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Eur J Cardiothorac Surg 1999;16:233-239
© 1999 Elsevier Science NL

Intermittent warm blood cardioplegia does not provide adequate myocardial resuscitation after global ischaemia

Anders B. Ericsson, Tsutomu Kawakami, Jarle Vaage

Department of Thoracic Surgery, Karolinska Hospital, S-171 76, Stockholm, Sweden

Corresponding author. Tel.: +46-8-51-77-34-34; fax: +46-8-32-27-01


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 
Objective: Intermittent warm blood cardioplegia is controversial, and many surgeons consider it inadequate for myocardial protection. The purpose of this study was to compare intermittent and continuous warm blood cardioplegia as resuscitation in hearts exposed to global ischaemia. Methods: Pigs were put on cardiopulmonary bypass (CPB) and subjected to 30 min of warm, "unprotected", global ischaemia, followed by continuous (n=7) or intermittent (n=10, 12 ml/kg every 10 min) warm (34°C) antegrade blood cardioplegia for 45 min (delivery pressure 75–80 mmHg) and weaned from CPB 45 to 60 min later. Indices of left ventricular function were acquired with the conductance catheter technique and pressure–volume loops at baseline and after 90 min of reperfusion. Results: Cardioplegia was delivered during 17% of the cross-clamp time. Global left ventricular function, evaluated by preload recruitable stroke work (PRSW), was unchanged after continuous cardioplegia; 95 (76–130) (median (quartile interval)) to 91 (90–104) erg/mlx103, but decreased after intermittent cardioplegia; 122 (100–128) to 64 (23–93) erg/mlx103. Two pigs in the intermittent group weaned from CPB, but died before post-bypass measurement. A 95% confidence interval for the difference in post-bypass mean PRSW was estimated as 32±30 erg/mlx103 (corresponding to P=0.04 for comparison between treatments). The end-diastolic pressure–volume relation (EDPVR) increased from 0.17 (0.14–0.20) (continuous) and 0.15 (0.12–0.22) (intermittent) mmHg/ml to 0.27 (0.22–0.33) (P=0.018) and 0.39 (0.25–0.66) (P=0.005) mmHg/ml, respectively, indicating deterioration in diastolic function. No difference between groups was found in EDPVR, stiffness constant, troponin T release or myocardial water content. Conclusion: Following acute global ischaemia left ventricular global function was, in this model, less preserved using warm intermittent compared to warm continuous cardioplegia.

Key Words: Myocardial protection • Blood cardioplegia • Warm cardioplegia • Intermittent warm cardioplegia • Pig


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 References
 
Continuous warm blood cardioplegia is claimed to provide a superior myocardial protection avoiding hypothermia, ischaemia and reperfusion injury, thus preserving mitochondrial, membrane, and enzymatic function [1]. However, most surgeons consider continuous infusion of cardioplegia cumbersome. Thus in practice warm cardioplegic perfusion is being interrupted during shorter or longer intervals to better visualise the operating field, converting the continuous perfusion to an intermittent one. Many studies on ‘continuous’ warm blood cardioplegia have in fact been studies on warm intermittent rather than continuous cardioplegia. In Lichtenstein's original publication on warm heart surgery it is stated that cardioplegic perfusion is occasionally turned off for 10 to 15 min [2]. In a later randomised trial a mean of 48% of the cross-clamp time was off cardioplegia, the highest mean for any surgeon being 64% [3]. In that study the longest ischaemic time off cardioplegia is on average 11 min, and further analysis suggests that warm blood cardioplegia interrupted for more than 13 min is a risk factor for adverse outcome [4].

The practice of interrupting cardioplegic delivery influenced surgeons to specifically address the intermittency of warm cardioplegia [5–18]. The majority of these studies conclude that intermittent warm blood cardioplegia in the protocols used is safe and provides a myocardial protection equivalent or superior to the various regimens of myocardial protection used for comparison. Indeed, Calafiore et al. [12] claim that intermittent warm blood cardioplegia given during only 12% of the total cross-clamp time and with ischaemic episodes of up to 15 min ‘is a safe, reliable, and effective technique of myocardial protection’. However, in the warm cardioplegic heart an oxygen debt occurs at 3.5 min of ischaemia [6], and some studies conclude that interruptions of warm blood cardioplegia for 7 or 10 min episodes cause ischaemic damage with detrimental functional and structural effects [7,8].

