Influence of Morphine or Ketamine or Saline Applied During In-hospital Cardiopulmonary Resuscitation on Early Survival

Summary

A small numbers of patients (10-15%) treated with cardiopulmonary resuscitation (CPR) are discharged from hospitals with a favorable neurologic outcome. However, a higher incidence of chest injuries (30-70%), mainly rib and sternum fractures, are observed among the survivors. It's no surprise that 6 months after cardiac arrest (CA) 50-70% of the patients who have survived continue to have pain and stress-related problems. Based on the need for the pain/stress treatment in these patients and several experimental evidences demonstrating neuroprotective features of anesthetics it is logical to presume that application of anesthesia during CPR may be indicated. In rodents exposed to hypoxic gas (5% 02, 95% N2) for 70 min, all seven animals died at the end of the experiments in the naloxone pre-treated group while only one out of seven rats died in the morphine pre-treated group, and five of seven rats died in the control group. In human volunteers, intravenously administered 60 mg of morphine did not alter cerebral blood flow and cerebral vascular resistance but markedly depressed cerebral oxygen uptake. Interestingly, in critical patients, morphine even in low doses is effective in relieving dyspnea by altering central perception and decreasing anxiety. In rats, morphine demonstrates dose- depending reduction of cerebral glucose utilization in limbic and forebrain regions. Thus, the main points of application for morphine in treatment of CA may be a reduction of oxygen/glucose consumption. Pre-treatment of zebrafish with ketamine protects against cardiac arrest-induced brain injury by inhibiting Ca2+ wave propagation and consequently it improves survival rate. Inhibition of NMDA receptors by ketamine reduces neuronal apoptosis and attenuates the systemic inflammatory response to tissue injury. The sympathomimetic effects of ketamine may facilitates recovery of systemic blood pressure during CPR. Retrospective investigations demonstrate that patients who are treated with opioids before or during CA have a statistically significantly higher survival rate and much better neurological outcome compared to untreated patients. Experimental studies have a limitation as all animals are treated with anesthesia and therefore survival rate varies between 50-90%. Thus, prospective research is urgently needed to investigate the influence of morphine or/and ketamine on survival and neurological outcome in patients with CA.

