Elsevier

Resuscitation

Volume 82, Issue 4, April 2011, Pages 371-377
Resuscitation

Mini-review
Emerging pharmaceutical therapies in cardiopulmonary resuscitation and post-resuscitation syndrome☆

https://doi.org/10.1016/j.resuscitation.2010.12.017Get rights and content

Abstract

Objective

The medication used in cardiopulmonary resuscitation (CPR) has by no means yielded the expected prognostic benefit. This review focuses on drugs that are currently under investigation as part of novel therapeutic strategies in CPR and post-resuscitation care.

Data sources

The main categories of drugs under investigation were identified in position papers regarding gaps in scientific knowledge and research priorities in CPR. The electronic bases of Medline via PubMed and the ClinicalTrials.gov registry were searched. Research terms were identified using the MESH database and were combined thereafter. Initial search terms were “cardiac arrest”, “cardiopulmonary resuscitation”, “post-cardiac arrest syndrome” combined with “drugs” and also the names of pharmaceutical categories and related drugs.

Results

Novel pharmaceutical approaches rely on a better understanding of the pathophysiology of cardiac arrest and post-resuscitation syndrome. Some medications are targeted primarily towards enhancing the return of spontaneous circulation and increasing survival rates, while others mostly aim at the attenuation of post-arrest myocardial and neurological impairment. Only a few of these therapies are currently being evaluated for clinical use. Despite the remarkable variability in study quality and success in achieving therapeutic targets, results for most therapies seem encouraging and support the continuation of research.

Conclusion

New pharmaceutical modalities are being investigated for future use in CPR. Currently, none has been unequivocally accepted for clinical use, while only a few of them are undergoing clinical testing. This research is likely to continue, in view of the unsatisfactory results of current pharmaceutical therapies and the encouraging results of preliminary studies.

Section snippets

Vasopressor drugs

Despite a lack of sound documentation, adrenaline is administered during CPR in an effort to redistribute cardiac output in favour of vital organs, augment coronary perfusion pressure and increase rates of ROSC. Noradrenaline and phenylephrine are not superior to adrenaline.3, 4 Vasopressin is a potent vasoconstrictor that activates V1a receptors on arterial smooth muscle cells. It remains active during tissue hypoxia and acidosis and lacks the drawbacks of β-adrenergic stimulation. Animal

Corticosteroids

Haemodynamic instability is common post-ROSC. Cortisol levels often remain low or rise insufficiently to match patient needs during haemodynamic stress. This relative adrenal insufficiency is common, occurring in 43–52% of patients post-ROSC, but often remains undetected.12

Most studies suggest that serum cortisol levels are higher in survivors of CA,13 and patients who fail to increase cortisol levels often die due to refractory post-CA shock. There are, however, reports that ACTH and free

β-Blockers

Endogenous catecholamines are often markedly elevated during CA, and this may result in myocardial damage, through stimulation of β-adrenergic receptors and the resulting increase of myocardium oxygen demand both in the fibrillating heart19 and post-ROSC. These effects are linked to myocardial dysfunction and the induction of malignant arrhythmias in patients surviving CA.

β-Adrenergic inhibition was first tested as a means of myocardial protection in acute myocardial infarction. In these

Sodium–hydrogen exchanger inhibitors

The Na+–H+ exchanger (NHE) is a transmembrane pump that is found in most tissues and plays a pivotal role in the regulation of intracellular pH by removing H+ in exchange for Na+ entry into the cells.31 Of the 5 isoforms of NHE, isoform 1 (NHE1) is cardiac-specific. Acidosis and ischaemia are the most powerful stimuli of NHE1. Yet, NHE1 remains activated not only during CA, but also during reperfusion. The low blood flow at the beginning of reperfusion cannot reverse ischaemia but can wash out

Erythropoietin (Epo)