Most investigators have studied warm intermittent cardioplegia in the normal heart, evaluating its safety and trying to establish a longest safe interval without cardioplegia. In this study we investigated intermittent warm cardioplegia as resuscitation in the already ischaemic and compromised heart. We used a porcine model with 30 min of global, normothermic, ‘unprotected’ ischaemia, followed by resuscitation for 45 min with warm antegrade intermittent or continuous blood cardioplegia. Variables studied were post-bypass left ventricular function, release of troponin T and myocardial water content.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 References
 
All animals received humane care in compliance with the European Convention on Animal Care. The study was approved by the Ethics Committee for Animal Research at Karolinska Institutet, Stockholm, Sweden.

2.1. Anaesthesia and surgical procedures
Pigs with a body weight of 40 (39–42) kg (median (quartile interval)) were premedicated with intramuscular ketamine hydrochloride (20 mg/kg) and atropine sulphate (0.5 mg). Anaesthesia was induced with intravenous sodium pentobarbital (15 mg/kg) and maintained by a cocktail (0.35 ml/kg per h) containing 2 mg fentanyl citrate, 25 mg midazolam and 24 mg pancuronium bromide in a volume of 57 ml. The infusion was preceded by a bolus of 0.15 ml/kg. The pigs were intubated and ventilated with a volume-cycled ventilator (Engström 300, Datex-Engström AB, Bromma, Sweden).

Catheters were inserted into the right femoral artery and vein for drug and fluid administration, blood sampling, and pressure monitoring. A catheter and a temperature probe were surgically introduced into the urinary bladder. An electrocardiogram was recorded by surface electrodes. A Swan-Ganz catheter (Baxter Healthcare Corp., Santa Ana, CA) was placed in the pulmonary artery through the right external jugular vein for pressure monitoring, cardiac output measurements, and injections of hypertonic saline solution for parallel conductance calibrations.

The pericardium was opened after a median sternotomy. A 5F transducer-tipped pressure catheter (Mikro-Tip, Millar Instruments Inc., Houston, TZ) and a 7F, 12-pole conductance catheter (Cordis Webster, Baldvin Park, CA) was introduced into the left ventricle through a stab wound in the apex. The tip of the conductance catheter was brought through the aortic valve. A proper position of the catheter was confirmed before each set of measurements by inspection of the individual segmental volume signals.

After heparinisation (activated clotting time >480 s), the ascending aorta was cannulated for cardiopulmonary bypass (CBP) with a 20F arterial cannula. Venous return was through a 32F two-stage cannula in the right atrium. CPB was initiated with a flow of 75 to 90 ml/kg per min using a roller pump (7400, Sarns Inc./3M Health Care, Ann Arbor, MI) and a membrane oxygenator (Maxima, Medtronic Blood System, Anaheim, CA) primed with Ringer's acetate solution and Dextran 70 (Macrodex, Medisan Pharmaceuticals, Uppsala, Sweden). During CPB the temperature was allowed to drift to 34°C. The left ventricle was vented by a 16F catheter inserted through the left atrial appendage and connected to the venous line for passive drainage. A cardioplegia cannula was inserted into the aortic root with a side branch for pressure monitoring.

2.2. Data acquisition
Haemodynamic and mechanical data were acquired during disconnection of the ventilation in end-expiration to minimise the effects of intrathoracic pressure variations. The mechanical data were acquired during variable loaded beats by occluding the inferior vena cava for 10 to 15 s. Every measurement was repeated at least twice.

The conductance catheter was connected to a Leycom Sigma-5-DF signal-conditioner processor (CardioDynamics BV, Zoetermeer, The Netherlands). The volume and pressure signals were processed (Conductance-PC software, CardioDynamics BV), and the left ventricular pressure–volume loops were displayed on-line and stored on the computer hard disk. The volume signal was corrected to absolute volume by calibrating the signal for parallel conductance, to cardiac output measured by thermodilution and to the blood resistivity. The principle and technique for volume measurement have previously been presented in detail [19–21].

2.3. Data analysis and calculations
Haemodynamics. End-diastole was defined as the lower right-hand corner of the pressure–volume loop. Left ventricular end-diastolic pressure (EDP) and volume (EDV) were measured. Stroke work (SW) was calculated as the area within the pressure–volume loop. The time constant of left ventricular isovolumic pressure relaxation ({tau}) was calculated as the time required for the left ventricular pressure at maximum negative dP/dt to be reduced by half [22].

Mechanical data. Global left ventricular function was quantitated by the slope (Mw) of the preload recruitable stroke work relation (PRSW), and by V0, its x-axis (volume) intercept by the equation [23]:

Left ventricular diastolic function was quantitated by the stiffness constant (ß) and by the slope (Eed) of the linear end-diastolic pressure–volume relationship (EDPVR) by the equations ({alpha} is the y-axis and Vd the x-axis intercept):


2.4. Myocardial water content
A transmural sample of the left ventricular anterolateral wall was taken at the end of the experiment for measurement of the wet weight/dry weight ratio. The water content (in per cent) was determined by the following formula: 100x(wet weight-dry weight)/wet weight.

