Clinical Pharmacokinetics

, Volume 7, Issue 3, pp 234–251 | Cite as

Effect of Cardiopulmonary Bypass on the Pharmacokinetics of Drugs

  • Frederick O. Holley
  • Katherine V. Ponganis
  • Donald R. Stanski


The cardiopulmonary bypass apparatus must temporarily substitute for the cardiac and pulmonary function of the patient undergoing heart surgery. In order to meet the metabolic needs of the patient and the technical demands of the surgeon, within the limits of engineering technology, a number of major alterations are made in normal physiology. The patient is typically cooled to 27°C and perfused with a non-pulsatile flow of blood which has been diluted with saline to a haematocrit in the mid-20s. Blood flow and pressure are often considerably less than normal. Blood coagulation is prevented by administration of a massive dose of heparin. Central redistribution of blood flow, elaboration of stress-reactant hormones, and fluid and electrolyte shifts occur in response to these changes. In the postoperative period, these alterations are reversed, and normal physiology is restored.

Effects upon the pharmacokinetics of drugs are anticipated. The clearance of many drugs may be reduced. Protein binding is diminished by haemodilution, but may rise above normal in the postoperative period for basic drugs which bind to α1-acid glycoprotein. Changes in volume of distribution depend upon the opposing influences of protein binding and reduced peripheral perfusion. Previous studies on the pharmacokinetics of drugs during and after cardiopulmonary bypass illustrate many of these effects. The clearance of digoxin, fentanyl, and the cephalosporins is reduced after cardiopulmonary bypass, and the volume of distribution of cefazolin is increased during cardiopulmonary bypass. Studies of digitoxin and propranolol are also reviewed.

Many of the investigations in this area of study have been limited by logistical and methodological factors. Thus, the effects of cardiopulmonary bypass on the pharmacokinetics of drugs are incompletely understood, and the subject merits further attention.


Fentanyl Propranolol Digoxin Cardiopulmonary Bypass Digitoxin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akl, B.E. and Richardson, G.: Serum cefazolin levels during cardiopulmonary bypass. Annals of Thoracic Surgery 29: 109–112 (1980).PubMedCrossRefGoogle Scholar
  2. Alderman, E.I.; Coltart, J.; Wettach, G.E. and Harrison, D.C.: Coronary artery syndromes after sudden propranolol withdrawal. Annals of Internal Medicine 81: 625–627 (1974).PubMedGoogle Scholar
  3. Aronson, J.K.: Clinical Pharmacokinetics of digoxin 1980. Clinical Pharmacokinetics 5: 137–149 (1980).PubMedCrossRefGoogle Scholar
  4. Aziz, N.A.; Gambertoglio, J.G.; Lin, E.T.; Grausz, H. and Benet, L.Z.: Pharmacokinetics of cefamandole using a HPLC assay. Journal of Pharmacokinetics and Biopharmaceutics 6: 153–164 (1978).PubMedGoogle Scholar
  5. Benowitz, N.; Forsyth, R.P.; Melmon, K.L. and Rowland, M.: Lidocaine disposition kinetics in monkey and man. I. Prediction by a perfusion model. Clinical Pharmacology and Therapeutics 16: 87–98 (1974a).PubMedGoogle Scholar
  6. Benowitz, N.; Forsyth, R.P.; Melmon, K.L. and Rowland, M.: Lidocaine disposition kinetics in monkey and man. II. Effects of hemorrhage and sympathomimetic drug administration. Clinical Pharmacology and Therapeutics 16: 99–109, (1974b).PubMedGoogle Scholar
