Clinical Pharmacokinetics

, Volume 47, Issue 7, pp 449–462 | Cite as

Clinical Relevance of Pharmacokinetics and Pharmacodynamics in Cardiac Critical Care Patients

  • Federico Pea
  • Federica Pavan
  • Mario Furlanut
Review Article


Pharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug in order to ensure and maintain therapeutically effective concentrations at the action sites. In cardiac critical care patients, various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs. Gastrointestinal drug absorption may be erratic and unpredictable in the early postoperative period, and so patients may be unresponsive to oral therapy; thus the intravenous route should be preferred for life-saving drugs whenever feasible. Variations in the extracellular fluid content as a response to the trauma of surgery and the fluid load or significant drug loss through thoracic drainages may significantly lower plasma concentrations of extracellularly distributed hydrophilic antimicrobials (β-lactams, aminoglycosides and glycopeptides). Drug metabolism may be altered by the systemic inflammatory response and/or multiple organ failure and/or drug-drug pharmacokinetic interactions that can potentially occur during polytherapy, especially in immunosuppressed cardiac transplant patients. Instability of renal function may promote significant changes in body fluid concentrations of renally eliminated drugs, even in a brief period of hours. Finally, the application of extracorporeal circulation by means of cardiopulmonary bypass may significantly alter the disposition of several drugs during the operation because of acute haemodilution, hypoalbuminaemia, hypothermia and/or adsorption to the bypass equipment. Accordingly, to avoid either overexposure and the consequent increased risk of toxicity or underexposure and the consequent risk of therapeutic failure in critically ill cardiac patients, the dosing regimens of several drugs are expected to be significantly different from those suggested for clinically stable patients. Additionally, therapeutic drug monitoring may be helpful in the management of drug therapy and should be routinely used to guide individualized dose adjustments for (i) immunosuppressants whenever cytochrome P450 3A4 isoenzyme inhibitors (e.g. macrolide antibacterials, azole antifungals) or inducers (e.g. rifampicin [rifampin]) are added to or withdrawn from the regimen; and (ii) glycopeptide and aminoglycoside antibacterials whenever haemodynamically active agents (such as dopamine, dobutamine and furosemide [frusemide]) are added to or withdrawn from the regimen, and also whenever significant changes of haemodynamics and/or of renal function occur.


Remifentanil Glycopeptide Sirolimus Enflurane Cefamandole 
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.



No sources of funding were used to assist in the preparation of this review. Federico Pea has been a consultant for Pfizer and Sanofi-Aventis, and has been on the speakers’ bureau for Pfizer, Sanofi-Aventis, Abbott, Bayer, Gilead, GlaxoSmithKline and Merck Sharp & Dohme. Mario Furlanut has received grant support from GlaxoSmithKline and Sanofi-Aventis. Federica Pavan has no potential conflicts of interest.


  1. 1.
    Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005; 44: 1009–34PubMedCrossRefGoogle Scholar
  2. 2.
    Mattei P, Rombeau JL. Review of the pathophysiology and management of postoperative ileus. World J Surg 2006; 30: 1382–91PubMedCrossRefGoogle Scholar
  3. 3.
    Murphy DB, Sutton JA, Prescott LF, et al. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 1997; 87: 765–70PubMedCrossRefGoogle Scholar
  4. 4.
    Wallden J, Thorn SE, Wattwil M. The delay of gastric emptying induced by remifentanil is not influenced by posture. Anesth Analg 2004; 99: 429–34PubMedCrossRefGoogle Scholar
  5. 5.
    Banner NR, David OJ, Leaver N, et al. Pharmacokinetics of oral cyclosporine (Neoral) in heart transplant recipients during the immediate period after surgery. Transpl Int 2002; 15: 649–54PubMedCrossRefGoogle Scholar
  6. 6.
