marquez JM, Kang YG, Shaw BW Jr: Liver transplantation: hemodynamic and electrolyte changes seen immediately following revascularization. Anesth Analg 1984; 63:175-246. 17. Dzik WH, Kirkley SA: Citrate toxicity during massive blood transfusion. Trans[us Med Rev 1988; 2:76-94. 18. Marquez JM: Citrate intoxication during hepatic transplantation, in Winter PM, Kang YG (eds): Hepatic Transplantation. New York, Praeger, 1986, pp 110-119. 19. Gray TA, Buckley BM, Sealey M, et al.: Is calcium important for hemodynamic
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stability during liver transplantation? Transplant Proc 1985; 17:290-292. Gray TA, Buckley BM, Sealey MM, et a/.: Plasma ionized calcium monitoring during liver transplantation. Transplantation 1986; 41:335-339. Marquez J, Martin D, Virji MA, et al.: Cardiovascular depression secondary to ionic hypocalcemia during hepatic transplantation in humans. Anesthesiology 1986; 65:457--461. 22. Wu AHB, Bracey A, Bryan-Brown CW: Ionized calcium monitoring during liver transplantation. Arch Pathol Lab Med 1987; 111:935-938. Porte RJ, Knot EAR, Bontempo FA: Hemostasis in liver transplantation. Gastroenterology 1989; 97:488-501. Lewis JH, Bontempo FA, Awad SA, Kang YG, Kiss JE, Ragni MV, Spero JA, Starzl TE: Liver transplantation: intraoperative changes in coagulation factors in 100 first transplants. Hepatology 1989; 9:710-714. Dzik WH, Arkin CF, Jenkins RL, Stump DC: Fibrinolysis during liver transplantation in humans: role of tissue-type plasminogen activator. Blood 1988; 71: 1090-1095. Bakker CM, Metselaar HJ, Groenland TN, Gomes JM, Knot EAR, Hesselink EJ, Schalm SW, Stibbe J, Terpstra OT: Increased tissue-type plasminogen activator activity in orthotopic but not heterotopic liver transplantation: the role of the anhepatic period. Hepatology 1992; 16:40 A. A.08. Lewis JH, Bontempo FA, Ragni MV, Starzl TE: Antithrombin III levels during liver transplantation. Transplant Proc 1989; 21:3543-3544. Sato M, Nashan B, Ringe B, Grosse H, Barthels M, Pichylmayr R: Coagulation disorder during liver transplantation. Blood Coag Fibrinolysis 1991; 2:225-31.