Is remote ischaemic preconditioning of benefit to patients undergoing cardiac surgery?

Abstract

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether remote ischaemic preconditioning (RIPC) is of benefit to patients undergoing cardiac surgery. Altogether, more than 264 papers were found using the reported search, 16 of which represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that RIPC is a safe protocol which could potentially be used in cardiac surgery to provide additional cardiac protection against ischaemia reperfusion injury, although it may not be appropriate for patients on K⁺ ATPase channel blockers (sulphonylureas) as they seem to eliminate the effect of RIPC. In our study, we found two meta-analyses of cardiac surgery with or without RIPC. Both unequivocally showed 0.81 and 0.74 standardized mean reduction in myocardial necrosis markers in patients receiving RIPC and cardiac or vascular surgery. No difference in perioperative myocardial infarction incidence or 30-day mortality were found. In adult cardiac surgery, we found 11 randomized control trials (RCTs) ranging in size from 45 to 162 patients. Two representative studies reported no difference in postoperative cardiac troponin I concentration in RIPC vs. controls. In one of the studies (CABG ± RIPC) no additional benefit could have been observed for RIPC regarding intra-aortic balloon pump usage (controls 8.5 vs. RIPC 7.5%), inotropic support (39 vs. 50%) or vasoconstrictor usage (66 vs. 64%). On the other hand, in the other study [CABG ± AVR (aortic valve replacement)  ± RIPC] significant reduction of troponin I at 8 h postoperatively (controls, 2.90 µg/l vs. RIPC, 2.54 µg/l, P = 0.043) was shown. Marked reduction in cardiac necrosis markers was also found in several smaller RCTs concerning coronary artery bypass grafting (CABG) patients receiving RIPC preoperatively: with cold crystalloid cardioplegia (44.5% reduction), with cross-clamping and fibrillation (43% reduction) and with cold blood cardioplegia (42.4% reduction). The proof of concept trials summarized here give some early evidence that RIPC may potentially provide some reduction in myocardial injury. If confirmed, in future clinical studies this technique may one day lead to a method to reduce reperfusion injury in clinical practice.

INTRODUCTION

A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1].

THREE-PART QUESTION

In [patients undergoing cardiac surgery] is [remote ischaemic preconditioning, RIPC] versus [routine myocardial protection alone] superior in terms of [Myocardial Protection]?

CLINICAL SCENARIO

You are reviewing a 68-year old accountant who underwent emergent coronary artery bypass grafting (CABG) overnight. He has developed a low cardiac output syndrome. After reviewing the patient's data you see that he had cold blood cardioplegia every 20 min with warm induction and also a 'hot shot' at the end. You conclude that this was the best possible myocardial protection strategy that could have been used so you wonder whether in addition RIPC, a novel method for cardiac protection, added to the regular cardioprotective protocol, would have improved his postoperative myocardial function. Therefore, you resolve to check the literature yourself.

SEARCH STRATEGY

Medline was searched using OVID SP interface from 1950 to October 2011: (exp Ischemic Preconditioning, Myocardial/OR exp Ischemic Preconditioning/OR ischaemic preconditioning.mp OR ischaemic preconditioning.mp AND (remote.mp)). In addition, the references of all papers deemed relevant were crosschecked and the 'related citations' function was used in PubMed. Finally, similar searches were performed in EMBASE and Cochrane Central Registry of Controlled Trials.

SEARCH OUTCOME

Two hundred and sixty four papers were found using the reported search. Sixteen papers were identified that provided the best evidence to answer the question. These are presented in Table 1. Two meta-analyses and 14 randomized controlled trials were found to be the most representative to address the question.

Table 1:

Best evidence papers

Author, date and country Study type (level of evidence)	Patient group	Outcomes	Key results	Comments
Hisato Takagi et al. Am J Cardiol 2008, Japan [2] Pooled analysis (level 1A)	n = 184 patients Patients from four RCTs undergoing cardiac or vascular surgery RIPC vs. controls	Primary end point: reduction in level of biochemical markers of myocardial injury	Significant reduction in myocardial injury markers with RIPC relative to control: standardized mean difference −0.81 (95% CI = −1.29 to −0.33; P = 0.001)	Abdominal aortic aneurysm trials included one paediatric cardiac and two CABG trials
Hisato Takagi et al. Vasc Endovasc Surg 2011, Japan [3] Pooled analysis (level 1A)	n = 482 patients Nine RCTs of RIPC in cardiac and vascular surgery: - three adult cardiac; - two paediatric cardiac; - three abdominal aortic aneurysm; - one carotid endarterectomy RIPC vs. controls	Early mortality (in-hospital = 30 days) Myocardial injury markers: troponin levels Perioperative myocardial infarction (PMI)	No significant advantage in 30 days mortality and PMI associated with RIPC. RIPC was found to reduce postoperative serum troponin (RIPC—334 patients of 6 trials: −0.74 (95% CI = −0.97 to −0.52) P < 0.00001 in patients undergoing cardiac or vascular surgery	Five cardiac surgical trials and four vascular with no aortic cross clamping and CPB
Rahman et al. Circulation 2010, UK [4] Randomized controlled trial (level 1B)	n = 162 patients Elective and urgent CABG patients ± RIPC RIPC protocol: 5 min ischaemia—5 min reperfusion, 3 cycles (upper extremity) Time from RIPC to bypass: 74 SD 16 min	Primary end point: cTnT level reduction	48 h cTnT AUC not different as indicated by general linear model: RIPC 30.1 (95% CI = 22.1–38.1) vs. controls 27.7 (95% CI = 18.9–39) ng/48 h/ml−1; P = 0.721	Intermittent cold blood cardioplegia The longest time from RIPC to the global cardiac ischaemia might have offended the protocol
			12-h low cardiac output episodes—incidence,  n (%) controls vs. RIPC: 20 (24) vs. 27 (34), P = 0.22
			Postoperative IABP, n (%) controls vs. RIPC—7 (9) vs. 6 (8), P = 0.52
			Postoperative vasconstrictor usage, n (%) controls vs. RIPC−54 (66) vs. 51 (64), P = 0.87
			Inotrope usage, n (%) controls vs. RIPC—32 (39) vs. 40 (50), P = 0.15
			Extubation time, min (range). Controls vs. RIPC—937 (766, 1402) vs. 895 (675, 1180), P = 0.28
Wagner et al. Interact CardioVasc Thorac Surg 2010, Czech Republic [5] Randomized controlled trial (level 1B)	n = 101 patients	Primary end point: cTnI level reduction	Late phase RIPC reduced postoperative troponin I level at 8 h postoperatively: RIPC—2.54 µg/l (95% CI = 1.01–3.89) vs. controls—2.90 µg/l (95% CI = 1.60–6.32); P = 0.043 No advantages of RIPC at 16 and 24 h postoperatively	Cold crystalloid cardioplegia (St. Thomas solution) This study used second window of protection or ‘late phase preconditioning’
	Patients randomized into control n = 34, RIPC n = 32, and tramadol group n = 31 (the last excluded from this analysis)
	CABG ± AVR ± RIPC
	RIPC protocol—18 h preoperatively: 5 min ischaemia—5 min reperfusion, 3 cycles (upper extremity)
Hausenloy et al. Lancet 2007, UK [6] Randomized controlled trial (level 1B)	n = 57 patients	Primary end point: cTnT level reduction	Reduction of troponin T level in CABG + RIPC group vs. controls: Total troponin reduction at 72 h postoperatively: 43% in the RIPC group—20.58 µg/l SD 9.58—RIPC vs. 36.12 µg/l SD 26.08—controls (mean difference 15.55 µg/l SD 5.32; 95% CI = 4.88, 26.21; P = 0.005)	Two cardioprotective methods used: - cardioplegic arrest and - intermittent cross clamping and fibrillation
	CABG vs. CABG and RIPC
	RIPC protocol: 5 min ischaemia—5 min reperfusion, 3 cycles (upper extremity) Time from RIPC to bypass: ‘no more than 45 min before aorta cross clamping’