    Parke J, Charles BG. Factors affecting oral cyclosporin disposition after heart transplantation: bootstrap validation of a population pharmacokinetic model. Eur J Clin Pharmacol 2000; 56: 481–7PubMedCrossRefGoogle Scholar
  7. 7.
    Berger MM, Berger-Gryllaki M, Wiesel PH, et al. Intestinal absorption in patients after cardiac surgery. Crit Care Med 2000; 28: 2217–23PubMedCrossRefGoogle Scholar
  8. 8.
    Kennedy JM, Riji AM. Effects of surgery on the pharmacokinetic parameters of drugs. Clin Pharmacokinet 1998; 35: 293–312PubMedCrossRefGoogle Scholar
  9. 9.
    Brandstrup B, Svensen C, Engquist A. Hemorrhage and operation cause a contraction of the extracellular space needing replacement: evidence and implications? A systematic review. Surgery 2006; 139: 419–32PubMedCrossRefGoogle Scholar
  10. 10.
    Brandstrup B. Fluid therapy for the surgical patient. Best Pract Res Clin Anaes-thesiol 2006; 20: 265–83CrossRefGoogle Scholar
  11. 11.
    Brunner M, Pernerstorfer T, Mayer BX, et al. Surgery and intensive care procedures affect the target site distribution of piperacillin. Crit Care Med 2000; 28: 1754–9PubMedCrossRefGoogle Scholar
  12. 12.
    Bellomo R. The cytokine network in the critically ill. Anaesth Intensive Care 1992; 20: 288–302PubMedGoogle Scholar
  13. 13.
    Dorman T, Swoboda S, Zarfeshenfard F, et al. Impact of altered aminoglycoside volume of distribution on the adequacy of a three milligram per kilogram loading dose. Critical Care Research Group. Surgery 1998; 124: 73–8PubMedCrossRefGoogle Scholar
  14. 14.
    Zaske DE, Cipolle RJ, Strate RJ. Gentamicin dosage requirements: wide interpatient variations in 242 surgery patients with normal renal function. Surgery 1980; 87: 164–9PubMedGoogle Scholar
  15. 15.
    Kloth DD, Tegtmeier BR, Kong C, et al. Altered gentamicin pharmacokinetics during the perioperative period. Clin Pharm 1985; 4: 182–5PubMedGoogle Scholar
  16. 16.
    Fuhs DW, Mann HJ, Kubajak CA, et al. Intrapatient variation of aminoglycoside pharmacokinetics in critically ill surgery patients. Clin Pharm 1988; 7: 207–13PubMedGoogle Scholar
  17. 17.
    Russell JA. Management of sepsis. N Engl J Med 2006; 355: 1699–713PubMedCrossRefGoogle Scholar
  18. 18.
    Roberts JA, Lipman J. Antibacterial dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet 2006; 45: 755–73PubMedCrossRefGoogle Scholar
  19. 19.
    Jones DP, Aw TY, Shan XQ. Drug metabolism and toxicity during hypoxia. Drug Metab Rev 1989; 20: 247–60PubMedCrossRefGoogle Scholar
  20. 20.
    Takala J. Determinants of splanchnic blood flow. Br J Anaesth 1996; 77: 50–8PubMedCrossRefGoogle Scholar
  21. 21.
    Park GR, Pichard L, Tinel M, et al. What changes drug metabolism in critically ill patients? Two preliminary studies in isolated human hepatocytes. Anaesthesia 1994; 49: 188–9PubMedCrossRefGoogle Scholar
  22. 22.
    Park GR. Molecular mechanisms of drug metabolism in the critically ill. Br J Anaesth 1996; 77: 32–49PubMedCrossRefGoogle Scholar
  23. 23.
    Braun JP, Schroeder T, Buehner S, et al. Splanchnic oxygen transport, hepatic function and gastrointestinal barrier after normothermic cardiopulmonary bypass. Acta Anaesthesiol Scand 2004; 48: 697–703PubMedCrossRefGoogle Scholar
  24. 24.