  7. Blaschke, T.F.: Protein binding and kinetics of drugs in liver disease. Clinical Pharmacokinetics 2: 32–44 (1977).PubMedCrossRefGoogle Scholar
  8. Borga, O.; Piafsky, K.M. and Nilsen, O.G.: Plasma protein binding of basic drugs. I. Selective displacement from α1-acid glycoprotein by tris (2-butoxyethyl) phosphate. Clinical Pharmacology and Therapeutics 22: 539–544 (1977).PubMedGoogle Scholar
  9. Bovill, J.G. and Sebel, P.S.: Pharmacokinetics of high dose fentanyl. British Journal of Anaesthesia 52: 795–801 (1980).PubMedCrossRefGoogle Scholar
  10. Carruthers, S.G.; Cleland, J.; Kelly, J.G.; Lyons, S.M. and McDevitt, D.G.: Plasma and tissue digoxin concentrations in patients undergoing cardiopulmonary bypass. British Heart Journal 37: 313–320 (1975).PubMedCrossRefGoogle Scholar
  11. Cartwright, D.P.; Chapman, J.C.; David, J.R. and Scoggins, A.M.: Pharmacokinetics of high-dose fentanyl (corresp.). British Journal of Anaesthesia 53: 780 (1981).PubMedCrossRefGoogle Scholar
  12. Chou, R.C. and Levy, G.: Does heparin cause inhibition of drug-protein binding in vivo? (abstr.). Clinical Pharmacology and Therapeutics 29: 236 (1981).Google Scholar
  13. Coltart, D.J.; Chamberlain, D.A.; Howard, M.R.; Kettlewell, M.G. and Smith, T.W.: Effect of cardiopulmonary bypass on plasma digoxin concentrations. British Heart Journal 33: 334–338 (1971).PubMedCrossRefGoogle Scholar
  14. Craig, W.A.; Evenson, M.A. and Ramgopal, V.: The effect of uremia, cardiopulmonary bypass and bacterial infection on serum protein binding; in Benet (Ed) Effect of Disease States on Drug Pharmacokinetics, pp. 125–136 (American Pharmaceutical Association, Washington DC 1976).Google Scholar
  15. Csicsko, J.F.; Schatzlein, M.H. and King, R.D.: Immediate postoperative digitalization in the prophylaxis of supra-ventricular arrhythmias following coronary artery bypass. Journal of Thoracic and Cardiovascular Surgery 81: 419–422 (1981).PubMedGoogle Scholar
  16. Desmond, P.V.; Roberts, R.K.; Wood, A.J.J.; Dunn, G.D.; Wilkinson, G.R. and Schenkerz, S.: Effect of heparin administration on plasma binding of benzodiazepines. British Journal of Clinical Pharmacology 9: 171–175 (1980).PubMedCrossRefGoogle Scholar
  17. Dieter, R.A.; Neville, W.E. and Pifarre, R.: Hypokalaemia following hemodilution on cardiopulmonary bypass. Annals of Surgery 171: 17–23 (1969).CrossRefGoogle Scholar
  18. Feinberg, H. and Levitsky, S.: Postbypass treatment. Annals of Thoracic Surgery 20: 106–113 (1975).PubMedCrossRefGoogle Scholar
  19. Fielding, P.E.; Shore, V.G. and Fielding, C.J.: Lipoprotein lipase: Properties of the enzyme isolated from post heparin plasma. Biochemistry 13: 4318–4323 (1974).PubMedCrossRefGoogle Scholar
  20. Fisher, R.D.; Grunfeld, J.P. and Barger, A.C.: Intrarenal distribution of blood flow in diabetes insipidus. Role of ADH. American Journal of Physiology 219: 1348–1358 (1970).PubMedGoogle Scholar
  21. Giacomini, K.M.; Giacomini, J.C. and Blaschke, T.F.: Absence of effect of heparin on the binding of prazosin and phenytoin to plasma proteins. Biochemical Pharmacology 29: 3337–3340 (1980a).PubMedCrossRefGoogle Scholar
  22. Giacomini, K.M.; Swezey, S.E.; Giacomini, J.C. and Blaschke, T.F.: Administration of heparin causes in vitro release of non-esterified fatty acids in human plasma. Life Sciences 27: 771–780 (1980b).PubMedCrossRefGoogle Scholar
