- Email: [email protected]
Serum Vasopressin Concentrations During Orthotopic Liver Transplantation
Serum Vasopressin Concentrations During Orthotopic Liver Transplantation M.T. Keegan, B. Gali, D.R. Brown, B.A. Harrison, D.J. Plevak, and J.Y. Findlay ABSTRACT Background. We report measurements of the temporal response of serum vasopressin concentrations in the period after reperfusion of the liver graft during orthotopic liver transplantation (OLT). Methods. Vasopressin concentrations were determined in 11 adult patients undergoing OLT by radioimmunoassay of samples collected after induction, at 5 minutes prior to reperfusion, and at 10, 20, 30, 40, 50, 60, 90, and 120 minutes after reperfusion. Results. Pre-incision vasopressin concentrations ranged from ⬍0.5 to 2.6 pg/mL (reference serum vasopressin, ⬍1.7 pg/mL). Overall, levels increased before reperfusion, but fell thereafter. Individual patients manifested elevated levels during the period after reperfusion. Values immediately before reperfusion exhibited most variability, ranging from 0.8 to 40 pg/mL (median, 15; interquartile range [IQR], 4 –29) Median vasopressin concentrations 10 minutes postreperfusion were 7.6 pg/mL (IQR, 3–27). Only 3 of the 11 patients failed to generate vasopressin levels ⬎20 pg/mL. In each of these patients, hemodynamics were satisfactory without the need for additional pressor infusion. Maximum vasopressin concentration measured in any patient was 85 pg/mL. There was no correlation between vasopressin concentration and mean blood pressure or systemic vascular resistance index. Conclusion. Vasopressin concentrations during OLT vary widely and are elevated periodically during the anhepatic and postreperfusion stages, with no apparent relationship between vasopressin concentrations and blood pressure. Although vasopressin concentrations were not as high as those measured during some other clinical situations, these data suggest that a relative vasopressin deficiency is not a direct cause of hypotension during OLT. ELATIVE vasopressin deficiency occurs in patients with septic shock and infusion of vasopressin has been used therapeutically to treat systemic vasodilation during inflammatory states.1–5 Patients with end-stage liver disease manifest a similar hyperdynamic, vasodilated state, although cirrhosis is associated with increased vasopressin levels.6 Variceal bleeding owing to portal hypertension may be treated with high-dose vasopressin or one of its analogs, such as terlipressin.7 Vasopressin and its analogs have shown promise as a therapy for cirrhotic patients with the hepatorenal syndrome.8 –12 Vasodilation, with accompanying hypotension, may occur after reperfusion of the liver graft during orthotopic liver transplantation (OLT). Serum vasopressin concentrations during OLT have not previously been measured and the
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temporal course of the changes in vasopressin concentration in this patient population is unknown. The specific aim of this study was to define the temporal response of serum vasopressin concentration in the period
From the Department of Anesthesiology (M.T.K., B.G., D.R.B., D.J.P., J.Y.F.), Mayo Clinic College of Medicine, Rochester, Minnesota; and the Department of Anesthesiology (B.A.H.), Mayo Clinic College of Medicine, Jacksonville, Florida. Supported by a Mayo Clinic Rochester Dept of Anesthesiology Grant to MTK. Address reprint requests to Mark T. Keegan, MB, MRCPI, Department of Anesthesiology, Charlton 1145, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905. E-mail: keegan.mark@ mayo.edu
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.04.051
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 42, 2594 –2598 (2010)
SERUM VASOPRESSIN CONCENTRATIONS
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of potentially greatest hemodynamic instability during OLT, namely, the period after reperfusion of the liver graft. We hypothesized that reduced vasopressin concentration would be associated with postreperfusion hypotension. Identification of a vasopressin deficiency during this period would suggest that administration of exogenous vasopressin is appropriate as a treatment for postreperfusion hypotension. METHODS After institutional review board approval and informed consent, 11 adult patients undergoing OLT were studied. Exclusion criteria included preexisting renal failure (defined by the need for renal replacement therapy or a baseline creatinine ⬎2 mg/dL), pregnancy, age ⬍18 years, use of DDAVP or vasopressin infusion within 48 hours prior to surgery, repeat OLT, OLT with concomitant transplant of another organ (e.g., liver/kidney transplant), and acute liver failure. OLT was performed under general endotracheal anesthesia using a balanced anesthetic technique. After induction with midazolam, fentanyl, and propofol, anesthesia was maintained with isoflurane in an oxygen/air mixture. Approximately 20 –25 g/kg of fentanyl were administered over the duration of the procedure. Muscle relaxant (cisatracurium) was administered at the discretion of the anesthesiologist. Invasive hemodynamic monitoring, including brachial and pulmonary artery catheters, was used in all cases. Dopamine was administered throughout the duration of the procedure as part of our institutional OLT management protocol. The dopamine infusion was initiated at 2 g/kg/min and increased to 4 g/kg/min before reperfusion of the liver allograft. At the time of reperfusion, calcium chloride (1 g) and epinephrine boluses (10 g) were administered at the discretion of the anesthesiologist. No patient received intraoperative exogenous vasopressin. Liver transplantation was performed using conventional surgical techniques, including the piggyback technique, which avoids complete cross clamping of the inferior vena cava.13 Blood samples (5 mL) were obtained after induction of anesthesia but before surgical incision, at 5 minutes before reperfusion of the liver graft, and at 10, 20, 30, 40, 50, 60, 90, and 120 minutes after reperfusion. The intraoperative anesthesiology team collected the blood samples, drawn from an arterial catheter. Samples were transferred, on ice, to an on-site laboratory for analysis. Vasopressin testing was performed on 2.5 mL of EDTA plasma by radio-
immunoassay. The reference range for vasopressin testing on platelet-poor EDTA plasma from healthy volunteers after overnight fasting in our laboratory is ⬍1.7 pg/mL. The reasons for OLT, duration of anesthesia and surgery, estimated blood loss, fluids and blood products administered, hemodynamic parameters, and use of vasoactive medications to meet hemodynamic goals were obtained by review of the medical records. Descriptive data are summarized as mean (standard deviation [SD]) or median (interquartile range [IQR]), as appropriate, depending on the distribution of the data. Linear regression was used to examine the relationship between serum vasopressin concentration and a variety of hemodynamic parameters including mean arterial pressure, systemic vascular resistance index (SVRI), cardiac index, heart rate, mean pulmonary artery pressure, and stroke volume index. Data analyses were performed using SPSS 11.5 (SPSS Inc., Chicago, Ill) and MedCalc Version 9.1 (MedCalc Software, Mariakerke, Belgium.)