Venugopal et al. Heart 2009, UK [7] Randomized controlled trial (level 1B)	n = 45 patients	Primary end point: reduction in serum cTnT level	Reduction in troponin T level over 72 h in RIPC group: AUC: mean 18.16 µg/l SD 6.67—RIPC vs. mean 31.53 µg/l SD 24.04—controls; mean reduction 42.4% – 13.37 µg/l at 72 h with RIPC (95% CI = 2.41 to 24.33 µg/l; P = 0.019)	Cold blood cardioplegia Key result remained significant (P = 0.017) when correction for the difference in cross-clamp time and bypass time was applied by means of linear univariate regression model
	CABG ± AVR vs. CABG ± AVR + RIPC
	23% in controls had concomitant AVR in controls vs. 13% in RIPC
	RIPC protocol: 5 min ischaemia—5 min reperfusion, 3 cycles (upper extremity) Time from RIPC to bypass: ‘60 min before aortic cross-clamp’
Ali et al. J Coll Phys Surg Pak 2010, Pakistan [8] Randomized controlled trial (level 1B)	n = 100 patients	Primary end point: serum CKMB reduction	CKMB level reduction at every postoperative stage, except at 24 h: - 8 h–27.22 iu/l SD 7.69 RIPC vs. 30.24 iu/l SD 4.64 controls; P = 0.026; -16 h–33.3 iu/l SD 9.45 RIPC vs. 37.2 iu/l SD 7.07 controls; P = 0.021; - 24 h–22.74 iu/l SD 6.89 RIPC vs. 25.22 iu/l SD 5.69 controls;  P = 0.052; - 72 h–17.20 iu/l SD 4.83 vs. 19.72 iu/l SD 3.39 controls; P = 0.0032	Warm blood cardioplegia
	CABG as an elective procedure ± RIPC
	RIPC protocol: 5 min ischaemia—5 min reperfusion, 3 cycles (upper extremity) Time from RIPC to bypass: ‘before placing patient on bypass’
Karuppasamy et al. Basic Res Cardiol 2011,UK [15] Randomized controlled trial (level 1B)	n = 54 patients	Primary end point: troponin I reduction after 48 h. Additionally CK-MB and NT-pro-BNP serial measurements	There was no statistically significant difference in postoperative cTnI, BNP and CKMB between RIPC and conrols. The area under the curve (AUC) for cTnI was similar in both groups	Intermittent aortic cross-clamping and intermittent cold blood cardioplegia
	CABG ± valve surgery (mainly AVR)
	RIPC protocol: 5 min ischaemia—5 min reperfusion, 3 cycles (upper extremity) Time from RIPC to coronary occlusion: ‘RIPC immediately after anaesthesia induction’
Thielmann et al. Basic Res Cardiol 2010, Germany [9] Randomized controlled trial (level 1B)	n = 53 patients	Primary end point: reduction in serum cTnI	Postoperative concentration of cTnI significantly lower in RIPC group at 6, 12, 24 and 48 h: P < 0.0001. - cTnI AUC at 72 h postoperatively: RIPC—259 ng/ml SD 176 vs. controls—477 ng/ml SD 388, 44.5% reduction in cTnI Postopeartive cTnI peak reduced in RIPC 8.9 ng/ml SD 4.4 vs. controls 13.7 ng/ml SD 7.7; P = 0.008	Cold crystalloid cardioplegia
	CABG as an elective procedure ± RIPC
	RIPC protocol: 5 min ischaemia—5 min reperfusion, 3 cycles (upper extremity) Time from RIPC to bypass: ‘54 SD 14 min’
Hong et al. Anaesth Intensive Care 2010, Republic of Korea [10] Randomized controlled trial (level 1B)	n = 130 patients	Primary end point: reduction in cTnI postoperatively	In the RIPC group total TnI concentration was reduced by 23% as confirmed by the AUC comparison at 72 h postoperatively, yet this has not reached statistical significance: RIPC 53.2 SD 72.9 vs. controls 67.4 SD 97.7; P = 0.281. [ng/ml]	First RIPC applied in off-pump CABG patients
	Elective off-pump CABG patients
	RIPC protocol: 5 min ischaemia—5 min reperfusion, 4 cycles Time from RIPC to coronary occlusion 19.2 SD 10.8 min
Wu et al. Circ J 2011, China [12] Randomized controlled trial (level 1B)	n = 75 patients	Primary end point: reduction in serum cTnI	RIPC achieved by lower leg ischaemia provided significant reduction of cTnI at all postoperative stages in comparison with controls Lower dobutamine requirements at 4 and 8 h postoperatively No difference in Cardiac Index in all groups postoperatively	Cold blood cardioplegia
	Mitral valve replacement ± tricuspid valve repair
	RIPC protocol: 5 min ischaemia—5 min reperfusion, 3 cycles. (upper extremity), n = 25 patients. 10 min ischaemia—10 min reperfusion, 2 cycles (lower extremity), n = 25 patients Time from RIPC to bypass: 'after induction of anaesthesia'