  23. Goldmann, D.A.; Hopkins, C.C.; Karchmer, A.W.; Abel, R.M.; McEnany, T.; Akins, C.; Buckley, M.J. and Moellering, R.C.: Cephalothin prophylaxis in cardiac surgery. Journal of Thoracic and Cardiovascular Surgery 73: 470–479 (1977).PubMedGoogle Scholar
  24. Gordon, R.J.; Ravin, M.; Rawitscher, R.E. and Diacoff, G.R.: Changes in arterial pressure, viscosity, and resistance during cardiopulmonary bypass. Journal of Thoracic and Cardiovascular Surgery 69: 552–561 (1975).PubMedGoogle Scholar
  25. Hirvonen, J.; Huttunen, P.; Nuutinen, L. and Pekkarinen, A.: Catecholamines and free fatty acids in plasma of patients undergoing cardiac operations with hypothermia and bypass. Journal of Clinical Pathology 31: 949–955 (1978).PubMedCrossRefGoogle Scholar
  26. Hug, C.C. and Murphy, M.R.: Tissue redistribution of fentanyl and termination of its effects in rats. Anesthesiology 55: 369–375 (1981).PubMedCrossRefGoogle Scholar
  27. Hug, C.C.; Murphy, M.R.; Rigel, E.P. and Olsen, W.A.: Pharmacokinetics of morphine injected intravenously into the anesthetized dog. Anesthesiology 54: 38–47 (1981).PubMedCrossRefGoogle Scholar
  28. Iisalo, E.: Clinical pharmacokinetic of digoxin. Clinical Pharmacokinetics 2: 1–16 (1977).PubMedCrossRefGoogle Scholar
  29. Johnson, M.D.; Park, C.S. and Malvin, R.L.: Antidiuretic hormone and the distribution of renal cortical blood flow. American Journal of Physiology 232: F111–F116 (1977).PubMedGoogle Scholar
  30. Kaplan, J.A.; Dunbar, R.W.; Bland, J.W.; Sumpter, R. and Jones, E.L.: Propranolol and cardiac surgery: A problem for the anesthesiologist?. Anesthesia and Analgesia 54: 571–578 (1975).PubMedGoogle Scholar
  31. Kessler, K.M.; Leech, R.C. and Spann, J.F.: Blood collection techniques, heparin and quinidine protein binding. Clinical Pharmacology and Therapeutics 25: 204–210 (1979).PubMedGoogle Scholar
  32. Kolata, G.B.: Consensus on bypass surgery. Science 211: 42–43 (1981).PubMedCrossRefGoogle Scholar
  33. Koska, A.J.; Romagnoli, A. and Kramer, W.G.: Effect of cardiopulmonary bypass on fentanyl distribution and elimination. Clinical Pharmacology and Therapeutics 29: 100–105 (1981).PubMedCrossRefGoogle Scholar
  34. Krauss, R.M.; Levy, R.I. and Fredrickson, D.S.: Selective measurement of two lipase activities in postheparin plasma from normal subjects and patients with hyperlipoproteinemia. Journal of Clinical Investigation 54: 1107–1124 (1974).PubMedCrossRefGoogle Scholar
  35. Krasula, R.W.; Hastreiter, A.R.; Levitsky, S.; Yanagi, R. and Soyka, L.F.: Serum, atrial, and urinary digoxin levels during cardiopulmonary bypass in children. Circulation 49: 1047–1052 (1974).PubMedCrossRefGoogle Scholar
  36. Kurtzman, N.A.; Rogers, P.W.; Boonjarcken, S. and Arruda, J.A.L.: Effect of infusion of pharmacologic amounts of vasopressin on renal electrolyte excretion. American Journal of Physiology 228: 890–894 (1975).PubMedGoogle Scholar
  37. LaRosa, J.C.; Levy, R.I.; Windmueller, H.G. and Fredrickson, D.S.: Comparison of the triglyceride lipase of liver, adipose tissue, and postheparin plasma. Journal of Lipid Research 13: 356–363 (1972).PubMedGoogle Scholar
  38. Larsen, J.A.: The effect of cooling on liver function in cats. Acta Physiologica Scandinavica 81: 197–207 (1971).PubMedCrossRefGoogle Scholar