2.5. Troponin T
Troponin T concentration in serum was analysed in arterial blood sampled immediately before cross-clamping aorta and post-bypass after 90 min of reperfusion (Enzymun-Test troponin T, Boehringer Mannheim GmbH, Mannheim, Germany).

2.6. Experimental protocol
Pigs were randomised to continuous (n=8) or intermittent (n=10) warm (34°C) blood cardioplegia. Baseline haemodynamic and mechanical data were recorded followed by cannulation for totally vented CPB, which was started. The aorta was then clamped. The hearts were not fibrillated and continued to beat for up to 10 min. After 30 min of "unprotected" global, normothermic ischaemia, cardioplegic perfusion was begun and given continuously or intermittently during 45 min. During delivery of cardioplegia, cardioplegic flow was continuously adjusted to maintain an aortic root pressure of 75 to 80 mmHg in both groups. In the continuous group, an initial dose of 12 ml/kg high-potassium cardioplegia was given, followed by a continuous infusion of a low-potassium cardioplegia (Table 1). In the intermittent group, an infusion of 12 ml/kg high potassium cardioplegia was given and then repeated every 10 min after stop of the prior bolus. During the last 2 min before unclamping, cardioplegia was given in the intermittent group irrespective of the time from the prior bolus. Cardioplegic flow was registered at 5, 15, 25, 35, and 45 min of delivery in the continuous group and during times of delivery in the intermittent group. After 45 min the cardioplegic perfusion was stopped, the aorta unclamped, and rewarming begun. The left ventricular vent was discontinued after another 30 min, and during 45 to 60 min after unclamping all pigs were weaned off CBP and decannulated. No inotropic support was used. After another 30 min haemodynamic and mechanical data were acquired. At the end of the experiment the pigs were given a lethal intravenous injection of pentobarbital and potassium.


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  		Table 1. Content of cardioplegic solution mixed 1:4 with blood

 
2.7. Statistical analysis
Data are presented as median and quartile limits except when otherwise stated (Statistica, StatSoft Inc., Tulsa, OK). In analysing cardioplegic flow a 95% confidence interval (95% CI) for the regression coefficient, based on individual slopes, is given. Two pigs, dying of cardiac failure in the intermittent group, were assigned worst rank for the analysis of mechanical data (Mw=0; and V0, Eed, and ß assigned the highest value for any other pig in the study). For analysis of post-bypass haemodynamic data and troponin T, only surviving animals were used. Wilcoxon matched pairs test was used for within group comparisons and Mann–Whitney U test between groups. Due to a skewed randomisation, treatment effects (baseline post-bypass Mw) became correlated to baseline values. To accomplish an unbiased estimate of the difference between treatments, avoiding a "regression to the mean effect", only post-bypass values were considered in the analysis of haemodynamic and mechanical data.

In presenting a 95% confidence interval for the difference between post-bypass Mw, a `trimmed mean' was used to compensate for the two non-surviving pigs in the intermittent group, and thus two pigs were excluded in the upper tail of this group. An unbiased estimate of the standard deviation in this group was then calculated using (P75-P25)/1.349. In such a way standard error for the difference between means could be calculated using corrected degrees of freedom.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 References
 
Two pigs given intermittent cardioplegia died of cardiac failure after weaning from CBP but before post-bypass measurement (see statistical analysis). One pig in the continuous group having a baseline troponin T value several standard deviations above mean for both groups, indicating preoperative cardiac ischaemia, was excluded (1.57 versus 0.19 µg/l (standard deviation 0.11)) giving seven pigs in the continuous and ten in the intermittent group for final analysis.

3.1. Cardioplegia and haemodynamics
Total amount of delivered cardioplegia to each animal in the intermittent and continuous group were 2.5 l (2.4–2.6 l) and 13.4 l (10.1–15.4 l), respectively. Intermittent cardioplegia was delivered five times during totally 17% (16–21%) of the cross-clamp time. In this group average median cardioplegic flow during times of delivery was 312 (250–359) ml/min. Given at constant perfusion pressure it declined with a mean rate of 1.3 (95%CI: 0.1 to 2.4) ml/min2 between infusions. In the continuous group cardioplegic flow declined 2.3 (95%CI: 0.4 to 4.2) ml/min2 having an average median flow of 265 (250–326) ml/min.

The number of defibrillations were 1.0 (1.0–2.0; max 6) and 1.0 (0.0–1.0; max 4) in the intermittent and continuous groups, respectively (p>0.2). Two pigs in each group resumed sinus rhythm spontaneously after unclamping.