Timeline

Start

2021-10-01

Primary completion

2025-01-01

Completion

2026-01-01

Publications

• Background Safar P. Cerebral resuscitation after cardiac arrest: a review. Circulation. 1986 Dec;74(6 Pt 2):IV138-53.
• Background Schmitt KR, Tong G, Berger F. Mechanisms of hypothermia-induced cell protection in the brain. Mol Cell Pediatr. 2014 Dec;1(1):7. doi: 10.1186/s40348-014-0007-x. Epub 2014 Dec 1.
• Background Siesjo BK, Bengtsson F, Grampp W, Theander S. Calcium, excitotoxins, and neuronal death in the brain. Ann N Y Acad Sci. 1989;568:234-51. doi: 10.1111/j.1749-6632.1989.tb12513.x. No abstract available.
• Background Robinson MB, Coyle JT. Glutamate and related acidic excitatory neurotransmitters: from basic science to clinical application. FASEB J. 1987 Dec;1(6):446-55. doi: 10.1096/fasebj.1.6.2890549.
• Background Fonnum F. Glutamate: a neurotransmitter in mammalian brain. J Neurochem. 1984 Jan;42(1):1-11. doi: 10.1111/j.1471-4159.1984.tb09689.x. No abstract available.
• Background Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988 Oct;1(8):623-34. doi: 10.1016/0896-6273(88)90162-6. No abstract available.
• Background Nicholls D, Attwell D. The release and uptake of excitatory amino acids. Trends Pharmacol Sci. 1990 Nov;11(11):462-8. doi: 10.1016/0165-6147(90)90129-v.
• Background Bondy SC, LeBel CP. The relationship between excitotoxicity and oxidative stress in the central nervous system. Free Radic Biol Med. 1993 Jun;14(6):633-42. doi: 10.1016/0891-5849(93)90144-j.
• Background Bernardi P, Rasola A. Calcium and cell death: the mitochondrial connection. Subcell Biochem. 2007;45:481-506. doi: 10.1007/978-1-4020-6191-2_18.
• Background Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem. 1999;68:383-424. doi: 10.1146/annurev.biochem.68.1.383.
• Background Sheleg SV, Lobello JR, Hixon H, Coons SW, Lowry D, Nedzved MK. Stability and autolysis of cortical neurons in post-mortem adult rat brains. Int J Clin Exp Pathol. 2008 Jan 1;1(3):291-9.
• Background Calderon LM, Guyette FX, Doshi AA, Callaway CW, Rittenberger JC; Post Cardiac Arrest Service. Combining NSE and S100B with clinical examination findings to predict survival after resuscitation from cardiac arrest. Resuscitation. 2014 Aug;85(8):1025-9. doi: 10.1016/j.resuscitation.2014.04.020. Epub 2014 Apr 30.
• Background Phillips KF, Deshpande LS, DeLorenzo RJ. Hypothermia reduces calcium entry via the N-methyl-D-aspartate and ryanodine receptors in cultured hippocampal neurons. Eur J Pharmacol. 2013 Jan 5;698(1-3):186-92. doi: 10.1016/j.ejphar.2012.10.010. Epub 2012 Oct 17.
• Background Tamura Y, Shintani M, Inoue H, Monden M, Shiomi H. Regulatory mechanism of body temperature in the central nervous system during the maintenance phase of hibernation in Syrian hamsters: involvement of beta-endorphin. Brain Res. 2012 Apr 11;1448:63-70. doi: 10.1016/j.brainres.2012.02.004. Epub 2012 Feb 9.
• Background Borlongan CV, Hayashi T, Oeltgen PR, Su TP, Wang Y. Hibernation-like state induced by an opioid peptide protects against experimental stroke. BMC Biol. 2009 Jun 17;7:31. doi: 10.1186/1741-7007-7-31.
• Background Zhang Y, Wu YX, Hao YB, Dun Y, Yang SP. Role of endogenous opioid peptides in protection of ischemic preconditioning in rat small intestine. Life Sci. 2001 Jan 19;68(9):1013-9. doi: 10.1016/s0024-3205(00)01004-3.
• Background Addison PD, Neligan PC, Ashrafpour H, Khan A, Zhong A, Moses M, Forrest CR, Pang CY. Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction. Am J Physiol Heart Circ Physiol. 2003 Oct;285(4):H1435-43. doi: 10.1152/ajpheart.00106.2003. Epub 2003 Jun 5.
• Background Romano MA, Seymour EM, Berry JA, McNish RA, Bolling SF. Relative contribution of endogenous opioids to myocardial ischemic tolerance. J Surg Res. 2004 May 1;118(1):32-7. doi: 10.1016/j.jss.2003.12.006.