    Brown KA, Brain SD, Pearson JD, et al. Neutrophils in development of multiple organ failure in sepsis. Lancet 2006; 368: 157–69PubMedCrossRefGoogle Scholar
  25. 25.
    Renton KW. Cytochrome P450 regulation and drug biotransformation during inflammation and infection. Curr Drug Metab 2004; 5: 235–43PubMedCrossRefGoogle Scholar
  26. 26.
    Carcillo JA, Doughty L, Kofos D, et al. Cytochrome P450 mediated-drug metabolism is reduced in children with sepsis-induced multiple organ failure. Intensive Care Med 2003; 29: 980–4PubMedGoogle Scholar
  27. 27.
    Asimakopoulos G. Systemic inflammation and cardiac surgery: an update. Perfusion 2001; 16: 353–60PubMedGoogle Scholar
  28. 28.
    Pea F, Furlanut M. Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions. Clin Pharmacokinet 2001; 40: 833–68PubMedCrossRefGoogle Scholar
  29. 29.
    Pea F, Brollo L, Lugano M, et al. Therapeutic drug monitoring-guided high teicoplanin dosage regimen required to treat a hypoalbuminemic renal transplant patient undergoing continuous venovenous hemofiltration. Ther Drug Monit 2001; 23: 587–8PubMedCrossRefGoogle Scholar
  30. 30.
    Saad AH, DePestel DD, Carver PL. Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy 2006; 26: 1730–44PubMedCrossRefGoogle Scholar
  31. 31.
    Balayssac D, Authier N, Cayre A, et al. Does inhibition of P-glycoprotein lead to drug-drug interactions? Toxicol Lett 2005; 156: 319–29PubMedCrossRefGoogle Scholar
  32. 32.
    Page 2nd RL, Miller GG, Lindenfeld J. Drug therapy in the heart transplant recipient: part IV. Drug-drug interactions. Circulation 2005; 111: 230–9PubMedCrossRefGoogle Scholar
  33. 33.
    Yamreudeewong W, DeBisschop M, Martin LG, et al. Potentially significant drug interactions of class III antiarrhythmic drugs. Drug Saf 2003; 26: 421–38PubMedCrossRefGoogle Scholar
  34. 34.
    Nicolau DP, Uber WE, Crumbley 3rd AJ, et al. Amiodarone-cyclosporine interaction in a heart transplant patient. J Heart Lung Transplant 1992; 11: 564–8PubMedGoogle Scholar
  35. 35.
    Mamprin F, Mullins P, Graham T, et al. Amiodarone-cyclosporine interaction in cardiac transplantation. Am Heart J 1992; 123: 1725–6PubMedCrossRefGoogle Scholar
  36. 36.
    Chitwood KK, Abdul-Haqq AJ, Heim-Duthoy KL. Cyclosporine-amiodarone interaction. Ann Pharmacother 1993; 27: 569–71PubMedGoogle Scholar
  37. 37.
    Nalli N, Stewart-Teixeira L, Dipchand AI. Amiodarone-sirolimus/tacrolimus interaction in a pediatric heart transplant patient. Pediatr Transplant 2006; 10: 736–9PubMedCrossRefGoogle Scholar
  38. 38.
    Ma B, Prueksaritanont T, Lin JH. Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos 2000; 28: 125–30PubMedGoogle Scholar
  39. 39.
    Sadaba B, Lopez de Ocariz A, Azanza JR, et al. Concurrent clarithromycin and cyclosporin A treatment. J Antimicrob Chemother 1998; 42: 393–5PubMedCrossRefGoogle Scholar
  40. 40.
    Gomez G, Alvarez ML, Errasti P, et al. Acute tacrolimus nephrotoxicity in renal transplant patients treated with clarithromycin. Transplant Proc 1999; 31: 2250–1PubMedCrossRefGoogle Scholar
  41. 41.