RESULTS
Samples were obtained from 11 patients, identified as A to K. The median age of the patients was 58 years (IQR, 51– 61). The median duration of the anesthetic procedure was 453 minutes (IQR, 379 –562) and the median duration of the operative procedure was 346 minutes (IQR, 287– 454). Epinephrine and phenylephrine infusions were administered to patient D, but otherwise the only continuous infusion of vasoactive medication administered was dopamine. The median (IQR) volumes of fluids administered were: Packed red blood cells 600 ml (301–1210), cell saver 450 mL (0 –1130), crystalloid 8500 mL (750 –1220), and colloid 100 mL (0 –2640). All but 1 patient (patient I) survived to hospital discharge. Patient I suffered from persistent cellular rejection and neurologic dysfunction. Withdrawal of support occurred 2 months after transplantation. Details of individual patients are provided in Table 1. In 1 patient (patient D), sampling was abandoned because of hemodynamic instability and the need to remove, and then reimplant, the liver allograft. Two other values were missing, 1 in each of 2 patients (I and K). A total of
Table 1. Patient Characteristics and Intraoperative Variables Patient
Reason for OLT
Age
MELD
LDLT
Anesthesia Duration (min)
Surgery Duration (min)
RBCs (mL)
Cell Saver (mL)
Crystalloid (mL)
Colloid (mL)
A B C D E F G H I J K
Autoimmune Cryptogenic PSC cholangio HCC Carcinoid PSC cholangio PSC PSC Alcoholic A1AT and HCC Amyloidosis
58 58 56 54 64 64 28 45 61 58 57
26 17 14 28 6 6 20 8 24 14 24
No No No No LDLT LDLT No LDLT No No No
530 379 686 691 453 467 315 562 323 433 451
428 287 559 550 379 324 231 454 227 346 331
4500 1056 301 6540 0 600 600 0 301 1210 950
7650 670 1125 6975 0 0 450 0 200 866 400
8025 7965 12793 18076 6314 9954 7541 8998 7495 8487 12018
3000 0 991 2500 1000 0 0 3000 1003 2515 0
Abbreviations: MELD, Model for End-Stage Liver Disease Score; LDLT, living donor liver transplantation; RBCs, red blood cells; PSC, primary sclerosing cholangitis; Cholangio; cholangiocarcinoma; HCC, hepatocellular carcinoma; A1AT, alpha-1-anti-trypsin deficiency.
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KEEGAN, GALI, BROWN ET AL Table 2. Serum Vasopressin Concentrations (pg/mL) in 11 Patients During OLT Minutes After Reperfusion
Patient
Pre-Incision
Pre-Reperfusion
10
20
30
40
50
60
90
120
A B C D E F G H I J K
0.7 ⬍0.5 ⬍0.5 ⬍0.5 ⬍0.5 0.8 0.8 ⬍0.5 2.6 2.1 ⬍0.5
15 15 0.8 38 3.8 40 7.1 12 20 0.5 29
85 9.9 1.2 — 2.6 27 5 3.6 19 5.3 27
25 7.1 1 — 2.4 12 16 4.3 21 5.9 11
7.5 1.7 0.7 — 11 6.6 7.4 22 17 5 13
3.4 1.9 0.8 — 2.3 5.7 52 9.2 17 9.3 22
3 4.6 1 — 2 4.5 45 5.6 — 11 9.5
4.1 13 0.6 — 1.2 21 23 2.9 27 5.4 —
1.9 2.7 1.3 — 68 19 11 5.5 7.7 3.4 51
2.8 13 1.1 — 19 14 8.6 0.8 6.4 4 12
100 serum vasopressin concentrations were measured. The individual patient values are presented in Table 2. Pre-incision vasopressin concentrations were relatively low. Nine of the pre-incision values were within the reference range; the 2 values above the reference range were minimally elevated. Otherwise, there was great heterogeneity in the data. Overall, the levels pre-reperfusion and at 10 minutes postreperfusion tended to be highest. The median (IQR) value before reperfusion was 15 pg/mL (4 –29) and the median for the point 10 minutes post-reperfusion was 7.6 pg/mL (3– 27). However, data collected at these timepoints demonstrated great variability, ranging from normal to 85 pg/mL. Thereafter, the median values tended to decrease, although individual patients manifested elevated levels in isolation. Only 3 of the 11 patients (B, C, J) failed to generate vasopressin levels ⬎20 pg/mL at some point. In each of these patients, hemodynamics were satisfactory without the need for additional pressor infusion. The maximum vasopressin concentration measured in any patient was 85 pg/mL (patient A). Graphs of serial serum vasopressin concentrations for each patient are shown in Figure 1. Median serum vasopressin concentrations for each time-point are shown in
Figure 2. The relationship between vasopressin concentration and mean arterial blood pressure is shown in Figure 3. The coefficient of determination (r2) was only 0.06, indicating that there was poor correlation between serum vasopressin concentration and mean arterial blood pressure. Similarly, r2 values for the relationships between serum vasopressin concentrations and SVRI, cardiac index, heart rate, mean pulmonary artery pressure, and stroke volume index were also low at 0.02, 0.01, 0.02, 0.01, and 0.01, respectively, indicating very poor correlation between vasopressin concentration and hemodynamic variables during OLT. DISCUSSION
Patients with end-stage liver disease undergoing OLT were able to generate a vasopressin response to the stress of surgery. Pre-incision vasopressin concentrations were low, increased around the time of reperfusion, and fell thereafter. The most notable aspect of our study was the heterogeneity of the vasopressin response, with values immediately before reperfusion exhibiting the most variability, ranging from 0.8 to 40 pg/mL. Only 3 patients (who were
Serum vasopressin concentration (pg/ml)
90 80
A
70
B C
60
D
50
E
40
G
F H
30
I
20
J K
10
0 12
0
0 11
90
10
70
80
60
40
50
30
10
20
Ba
se Pr line e re pe rf
0
Time relative to reperfusion (minutes)
Fig 1. Serial vasopressin concentrations for each patient after reperfusion of the liver allograft.
