Conference Lectures
Remote Ischemic Preconditioning in Cardiac Surgery
By
Dr.Madan Mohan Maddali
Senior Consultant in Anesthesia
Royal Hospital, Muscat,
Oman
Email: madanmaddali@hotmail.com
The concept of remote ischemic preconditioning [RIPC] including the proposed mechanisms of action are detailed in this review. Efficacy of RIPC in cardiac surgery based on clinical trials is mentioned. The future directions for RIPC implementation are highlighted.
Keywords: Ischemic Preconditioning, Myocardial; Cardiac Surgical Procedures
Introduction
Transient, brief periods of ischemia are considered to trigger pathways that confer protection against a subsequent, more prolonged ischemia in the same tissue. This phenomenon is known as ischemic preconditioning [IPC]. When the precedent ischemic stimulus is applied to a distant site from the organ or tissue that is afterwards exposed to ischemic injury, then the preconditioning is remote, and this procedure is known as remote ischemic preconditioning [RIPC] [1].
This concept of RIPC was evolved by Przyklenk and colleagues as early as 1993 in animal models that showed that a brief circumflex artery occlusion reduced the myocardial infarct size induced by subsequent sustained occlusion of the left anterior descending artery [2]. After that, it was found that brief ischemia of non-cardiac tissues such as kidney, intestine, or the limbs also could protect the heart from ischemia-reperfusion injury. This concept was applied rapidly in cardiovascular surgery [3].
Potential Mechanisms Of Remote Ischemic Preconditioning:
Remote ischemic preconditioning appears to offer two distinct phases of endothelial ischemia–reperfusion injury protection in humans, both of which are mediated from the autonomic nervous system. The early, short phase is activated immediately after preconditioning and vanishes within 4 h, whereas the second, prolonged phase presents 24 h after the preconditioning stimulus and lasts for at least 48 hours [4, 5].
Although the mechanisms through which RIPC protects the myocardium are unclear, there are 3 main possible hypotheses [Figure-1]. Firstly, studies have shown that this protective effect can be abolished by the ganglionic blocker, hexamethonium, or by pretreatment of sensory nerves with capsaicin, implicating a neuronal pathway in the protective mechanism [6, 7]. Secondly, Konstantinov et al demonstrated that RIPC also can protect the denervated transplanted heart, suggesting a humoral mechanism [8]. Furthermore, RIPC also modifies gene expression and suppresses the proinflammatory response to ischemia-reperfusion injury, which also may contribute partially to its protective effect [9].
Clinical trials on RIPC in patients undergoing open cardiac surgery
There are about 13 randomized clinical trials evaluating the safety and efficacy of RIPC in patients undergoing open cardiac surgery [Table-1]. RIPC has been found to be safe and useful in pediatric cardiac surgery ameliorating systemic inflammatory response and offering protection against myocardial and pulmonary ischemia–reperfusion injury. Postoperative lower rates of myocardial (troponin T release) and lung injury (airway resistance) were also observed although RIPC appeared to afford no protection against renal problems in children undergoing cardiac surgery.
As for adult cardiac surgery, beneficial effects of RIPC were suggested by various authors across the spectrums of complex valvular heart surgery to on pump and off pump CABG surgery. The best protocol for RIPC in adult cardiac surgery appears to be three cycles of 5-min right upper limb ischemia followed by 5-min reperfusion before CABG. This protocol was associated with reduced levels of cardiac markers for myocardial injury.
Contrary to the belief that RIPC has beneficial effects during cardiac surgery, Rahman et al found no correlation of RIPC with troponin release, blood hemodynamics, renal dysfunction, lung injury, or total hospital/ICU stay in patients undergoing CABG surgery [10].. However, it should be taken into consideration that patients with angina or with an acute coronary syndrome within 30 days of surgery were not excluded in this study protocol.
RIPC protocols (including ischemia–reperfusion sequences, cuff pressures, limb choice, and RIPC time) vary significantly among trials and to date, an optimal protocol for the induction of RIPC has not been established yet. Likewise, the potential effects of age, race, drugs, and co morbidity on RIPC response have not been adequately investigated so far
RIPC protocols need to be tested in high-risk surgical patients, to examine if the potential effects of preconditioning could be further amplified. The RICO trial, a large multicenter RCT to determine the effect of preconditioning on atrial fibrillation and other outcomes following CABG, is already on the way (11.). Finally, other future clinical trials could examine the effect of RIPC during ambulance transfer in patients with acute myocardial infarction, a practice which not only might salvage valuable ischemic tissue but may also prolong therapeutic window for thrombolysis.
In conclusion, RIPC seems to be an inexpensive, safe, and well-tolerated procedure that ameliorates ischemia reperfusion injury in remote organs. RIPC, through limb ischemia, is a non-invasive method that can be performed by someone other than a surgeon and does not interfere with the surgical progress, making it acceptable to surgeons and feasible in most clinical situations. Potential protective effects of RIPC on different clinical settings (various procedures, age limits, and co morbidities), as well as an optimal protocol for the procedure, need to be further determined in large-scale multicenter RCTs.
References
- Veighey K, Macallister RJ. Clinical applications of remote ischemic preconditioning. Cardiol. Res. Pract. 2012;2012:62068
- Przyklenk K., Bauer B., Ovize M.,et al: Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87 1993; 893-899
- Yang L, Wang G, Du Y, Ji B, Zheng Z.Remote ischemic preconditioning reduces cardiac troponin I release in cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth. 2014 Jun;28(3):682-9
- Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106:2881–2883
- Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ. Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system. J. Am. Coll. Cardiol. 2005;46:450–456
- Gho B.C., Schoemak er R.G., van den Doel M.A.,et al : : Myocardial protection by brief ischemia in noncardiac tissue. Circulation 1996; 94: 2193-2200
- Tang Z.L., Dai W., Li Y.J.,et al: Involvement of capsaicin-sensitive sensory nerves in early and delayed cardioprotection induced by a brief ischaemia of the small intestine. Naunyn Schmiedebergs Arch Pharmacol 1999; 359: 243-247
- Konstantinov I.E., Li J., Cheung M.M.,et al: Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism. Transplantation 2005; 79: 1691-1695
- Konstantinov I.E., Arab S., Kharbanda R.K.,et al: The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics 2004; 19: 143-150
- Rahman, I. A., J. G. Mascaro, R. P. Steeds, M. P. Frenneaux, P. Nightingale, P. Gosling, et al. 2010. Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment? Circulation 122:S53–S59
- Brevoord, D., M. W. Hollmann, S. G. De Hert, E. H. van Dongen, B. G. Heijnen, A. de Bruin, et al. 2011. Effect of remote ischemic conditioning on atrial fibrillation and outcome after coronary artery bypass grafting (RICO-trial). BMC Anesthesiol. 11:11
Table-1. Safety and efficacy of remote ischemic preconditioning (RIPC) in randomized clinical trials (RCTs) of open heart surgery