• Background Peart JN, Gross GJ. Exogenous activation of delta- and kappa-opioid receptors affords cardioprotection in isolated murine heart. Basic Res Cardiol. 2004 Jan;99(1):29-37. doi: 10.1007/s00395-003-0430-y. Epub 2003 Sep 29.
• Background Zhang J, Haddad GG, Xia Y. delta-, but not mu- and kappa-, opioid receptor activation protects neocortical neurons from glutamate-induced excitotoxic injury. Brain Res. 2000 Dec 8;885(2):143-53. doi: 10.1016/s0006-8993(00)02906-1.
• Background Zhang J, Gibney GT, Zhao P, Xia Y. Neuroprotective role of delta-opioid receptors in cortical neurons. Am J Physiol Cell Physiol. 2002 Jun;282(6):C1225-34. doi: 10.1152/ajpcell.00226.2001.
• Background Endoh H, Taga K, Yamakura T, Sato K, Watanabe I, Fukuda S, Shimoji K. Effects of naloxone and morphine on acute hypoxic survival in mice. Crit Care Med. 1999 Sep;27(9):1929-33. doi: 10.1097/00003246-199909000-00035.
• Background Endoh H, Honda T, Ohashi S, Shimoji K. Naloxone improves arterial blood pressure and hypoxic ventilatory depression, but not survival, of rats during acute hypoxia. Crit Care Med. 2001 Mar;29(3):623-7. doi: 10.1097/00003246-200103000-00027.
• Background Kuklin V. Survival rate in patients after sudden cardiac arrest at the university hospital of northern Norway treated with or without opioids: A retrospective evaluation. Saudi J Anaesth. 2013 Jul;7(3):310-4. doi: 10.4103/1658-354X.115355.
• Background Elmer J, Lynch MJ, Kristan J, Morgan P, Gerstel SJ, Callaway CW, Rittenberger JC; Pittsburgh Post-Cardiac Arrest Service. Recreational drug overdose-related cardiac arrests: break on through to the other side. Resuscitation. 2015 Apr;89:177-81. doi: 10.1016/j.resuscitation.2015.01.028. Epub 2015 Feb 4.
• Background Alle H, Roth A, Geiger JR. Energy-efficient action potentials in hippocampal mossy fibers. Science. 2009 Sep 11;325(5946):1405-8. doi: 10.1126/science.1174331.
• Background Xu DJ, Wang B, Zhao X, Zheng Y, Du JL, Wang YW. General anesthetics protects against cardiac arrest-induced brain injury by inhibiting calcium wave propagation in zebrafish. Mol Brain. 2017 Sep 4;10(1):44. doi: 10.1186/s13041-017-0323-x.
• Background Sterz F, Leonov Y, Safar P, Radovsky A, Stezoski SW, Reich H, Shearman GT, Greber TF. Effect of excitatory amino acid receptor blocker MK-801 on overall, neurologic, and morphologic outcome after prolonged cardiac arrest in dogs. Anesthesiology. 1989 Dec;71(6):907-18. doi: 10.1097/00000542-198912000-00014.
• Background Davis S, Helfaer MA, Traystman RJ, Hurn PD. Parallel antioxidant and antiexcitotoxic therapy improves outcome after incomplete global cerebral ischemia in dogs. Stroke. 1997 Jan;28(1):198-204; discussion 204-5. doi: 10.1161/01.str.28.1.198.
• Background Xiao F, Pardue S, Arnold T, Carden D, Alexander JS, Monroe J, Sharp CD, Turnage R, Conrad S. Effect of ifenprodil, a polyamine site NMDA receptor antagonist, on brain edema formation following asphyxial cardiac arrest in rats. Resuscitation. 2004 May;61(2):209-19. doi: 10.1016/j.resuscitation.2003.12.022.
• Background Bendel S, Springe D, Pereira A, Grandgirard D, Leib SL, Putzu A, Schlickeiser J, Jakob SM, Takala J, Haenggi M. Do different anesthesia regimes affect hippocampal apoptosis and neurologic deficits in a rodent cardiac arrest model? BMC Anesthesiol. 2015 Jan 15;15:2. doi: 10.1186/1471-2253-15-2.
• Background Koller AC, Salcido DD, Callaway CW, Menegazzi JJ. Resuscitation characteristics and outcomes in suspected drug overdose-related out-of-hospital cardiac arrest. Resuscitation. 2014 Oct;85(10):1375-9. doi: 10.1016/j.resuscitation.2014.05.036. Epub 2014 Jun 26.
• Background Walker A, McClelland H, Brenchley J. The Lazarus phenomenon following recreational drug use. Emerg Med J. 2001 Jan;18(1):74-5. doi: 10.1136/emj.18.1.74.

Drugs

Indications