Besides its action on erythroid progenitor cells, Epo has a protective role against ischaemia/reperfusion injury in many tissues, including myocardium and brain. When it binds to its receptor, Epo triggers a series of phosphorylations of intracellular protein kinases, such as JAK2 and PI3K, leading to activation of protein kinase Akt, which in its turn orchestrates the inhibition of cellular apoptotic mechanisms.41 Several experimental studies have shown the cardioprotective actions of Epo

Inotropes

Inotropes are currently recommended in post-CA syndrome for treatment of myocardial dysfunction, despite the fear of aggravation of focal ischaemia and dependency.48

Dobutamine is effective in mitigating post-ROSC myocardial dysfunction,49 but as a result of its β-adrenergic effects it increases myocardium oxygen demands. Levosimendan, a calcium-sensitising inotropic drug, lacks β-adrenergic effects and does not increase intracellular calcium. It exerts its action through two mechanisms: (a) it

δ-Opioid agonists

Myocardial hibernation is associated with down-regulation of myocardial metabolism and oxygen consumption, as well as protection of cardiomyocytes from ischaemic injury. Mammalian hibernation seems to be the result of a cyclic variation of opiate-like compounds in serum. Activation of endogenous δ-opioid receptors in animals reduces the size of an infarction induced by myocardial ischaemia.55 In a rat CA model, the δ-opioid agonist pentazocine, administered after VF induction, dramatically

Thrombolysis

Acute myocardial infarction and pulmonary embolism are the most frequent causes of OHCA. Thrombolytic therapy was introduced into CPR research in the hope of removing obstructive clots from the pulmonary or coronary circulation and restoring spontaneous circulation. Animal data supported the idea that thrombolytic therapy could prevent post-resuscitation no-reflow phenomena in the cerebral circulation, thus improving the neurological outcome.59

Initial reports coming from small case series,

Hypothermia

Mild therapeutic hypothermia (32-34 °C) is a well established neuroprotective treatment for comatose survivors of CA. Apart from several cooling devices, endogenous substances can cause hypothermia. Neurotensin is a tridecapeptide expressed in mammal brain and gastrointestinal tract that can produce hypothermia by downward shifting the temperature set point in the hypothalamus (‘regulated hypothermia’). Continuous intracerebroventricular infusion of neurotensin in rats led to a dose-dependent

ATP-sensitive potassium channel activators

ATP-sensitive potassium channels are located in the sarcolemma of the cardiomyocyte (sKATP) and in mitochondrial membrane (mitoKATP). Animal studies have shown that activation of mitoKATP leads to protection of myocardial and brain cells from ischaemia and is related to ischaemic preconditioning. In ischaemic preconditioning, transient, brief exposures of the heart to ischaemia lead to a significant reduction in infarct size following subsequent exposure to lethal ischaemic stimuli. The

Other drugs

This review covers some major axes relating to ongoing research into CPR, but is far from covering the entire spectrum. There have been other, albeit more isolated, attempts to test the effects of various medications, all seeking to enhance ROSC and keep VF reversible,71 while there is also ongoing research into myocardial and brain protection that might also affect CA research.72, 73

Conclusions

New pharmaceutical strategies in CPR should address two major problems: making CPR more effective in achieving ROSC and at the same time offering protection to vital organs. This effort is a continuum, starting during CPR and continuing, in combination with non-pharmaceutical treatment modalities, post-ROSC. Some forthcoming treatments rely on expectations for possible benefits from the innovative use of long-standing therapies. Others look to a better understanding of the mechanisms underlying

Conflict of interest

No conflicts of interest to declare.

References (73)

  • R.V. Ditchey et al.

    Phenylephrine plus propranolol improves the balance between myocardial oxygen supply and demand during experimental cardiopulmonary resuscitation

    Am Heart J

    (1994)
  • M.B. Skrifvars et al.

    A multiple logistic regression analysis of in-hospital factors related to survival at six months in patients resuscitated from out-of-hospital ventricular fibrillation

    Resuscitation

    (2003)
  • J. Orlowski et al.

    Na+/H+ exchangers of mammalian cells

    J Biol Chem

    (1997)
  • I.M. Ayoub et al.

