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Three Part Question

In [patients undergoing cardioplegic cardiopulmonary bypass] is [blood cardioplegia or crystalloid cardioplegia] superior [for myocardial protection].

Clinical Scenario

You have always used blood cardioplegia but you start to work for a consultant who uses crystalloid cardioplegia. He evangelically states that crystalloid is cheaper, quicker and gives you a better view when performing distal coronary artery anastomoses. You have always been told that blood is superior as it is a more physiological buffer and has an important oxygen carrying capacity. You then realise that you have never actually read a single paper on the comparison between these two solutions even though you use it every day and resolve to look up the evidence.

Search Strategy

Medline 1950–Feb 2008 using the OVID interface.
[blood.mp] AND [crystalloid.mp] AND [cardioplegia.mp OR cardioplegic.mp OR exp cardioplegic solutions/].

Search Outcome

Medline found 501 abstracts. We chose to exclude RCTs with fewer than 50 patients and selected 22 papers as representing the best evidence on this topic.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Guru et al, 2006, Canada	Meta-analysis of 34 randomised controlled trials Total 5044 patients. 2582 received blood cardioplegia and 2462 patients received crystalloid cardioplegia Most trials assessed at least 1 co-intervention including temperature (warm vs. cold), timing (intermittent vs. continuous), and/or route of delivery (antegrade, antegrade/retrograde) Elective CABG surgery trials (n=18). Valve (n=16)	Meta-analysis of RCTs (level 1a)	Low output syndrome LOS	Decreased for BCP (OR, 0.54; 95% CI 0.34–0.84; P=0.006) 879 patients, 10 trials	The LOS and CK-MB data suffered due to the lack of data from the two largest studies that had 1000 and 1400 patients in. Thus only 10 trials available for the LOS data and 7 for CK-MB. The lack of the Ovrum study in the low output syndrome category is curious as Ovrum collected data on IABP use and inotrope use and Guru successfully contacted Ovrum for their study, but clearly did not ask for these data which presumably would all have been available The other large study by Martin also presented IABP use, MI and inotrope use, although they did not respond to Guru et al.
			Incidence of MI	OR 0.78; 95% CI 0.54–1.13 4316 patients, 23 trials
			Incidence of death	OR 0.80; 95% CI 0.46–1.40 4022 patients, 17 trials
			CKMB release after surgery at 24 h	Reduced with blood cardioplegia WMD 5.9 U/l; 95% CI 1.6–10.2; P=0.007; 821 patients, 7 trials
Ovrum et al, 2004, Norway	1440 consecutive patients who had lone CABG by one of two surgeons from Jan 2000-April 2003. Bypass at 32 degrees. Cardioplegia given as follows: 500–800 ml initially and 100–300 ml given if electrical activity seen 2.5% redo operations 19% within 1 week of first symptoms All postoperative care unified for all patients Groups: Crystalloid antegradecardioplegia group CCP, n=719; temp 4–6° (Mean 810 ml given) Blood antegrade cardioplegia group BCP, n=721; 20 mmol/l Potassium, temp 6–10°, (Mean 817 ml given)	PRCT (level 1b)	Perioperative MI %	C 0.4 to B 0.9 P-value 0.48	The largest RCT performed Informed consent was not obtained from the patients as 'both methods of myocardial protection are univerally accepted' No difference also seen in groups with age over 70, EF <0.5, redo operation, and higher EuroSCORE or bypass times
			Hospital mortality, 30 days %	CCP 0.4% (3 patients) BCP 0.6% (4 patients) P=0.071
			Postop AF %	CCP 28.5% BCP 30.3% P=0.49
			Stroke %	CCP 1.1% BCP 0.7% P=0.46
			Ventilatory support (h)	CCP 1.8±1.3 BCP 1.9±1.1 P=0.26
			Inotropic support >30 min %	CCP 0.7% BCP 2.5% P=0.07
Martin et al, 1994, USA	1001 patients having elective coronary artery bypass from March 1991-July 1992. RCT designed to study warm blood cardioplegia vs cold blood cardioplegia with systemic hypothermia BCP (493 patients): initial warm induction antegrade of high potassium solution (20 mEq/l).Then continuous retrograde warm blood cardioplegia with low potassium (10 mEq/l) with CPB at 37° CCP (508 patients): intermittent antegrade cold crystalloid cardioplegia (8°, 23 mEq/l Potassium) and CPB at 28°. 1 l initially then intermittently with slush cooling of the myocardium	PRCT (level 1b)	Q wave infarction	BCP 1.4% CCP 0.8% P=NS	The second largest PRCT The confounding factor is that the benefit in neurological outcome is likely to have been from the systemic hypothermia rather than the cardioplegic solution, and there were no non-neurologically difference outcomes The following discussion implies that this study had to be stopped early due to the adverse neurological event rate although this is not mentioned in the paper
			Mortality	BCP 1.0% CCP 1.6% P=NS
			Aortic cross-clamp time	BCP 46±23 min CCP 40±21 min P=NS
			Neurological events	BCP 4.5% CCP 1.4% P<0.005
Rinne et al, 1993, Finland	100 patients elective (CABG): Antegrade intermittent cold blood cardioplegia (BCP) Antegrade intermittent cold crystalloid cardioplegia (CCP)	PRCT (level 1b)	CK-MB values	After 1 h (58.8±26.7 vs. 74.5±31.5 U/l, P=0.0098 by t-test, similar in both after 10 h	Short time follow-up. The study period covered the time from commencement of anaesthesia to the first postoperative morning Spontaneous conversion in half of BCP patients but none of the CCP patients