Fig 2. Serial median vasopressin concentrations after reperfusion of the liver allograft in 11 patients undergoing OLT.
Serum vasopressin concentration (pg/ml)
SERUM VASOPRESSIN CONCENTRATIONS
2597
90 80 70 60 50 40 30 20 10 0 40
60
80
100
120
Mean arterial blood pressure (mmHg)
Fig 3. The relationship between vasopressin concentration and mean arterial blood pressure. The r2 was only 0.06, indicating that there was a poor correlation between serum vasopressin concentration and mean arterial blood pressure. Similar “scattergrams” were also found when vasopressin was plotted against a variety of other intraoperative hemodynamic variables.
hemodynamically stable) failed to generate vasopressin levels ⬎20 pg/mL at some point and the highest level recorded was 85 pg/mL. There was no correlation between vasopressin concentration and mean arterial blood pressure, SVRI, and a variety of other hemodynamic variables. The mean vasopressin concentration during the period immediately before reperfusion and in the 60 minutes after reperfusion was 12.6 pg/mL. This value is slightly higher than levels typically seen in patients with vasodilatory shock (mean concentrations, ⬍10 pg/mL.)2 The concentrations seen in patients undergoing OLT were considerably lower, however, than those reported in patients with cardiogenic shock, during cardiopulmonary bypass (mean concentrations approximately 198 pg/mL) or in patients after cardiac arrest (mean concentrations, 70 –193 pg/mL). There is increasing interest in the use of vasopressin in the syndrome of “irreversible shock” and in resuscitation of critically ill patients with vasodilatory shock, although the optimum dose is controversial.3,14 –17 Vasopressin has also been suggested as a “rescue” vasopressor agent in the operating room.18 Patients with intraoperative septic shock, uncontrolled hemorrhagic shock,19 –21 anaphylactic shock,22 hypotension during spinal anesthesia,23 and shock after cardiac surgery24 –27 may benefit from vasopressin administration. Patients with end-stage liver disease manifest a vasodilated state.28 There is a complex interaction between vasodilators and vasoconstrictors in patients with cirrhosis. Some investigators have used vasopressin and its analogs in such patients to treat hypotension or hepatorenal syndrome. Others, however, have suggested the use of antidiuretic hormone antagonists to treat hyponatremia.29 –31 In a porcine hepatic hemorrhagic shock model, vasopressin conferred a survival advantage over treatment with epinephrine or fluid. In contrast with treatment with epinephrine or fluid, vasopressin did not increase hepatic hemorrhage, perhaps because of its vasoconstrictor effects on the truncal and mesenteric arteries.32–34 Vasopressin may thus have
some advantages compared to other vasoactive medications during liver surgery. There is a paucity of data regarding the concentration of vasopressin in the serum of patients undergoing OLT or the impact of low-dose vasopressin administration on hemodynamics during this procedure. Roth35 describes the use of a vasopressin bolus in a single patient undergoing OLT to treat refractory hypotension in the period after reperfusion of the liver allograft. Although the patient’s hemodynamics seemed to improve after administration of low-dose vasopressin, measurements of serum vasopressin concentrations were not performed, so a vasopressin deficiency, although suspected, could not be proven. Although there has been a study of the administration of a vasopressin infusion during OLT, this was to investigate the hormone’s influence on surgical bleeding and used significantly higher doses of vasopressin than are used in sepsis.36 Furthermore, serum vasopressin concentrations were not measured. Our study is limited in that it is of a relatively small group of patients. Serum osmolality, a potent controller of vasopressin secretion, was not measured in conjunction with serum vasopressin concentrations.2 In addition, the variable amounts of fluids and transfusions administered may have lead to a “wash-out” effect, which may have reduced vasopressin levels in some patients and not others. Most measurements were made during the period after reperfusion in an effort to ascertain vasopressin concentrations in the period of greatest hemodynamic instability. We may have missed elevated serum vasopressin concentrations in the pre-anhepatic and anhepatic stages of OLT. Furthermore, given the heterogeneity of the data, the decision to focus on the period after reperfusion (at which time a variety of vasoactive mediators are released from the graft and the poorly perfused gut) may have been unwise. Finally, patients in our study had dopamine administered during the transplant procedure. The effect of low-dose dopamine on vasopressin concentration is not known, although its administration has been shown to suppress other endogenous hormones.37 Further investigations regarding manipulation of the vasopressin system are warranted as the results could have significant impact on intraoperative care. It would be interesting to examine the impact of a continuous vasopressin infusion on the intraoperative hemodynamics and serum vasopressin concentrations. Studies examining the perioperative (as opposed to just intraoperative) changes in vasopressin concentration are also required. In conclusion, vasopressin concentrations during OLT vary widely and are elevated at least periodically during the anhepatic and post-reperfusion stages of OLT, with no apparent relationship between vasopressin concentrations and a variety of hemodynamic parameters, including blood pressure and SVRI. Although vasopressin concentrations were not as high as those measured during some other clinical situations, these data suggest that a relative vasopressin deficiency is not a direct cause of hypotension during OLT.