    Harnett JD, Parfrey PS, Paul MD, et al. Erythromycin-cyclosporine interaction in renal transplant recipients. Transplantation 1987; 43: 316–8PubMedCrossRefGoogle Scholar
  42. 42.
    Padhi ID, Long P, Basha M, et al. Interaction between tacrolimus and erythromycin. Ther Drug Monit 1997; 19: 120–2PubMedCrossRefGoogle Scholar
  43. 43.
    Claesson K, Brattstrom C, Burke JT. Sirolimus and erythromycin interaction: two cases. Transplant Proc 2001; 33: 2136PubMedCrossRefGoogle Scholar
  44. 44.
    Canafax DM, Graves NM, Hilligoss DM, et al. Interaction between cyclosporine and fluconazole in renal allograft recipients. Transplantation 1991; 51: 1014–8PubMedCrossRefGoogle Scholar
  45. 45.
    Gomez DY, Wacher VJ, Tomlanovich SJ, et al. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Pharmacol Ther 1995; 58: 15–9PubMedCrossRefGoogle Scholar
  46. 46.
    Irani S, Fattinger K, Schmid-Mahler C, et al. Blood concentration curve of cyclosporine: impact of itraconazole in lung transplant recipients. Transplantation 2007; 83: 1130–3PubMedCrossRefGoogle Scholar
  47. 47.
    Sansone-Parsons A, Krishna G, Martinho M, et al. Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus. Pharmacotherapy 2007; 27: 825–34PubMedCrossRefGoogle Scholar
  48. 48.
    Romero AJ, Le Pogamp P, Nilsson LG, et al. Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther 2002; 71: 226–34PubMedCrossRefGoogle Scholar
  49. 49.
    Rothenburger M, Zuckermann A, Bara C, et al. Recommendations for the use of everolimus (Certican) in heart transplantation: results from the second German-Austrian Certican Consensus Conference. J Heart Lung Transplant 2007; 26: 305–11PubMedCrossRefGoogle Scholar
  50. 50.
    Hebert MF, Roberts JP, Prueksaritanont T, et al. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992; 52: 453–7PubMedCrossRefGoogle Scholar
  51. 51.
    Hebert MF, Fisher RM, Marsh CL, et al. Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol 1999; 39: 91–6PubMedCrossRefGoogle Scholar
  52. 52.
    Zimmerman JJ. Exposure-response relationships and drug interactions of sirolimus. AAPS J 2004; 6: e28PubMedCrossRefGoogle Scholar
  53. 53.
    Rae JM, Johnson MD, Lippman ME, et al. Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther 2001; 299: 849–57PubMedGoogle Scholar
  54. 54.
    Niemi M, Backman JT, Fromm MF, et al. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet 2003; 42: 819–50PubMedCrossRefGoogle Scholar
  55. 55.
    Yates RB, Stafford-Smith M. The genetic determinants of renal impairment following cardiac surgery. Semin Cardiothorac Vasc Anesth 2006; 10: 314–26PubMedCrossRefGoogle Scholar
  56. 56.
    Pea F, Porreca L, Baraldo M, et al. High vancomycin dosage regimens required by intensive care unit patients cotreated with drugs to improve haemodynamics following cardiac surgical procedures. J Antimicrob Chemother 2000; 45: 329–35PubMedCrossRefGoogle Scholar
  57. 57.
    Mets B. The pharmacokinetics of anesthetic drugs and adjuvants during cardiopulmonary bypass. Acta Anaesthesiol Scand 2000; 44: 261–73PubMedCrossRefGoogle Scholar
  58. 58.
    Buylaert WA, Herregods LL, Mortier EP, et al. Cardiopulmonary bypass and the pharmacokinetics of drugs: an update. Clin Pharmacokinet 1989; 17: 10–26PubMedCrossRefGoogle Scholar
  59. 59.
    Wood M. Plasma drug binding: implications for anesthesiologists. Anesth Analg 1986; 65: 786–804PubMedGoogle Scholar
  60. 60.
