Alexander , David , Aaron , and Liberato: Limited Sanguineous Reperfusion Reduces Ventricular Fibrillation Following Intermittent Cold Crystalloid Cardioplegic Arrest.


A still and bloodless operative field provides the surgeon with optimal conditions to perform delicate coronary anastomosis, while effective myocardial protection avoids myocardial injury during this process.1 Cold crystalloid cardioplegia has been the cornerstone of this strategy by inducing electromechanical arrest and further reducing oxygen demand with hypothermia.2 In spite of demonstrable improvements attributed to blood-based hyperkalaemic solutions,3,4 including superior preservation of myocardial and coronary endothelial function,5,6 especially in the setting of a dysfunctional or ischaemic myocardium,7-9 crystalloid solutions remain in widespread use. The technique of warm substrate-enhanced sanguineous reperfusion, delivered under controlled flow and pressure, is recognized as a valuable adjunct to blood-based cardioplegia, but is not part of the crystalloid protocol. Popularly known as the ‘hot shot’, it provides endogenous oxygen free radical scavengers and prevents myocardial substrate derangement.10,11 However, simple normokalaemic blood reperfusion, under certain conditions, and without substrate enhancement, may still attenuate reperfusion injury by providing acid-base homeostasis via the bicarbonate buffering system.12 The method of its administration may partly reproduce the controlled pressure and flow conditions in the hot shot, by limiting the initial blood flow during early reperfusion.

The occurrence of early ventricular fibrillation (VF) after cross-clamp removal is a manifestation of reperfusion injury,13 the consequences of which also include myocardial stunning,14 microvascular obstruction15 and myocardial necrosis.16 Reperfusion-induced arrhythmias are reduced by cardioplegic protection during ischaemia and their occurrence bears an inverse relationship to ischaemic time.17 The prevention of VF by pharmacologic means has been attempted with a view to reducing subsequent myocardial damage.18

In this study we retained the protocol of antegrade intermittent cold crystalloid cardioplegic arrest and combined this with limited sanguineous normokalaemic reperfusion, initially allowing flow only via the ITA, before establishing full reperfusion by cross-clamp removal. We measured the occurrence of early VF as a marker of reperfusion injury and investigated this method of reperfusion as a possible means of attenuating this injury.


Patients requiring coronary revascularization of two or more coronary arteries, including at least one internal thoracic artery (ITA) anastomosis, were randomized to a control or study group in this prospective trial. Patients requiring routine or urgent (performed during the same week as referral) surgery were recruited whereas patients requiring emergency surgery were excluded. Informed consent was obtained from each patient and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priory approval by our institution’s human research committee.

Normothermic cardiopulmonary bypass was employed. After application of the aortic cross-clamp, cold crystalloid cardioplegia (St Thomas’ I solution) was administered into the aortic root as an initial dose of 500ml, and continued when necessary if complete cardiac standstill and uniform cooling was not attained (figure 1).

This initial dose was followed by additional 100ml doses after each distal anastomosis. This additional dose was omitted before the last (ITA) anastomosis to the left anterior descending artery (LAD). No topical cooling of the heart was employed. Patients were prospectively randomized into a control or study group. In the control group (n=100) the aortic cross-clamp was removed concomitantly with ITA reperfusion. In the study group (n=100) the ITA was allowed to perfuse the heart for 3 minutes before the aortic cross-clamp was removed (figure 2). Cardiopulmonary blood flow was transiently reduced during cross-clamp removal. Manipulation of the heart was avoided during the 3 minute ITA reperfusion period in the study group and during the 3 minutes after cross-clamp removal in the control group. The occurrence of VF was recorded from the moment of reperfusion, by whichever method, until the weaning of the patient from cardiopulmonary bypass.

Figure 1.

Initial dose of cardioplegia


Table 1:

Patient characteristics

study control p value
age 58.8±8.8 57.2±9.2 0.21
female 15 8 0.12
ischaemic time* 35.60±8.65 35.77±10.64 0.89
ejection fraction** 63.57±13.65 60.76±14.36 0.16
urgent surgery 31 24 0.36
EuroSCORE 4.96±1.56 4.99±1.99 0.91

* mean ischaemic time for entire groups

** ejection fraction measured by ventriculography

Statistical Methods

Means and standard deviations were used to measure central tendency and dispersion for continuous variables and frequency tables and crosstabs were used to describe categorical variables. The Independent samples t-test was used to compare mean ages and mean ischaemic times between the study and control groups given that both variables satisfied the normality assumption. The Mann Whitney test was used to compare the initial dose of cardioplegia in the two groups, which did not satisfy a normal distribution. The chi square test was used to compare the incidence of ventricular fibrillation in the study and control groups for different number of grafts. In both tests a 0.05 level of significance was adopted.


