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Pharmacology and Therapeutic Hypothermia

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Therapeutic Hypothermia After Cardiac Arrest

Abstract

Various randomized clinical trials have demonstrated the beneficial effects of therapeutic hypothermia on survival and neurological function following cardiac arrest [1–4]. Despite these well-documented outcomes, a number of physiologic and metabolic complications have been identified [see Chap. 8] [5]. More specifically, data examining the impact of reducing patients’ core body temperature to 32–34°C on drug disposition and therapeutic response remains incomplete [6–8]. Given the number of pharmacologic agents provided to patients following cardiac arrest, knowledge of the impact of therapeutic hypothermia on their pharmacokinetic, pharmacodynamic, efficacy and safety parameters is paramount. This chapter includes an in-depth review of both animal and human data as well as provides recommendations for clinical use for pharmacologic agents routinely used in the management of patients undergoing therapeutic hypothermia following cardiac arrest.

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References

  1. Hachimi-Idrissi S, Corne L, Ebinger G, et al. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation. 2001;51:275–81.

    Article  CAS  PubMed  Google Scholar 

  2. HACA Investigators. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–56.

    Article  Google Scholar 

  3. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–63.

    Article  PubMed  Google Scholar 

  4. Lundbye JB, Rai M, Ramu B, et al. Therapeutic hypothermia is associated with improved neurologic outcomes and survival in cardiac arrest survivors of non-shockable rhythms. Resuscitation. 2012;83:202–7.

    Article  PubMed  Google Scholar 

  5. Polderman KH. Mechamisms of action, physiologic effects, and complications of hypothermia. Crit Care Med. 2009;37(7 Suppl):S186–202.

    Article  PubMed  Google Scholar 

  6. Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med. 2007;35:2196–204.

    Article  CAS  PubMed  Google Scholar 

  7. Van den Broek MP, Groenendaal F, Egberts AC, et al. Effects of hypothermia on pharmacokinetics and pharmacodynamics. A systematic review of preclinical and clinical studies. Clin Pharmacokinet. 2010;49:277–94.

    Article  CAS  PubMed  Google Scholar 

  8. Zhou J, Poloyac SM. The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function. Expert Opin Drug Metab Toxicol. 2011;7:803–16.

    Article  CAS  PubMed  Google Scholar 

  9. Anzenbacher P, Anzenbacherova E. Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci. 2001;58:737–47.

    Article  CAS  PubMed  Google Scholar 

  10. Lin JH, Lu AY. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet. 1998;35:361–90.

    Article  CAS  PubMed  Google Scholar 

  11. Fritz HG, Holzmary M, Walter B, et al. The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs. Anesth Analg. 2005;100:996–1002.

    Article  CAS  PubMed  Google Scholar 

  12. Gepts E, Camu F, Cockshott I, et al. Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth Analg. 1987;66:1256–63.

    Article  CAS  PubMed  Google Scholar 

  13. Morgan DJ, Campbell GA, Crankshaw DP. Pharmacokinetics of propofol when given by intravenous infusion. Br J Clin Pharmacol. 1990;30:144–8.

    Article  CAS  PubMed  Google Scholar 

  14. Cockshott I, Douglas E, Prys-Roberts C, et al. The pharmacokinetics of propofol during and after intravenous infusion in man. Eur J Anaesthesiol. 1990;7:265–75.

    Google Scholar 

  15. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30:119–41.

    Article  PubMed  Google Scholar 

  16. Leslie K, Sessler DI, Bjorksten AR, et al. Mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium. Anesth Analg. 1995;80:1007–14.

    CAS  PubMed  Google Scholar 

  17. Kang TM. Propofol infusion syndrome in critically ill patients. Ann Pharmacother. 2002;36:1453–6.

    Article  PubMed  Google Scholar 

  18. Fukuoka N, Aibiki M, Tsukamoto T, et al. Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia. Resuscitation. 2004;60:225–30.

    Article  CAS  PubMed  Google Scholar 

  19. Hostler D, Zhou J, Tortorici MA. Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. Drug Metab Dispos. 2010;38:781–8.

    Article  CAS  PubMed  Google Scholar 

  20. Ariano RE, Kassum DA, Aronson KJ. Comparison of sedative recovery time after midazolam versus diazepam administration. Crit Care Med. 1994;22:1492–6.

    Article  CAS  PubMed  Google Scholar 

  21. Malacrida R, Fritz ME, Suter P, et al. Pharmacokinetics of midazolam administered by continuous infusion to intensive care patients. Crit Care Med. 1992;20:1123–6.