			Myocardial infarctions	(BCP: 3/51 v CCP: 3/49, P=0.68)
Shanewise et al, 1998, USA	61 patients undergoing re-operative CABG. All patients cooled to 25 degrees. All cardioplegia given 600 ml antegrade and 600 ml retrograde every 20 min and 100 ml down every graft with Plegisol with 18 mEq/l potassium Randomised to Blood cardioplegia 4:1 with plegisol n=31. Crystalloid cardioplegia n=30.	PRCT (level 1b)	Region wall motion as measured by TOE pre-and post bypass	No significant differences in regional wall motion abnormalities	Small study 5 patients had un-interpretable TOE studies No postoperative outcome measures
Shirlak et al, 2003, Turkey	100 patients having first time elective coronary artery bypass grafting. Systemic temperature 32° Both groups received intial bolus of 10-15 ml/kg antegrade then every 20 min 400 ml BCP group was temp 32–34°, and potassium concentration was 16 mEq/l CCP was at 4–6°. Potassium 16 mEq/l	PRCT (level 1b)	Death	None	Incidence of conduction disturbances was significantly increased in the crystalloid CP group (P=0.019)
			Inotropes	BCP 2 CCP 3
			Low cardiac output	BCP 2 CCP 3
			ICU stay	BCP 31±8 days CCP 35±10 days
			Hospital stay	BCP 8.4±1.7 days CCP 14.4±3.1 days P=0.004)
			CK, CK-MB, LDH and troponin T levels	No significant differences
			Conduction defects	BCP 8% CCP 24% P=0.019
Brat et al, 2000, Czechoslovakia	60 pts undergoing CABG with left ventricular ejection fraction <35% Cold blood cardioplegia vs cold cystalloid cardioplegia Antegrade/intermittent	PRCT (level 1b)	Death	No death in either group	In the early hours after operation in the group with the blood cardioplegia they found significantly better haemodynamic data (LVSWI, RVSWI) and significantly lower enzyme release
			MI	No significant difference
Gasier et al, 2000, Poland	122 pts CABG Patients randomised to cold BCP or cold CCP delivered by intermittent antegrade and retrograde infusion Randomised groups further divided into normal and low EF groups Group I (47 pts, LVEF <40%) and group II (75 pts, LVEF >40%)	PRCT (level 1b)	The following parameter were measured: Left ventricular ejection fraction (LVEF) and Left ventricular wall motion, score index (WMSI), and area asynergy (AA)	The results of clinical assessment in both groups showed improvement of quality of life. The constant improvement of LVEF and WMSI was observed in group I in contrast to group II	There were no significant differences in postoperative left ventricular systolic function between subgroups
Isomura et al, 1995, Japan	55 patients had CABG Warm BCP (n=29) or cold CCP (n=26) antegrade	PRCT (level 1b)	Myocardial oxygen extraction	The warm group was significantly greater than in the cold group 1 min after reperfusion (P<0.02)
			Rhythm	The heart returned to sinus rhythm spontaneously in 90% of the patients with warm cardioplegia and 15.4% of those with a cold heart (P<0.01)
			CK-MB or MDA release	Not significant in either group
Lajos et al, 1993, USA	163 patients CABG CCP (group 1) Antegrade/intermittently Warm BCP (group 2) antegrade high potassium blood cardioplegia then continuous retrograde blood cardioplegia Cold BCP, (group 3) antegrade/retrograde	PRCT (level 1b)	Supraventricular tachycardia	Warm BCP 29% Cold CCP 22% Cold BCP 18%	No differences in cardiac output, cardiac index, left ventricular stroke work index 2 deaths in warm BCP and 3 of 4 strokes were in warm BCP
			ECG changes	Not significant
			Lactate dehydrogenase and total CPK and isoenzyme (MB) studies	Showed identical levels (NS)
			Oxygen consumption	Warm heart 1.3-1.6 ml O2/100 ml flow Cold heart 0.5-0.6ml O2/100 ml flow
Hendrikx et al, 1999, Belgium	62 patients undergoing elective CABG but with EF below 40% Randomised to CCP or BCP but both given antegrade cold intermittent Cardiac troponin I before the operation, immediately after unclamping, at 6, 9, 12 and 24 h, and daily thereafter for 5 days	PRCT (level 1b)	Myocardial infarction	None in either group
			Cardiac troponin I	Aprotinin administration was associated with lower cardiac troponin I release in both groups. No between groupo difference
Elwatidy et al, 1999, Saudi Arabia	128 patients undergoing CABG, CPB at 25-28° Group I (n=47) antegrade/ retrograde BCP. 1 l of 4:1 cardioplegia given 16 mEq/l potassium at 37°. Then continuous retrograde cardioplegia 8 mEq/l potassium tepid (28–32°). At the end, 1 L of warm blood cardioplegia given retrograde as a hotshotpotassium tepid (28–32°). Group II (n=40) antegrade/ retrograde cold BCP with topical cooling. 8° 1 l initially 16 mEq/l then 500 ml of retrograde every 20 min, low potassium then 1 L of warm retrograde cardioplegia at the end Group III (n=41) antegrade CCP with topical cooling, temp 4°, 10 mmEq/l of Potassium. 1 l initially then 250 ccs after each distal anastomosis	PRCT (level 1b)	Low cardiac output	Group I 6.3% Group II 15% Group III 12% p=NS	Tepid blood cardioplegia showed superiority in metabolic and functional recovery whereas crystalloid cardioplegia had the highest incidence of postoperative arrhythmias. There was no significant statistical difference betweent the 3 groups in hospital mortality and morbidity