  39. Lillehei, R.C.; Longerbeam, J.K.; Bloch, J.H. and Manax, W.G.. The nature of irreversible shock: Experimental and clinical observations. Annals of Surgery 160: 682–710 (1964).PubMedCrossRefGoogle Scholar
  40. Lundberg, S.: Renal function during anaesthesia and open-heart surgery in man. Acta Anaesthesiologica Scandinavica (Suppl.) 27: 1–81 (1967).Google Scholar
  41. Lunn, J.K.; Stanley, T.H.; Eisele, J.; Webster, L. and Woodward, A.: High dose fentanyl anesthesia for coronary artery surgery: Plasma fentanyl concentrations and influence of nitrous oxide on cardiovascular responses. Anesthesia and Analgesia 58: 390–395 (1979).PubMedCrossRefGoogle Scholar
  42. Many, M.; Soroff, H.S.; Birtwell, W.C.; Wise, H.M. and Deterling, R.A.: The physiologic role of pulsatile and non-pulsatile blood How. Archives of Surgery 97: 917–923 (1968).PubMedCrossRefGoogle Scholar
  43. Mavroudis, C.: To pulse or not to pulse. Annals of Thoracic Surgery 25: 259–271 (1978).PubMedCrossRefGoogle Scholar
  44. McAllister, R.G.; Bourne, D.M.; Tan, T.G.; Erickson, J.L.; Wachtel, C.C. and Todd, E.P.: Effects of hypothermia on propranolol kinetics. Clinical Pharmacology and Therapeutics 25: 1–7 (1979).PubMedGoogle Scholar
  45. McClain, D.A. and Hug, C.C.: Intravenous fentanyl kinetics. Clinical Pharmacology and Therapeutics 28: 106–114 (1980).PubMedCrossRefGoogle Scholar
  46. McDevitt, D.C.; Frisk-Holmberg, M.; Hollifield, J.W. and Shand, D.G.: Plasma binding and the affinity of propranolol for a beta receptor in man. Clinical Pharmacology and Therapeutics 20: 152–157 (1976).PubMedGoogle Scholar
  47. Miller, K.W.; Chan, K.K.H.; McCoy, H.G.; Fischer, R.P.; Lindsay, W.G. and Zaske, D.E.: Cephalothin kinetics before, during, and after cardiopulmonary bypass surgery. Clinical Pharmacology and Therapeutics 26: 54–62 (1979).PubMedGoogle Scholar
  48. Miller, K.W.; McCoy, H.G.; Chan, K.K.H.; Fischer, R.P.; Lindsay, W.G.; Seifert, R.D. and Zaske, D.E.: Effect of cardiopulmonary bypass on cefazolin disposition. Clinical Pharmacology and Therapeutics 27: 550–556 (1980).PubMedCrossRefGoogle Scholar
  49. Morrison, J. and Killip, T.: Serum digitalis and arrhythmia in patients undergoing cardiopulmonary bypass. Circulation 47: 341–352 (1973).PubMedCrossRefGoogle Scholar
  50. Nadjmabadi, M.L.T.; Rastan, H. and Saidi, M.T.: Haemodynamic effects of acute intra-operative haemodilution in open heart surgery. Anaesthesist 27: 364–369 (1978).PubMedGoogle Scholar
  51. Nagaoka, H.; Yamada, T.; Hatano, R.; Tsukuura, T.; Sakamoto, T.; Katori, M. and Murakami, T.: Clinical significance of bradykinin liberation during cardiopulmonary bypass and its prevention by a Kallikrein inhibitor. Japanese Journal of Surgery 5: 222–233 (1975).PubMedCrossRefGoogle Scholar
  52. Nightingale, C.H.; Greene, D.S. and Quintiliani, R.: Pharmacokinetics and clinical use of cephalosporin antibiotics. Journal of Pharmaceutical Sciences 64: 1899–1927 (1975).PubMedCrossRefGoogle Scholar
  53. Persson, A.E.; Schnermann, J.; Ulfendahl, H.R.; Wolgast, M. and Wunderlich, P.: The effect of water diuresis and antidiuretic hormone on the regional renal red cell flow. Acta Physiologica Scandinavica 90: 193–201 (1974).PubMedCrossRefGoogle Scholar