    Article  CAS  PubMed  Google Scholar 

  22. Bauer TM, Ritz R, Haberthur C, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet. 1995;246:145–7.

    Article  Google Scholar 

  23. Chamorro C, Borrallo JM, Romera MA, et al. Anesthesia and analgesia protocol during therapeutic hypothermia after cardiac arrest: a systematic review. Anesth Analg. 2010;110:1328–35.

    Article  CAS  PubMed  Google Scholar 

  24. Holzer M. Targeted temperature management of comatose survivors of cardiac arrest. N Engl J Med. 2010;363:1256–64.

    Article  CAS  PubMed  Google Scholar 

  25. Nolan JP, Neumar RW, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A scientific statement from the International Liaison Committee on Resuscitaiton; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation. 2008;19:350–9.

    Article  Google Scholar 

  26. Castren M, Silfvast T, Rubertsson S, et al. Scandinavian clinical practice guidelines for therapeutic hypothermia and post-resuscitation care after cardiac arrest. Acta Anaesthesiol Scand. 2009;53:280–8.

    Article  CAS  PubMed  Google Scholar 

  27. Murray MJ, Cowen J, DeBlock H, et al. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med. 2002;30:142–56.

    Article  CAS  PubMed  Google Scholar 

  28. Warr J, Thiboutot Z, Rose L, et al. Current therapeutic uses, pharmacology, and clinical considerations of neuromuscular blocking agents for critically ill adults. Ann Pharmacother. 2011;45:1116–26.

    Article  PubMed  Google Scholar 

  29. Heier T, Caldwell JE. Impact of hypothermia on the response to neuromuscular blocking drugs. Anesthesiology. 2006;104:1070–80.

    Article  PubMed  Google Scholar 

  30. Miller RD, Agoston S, van der Pol F, et al. Hypothermia and the pharmacokinetics and pharmacodynamics of pancuronium in the cat. J Pharmacol Exp Ther. 1978;207:532–8.

    CAS  PubMed  Google Scholar 

  31. Horrow JC, Bartkowski RR. Pancuronium, unlike other nondepolarizing relaxants, retains potency at hypothermia. Anesthesiology. 1983;58:357–61.

    Article  CAS  PubMed  Google Scholar 

  32. Beaufort TM, Proost JH, Maring JG, et al. Effect of hypothermia on the hepatic uptake and biliary excretion of vecuronium in the isolated perfused rat liver. Anesthesiology. 2001;94:270–9.

    Article  CAS  PubMed  Google Scholar 

  33. Heier T, Caldwell JE, Sessler D, et al. Mild intraoperative hypothermia increases duration of action and spontaneous recovery of vecuronium blockade during nitrous oxide-isoflurane anesthesia in humans. Anesthesiology. 1991;74:815–9.

    Article  CAS  PubMed  Google Scholar 

  34. Heier T, Caldwell JE, Sharma ML, et al. Mild intraoperative hypothermia does not change the pharmacodynamics (concentration-effect relationship) of vecuronium in humans. Anesth Analg. 1994;78:973–7.

    Google Scholar 

  35. Caldwell JE, Heier T, Wright PMC, et al. Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium. Anesthesiology. 2000;92:84–93.

    Article  CAS  PubMed  Google Scholar 

  36. Cammu G, Coddens J, Hendrickx J, et al. Dose requirements of infusions of Cisatracurium or ­rocuronium during hypothermic cardiopulmonary bypass. Br J Anaesth. 2000;84:897–90.

    Article  Google Scholar 

  37. Denny NM, Kneeshaw JD. Vecuronium and atracurium infusions during hypothermic cardiopulmonary bypass. Anaesthesia. 1986;41:919–22.

    Article  CAS  PubMed  Google Scholar 

  38. Buzello W, Schluermann D, Schindler M, et al. Hypothermic cardiopulmonary bypass and neuromuscular blockade by pancuronium and vecuronium. Anesthesiology. 1985;62:201–4.

    Article  CAS  PubMed  Google Scholar 

  39. Diefenbach C, Abel M, Buzello W. Greater neuromuscular blocking potency of atracurium during hypothermic than during normothermic cardiopulmonary bypass. Anesth Analg. 1992;75:275–8.

    Article  Google Scholar 

  40. Futter EM, Whalley DG, Wunands JE, et al. Pancuronium requirements during hypothermic cardiopulmonary bypass in man. Anaesth Intensive Care. 1983;11:216–9.

    CAS  PubMed  Google Scholar 

  41. Smeulers NJ, Wierda MKJ, van den Boek L, et al. Effects of hypothermic cardiopulmonary bypass on the pharmacodynamics and pharmacokinetics of rocuronium. J Cardiothorac Vasc Anesth. 1995;9:700–5.