			Spontaneous defibrillation	Group I 95% Group II 2.5% Group III 14.6%
			CK-MB levels	Lower in group I vs the other 2 groups, (P=0.0013, 0.04)
			ICU stay, ventilation time or hospital complications	There was no significant difference between the 3 groups
			Post-op arrhythmia	Group I 14.7% Group II 12.5% Group III 29% P=NS
Biagioli et al, 1993, Italy	96 patients undergoing elective CABG CCP 55 patients received antegrade intermittent cold cardioplegia BCP 41 patients antegrade-retrograde cold blood cardioplegia, and 'hot shot' reperfusion	PRCT (level 1b)	Cardiac enzymes	Lower in BCP group
			MI	BCP 1/41 CCP 2/55
			Myocardial function	Improved in both groups but better in BCP group
Mullen et al, 1987, Canada	80 patients undergoing elective first time CABG Intermittent cold antegrade cardioplegia - BCP/CCP	PRCT (level 1b)	LV performance better	Higher LV stroke work index at a similar LV end-diastolic volume index (EDVI) P=0.01	Intraoperatively, blood cardioplegia resulted in significantly warmer LV and RV temperatures (left ventricle: 15.5±0.2 °C with blood cardioplegia and 12.6±0.3 °C with crystalloid cardioplegia (P<0.0001)
			LV systolic function	Similar systolic blood pressures at smaller LV end-systolic volume indexes (ESVI) P=0.04, and improved LV diastolic function
Ibrahim et al, 1999, UK	50 patients undergoing CABG with an EF <40% Cold cardioplegia in both groups - CCP (n=25), BCP (n=25)	PRCT (level 1b)	Haemodynamic data	Similar in both groups
			Mortality	No deaths in either groups
			Early postoperative ventricular dysfunction	Recovered significantly (P=0.043) more rapidly by 2 h in the blood-based St Thomas' cardioplegia group of patients
Wandschneider et al, 1994, Austria	Group A (53 patients) BCP combined ante-and retrograde cold blood Group B (47 patients) CCP combined ante-and retrograde cold blood	PRCT (level 1b)	Hospital stay	Did not differ between the two groups
			MI	BCP 3.7%, CCP 6.3%; P<0.01
			30 day mortality	BCP 0%, CCP 3.2%; P<0.01
			Inotrope use	More frequent in CCP
Fremes et al, 1984	90 patients undergoing elective CABG BCP (n=43) CCP (n=47) Antegrade/intermittent cold cardioplegia	PRCT (level 1b)	Myocardial infarction	BCP 0 CCP 5 P=0.06	They conclude that blood cardioplegia may impreove the clinical results in patients with unstable angina and in other high-risk patients
			Cardiac production of lactate	BCP 0.5±0.9 mmol/l; CCP 0.9±0.9 mmol/l; P<0.05
			Myocardial performance	Better with blood cardioplegia (P<0.01 by multivariate analysis)
Pichon et al, 1997, France	70 patients undergoing elective CABG Cold antegrade intermittent cardioplegia Randomised to CCP/BCP	PRCT (level 1b)	Total TnI release	CCP 11.2±8.9 BCP 7.8±8.6 µg, P<0.02	The need for electrical defibrillation after aortic unclamping was related to a higher release of CTnI
			Myocardial infarction	3 patients in each group had ECG evidence of perioperative myocardial infarction
Jin et al, 1995, UK	64 patients undergoing aortic valve replacement with or without CABG Antegrade (CCP 21 patients) Antegrade/retrograde cold (CBP 23 patients) Continuous retrograde warm (BCP 20 patients)	PRCT (level 1b)	Contraction velocity	Significant from 0.5 h with CBP; however no significant increase occurred until 12 h with CCP and until 20 h with warm BCP	LV stroke work index was maintained with CBP throughout the postoperative period with less inotropic
			LV peak circumferential wall stress before and after cross-clamp removal	There was a similar fall in at constant LV end-diastolic dimension in each group
			Inotropic drug	9 patients after CBP 14 patients after CCP 18 after warm BCP
Christakis et al, 1986,	140 patients undergoing urgent CABG for unstable angina BCP (n=70) CCP (n=70) Cold Antegrade/intermittent	PRCT (level 1b)	Operative mortality rate	BCP 0% CCP 5% P<0.05	A multivariate analysis identified the type of cardioplegic protection (p+0.008) and age (P=0.05) as significant independeant predictors of postoperative morbidity
			MI	BCP 4% CCP 13.5% P<0.05
			LOS	BCP 10% CCP 19% P<0.05
Iverson et al, 1984, USA	207 consecutive patients undergoing CABG randomised to: BCP 101 patients antegrade cold blood cardioplegia CCP 106 patients intermittent antegrade cold crystalloid cardioplegia	PRCT (level 1b)	Left ventricular work index	Slight but significant improvement with blood cardioplegia
			CK	Slight but significant improvement with blood cardioplegia
Jacquet et al, 1999, Belgium	200 patients undergoing elective CABG 1995-1996 BCP 108 patients intermittent antegrade blood cardioplegia. 1400 ml. Systemic normothermia CCP 92 patients antegrade and retrograde cold crystalloid cardioplegia with systemic hypothermia. 500 ml induction 14 mEq/l. Potassium antegrade then 500 ml retrograde. Additional 500 ml CCP every 60 min	PRCT (level 1b)	Deaths	CCP 3/92 BCP 3/108	No differences in IABP use or inotrope usage
			Q wave MI	CCP 5/92 BCP 5/108
			Stroke	CCP 2/92 BCP 5/108
			VF on cross clamp release	CCP 15/92 BCP 4/108 P=0.01
			Vasoconstrictors on bypass	CCP 15/92 BCP 57/108 P=0.0001