    McAllister Jr RG, Tan TG. Effect of hypothermia on drug metabolism: in vitro studies with propranolol and verapamil. Pharmacology 1980; 20: 95–100PubMedCrossRefGoogle Scholar
  61. 61.
    Larsen JA. The effect of cooling on liver function in cats. Acta Physiol Scand 1971; 81: 197–207PubMedCrossRefGoogle Scholar
  62. 62.
    Koren G, Crean P, Klein J, et al. Sequestration of fentanyl by the cardiopulmonary bypass (CPBP). Eur J Clin Pharmacol 1984; 27: 51–6PubMedGoogle Scholar
  63. 63.
    Skacel M, Knott C, Reynolds F, et al. Extracorporeal circuit sequestration of fentanyl and alfentanil. Br J Anaesth 1986; 58: 947–9PubMedCrossRefGoogle Scholar
  64. 64.
    Krivoy N, Yanovsky B, Kophit A, et al. Vancomycin sequestration during cardiopulmonary bypass surgery. J Infect 2002; 45: 90–5PubMedCrossRefGoogle Scholar
  65. 65.
    Fellinger EK, Leavitt BJ, Hebert JC. Serum levels of prophylactic cefazolin during cardiopulmonary bypass surgery. Ann Thorac Surg 2002; 74: 1187–90PubMedCrossRefGoogle Scholar
  66. 66.
    Caffarelli AD, Holden JP, Baron EJ, et al. Plasma cefazolin levels during cardiovascular surgery: effects of cardiopulmonary bypass and profound hypothermic circulatory arrest. J Thorac Cardiovasc Surg 2006; 131: 1338–43PubMedCrossRefGoogle Scholar
  67. 67.
    Menges T, Sablotzki A, Welters I, et al. Concentration of cefamandole in plasma and tissues of patients undergoing cardiac surgery: the influence of different cefamandole dosage. J Cardiothorac Vasc Anesth 1997; 11: 565–70PubMedCrossRefGoogle Scholar
  68. 68.
    Nascimento JW, Cannona MJ, Strabelli TM, et al. Systemic availability of prophylactic cefuroxime in patients submitted to coronary artery bypass grafting with cardiopulmonary bypass. J Hosp Infect 2005; 59: 299–303PubMedCrossRefGoogle Scholar
  69. 69.
    Mand’ák J, Pojar M, Malakova J, et al. Tissue and plasma concentrations of cephuroxime during cardiac surgery in cardiopulmonary bypass: a microdialysis study. Perfusion 2007; 22: 129–36PubMedCrossRefGoogle Scholar
  70. 70.
    Miglioli PA, Merlo F, Grabocka E, et al. Effects of cardio-pulmonary bypass on vancomycin plasma concentration decay. Pharmacol Res 1998; 38: 275–8PubMedCrossRefGoogle Scholar
  71. 71.
    Kitzes-Cohen R, Farin D, Piva G, et al. Pharmacokinetics of vancomycin administered as prophylaxis before cardiac surgery. Ther Drug Monit 2000; 22: 661–7PubMedCrossRefGoogle Scholar
  72. 72.
    Ortega GM, Marti-Bonmati E, Guevara SJ, et al. Alteration of vancomycin pharmacokinetics during cardiopulmonary bypass in patients undergoing cardiac surgery. Am J Health Syst Pharm 2003; 60: 260–5PubMedGoogle Scholar
  73. 73.
    Miglioli PA, Merlo F, Fabbri A, et al. Teicoplanin concentrations in serum, pericardium, pericardial fluid and thoracic wall fat in patients undergoing cardio-pulmonary bypass surgery. J Antimicrob Chemother 1997; 39: 229–33PubMedCrossRefGoogle Scholar
  74. 74.
    Martin C, Bourget P, Alaya M, et al. Teicoplanin in cardiac surgery: intraoperative pharmacokinetics and concentrations in cardiac and mediastinal tissues. Antimicrob Agents Chemother 1997; 41: 1150–5PubMedGoogle Scholar
  75. 75.