  54. Philbin, D.M.; Coggins, C.H.; Wilson, N. and Sokoloski, J.: Antidiuretic hormone levels during cardiopulmonary bypass. Journal of Thoracic and Cardiovascular Surgery 73: 145–148 (1977).PubMedGoogle Scholar
  55. Philbin, D.M.; Levine, F.H.; Emerson, C.W.; Coggins, C.H.; Buckley, M.J. and Austen, W.G.: Plasma vasopressin levels and urinary flow during cardiopulmonary bypass in patients with valvular heart disease. Journal of Thoracic and Cardiovascular Surgery 78: 779–783 (1979).PubMedGoogle Scholar
  56. Piafsky, K.M.: Disease induced changes in the plasma binding of basic drugs. Clinical Pharmacokinetics 5: 246–262 (1980).PubMedCrossRefGoogle Scholar
  57. Piafsky, K.M.; Borgå, O.; Odar-Cederlof, I.; Johanssen, C. and Sjoqvist, F.: Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma α1-acid glycoprotein. New England Journal of Medicine 299: 1435–1439 (1978).PubMedCrossRefGoogle Scholar
  58. Plachetka, J.R.; Salomon, N.W. and Copeland, J.G.: Redistribution of propranolol following cardiopulmonary bypass (abstr.). Clinical Pharmacology and Therapeutics 29: 272–273 (1981).Google Scholar
  59. Polk, R.E.; Archer, G.L. and Lower, R.: Cefamandole kinetics during cardiopulmonary bypass. Clinical Pharmacology and Therapeutics 23: 473–480 (1980).Google Scholar
  60. Porter, C.A.; Kloster, F.E.; Herr, R.J.; Starr, A.; Griswold, H.E.; Kimsey, J. and Lenertz, H.: Relationship between alterations in renal hemodynamics during cardiopulmonary bypass and postoperative renal function. Circulation 34: 1005–1021 (1966).PubMedCrossRefGoogle Scholar
  61. Ream, A.K.: Cardiopulmonary bypass; in Ream and Fogdall (Eds) The Acute Cardiovascular Patient: Anesthesia and Intensive Care (Lippincott, Philadelphia. In press, 1982).Google Scholar
  62. Roffman, J.A. and Fieldman, A.: Digoxin and propranolol in the prophylaxis of supraventricular tachydysrhythmias after coronary bypass surgery. Annals of Thoracic Surgery 31: 496–501 (1981).PubMedCrossRefGoogle Scholar
  63. Romero, E.G.; Castillo-Olivares, J.L.; O’Connor, F.; Guardiola, J. and Aymerich, D.F.: The importance of calcium and magnesium ions in serum and cerebrospinal fluid during cardiopulmonary bypass. Journal of Thoracic and Cardiovascular Surgery 66: 668–672 (1973).PubMedGoogle Scholar
  64. Rossiter, S.J.; Stinson, E.B.; Oyer, P.E.; Miller, D.C.; Schapira, J.M.; Martin, R.P. and Shumway, N.E.: Prosthetic valve endocarditis. Journal of Thoracic and Cardiovascular Surgery 76: 795–803 (1978).PubMedGoogle Scholar
  65. Roth, R.A. and Wiersma, DA.: Role of the lung in total body clearance of circulating drugs. Clinical Pharmacokinetics 4: 355–367 (1979).PubMedCrossRefGoogle Scholar
  66. Routledge, P.A. and Shand, D.G.: Clinical pharmacokinetics of propranolol. Clinical Pharmacokinetics 4: 73–90 (1979).PubMedCrossRefGoogle Scholar
  67. Routledge, P.A.; Bjornsson, T.D.; Kitchell, B.B. and Shand, D.G.: Heparin administration increases plasma warfarin binding in man. British Journal of Clinical Pharmacology 8: 281–282 (1979).PubMedCrossRefGoogle Scholar
  68. Routledge, P.A.; Stargel, W.W.; Wagner, G.S. and Shand, D.G.: Increased alpha-1-acid glycoprotein and lidocaine disposition in myocardial infarction. Annals of Internal Medicine 93: 701–704 (1980).PubMedGoogle Scholar
  69. Salzman, E.W.: Measurement of platelet adhesiveness. Journal of Laboratory and Clinical Medicine 62: 724–735 (1963).PubMedGoogle Scholar