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REFERENCES 1. Landry DW, Levin HR, Gallant EM, et al: Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 95:1122, 1997 2. Treschan TA, Peters J: The vasopressin system: physiology and clinical strategies. Anesthesiology 105:599, 2006 3. Holmes CL, Patel BM, Russell JA, et al: Physiology of vasopressin relevant to management of septic shock. Chest 120:989, 2001 4. Malay MB, Ashton RC, Jr., Landry DW, et al: Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 47:699, 1999 5. Patel BM, Chittock DR, Russell JA, et al: Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 96:576, 2002 6. Arroyo V, Jimenez W: Complications of cirrhosis. II. Renal and circulatory dysfunction. Lights and shadows in an important clinical problem. J Hepatol 32:157, 2000 7. Ioannou GN, Doust J, Rockey DC: Systematic review: terlipressin in acute oesophageal variceal haemorrhage. Aliment Pharm Ther 17:53, 2003 8. Kiser TH, Fish DN, Obritsch MD, et al: Vasopressin, not octreotide, may be beneficial in the treatment of hepatorenal syndrome: a retrospective study. Nephrol Dialysis Transpl 20:1813, 2005 9. Moreau R, Durand F, Poynard T, et al: Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 122:923, 2002 10. Moreau R, Lebrec D: The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond. Hepatology 43:385, 2006 11. Eisenman A, Armali Z, Enat R, et al: Low-dose vasopressin restores diuresis both in patients with hepatorenal syndrome and in anuric patients with end-stage heart failure. J Intern Med 246:183, 1999 12. Arroyo V, Terra C, Gines P: New treatments of hepatorenal syndrome. Semin Liver Dis 26:254, 2006 13. Saggi BH, Farmer DG, Yersiz H, et al: Surgical advances in liver and bowel transplantation. Anesthesiol Clin North Am 22: 713, 2004 14. Robin JK, Oliver JA, Landry DW: Vasopressin deficiency in the syndrome of irreversible shock. J Trauma Inj Infect Crit Care 54:S149, 2003 15. Holmes CL, Walley KR: Vasopressin in the ICU. Curr Opin Crit Care 10:442, 2004 16. Patel BM, Chittock DR, Russell JA, et al: Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 96:576, 2002 17. Dellinger RP, Carlet JM, Masur H, et al: Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858, 2004 18. Jochberger S, Wenzel V, Dunser M: Arginine vasopressin as a rescue vasopressor agent in the operating room. Curr Opin Anesthesiol 18:396, 2005 19. Krismer AC, Wenzel V, Voelckel WG, et al: Employing vasopressin as an adjunct vasopressor in uncontrolled traumatic
KEEGAN, GALI, BROWN ET AL hemorrhagic shock. Three cases and a brief analysis of the literature. Anaesthesist 54:220, 2005 20. Sharma RM, Setlur R: Vasopressin in hemorrhagic shock. Anesth Analg 101:833, 2005 21. Stadlbauer KH, Wenzel V, Krismer AC, et al: Vasopressin during uncontrolled hemorrhagic shock: less bleeding below the diaphragm, more perfusion above. Anesth Analg 101:830, 2005 22. Kill C, Wranze E, Wulf H: Successful treatment of severe anaphylactic shock with vasopressin. Two case reports. Int Arch Allergy Immunol 134:260, 2004 23. Braun EB, Palin CA, Hogue CW: Vasopressin during spinal anesthesia in a patient with primary pulmonary hypertension treated with intravenous epoprostenol. Anesth Analg 99:36, 2004 24. Albright TN, Zimmerman MA, Selzman CH: Vasopressin in the cardiac surgery intensive care unit. Am J Crit Care 11:326, 2002 25. Argenziano M, Chen JM, Cullinane S, et al: Arginine vasopressin in the management of vasodilatory hypotension after cardiac transplantation. J Heart Lung Transpl 18:814, 1999 26. Argenziano M, Choudhri AF, Oz MC, et al: A prospective randomized trial of arginine vasopressin in the treatment of vasodilatory shock after left ventricular assist device placement. Circulation 96:II-286, 1997 27. Overand PT, Teply JF: Vasopressin for the treatment of refractory hypotension after cardiopulmonary bypass. Anesth Analg 86:1207, 1998 28. Carton EG, Rettke SR, Plevak DJ, et al: Perioperative care of the liver transplant patient: Part 1. Anesth Analg 78:120, 1994 29. Arroyo V, Jimenez W: Clinical need for antidiuretic hormone antagonists in cirrhosis. Hepatology 37:13, 2003 30. Wong F, Blei AT, Blendis LM, et al: A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebocontrolled trial. Hepatology 37:182, 2003 31. Schrier RW, Gross P, Gheorghiade M, et al: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355:2099, 2006 32. Raedler C, Voelckel WG, Wenzel V, et al: Treatment of uncontrolled hemorrhagic shock after liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin. Anesth Analg 98:1759, 2004 33. Voelckel WG, Raedler C, Wenzel V, et al: Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs. Crit Care Med 31:1160, 2003 34. Stadlbauer KH, Wagner-Berger HG, Raedler C, et al: Vasopressin, but not fluid resuscitation, enhances survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs. Anesthesiology 98:699, 2003 35. Roth JV: The use of vasopressin bolus to treat refractory hypotension secondary to reperfusion during orthotopic liver transplantation. Anesth Analg 103:261, 2006 36. Daloze PM, Arnoux R, Corman J, et al: Vasopressin use in human liver transplantation. Transplant Proc 19:2424, 1987 37. Van den Berghe G, de Zegher F: Anterior pituitary function during critical illness and dopamine treatment. Crit Care Med 24:1580, 1996