Comment(s)

Prof Fremes' Toronto group in 2006 performed a meta-analysis of 34 randomised controlled trials. Most were small and there were only two with more than 1000 patients in total and another three with more than 100 patients in the blood cardioplegia arm. In total there were 5000 patients included in these studies (but half were from two studies). They reported that the incidence of low output syndrome (LOS) was significantly lower with blood cardioplegia (BCP) with an odds ratio of 0.54 (95% CI 0.34–0.84) and the CK-MB release was higher by a weighted mean difference of 5.7 U/l with crystalloid cardioplegia (CCP) at 24 h (95% CI 1.6–10.2). There was no difference in the aggregated MI or mortality rates. However, there are significant weaknesses to these findings as the authors were unable to obtain any data on low output syndrome or CK-MB from the two studies containing more than 1000 patients, despite successfully contacting Ovrum's group which did collect some of this data [Ovrum, Martin]. Thus, the LOS aggregate finding was based on only 10 of the 34 trials (879 patients), and the CK-MB findings came from only seven trials. Furthermore, while CK-MB at 24 h appears in their abstract as a significant finding, in their full paper they report that there is no clinically significant difference at 1 h or 48 h post-operatively in CK-MB. Additionally, cold blood cardioplegia and warm blood cardioplegia studies are combined with a range of systemic temperatures.