    Article  CAS  PubMed  Google Scholar 

  42. McClain DA, Hugg CC. Intravenous fentanyl kinetics. Clin Pharmacol Ther. 1980;28:106–14.

    Article  CAS  PubMed  Google Scholar 

  43. Koren G, Barker C, Goresky G, et al. The influence of hypothermia on the disposition of fentanyl – human and animal studies. Eur J Clin Pharmacol. 1987;32:373–6.

    Article  CAS  PubMed  Google Scholar 

  44. Statler KD, Alexander HL, Vagni VA, et al. Moderate hypothermia may be detrimental after traumatic brain injury in fentanyl-anesthetized rats. Crit Care Med. 2003;31:1134–9.

    Article  CAS  PubMed  Google Scholar 

  45. Fritz HG, Holzmayr M, Walter B, et al. The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs. Anesth Analg. 2005;100:996–1002.

    Article  CAS  PubMed  Google Scholar 

  46. Empey PE, Miller TM, Philbrick AH, et al. Mild hypothermia decreases fentanyl and midazolam steady-state clearance in a rat model of cardiac arrest. Crit Care Med. 2012;40:1221–8.

    Article  CAS  PubMed  Google Scholar 

  47. Koska AJ, Romagnoli A, Kramer WG. Effect of cardiopulmonary bypass on fentanyl distribution and elimination. J Pharmacol Ther. 1981;29:100–5.

    Google Scholar 

  48. Koska AJ, Romagnoli A, Kramer WG. Pharmaco­dynamics of fentanyl citrate in patients undergoing aortocoronary bypass. Cardiovasc Dis. 1981;8:405–12.

    PubMed  Google Scholar 

  49. Gruber EM, Laussen PC, Costa A, et al. Stress response in infants undergoing cardiac surgery: a randomized study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion. Anesth Analg. 2001;92:882–90.

    Article  CAS  PubMed  Google Scholar 

  50. Kussman BD, Zurakowski D, Sullivan L, et al. Evaluation of plasma fentanyl concentrations in infants during cardiopulmonary bypass with low-­volume circuits. J Cardiothorac Vasc Anesth. 2005;19:316–21.

    Article  CAS  PubMed  Google Scholar 

  51. Ruggeri L, Landoni G, Guarracino F, et al. Remifentanil in critically ill cardiac patients. Ann Card Anaesth. 2011;14:6–12.

    PubMed  Google Scholar 

  52. Burkle H, Dunbar S, Van Aken H. Remifentanil: a novel, short-acting, mu-opioid. Anesth Analg. 1996;83:646–51.

    CAS  PubMed  Google Scholar 

  53. Russell D, Royston D, Rees PH, et al. Effect of temperature and cardiopulmonary bypass on the pharmacokinetics of remifentanil. Br J Anaesth. 1997;79:456–9.

    Article  CAS  PubMed  Google Scholar 

  54. Michelsen LG, Golford NHG, Lu W, et al. The pharmacokinetics of remifentanil in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Anesth Analg. 2001;93:1100–5.

    Article  CAS  PubMed  Google Scholar 

  55. Puig MM, Warner W, Tang CK, et al. Effects of temperature on the interaction of morphine with opioid receptors. Br J Anaesth. 1987;59:1459–64.

    Article  CAS  PubMed  Google Scholar 

  56. Bansinath M, Turndorf H, Puig MM. Influence of hypo and hyperthermia on disposition of morphine. J Clin Pharmacol. 1988;28:860–4.

    CAS  PubMed  Google Scholar 

  57. Roka A, Melinda KT, Vasarhelyi B, et al. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. 2008;121:e844–9.

    Article  PubMed  Google Scholar 

  58. Nielsen N, Hovdenes J, Nilsson F, et al. Outcome, timing, and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2009;53:926–34.

    Article  CAS  PubMed  Google Scholar 

  59. Harrington RA, Becker RC, Cannon CP, et al. Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 Suppl):670S–707.

    Article  CAS  PubMed  Google Scholar 

  60. Frelinger AL, Furman MI, Barnard MR, et al. Combined effects of mild hypothermia and glycoprotein IIb/IIIa antagonists on platelet-platelet and leukocyte-platelet aggregation. Am J Cardiol. 2003;92:1099–101.

    Article  CAS  PubMed  Google Scholar 

  61. Michelson AD, MacGregor H, Barnard MR, et al. Reversible inhibition of human platelet activation by hypothermia in vivo and in vitro. Thromb Haemost. 1994;71:633–40.

    CAS  PubMed  Google Scholar 

  62. Michelson AD, Barnard MR, Khuri SF, et al. The effects of aspirin and hypothermia on platelet function in vivo. Br J Haematol. 1999;104:64–8.

    Article  CAS  PubMed  Google Scholar 

  63. Lindenblatt N, Menger MD, Klar E, et al. Sustained hypothermia accelerates microvascular thrombus formation in mice. Am J Physiol Heart Circ Physiol. 2005;289:H2680–7.