Age (study 58.8±8.8, control 57.2±9.2, p=0.21), gender distribution (study 15% female, control 8% female, p=0.12) initial cardioplegia dose (study 584.5±143.5ml, control 590.2±133.6ml, p=0.856), and overall ischaemic times were similar in both groups (study 35.60±8.65, control 35.79±10.64, p=0.89). Study and control characteristics are presented in table 1. The distribution of grafts per case and their respective ischaemic times are shown in figure 3.

Figure 2.

Protocol for myocardial protection


Figure 3.

Mean ischaemic time ±SD clustered by group and number of grafts. Figures above bars indicate group size


Figure 4.

Incidence of ventricular fibrillation clustered by group and number of grafts


In the absence of VF, both control and study patients exhibited complete electrical quiescence or infrequent contractions during the 3 minutes of reperfusion. The incidence of ventricular fibrillation decreased with an increase in the number of grafts, down to a baseline of around 28% in the control group, and was significantly reduced in the study group for double (2/9, 22.2% vs 19/25, 76.0% p=0.004), triple (2/39, 4.9% vs 16/33, 48.5% p<0.001) and quadruple grafts (2/45, 4.4% vs 13/35, 28.7% p<0.001). VF did not occur with quintuple grafts in the study group, while it occurred in 2/7 patients (28.6%) in the control group (figure 4).


Although the separate manifestations of ischaemia-reperfusion injury are expressed to varying degrees depending on the length of ischaemia, it is generally accepted that their expression is quantitatively related to the magnitude of the ischaemic insult. Thus, infarct size19 and global ventricular dysfunction20 although attenuated by cardioplegic protection, bear a direct relationship to ischaemic duration. The incidence of reperfusion VF has been shown, in a blood-perfused animal model, to exhibit an inverse relationship with ischaemic time, even after crystalloid cardioplegia administration.17 This relationship is also manifest in the clinical setting of this study of global ischaemia and reperfusion during coronary surgery. The attenuation of reperfusion arrhythmias can therefore be interpreted as a surrogate of other deleterious effects of ischaemia-reperfusion.

Diverse strategies have been investigated with the aim of reducing reperfusion injury, especially in the percutaneous coronary intervention setting.21-24 The hot shot was popularized to provide such a protection in the surgical setting of global ischaemia. Our method of reperfusion differs from the hot shot not only in its composition, but also in its limited distribution, with reperfusion initially confined to the LAD territory. In spite of these fundamental differences this method of reperfusion significantly reduced the incidence of VF.

For the many surgeons who still employ crystalloid cardioplegia, we describe a simple modification of reperfusion, which significantly reduces reperfusion VF, a marker of other, more serious manifestations of the ischaemia-reperfusion injury. This method is simple to apply, does not significantly lengthen the surgery, incurs no additional equipment or cost, and significantly reduces the incidence of reperfusion VF thereby reducing the necessity for topical defibrillation.25


The study is relatively small and confined to a single surgeon practice. Patients who required emergency surgery were excluded and it is possible that in such cases this method of reperfusion may have been more beneficial. Other parameters of reperfusion injury, such as markers of myocardial damage, were not investigated in this study.


In conclusion we describe a method of limited sanguineous normokalaemic reperfusion via the internal thoracic artery, in the setting of coronary revascularisation using intermittent cold crystalloid cardioplegia. This simple, no-cost protocol significantly diminished the incidence the incidence of ventricular fibrillation, a marker of reperfusion-induced injury, and should improve myocardial protection and efficacy of the cold crystalloid cardioplegia technique.

Declarations of interest

The authors declare no conflicts of interest.


The authors agree to abide by the requirements of the “Statement of publishing ethics of the International Cardiovascular Forum Journal” [26].



Nicolini F, Beghi C, Muscari C, Agostinelli A, Budillon AM, Spaggiari I et al Myocardial protection in adult cardiac surgery: current options and future challenges. Eur J Cardiothorac Surg 2003; 24: 986–993 10.1016/S1010-7940(03)00475-5


Hendry PJ, Masters RG, Haspect A Is there a place for cold crystalloid cardioplegia in the 1990’s?. Ann Thorac Surg 1994; 58: 1690–1694 10.1016/0003-4975(94)91662-4


Barner HB Blood cardioplegia: a review and comparison with crystalloid cardioplegia. Ann Thorac surg 1991; 52: 1354–1367 10.1016/0003-4975(91)90034-N


Guru V, Omura J, Alghamdi AA, Weisel R, Fremes SE Is blood superior to crystalloid cardioplegia? A meta-analysis of randomized clinical trials. Circulation 2006; 114: 1331–1338 10.1161/CIRCULATIONAHA.105.001644


Qiu Y, Manché A, Hearse DJ Contractile and vascular consequences of blood versus crystalloid cardioplegia in the blood-perfused rat heart. Eur J Cardiothorac Surg 1993; 7: 137–145 10.1016/1010-7940(93)90036-B