    Lewis DR, Longman RJ, Wisheart JD, et al. The pharmacokinetics of a single dose of gentamicin (4 mg/kg) as prophylaxis in cardiac surgery requiring cardiopulmonary bypass. Cardiovasc Surg 1999; 7: 398–401PubMedCrossRefGoogle Scholar
  76. 76.
    Lonsky V, Dominik J, Mand’ák J, et al. Changes of the serum antibiotic levels during open heart surgery (ceftazidim, ciprofloxacin, clindamycin). Acta Medica (Hradec Kralove) 2000; 43: 23–7Google Scholar
  77. 77.
    Hudson RJ, Thomson IR, Jassal R, et al. Cardiopulmonary bypass has minimal effects on the pharmacokinetics of fentanyl in adults. Anesthesiology 2003; 99: 847–54PubMedCrossRefGoogle Scholar
  78. 78.
    Russell D, Royston D, Rees PH, et al. Effect of temperature and cardiopulmonary bypass on the pharmacokinetics of remifentanil. Br J Anaesth 1997; 79: 456–9PubMedCrossRefGoogle Scholar
  79. 79.
    Michelsen LG, Holford NH, Lu W, et al. The pharmacokinetics of remifentanil in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Anesth Analg 2001; 93: 1100–5PubMedCrossRefGoogle Scholar
  80. 80.
    Hammaren E, Yli-Hankala A, Rosenberg PH, et al. Cardiopulmonary bypass-induced changes in plasma concentrations of propofol and in auditory evoked potentials. Br J Anaesth 1996; 77: 360–4PubMedCrossRefGoogle Scholar
  81. 81.
    Dawson PJ, Bjorksten AR, Blake DW, et al. The effects of cardiopulmonary bypass on total and unbound plasma concentrations of propofol and midazolam. J Cardiothorac Vasc Anesth 1997; 11: 556–61PubMedCrossRefGoogle Scholar
  82. 82.
    Yoshitani K, Kawaguchi M, Takahashi M, et al. Plasma propofol concentration and EEG burst suppression ratio during normothermic cardiopulmonary bypass. Br J Anaesth 2003; 90: 122–6PubMedCrossRefGoogle Scholar
  83. 83.
    Hiraoka H, Yamamoto K, Okano N, et al. Changes in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding. Clin Pharmacol Ther 2004; 75: 324–30PubMedCrossRefGoogle Scholar
  84. 84.
    Takizawa E, Hiraoka H, Takizawa D, et al. Changes in the effect of propofol in response to altered plasma protein binding during normothermic cardiopulmonary bypass. Br J Anaesth 2006; 96: 179–85PubMedCrossRefGoogle Scholar
  85. 85.
    Goucke CR, Hackett LP, Barrett PH, et al. Blood concentrations of enflurane before, during, and after hypothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2007; 21: 218–23PubMedCrossRefGoogle Scholar
  86. 86.
    Cannona MJ, Malbouisson LM, Pereira VA, et al. Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery. Braz J Med Biol Res 2005; 38: 713–21CrossRefGoogle Scholar
  87. 87.
    Pea F, Viale P, Furlanut MI. Antimicrobial agents in elective surgery: prophylaxis or “early therapy”? J Chemother 2003; 15: 3–11PubMedGoogle Scholar
  88. 88.
    Miglioli PA, Merlo F, Calabro GB, et al. Cefazolin concentrations in serum during cardiopulmonary bypass surgery. Drugs Exp Clin Res 2005; 31: 29–33PubMedGoogle Scholar
  89. 89.
    Hudson RJ, Thomson IR, Jassal R. Effects of cardiopulmonary bypass on sufentanil pharmacokinetics in patients undergoing coronary artery bypass surgery. Anesthesiology 2004; 101: 862–71PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical SchoolUniversity of UdineUdineItaly

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