Li et al. J Surg Res 2010, China [11] Randomized controlled trial (level 1B)	n = 81 patients Adult valve replacement (MVR, AVR or AVR + MVR) ± RIPC RIPC protocol: 5 min ischaemia—5 min reperfusion, 3 cycles. (lower extremity) n = 26 in RIPC group, n = 27 in controls, the rest in remote perconditioning group Time from RIPC to bypass: ‘after induction of anaesthesia’	Primary end point: reduction in serum cTnI	The remote perconditioning group had significantly lower release of cTnI:	Cold blood cardioplegia used in all subjects. Diabetic patients included
			5 min before declamping: controls vs. preconditioning vs. perconditioning: 0.15 ± 0.10 vs.0.13 ± 0.08 vs 0.10 ± 0.04 ng/ml, P < 0.05
			30 min after declamping: controls vs. preconditioning vs.perconditioning: 0.40 ± 0.24 vs. 0.41 ± 0.40 vs. 0.24 ± 0.13 ng/ml, P < 0.043
			In perconditioning group higher incidence of spontaneous resuscitation was observed
Choi et al. J Thorac Cardiovasc Surg 2011, Republic of Korea [16] Randomized controlled trial (level 2B)	n = 76 patients	Primary end point: kidney injury Secondary end point: CKMB at 12 and 24 h postoperatively	CKMB was significantly lower in RIPC group at 24 h in comparison to controls (RIPC: mean 23.4 ng/ml SD 9.1 vs.  mean 32.0 ng/ml SD 19.1; P = 0.017)	Blood cardioplegic protection Cardiac injury assessed as a secondary end point
	Complex valvular heart surgery: CABG ± valve replacement or double valve replacement or repair or Bentall procedure ± RIPC
	RIPC: 10 min ischaemia—10 min reperfusion, 3 cycles. (lower extremity) Time from RIPC to coronary occlusion: ‘10 min at least’
Luo et al. Cardiol Young  2011, China [13] Randomized controlled trial (level 1B)	n = 60 patients	Primary end points: troponin I, CK-MB levels	Both postconditioning (POC) and RIPC reduced: - CK-MB peak release POC 86.1 ± 24.1 u/l and RIPC 92.8 ± 20.6 u/l vs. 111.0 ± 44.6 u/l in controls. (P < 0.05) - Troponin I release POC 0.28 ± 0.10 ng/ml and RIPC 0.26 ± 0.09 ng/ml vs. 0.49 ± 0.19 ng/ml in controls. (P < 0.05) - Dobutamine for 24 h (mg/kg/min): POC 2.06 ± 1.5 vs. RIPC 1.96 ± 1.3 vs. controls: 3.66 ± 2.4 at P = 0.036	Cold blood cardioplegia and moderate hypothermic bypass at 32°C
	Elective VSD closure—paediatric cardiac surgery RIPC protocol: 5 min ischaemia—5 min reperfusion, 3 cycles. (lower extremity) n = 20 Ischaemic postconditioning: 30 s of aorta declamping after cardioplegic arrest and 30 s of clamping—repeated three times over 3 min—n = 20 patients Time from RIPC to coronary occlusion: ‘RIPC immediately after anaesthesia induction’
Zhou et al. Pediatr Cardiol 2010, China [14] Randomized controlled trial (level 1B)	n = 60 patients	Primary end point: TnI, CK MB and LDH reduction	Although higher baseline myocardial injury markers (LDH, CKMB, TnI), the RIPC group developed lower cardiac injury than the control group - LDH: at 4, 12, 24 h postoperatively—P = 0.013; 0.000; 0.000; 0.000, respectively - CK-MB: at all time points 2, 4, 12, 24 h postoperatively—P = 0.049; 0.000; 0.000; 0.000, respectively - TnI: at 2nd and 4th h postoperatively—P = 0.007; 0.000, respectively	Cardioplegic arrest Combination of the first and the second window of protection
	Elective VSD closer by median sternotomy with or without mild pulmonary hypertension ± RIPC
	Prevalence of mild pulmonary hypertension did not differ among the groups: 21/30 in controls and 19/30 in RIPC
	Late and early phase RIPC: 5 min ischaemia—5 min reperfusion, 2 cycles. This was repeated twice prior the surgery: ‘24 h and 1 h before the surgery  (upper extremity)’
Cheung et al. J Am Coll Cardiol 2006,  Canada [17] Randomized controlled trial (level 1B)	n = 37 patients	Primary end point: cTnI level reduction	Significant reduction in troponin I level at all stages postoperatively (P = 0.04)	Blood cardioplegia in all patients No exact figures for troponin I levels given Study with small group of patients enrolled
	Congenital heart defect correction vs. congenital heart defect correction and RIPC
	RIPC protocol: 5 min ischaemia—5 min reperfusion, 4 cycles (lower extremity) Time from RIPC to bypass: ‘5–10 min’