The largest prospective randomised controlled trial (PRCT) was by Ovrum et al. in 2004. Two surgeons performed 1440 CABG procedures randomised to either cold CCP or cold BCP. The clinical course, systemic temperature and delivery methods were unified for all patients and emergencies, redos and low EF patients were included. No differences were seen for perioperative myocardial infarction, or mortality. Additionally, in subgroups of patients at higher operative risk (female sex, age >70 years, unstable angina, diabetes, emergency operation, ejection fraction <0.50, crossclamping time >50 min, and EuroSCORE >4) were identical.

The other large trial was conducted by Martin et al. from 1990–1992. One thousand-and-one patients undergoing elective CABG were randomised to either (1) systemic hypothermia at 28° and intermittent 25 mEq/l potassium cold crystalloid cardioplegia or (2) antegrade high potassium (20 mEq/l) warm blood cardioplegia followed by continuous retrograde low potassium (19 mEq/l) warm blood cardioplegia. There was an unexpectedly high rate of perioperative strokes, delayed stroke and total neurologic events, which caused the study to be stopped early. At this stage there were no differences in mortality, IABP use, inotrope use, or hospital stay. When considering the blood vs. crystalloid debate, this paper confounds the issue, as despite its large size, both the equivalent myocardial outcomes and adverse neurological outcomes may be explained in terms of temperature rather than cardioplegic solution.

No other RCTs come near these two in terms of numbers, and only three have more than 100 patients in the blood cardioplegia group. Iverson et al. in 1984 reported slight but significant improvements in left ventricular stroke work index and creatinine kinase levels in an RCT of 207 patients, Lajos et al. compared three groups, warm BCP, cold BCP and cold CCP in 163 patients. There were no differences between the cold BCP and cold CCP groups but the warm heart consumed three times the myocardial oxygen of the cold heart and 3 of 4 strokes occurred in the warm BCP group. Jacquet et al. compared intermittent warm cardioplegia with antegrade and retrograde cold cardioplegia with systemic hypothermia in 200 patients. There were no differences in death, stroke, inotrope use or IABP but ventricular fibrillation after cross-clamp release was more common with crystalloid and more vasoconstrictors were needed on bypass with systemic normothermia and blood cardioplegia.

We selected a further 15 RCTs reporting over 50 patients (summarised in the Table). Of these, eight reported statistically significant clinical outcomes in favour of blood cardioplegia and five reported statistically significant differences in enzyme release in favour of blood cardioplegia. No studies reported findings in favour of crystalloid cardioplegia other than outcomes such as vasoconstrictor use on bypass and myocardial oxygen uptake during bypass, which occurred when cold crystalloid was compared to warm blood cardioplegia. Thus, the literature is far from conclusive. This is reflected in a survey of practice in the UK from 2004 which found that of the surgeons performing on-pump CABG, 56% use cold blood cardioplegia, 14% use warm blood cardioplegia, 14% use crystalloid cardioplegia, 21% use retrograde infusion and 16% do not use any cardioplegia, preferring cross-clamp fibrillation!

Clinical Bottom Line

The meta-analysis of 34 randomised trials by Prof Fremes (2006) found a significantly lower incidence of low output syndrome (LOS) and CK-MB release with blood cardioplegia. He found no differences in myocardial infarction or mortality. Ovrum (2006) randomised 1440 patients to antegrade cold blood or crystalloid and found no clinical differences, and the second paper by Martin (1994) of 1001 patients compared warm blood to cold crystalloid but the study had to be stopped due to a high incidence of neurological events in the warm blood group. We reviewed a further 18 randomised trials reporting over 50 patients. Of these, 10 reported some statistically significant clinical outcomes in favour of blood cardioplegia and five reported statistically significant differences in enzyme release in favour of blood cardioplegia.

References

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