    Cariporide given during resuscitation promotes return of electrically stable and mechanically competent cardiac activity

    Resuscitation

    (2010)
  • R.M. Mentzer et al.

    Sodium-hydrogen exchange inhibition by cariporide to reduce events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study

    Ann Thorac Surg

    (2008)
  • S.W. Boyce et al.

    Impact of sodium–hydrogen exchange inhibition by cariporide on death or myocardial inhibition in high-risk CABG patients: results of the CABG surgery cohort of the GUARDIAN study

    J Thorac Cardiovasc Surg

    (2003)
  • P. Incagnoli et al.

    Erythropoietin improved initial resuscitation and increased survival after cardiac arrest in rats

    Resuscitation

    (2009)
  • A. Cariou et al.

    Early high-dose erythropoietin and hypothermia after out-of-hospital cardiac arrest: a matched control study

    Resuscitation

    (2008)
  • S. Grmec et al.

    Erythropoietin facilitates the return of spontaneous circulation and survival in victims of out-of-hospital cardiac arrest

    Resuscitation

    (2009)
  • J.P. Nolan et al.

    Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication: a scientific statement from the International Liaison Committee on Resuscitation; 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 (Part 1)

    Int Emerg Nurs

    (2009)
  • A. Vasquez et al.

    Optimal dosing of dobutamine for treating post-resuscitation left ventricular dysfunction

    Resuscitation

    (2004)
  • L. Huang et al.

    Levosimendan improves postresuscitation outcomes in a rat model of CPR

    J Lab Clin Med

    (2005)
  • T. Xanthos et al.

    Combination pharmacotherapy in the treatment of experimental cardiac arrest

    Am J Emerg Med

    (2009)
  • J. Wang et al.

    Levosimendan improves post-resuscitation myocardial dysfunction after beta-adrenergic blockade

    J Lab Clin Med

    (2005)
  • Y. Shan et al.

    Opioid receptor agonist reduces myocardial ischemic injury when administered during early phase of myocardial ischemia

    Resuscitation

    (2010)
  • C.J. Gao et al.

    Effects of intracerebroventricular application of the delta opioid receptor agonist [d-Ala2, d-Leu5] enkephalin on neurological recovery following asphyxial cardiac arrest in rats

    Neuroscience

    (2010)
  • B.W. Böttiger et al.

    Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial

    Lancet

    (2001)
  • H.R. Arntz et al.

    Out-of-hospital thrombolysis during cardiopulmonary resuscitation in patients with high likelihood of ST-elevation myocardial infarction

    Resuscitation

    (2008)
  • E. Popp et al.

    Time course of the hypothermic response to continuously administered neurotensin

    Neuropeptides

    (2007)
  • G.C. Kane et al.

    Cardiac KATP channels in health and disease

    J Moll Cell Cardiol

    (2005)
  • D.W. Busija et al.

    Mitochondrial-mediated suppression of ROS production upon exposure of neurons to lethal stress: mitochondrial targeted preconditioning

    Adv Drug Deliv Rev

    (2008)
  • A.G. Reis et al.

    Magnesium in cardiopulmonary resuscitation: critical review

    Resuscitation

    (2008)

  • European Resuscitation Council Guidelines for Resuscitation 2005. Section 4. Adult advanced life support

    Resuscitation

    (2005)
  • T.M. Olasveengen et al.

    Intravenous drug administration during out-of-hospital cardiac arrest

    JAMA

    (2009)
  • M. Callaham et al.

    A randomized clinical trial of high-dose epinephrine and norepinehrine vs standard-dose epinephrine in prehospital cardiac arrest

    JAMA

    (1992)
  • T. Silfvast et al.

    Comparison of adrenaline and phenylephrine in out-of-hospital cardiopulmonary resuscitation. A double-blind study

    Acta Anaesthesiol Scand

    (1985)

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    ☆

    A Spanish translated version of the abstract of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2010.12.017.

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