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temporal course of the changes in vasopressin concentration in this patient population is unknown. The specific aim of this study was to define the temporal response of serum vasopressin concentration in the period
From the Department of Anesthesiology (M.T.K., B.G., D.R.B., D.J.P., J.Y.F.), Mayo Clinic College of Medicine, Rochester, Minnesota; and the Department of Anesthesiology (B.A.H.), Mayo Clinic College of Medicine, Jacksonville, Florida. Supported by a Mayo Clinic Rochester Dept of Anesthesiology Grant to MTK. Address reprint requests to Mark T. Keegan, MB, MRCPI, Department of Anesthesiology, Charlton 1145, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905. E-mail: keegan.mark@ mayo.edu
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.04.051
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2594
Transplantation Proceedings, 42, 2594 –2598 (2010)
SERUM VASOPRESSIN CONCENTRATIONS
2595
of potentially greatest hemodynamic instability during OLT, namely, the period after reperfusion of the liver graft. We hypothesized that reduced vasopressin concentration would be associated with postreperfusion hypotension. Identification of a vasopressin deficiency during this period would suggest that administration of exogenous vasopressin is appropriate as a treatment for postreperfusion hypotension. METHODS After institutional review board approval and informed consent, 11 adult patients undergoing OLT were studied. Exclusion criteria included preexisting renal failure (defined by the need for renal replacement therapy or a baseline creatinine ⬎2 mg/dL), pregnancy, age ⬍18 years, use of DDAVP or vasopressin infusion within 48 hours prior to surgery, repeat OLT, OLT with concomitant transplant of another organ (e.g., liver/kidney transplant), and acute liver failure. OLT was performed under general endotracheal anesthesia using a balanced anesthetic technique. After induction with midazolam, fentanyl, and propofol, anesthesia was maintained with isoflurane in an oxygen/air mixture. Approximately 20 –25 g/kg of fentanyl were administered over the duration of the procedure. Muscle relaxant (cisatracurium) was administered at the discretion of the anesthesiologist. Invasive hemodynamic monitoring, including brachial and pulmonary artery catheters, was used in all cases. Dopamine was administered throughout the duration of the procedure as part of our institutional OLT management protocol. The dopamine infusion was initiated at 2 g/kg/min and increased to 4 g/kg/min before reperfusion of the liver allograft. At the time of reperfusion, calcium chloride (1 g) and epinephrine boluses (10 g) were administered at the discretion of the anesthesiologist. No patient received intraoperative exogenous vasopressin. Liver transplantation was performed using conventional surgical techniques, including the piggyback technique, which avoids complete cross clamping of the inferior vena cava.13 Blood samples (5 mL) were obtained after induction of anesthesia but before surgical incision, at 5 minutes before reperfusion of the liver graft, and at 10, 20, 30, 40, 50, 60, 90, and 120 minutes after reperfusion. The intraoperative anesthesiology team collected the blood samples, drawn from an arterial catheter. Samples were transferred, on ice, to an on-site laboratory for analysis. Vasopressin testing was performed on 2.5 mL of EDTA plasma by radio-
immunoassay. The reference range for vasopressin testing on platelet-poor EDTA plasma from healthy volunteers after overnight fasting in our laboratory is ⬍1.7 pg/mL. The reasons for OLT, duration of anesthesia and surgery, estimated blood loss, fluids and blood products administered, hemodynamic parameters, and use of vasoactive medications to meet hemodynamic goals were obtained by review of the medical records. Descriptive data are summarized as mean (standard deviation [SD]) or median (interquartile range [IQR]), as appropriate, depending on the distribution of the data. Linear regression was used to examine the relationship between serum vasopressin concentration and a variety of hemodynamic parameters including mean arterial pressure, systemic vascular resistance index (SVRI), cardiac index, heart rate, mean pulmonary artery pressure, and stroke volume index. Data analyses were performed using SPSS 11.5 (SPSS Inc., Chicago, Ill) and MedCalc Version 9.1 (MedCalc Software, Mariakerke, Belgium.)