  70. Shepard, R.B. and Kirklin, J.W.: Relation of pulsatile flow to oxygen consumption and other variables during cardiopulmonary bypass. Journal of Thoracic and Cardiovascular Surgery 58: 694–702 (1969).PubMedGoogle Scholar
  71. Stanley, T.H.: Arterial pressure and deltoid muscle gas tensions during cardiopulmonary bypass in man. Canadian Anaesthetists’ Society Journal 25: 286–290 (1978).PubMedCrossRefGoogle Scholar
  72. Stanley, T.H.; Berman, L.; Green, O.; Robertson, D.H. and Roizen, M.: Fentanyl-oxygen anesthesia for coronary artery surgery: Plasma catecholamine and cortisol responses. Anesthesiology 51: S139 (1979a).CrossRefGoogle Scholar
  73. Stanley, T.H.; Philbin, D.M. and Coggins, C.H.: Fentanyl-oxygen anesthesia for coronary artery surgery: Cardiovascular and antidiuretic hormone responses. Canadian Anaesthetist’s Society Journal 26: 168–172 (1979b).CrossRefGoogle Scholar
  74. Storstein, L. and Janssen, H.: Studies on digitalis. VI. The effect of heparin on serum protein binding of digitoxin and digoxin. Clinical Pharmacology and Therapeutics 20: 15–23 (1976).PubMedGoogle Scholar
  75. Storstein, L.; Nitter-Hauge, S. and Fjeld, N.: Effect of cardiopulmonary bypass with heparin administration on digitoxin pharmacokinetics, serum electrolytes, free fatty acids, and renal function. Journal of Cardiovascular Pharmacology 1: 191–204 (1979).PubMedCrossRefGoogle Scholar
  76. Van der Vijgh, W.J.F. and Oe, P.L.: Pharmacokinetic aspects of digoxin in patients with terminal renal failure. III. Effect of heparin. International Journal of Clinical Pharmacology and Biopharmacy 15: 560–562 (1977).PubMedGoogle Scholar
  77. Viljoen, J.F.; Estefanous, F.G. and Kellner, G.A.: Propranolol and cardiac surgery. Journal of Thoracic and Cardiovascular Surgery 64: 826–830 (1972).PubMedGoogle Scholar
  78. Vöhringer, H.F.; Rietbrock, N.; Spurny, P.; Kuhlmann, J.; Hampl, H. and Baethke, R.: Disposition of digitoxin in renal failure. Clinical Pharmacology and Therapeutics 19: 387–395 (1976).PubMedGoogle Scholar
  79. Wells, P.H.; Hug, C.C. and Kaplan, J.A.: Maintenance of propranolol therapy by IV infusion (abstr.). Anesthesiology 53: S128 (1980).CrossRefGoogle Scholar
  80. Williams, D.J. and Steele, T.W.: Cephalothin prophylaxis assay during cardiopulmonary bypass. Journal of Thoracic and Cardiovascular Surgery 71: 207–211 (1976).PubMedGoogle Scholar
  81. Wood, M.; Shand, D.G. and Wood, A.J.J.: Propranolol binding in plasma during cardiopulmonary bypass. Anesthesiology 51: 512–516 (1979a).PubMedCrossRefGoogle Scholar
  82. Wood, M.; Shand, D.G. and Wood, A.J.J.: Altered drug binding due to the use of indwelling heparinized cannulas (heparin lock) for sampling. Clinical Pharmacology and Therapeutics 25: 103–108 (1979b).PubMedGoogle Scholar
  83. Yeh, T., Jr; Shelton, L. and Yeh, T.J.: Blood loss and bank blood requirement in coronary bypass surgery. Annals of Thoracic Surgery 26: 11–26 (1978).PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Australasia Pty Ltd. 1982

Authors and Affiliations

  • Frederick O. Holley
    • 1
  • Katherine V. Ponganis
    • 1
  • Donald R. Stanski
    • 1
  1. 1.Departments of Anesthesia and Medicine (Clinical Pharmacology)Stanford University School of Medicine Stanford, and Palo Alto Veterans Administration HospitalPalo AltoUSA

Personalised recommendations