Follette D, Fey K, Becker H, Foglia R, Steed D, Mulder DG et al Superiority of blood cardioplegia over asanguineous cardioplegia – an experimental and clinical study. Chirurgisches Forum 1980; 279–283


Kron IL Protection in the failing heart. Ann Thorac Surg 1999; 68: 1971–1973 10.1016/S0003-4975(99)01021-8


Flack JE, Cook JR, May SJ, Lemeshow S, Engelman RM, Rousou JA et al Does cardioplegia type affect outcome and survival in patients with advanced left ventricular dysfunction? Results from the CABG Patch Trial. Circulation 2000; 102: Suppl IIIIII-84–89 10.1161/01.CIR.102.suppl_3.III-84


Rosenkranz ER, Buckberg GD, Laks H, Mulder DG Warm induction of cardioplegia with glutamate enriched blood in coronary patients with cardiogenic shock who are dependent on inotropic drugs and intra-aortic balloon pump support. J Thorac Cardiovasc Surg 1983; 86: 507–518


Teoh KH, Christakis GT, Weisel RD, Fremes SE, Mickle DA, Pomaschin AD et al Accelerated myocardial metabolic recovery with terminal warm blood cardioplegia (hot shot). J Thorac Cardiovasc Surgery 1986; 91: 888–895


Caputo M, Dihmis WC, Bryan AJ, Suleiman MS, Angelini GD Warm blood hyperkalaemic reperfusion (‘hot shot’) prevents myocardial substrate derangement in patients undergoing coronary artery bypass surgery. Eur J Cardiothoracic Surg 1998; 13: 559–564 10.1016/S1010-7940(98)00056-6


Krieg BJ, Taghavi SM, Amidon GE In Vivo predictive dissolution: Transport analysis of the CO2, bicarbonate and in Vivo buffer system. J Pharm Sc 2014; 103: 3473–3490 10.1002/jps.24108


Hausenloy DJ, Yellon DM Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013; 123: 92–100 10.1172/JCI62874


Kloner RA, Bolli R, Marban E, Reinlib L, Braunwald E Medical and cellular implications of stunning, hibernation, and preconditioning: an NHLBI workshop. Circulation 1998; 97: 1848–1867 10.1161/01.CIR.97.18.1848


Ito H No-reflow phenomenon and prognosis in patients with acute myocardial infarction. Nat Clin Pract Cardiovasc Med 2006; 3: 499–506 10.1038/ncpcardio0632


Piper HM, Garcia-Dorado D, Ovize M A fresh look at reperfusion injury. Cardiovasc Res 1998; 38: 291–300 10.1016/S0008-6363(98)00033-9


Manché A, Edmondson SJ, Hearse DJ Dynamics of early postischemic myocardial functional recovery: Evidence for reperfusion-induced injury?. Circulation 1995; 92: 526–534 10.1161/01.CIR.92.3.526


Mauermann WJ, Pulido JN, Barbara DW, Abel MD, Li Z, Meade LA et al Amiodarone versus lidocaine and placebo for the prevention of ventricular fibrillation after aortic crossclamping: A randomized, double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg 2012; 144: 1229–1234 10.1016/j.jtcvs.2012.06.039


Yellon DM, Hausenloy DJ Myocardial reperfusion injury. N Eng J Med 2007; 357: 1121–1135 10.1056/NEJMra071667


Braunwald E, Kloner RA The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982; 66: 1146–1149 10.1161/01.CIR.66.6.1146


Frohlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J 2013; 34: 1714–1722 10.1093/eurheartj/eht090


O’Neill WW, Martin JL, Dixon SR, Bartorelli AL, Trabattoni D, Oemrawsingh PV et al Acute myocardial infarction with hyperoxemic therapy (AMIHOT): a prospective, randomized trial of intracoronary hyperoxemic reperfusion after percutaneous coronary intervention. J Am Coll Cardiol 2007; 50: 397–405 10.1016/j.jacc.2007.01.099


Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ et al Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomized trial. Lancet 2010; 375: 727–734 10.1016/S0140-6736(09)62001-8


Lønborg J, Vejlstrup N, Kelbæk H, Bøtker HE, Yong Kim W, Mathiasen AB et al Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2011; 33: 1491–1499 10.1093/eurheartj/ehr309


Simon C, Roscitano A, Capuano F, Benedetto U, Di Nucci G, Tonelli E et al Effect of topic defibrillation on serum markers of myocardial damage. Interact Cardiovasc Thorac Surg 2005; 5: 75–77 10.1510/icvts.2005.120220


Shewan LG, Coats AJS, Henein M Requirements for ethical publishing in biomedical journals. International Cardiovascular Forum Journal 2015; 2: 2 10.17987/icfj.v2i1.4)

Copyright (c) 2016 Alexander Manché, David Sladden, Aaron Casha, Liberato Camilleri

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.