RESULTS
Samples were obtained from 11 patients, identified as A to K. The median age of the patients was 58 years (IQR, 51– 61). The median duration of the anesthetic procedure was 453 minutes (IQR, 379 –562) and the median duration of the operative procedure was 346 minutes (IQR, 287– 454). Epinephrine and phenylephrine infusions were administered to patient D, but otherwise the only continuous infusion of vasoactive medication administered was dopamine. The median (IQR) volumes of fluids administered were: Packed red blood cells 600 ml (301–1210), cell saver 450 mL (0 –1130), crystalloid 8500 mL (750 –1220), and colloid 100 mL (0 –2640). All but 1 patient (patient I) survived to hospital discharge. Patient I suffered from persistent cellular rejection and neurologic dysfunction. Withdrawal of support occurred 2 months after transplantation. Details of individual patients are provided in Table 1. In 1 patient (patient D), sampling was abandoned because of hemodynamic instability and the need to remove, and then reimplant, the liver allograft. Two other values were missing, 1 in each of 2 patients (I and K). A total of
Table 1. Patient Characteristics and Intraoperative Variables Patient
Reason for OLT
Age
MELD
LDLT
Anesthesia Duration (min)
Surgery Duration (min)
RBCs (mL)
Cell Saver (mL)
Crystalloid (mL)
Colloid (mL)
A B C D E F G H I J K
Autoimmune Cryptogenic PSC cholangio HCC Carcinoid PSC cholangio PSC PSC Alcoholic A1AT and HCC Amyloidosis
58 58 56 54 64 64 28 45 61 58 57
26 17 14 28 6 6 20 8 24 14 24
No No No No LDLT LDLT No LDLT No No No
530 379 686 691 453 467 315 562 323 433 451
428 287 559 550 379 324 231 454 227 346 331
4500 1056 301 6540 0 600 600 0 301 1210 950
7650 670 1125 6975 0 0 450 0 200 866 400
8025 7965 12793 18076 6314 9954 7541 8998 7495 8487 12018
3000 0 991 2500 1000 0 0 3000 1003 2515 0
Abbreviations: MELD, Model for End-Stage Liver Disease Score; LDLT, living donor liver transplantation; RBCs, red blood cells; PSC, primary sclerosing cholangitis; Cholangio; cholangiocarcinoma; HCC, hepatocellular carcinoma; A1AT, alpha-1-anti-trypsin deficiency.
2596
KEEGAN, GALI, BROWN ET AL Table 2. Serum Vasopressin Concentrations (pg/mL) in 11 Patients During OLT Minutes After Reperfusion
Patient
Pre-Incision
Pre-Reperfusion
10
20
30
40
50
60
90
120
A B C D E F G H I J K
0.7 ⬍0.5 ⬍0.5 ⬍0.5 ⬍0.5 0.8 0.8 ⬍0.5 2.6 2.1 ⬍0.5
15 15 0.8 38 3.8 40 7.1 12 20 0.5 29
85 9.9 1.2 — 2.6 27 5 3.6 19 5.3 27
25 7.1 1 — 2.4 12 16 4.3 21 5.9 11
7.5 1.7 0.7 — 11 6.6 7.4 22 17 5 13
3.4 1.9 0.8 — 2.3 5.7 52 9.2 17 9.3 22
3 4.6 1 — 2 4.5 45 5.6 — 11 9.5
4.1 13 0.6 — 1.2 21 23 2.9 27 5.4 —
1.9 2.7 1.3 — 68 19 11 5.5 7.7 3.4 51
2.8 13 1.1 — 19 14 8.6 0.8 6.4 4 12
100 serum vasopressin concentrations were measured. The individual patient values are presented in Table 2. Pre-incision vasopressin concentrations were relatively low. Nine of the pre-incision values were within the reference range; the 2 values above the reference range were minimally elevated. Otherwise, there was great heterogeneity in the data. Overall, the levels pre-reperfusion and at 10 minutes postreperfusion tended to be highest. The median (IQR) value before reperfusion was 15 pg/mL (4 –29) and the median for the point 10 minutes post-reperfusion was 7.6 pg/mL (3– 27). However, data collected at these timepoints demonstrated great variability, ranging from normal to 85 pg/mL. Thereafter, the median values tended to decrease, although individual patients manifested elevated levels in isolation. Only 3 of the 11 patients (B, C, J) failed to generate vasopressin levels ⬎20 pg/mL at some point. In each of these patients, hemodynamics were satisfactory without the need for additional pressor infusion. The maximum vasopressin concentration measured in any patient was 85 pg/mL (patient A). Graphs of serial serum vasopressin concentrations for each patient are shown in Figure 1. Median serum vasopressin concentrations for each time-point are shown in
Figure 2. The relationship between vasopressin concentration and mean arterial blood pressure is shown in Figure 3. The coefficient of determination (r2) was only 0.06, indicating that there was poor correlation between serum vasopressin concentration and mean arterial blood pressure. Similarly, r2 values for the relationships between serum vasopressin concentrations and SVRI, cardiac index, heart rate, mean pulmonary artery pressure, and stroke volume index were also low at 0.02, 0.01, 0.02, 0.01, and 0.01, respectively, indicating very poor correlation between vasopressin concentration and hemodynamic variables during OLT. DISCUSSION
Patients with end-stage liver disease undergoing OLT were able to generate a vasopressin response to the stress of surgery. Pre-incision vasopressin concentrations were low, increased around the time of reperfusion, and fell thereafter. The most notable aspect of our study was the heterogeneity of the vasopressin response, with values immediately before reperfusion exhibiting the most variability, ranging from 0.8 to 40 pg/mL. Only 3 patients (who were
Serum vasopressin concentration (pg/ml)
90 80
A
70
B C
60
D
50
E
40
G
F H
30
I
20
J K
10
0 12
0
0 11
90
10
70
80
60
40
50
30
10
20
Ba
se Pr line e re pe rf
0
Time relative to reperfusion (minutes)
Fig 1. Serial vasopressin concentrations for each patient after reperfusion of the liver allograft.