PMI: perioperative myocardial infarction; CPB: cardiopulmonary bypass; AUC: area under the curve; RIPC: remote ischaemic preconditioning; RCT: randomized controlled trial; AVR: aortic valve replacement; VSD: ventricular septal defect; cTnI: cardiac troponin I; cTnT: cardiac troponin.

RESULTS

Two meta-analyses performed by the same group (Takagi et al.) in 2008 and 2011 included cardiac and vascular surgery trials [2, 3]. First meta-analysis of four RCTs of RIPC vs. controls gathered 184 subjects, 82 of whom were abdominal aortic aneurysm patients and remaining in coronary and paediatric cardiac surgery [2]. This pooled analysis showed 0.81 standardized mean reduction of myocardial necrosis markers in patients receiving RIPC. In 2011, an updated pooled analysis included nine RCT's of 482 patients undergoing cardiac or vascular surgery [3]. No difference in perioperative myocardial infarction or in-hospital mortality (30 days postoperatively) were found between RIPC and controls. The 2011 update showed the standardized mean reduction of 0.74 in myocardial necrosis markers among patients receiving RIPC.

Rahman et al. provided contrasting findings in a randomized controlled trial [4]. By prospective random allocation of 162 patients, either to isolated CABG and RIPC or CABG alone, the author did not show a single effect in postoperative haemodynamic functioning of patients submitted to RIPC nor did he observe a reduction in the total cTnI area under the curve (AUC) after 48 h. Additionally, no further benefit could have been observed for RIPC regarding intra-aortic balloon pump usage (controls, 8.5 vs. RIPC, 7.5%), inotropic support (39 vs. 50%), vasoconstrictor usage (66 vs. 64%), postoperative dialysis requirement (1.2 vs. 3.8%) and intubation time (median, 938 vs. 895 min). This study used the longest interval between RIPC protocol and aorta cross-clamping, with the anaesthesia being maintained by volatile anaesthetics such as isoflurane or enflurane, which might have been the reason for these negative results. Wagner et al. [5] used crystalloid cardioplegia and RIPC for cardiac protection in the adult patients suffering from triple vessel coronary artery disease with or without clinically significant aortic valve disease. In this group, the benefit from the RIPC has been documented by means of cTnI level reduction at the 8th h postoperatively [Table 1.]. The above mentioned data are consistent with the findings of Hausenloy et al. [6] and Venugopal et al. [7], who in their aptly designed trials involving CABG patients provided the evidence of nearly 43 and 42.4% reduction of the total postoperative troponin I in patients receiving RIPC. Ali et al. [8], in his study of coronary bypass adult population, found RIPC to provide enhanced protection by means of CKMB level reduction at the 8th, 16th and 48th h postoperatively. Thielmann et al. [9] went further to demonstrate the effect of RIPC in coronary artery bypass patients operated on with the use of cold crystalloid cardioplegia. In his study AUC, after 72 h postoperatively, indicated a reduction of total troponin I by 44.5%. Hong et al. [10] in a study of patients undergoing off-pump surgery showed a reduction of 23% of total troponin I, although this was not statistically significant after 72 h postoperatively. The author hypothesized that this might have been due to a low reperfusion injury associated with off-pump CABG in general. Only two studies concerning RIPC in isolated cardiac valve surgery have been carried out so far. Li et al. studied potential effects of RIPC and perconditioning (i.e. three 5 min long intervals of lower limb ischaemia and reperfusion, starting once the aorta is being cross-clamped) in adult patients submitted to heart valve surgery [11]. This RCT enrolled diabetic patients who were more likely to receive sulphonylureas, K+ ATPase channel blockers, which can abolish the effect of remote preconditioning and therefore their results should be approached with caution. Wu et al. found that patients submitted to mitral valve replacement could benefit from RIPC by the reduction of troponin I concentration and lower dobutamine support requirements postoperatively [12].

Three RCTs were designed in order to study the effect of RIPC in paediatric patients submitted to cardiac surgery. Two studies of Luo et al. [13] and Zhou et al. [14], having been the most representative so far, showed lower cardiac injury by means of troponin I and CK-MB reduction as well as lower requirement for postoperative dobutamine support in patients receiving RIPC.

There was no study reporting any RIPC-related side effects or a negative outcome in RIPC group during cardiac surgery.

CLINICAL BOTTOM LINE

The proof of concept trials summarized here give some early evidence that RIPC may potentially provide some reduction in myocardial injury. If confirmed, in future clinical studies this technique may one day lead to a method to reduce reperfusion injury in clinical practice.

Conflict of interest: none declared.