    Article  CAS  PubMed  Google Scholar 

  64. Xavier G, Kalb M, Marschalek C, et al. The effects of test temperature and storage temperature on platelet aggregation: a whole blood in vitro study. Anesth Analg. 2006;102:1280–4.

    Article  Google Scholar 

  65. Hogberg C, Erlinge D, Braun OO. Mild hypothermia does not attenuate platelet aggregation and may even increase ADP-stimulated platelet aggregation after clopidogrel treatment. Thromb J. 2009;7:2.

    Article  PubMed  Google Scholar 

  66. Bjelland TW, Hjertner O, Klepstad P, et al. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation. 2010;81:1627–31.

    Article  CAS  PubMed  Google Scholar 

  67. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol. 2001;45:1157–64.

    Article  Google Scholar 

  68. O’Donoghue M, Wiviott SD. Clopidogrel response variability and future therapies: clopidogrel: does on size fit all? Circulation. 2006;114:e600–6.

    Article  PubMed  Google Scholar 

  69. Han YS, Tveita T, Kondratiev TV, et al. Changes in cardiovascular β-adrenoceptor responses during hypothermia. Cryobiology. 2008;57:246–50.

    Article  CAS  PubMed  Google Scholar 

  70. McAllister RG, Bourne DW, Tan TG, et al. Effects of hypothermia on propranolol kinetics. Clin Pharmacol Ther. 1979;25:1–7.

    CAS  PubMed  Google Scholar 

  71. Carmona MJC, Malbouisson LMS, Pereira VA, et al. Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery. Braz J Med Biol Res. 2005;38:713–21.

    Article  CAS  PubMed  Google Scholar 

  72. Carmona MJC, Pereira VA, Malbouisson LMS, et al. Effect of cardiopulmonary bypass on the pharmacokinetics of propranolol and atenolol. Braz J Med Biol Res. 2009;42:574–81.

    Article  CAS  PubMed  Google Scholar 

  73. Booth BP, Brien JF, Marks GS, et al. The effects of hypothermic and normothermic cardiopulmonary bypass on glyceryl trinitrate activity. Anesth Analg. 1994;78:848–56.

    Article  CAS  PubMed  Google Scholar 

  74. Smith RP, Kruszyana H. Nitroprusside produces cyanide poisoning via a reaction with hemoglobin. J Pharmacol Exp Ther. 1974;191:557–63.

    CAS  PubMed  Google Scholar 

  75. Tinker JH, Michenfelder JD. Sodium nitroprusside: pharmacology, toxicology, and therapeutics. Anesthesiology. 1976;45:349–54.

    Google Scholar 

  76. Moore RA, Guller EA, Gallagher JD, et al. Effect of hypothermic cardiopulmonary bypass on nitroprusside metabolism. Clin Pharmacol Ther. 1985;37:680–3.

    Article  CAS  PubMed  Google Scholar 

  77. Wotkyns RS, Hirose H, Eiseman B. Prolonged hypothermia in experimental pneumococcal peritonitis. Surg Gynecol Obstet. 1958;107:363–9.

    CAS  PubMed  Google Scholar 

  78. Jones JH, Campbell PJ. Penicillin therapy of experimental staphylococcal septicemia in mice exposed to cold. J Pathol Bacteriol. 1962;84:433–7.

    Article  CAS  PubMed  Google Scholar 

  79. Klamerus KJ, Rodvold KA, Silverman NA, et al. Effect of cardiopulmonary bypass on vancomycin and netilmicin disposition. Antimicrob Agents Chemother. 1988;32:631–5.

    Article  CAS  PubMed  Google Scholar 

  80. Koren G, Barker C, Bohn D, et al. Influence of hypothermia on the pharmacokinetics of gentamicin and theophylline in piglets. Crit Care Med. 1985;13:844–7.

    Article  CAS  PubMed  Google Scholar 

  81. Mercer JM, Neyens RR. Aminoglycoside pharmacokinetic parameters in neurocritical care patients undergoing induced hypothermia. Pharmacotherapy. 2010;30:654–60.

    Article  CAS  PubMed  Google Scholar 

  82. Liu X, Borooah M, Stone J, et al. Serum gentamicin concentrations in encephalopathic infants are not affected by therapeutic hypothermia. Pediatrics. 2009;124:310–5.

    Article  PubMed  Google Scholar 

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Correspondence to William L. Baker Pharm.D., BCPS .

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Baker, W.L. (2012). Pharmacology and Therapeutic Hypothermia. In: Lundbye, J. (eds) Therapeutic Hypothermia After Cardiac Arrest. Springer, London. https://doi.org/10.1007/978-1-4471-2951-6_9

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