Fig 2. Serial median vasopressin concentrations after reperfusion of the liver allograft in 11 patients undergoing OLT.
Serum vasopressin concentration (pg/ml)
SERUM VASOPRESSIN CONCENTRATIONS
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90 80 70 60 50 40 30 20 10 0 40
60
80
100
120
Mean arterial blood pressure (mmHg)
Fig 3. The relationship between vasopressin concentration and mean arterial blood pressure. The r2 was only 0.06, indicating that there was a poor correlation between serum vasopressin concentration and mean arterial blood pressure. Similar “scattergrams” were also found when vasopressin was plotted against a variety of other intraoperative hemodynamic variables.
hemodynamically stable) failed to generate vasopressin levels ⬎20 pg/mL at some point and the highest level recorded was 85 pg/mL. There was no correlation between vasopressin concentration and mean arterial blood pressure, SVRI, and a variety of other hemodynamic variables. The mean vasopressin concentration during the period immediately before reperfusion and in the 60 minutes after reperfusion was 12.6 pg/mL. This value is slightly higher than levels typically seen in patients with vasodilatory shock (mean concentrations, ⬍10 pg/mL.)2 The concentrations seen in patients undergoing OLT were considerably lower, however, than those reported in patients with cardiogenic shock, during cardiopulmonary bypass (mean concentrations approximately 198 pg/mL) or in patients after cardiac arrest (mean concentrations, 70 –193 pg/mL). There is increasing interest in the use of vasopressin in the syndrome of “irreversible shock” and in resuscitation of critically ill patients with vasodilatory shock, although the optimum dose is controversial.3,14 –17 Vasopressin has also been suggested as a “rescue” vasopressor agent in the operating room.18 Patients with intraoperative septic shock, uncontrolled hemorrhagic shock,19 –21 anaphylactic shock,22 hypotension during spinal anesthesia,23 and shock after cardiac surgery24 –27 may benefit from vasopressin administration. Patients with end-stage liver disease manifest a vasodilated state.28 There is a complex interaction between vasodilators and vasoconstrictors in patients with cirrhosis. Some investigators have used vasopressin and its analogs in such patients to treat hypotension or hepatorenal syndrome. Others, however, have suggested the use of antidiuretic hormone antagonists to treat hyponatremia.29 –31 In a porcine hepatic hemorrhagic shock model, vasopressin conferred a survival advantage over treatment with epinephrine or fluid. In contrast with treatment with epinephrine or fluid, vasopressin did not increase hepatic hemorrhage, perhaps because of its vasoconstrictor effects on the truncal and mesenteric arteries.32–34 Vasopressin may thus have
some advantages compared to other vasoactive medications during liver surgery. There is a paucity of data regarding the concentration of vasopressin in the serum of patients undergoing OLT or the impact of low-dose vasopressin administration on hemodynamics during this procedure. Roth35 describes the use of a vasopressin bolus in a single patient undergoing OLT to treat refractory hypotension in the period after reperfusion of the liver allograft. Although the patient’s hemodynamics seemed to improve after administration of low-dose vasopressin, measurements of serum vasopressin concentrations were not performed, so a vasopressin deficiency, although suspected, could not be proven. Although there has been a study of the administration of a vasopressin infusion during OLT, this was to investigate the hormone’s influence on surgical bleeding and used significantly higher doses of vasopressin than are used in sepsis.36 Furthermore, serum vasopressin concentrations were not measured. Our study is limited in that it is of a relatively small group of patients. Serum osmolality, a potent controller of vasopressin secretion, was not measured in conjunction with serum vasopressin concentrations.2 In addition, the variable amounts of fluids and transfusions administered may have lead to a “wash-out” effect, which may have reduced vasopressin levels in some patients and not others. Most measurements were made during the period after reperfusion in an effort to ascertain vasopressin concentrations in the period of greatest hemodynamic instability. We may have missed elevated serum vasopressin concentrations in the pre-anhepatic and anhepatic stages of OLT. Furthermore, given the heterogeneity of the data, the decision to focus on the period after reperfusion (at which time a variety of vasoactive mediators are released from the graft and the poorly perfused gut) may have been unwise. Finally, patients in our study had dopamine administered during the transplant procedure. The effect of low-dose dopamine on vasopressin concentration is not known, although its administration has been shown to suppress other endogenous hormones.37 Further investigations regarding manipulation of the vasopressin system are warranted as the results could have significant impact on intraoperative care. It would be interesting to examine the impact of a continuous vasopressin infusion on the intraoperative hemodynamics and serum vasopressin concentrations. Studies examining the perioperative (as opposed to just intraoperative) changes in vasopressin concentration are also required. In conclusion, vasopressin concentrations during OLT vary widely and are elevated at least periodically during the anhepatic and post-reperfusion stages of OLT, with no apparent relationship between vasopressin concentrations and a variety of hemodynamic parameters, including blood pressure and SVRI. Although vasopressin concentrations were not as high as those measured during some other clinical situations, these data suggest that a relative vasopressin deficiency is not a direct cause of hypotension during OLT.
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REFERENCES 1. Landry DW, Levin HR, Gallant EM, et al: Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 95:1122, 1997 2. Treschan TA, Peters J: The vasopressin system: physiology and clinical strategies. Anesthesiology 105:599, 2006 3. Holmes CL, Patel BM, Russell JA, et al: Physiology of vasopressin relevant to management of septic shock. Chest 120:989, 2001 4. Malay MB, Ashton RC, Jr., Landry DW, et al: Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 47:699, 1999 5. Patel BM, Chittock DR, Russell JA, et al: Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 96:576, 2002 6. Arroyo V, Jimenez W: Complications of cirrhosis. II. Renal and circulatory dysfunction. Lights and shadows in an important clinical problem. J Hepatol 32:157, 2000 7. Ioannou GN, Doust J, Rockey DC: Systematic review: terlipressin in acute oesophageal variceal haemorrhage. Aliment Pharm Ther 17:53, 2003 8. Kiser TH, Fish DN, Obritsch MD, et al: Vasopressin, not octreotide, may be beneficial in the treatment of hepatorenal syndrome: a retrospective study. Nephrol Dialysis Transpl 20:1813, 2005 9. Moreau R, Durand F, Poynard T, et al: Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 122:923, 2002 10. Moreau R, Lebrec D: The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond. Hepatology 43:385, 2006 11. Eisenman A, Armali Z, Enat R, et al: Low-dose vasopressin restores diuresis both in patients with hepatorenal syndrome and in anuric patients with end-stage heart failure. J Intern Med 246:183, 1999 12. Arroyo V, Terra C, Gines P: New treatments of hepatorenal syndrome. Semin Liver Dis 26:254, 2006 13. Saggi BH, Farmer DG, Yersiz H, et al: Surgical advances in liver and bowel transplantation. Anesthesiol Clin North Am 22: 713, 2004 14. Robin JK, Oliver JA, Landry DW: Vasopressin deficiency in the syndrome of irreversible shock. J Trauma Inj Infect Crit Care 54:S149, 2003 15. Holmes CL, Walley KR: Vasopressin in the ICU. Curr Opin Crit Care 10:442, 2004 16. Patel BM, Chittock DR, Russell JA, et al: Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 96:576, 2002 17. Dellinger RP, Carlet JM, Masur H, et al: Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858, 2004 18. Jochberger S, Wenzel V, Dunser M: Arginine vasopressin as a rescue vasopressor agent in the operating room. Curr Opin Anesthesiol 18:396, 2005 19. Krismer AC, Wenzel V, Voelckel WG, et al: Employing vasopressin as an adjunct vasopressor in uncontrolled traumatic
KEEGAN, GALI, BROWN ET AL hemorrhagic shock. Three cases and a brief analysis of the literature. Anaesthesist 54:220, 2005 20. Sharma RM, Setlur R: Vasopressin in hemorrhagic shock. Anesth Analg 101:833, 2005 21. Stadlbauer KH, Wenzel V, Krismer AC, et al: Vasopressin during uncontrolled hemorrhagic shock: less bleeding below the diaphragm, more perfusion above. Anesth Analg 101:830, 2005 22. Kill C, Wranze E, Wulf H: Successful treatment of severe anaphylactic shock with vasopressin. Two case reports. Int Arch Allergy Immunol 134:260, 2004 23. Braun EB, Palin CA, Hogue CW: Vasopressin during spinal anesthesia in a patient with primary pulmonary hypertension treated with intravenous epoprostenol. Anesth Analg 99:36, 2004 24. Albright TN, Zimmerman MA, Selzman CH: Vasopressin in the cardiac surgery intensive care unit. Am J Crit Care 11:326, 2002 25. Argenziano M, Chen JM, Cullinane S, et al: Arginine vasopressin in the management of vasodilatory hypotension after cardiac transplantation. J Heart Lung Transpl 18:814, 1999 26. Argenziano M, Choudhri AF, Oz MC, et al: A prospective randomized trial of arginine vasopressin in the treatment of vasodilatory shock after left ventricular assist device placement. Circulation 96:II-286, 1997 27. Overand PT, Teply JF: Vasopressin for the treatment of refractory hypotension after cardiopulmonary bypass. Anesth Analg 86:1207, 1998 28. Carton EG, Rettke SR, Plevak DJ, et al: Perioperative care of the liver transplant patient: Part 1. Anesth Analg 78:120, 1994 29. Arroyo V, Jimenez W: Clinical need for antidiuretic hormone antagonists in cirrhosis. Hepatology 37:13, 2003 30. Wong F, Blei AT, Blendis LM, et al: A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebocontrolled trial. Hepatology 37:182, 2003 31. Schrier RW, Gross P, Gheorghiade M, et al: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355:2099, 2006 32. Raedler C, Voelckel WG, Wenzel V, et al: Treatment of uncontrolled hemorrhagic shock after liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin. Anesth Analg 98:1759, 2004 33. Voelckel WG, Raedler C, Wenzel V, et al: Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs. Crit Care Med 31:1160, 2003 34. Stadlbauer KH, Wagner-Berger HG, Raedler C, et al: Vasopressin, but not fluid resuscitation, enhances survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs. Anesthesiology 98:699, 2003 35. Roth JV: The use of vasopressin bolus to treat refractory hypotension secondary to reperfusion during orthotopic liver transplantation. Anesth Analg 103:261, 2006 36. Daloze PM, Arnoux R, Corman J, et al: Vasopressin use in human liver transplantation. Transplant Proc 19:2424, 1987 37. Van den Berghe G, de Zegher F: Anterior pituitary function during critical illness and dopamine treatment. Crit Care Med 24:1580, 1996