No difference was found in baseline or post-bypass haemodynamics between treatments, except a larger increase in heart rate after intermittent cardioplegia (Table 2). Tau ({tau}) decreased in both groups, probably due to the increased heart rate.


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  		Table 2. Hemodynamic data

 
3.2. Left ventricular global and diastolic function
PRSW, as a measure of left ventricular contractility, decreased after intermittent but not after continuous cardioplegia (Table 3 and Fig. 1). A 95% confidence interval for the difference in postoperative PRSW (Mw) was 32±30 erg/mlx103, indicating a P-value {approx}0.04, though P=0.079 when comparing post-bypass distributions by a conservative rank test (Table 3). EDPVR increased in both groups indicating deterioration in diastolic function, but ß was unchanged. No treatment difference was found in EDPVR, or ß (Table 3).


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  		Table 3. Mechanical data

 


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  		Fig. 1. Box plots of preload recruitable stroke work (PRSW) at baseline and post-bypass in the continuous and intermittent warm blood cardioplegia groups (see text for detailed protocol). The box represents the quartile interval, the line in the box marks the median, and the whiskers show the range of data. For P values see text.

 
3.3. Tissue water content
After 90 min of reperfusion myocardial water content was 80.5% (80.3–80.7%) and 81.3% (80.2–82.0%) after intermittent and continuous cardioplegia, respectively (P=0.16).

3.4. Troponin T
Troponin T concentration in arterial blood increased from baseline values of 0.15 (0.10–0.21) (intermittent) and 0.18 (0.16–0.20) (continuous) µg/l to 8.0 (6.0–10.4) (P=0.012) and 3.8 (1.5–12.0) (P=0.018) µg/l, respectively, post-bypass at 90 min of reperfusion without any difference between treatments (P>0.2).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
References
 
Experimental data on the efficacy of intermittent warm blood cardioplegia are quite divergent. In a porcine model subjected to 90 min of regional ischaemia before start of cardioplegia, Matsuura et al. [7] reported decreased wall motion scores and increased tissue necrosis after warm intermittent retrograde cardioplegia (7 min interruptions with ischaemia during 47% of total cross-clamp time), in comparison to continuous retrograde warm or intermittent antegrade/retrograde cold cardioplegia. Ko et al. [8] reported deterioration of global left ventricular function when warm antegrade cardioplegia was repeatedly interrupted for 10, but not for 5 min episodes. Conversely, Landymore et al. [11] demonstrated that intermittent perfusion with warm cardioplegia, in a dose of 10 ml/kg (during approximately 1.5 min) every 15 min after an initial dose of 30 ml/kg, is well tolerated with regard to left ventricular systolic function. Other investigators have also reported good results, but with ‘catch-up’ reperfusions for 5 to 10 min between ischaemic intervals [16,17]. Using magnetic resonance spectroscopy and Langendorff-perfused pig hearts, Tian et al. [13] showed that warm blood cardioplegia, given during six 5 min periods interrupted by six 10-min episodes of ischaemia, results in decreased phosphocreatine levels. These, however, return to normal during subsequent cardioplegic perfusions. ATP levels and intracellular pH decrease slightly, but return to normal during reperfusion. In the isolated blood-perfused canine heart three 15 min episodes, but not 20-min episodes, of normothermic ischaemia are well tolerated if alternated with four 15 min episodes of warm cardioplegia [18]. Systolic function and ATP levels recover to baseline values.

Most clinical investigators report superior or equal results using intermittent warm but compared to intermittent cold blood cardioplegia, as long as the ischaemic interval does not exceed 10 to 15 min. Pelletier et al. [10] randomised 200 patients to warm or cold cardioplegia given during 30–40% of the cross-clamp time with maximum delivery intervals of 15 min. They reported no difference in clinical outcome, but CK-MB and troponin T levels were lower in the warm group. Landymore et al. [15] randomised 40 patients to warm or cold cardioplegia given every 10 min without any difference in post-bypass left ventricular stroke work index, myocardial oxygen consumption or release of cardiac enzymes. Mezzetti et al. [14] randomised 30 mitral surgery patients to warm or cold intermittent cardioplegia. Despite warm cardioplegic delivery during only 9.5% of the cross-clamp time, post-bypass stroke work index decreased in the cold, but not in the warm group. In the warm group there was also a faster recovery of lactate extraction and a decrease in the release of oxidative metabolites suggesting a protective effect from ischaemia-reperfusion injury. However, in the study of Ali et al. [9] a cross-clamp time of more than 90 min, with warm cardioplegia delivered every 15 min, was associated with significantly more ECG changes and low cardiac output.

In our study resuscitation of the ischaemic myocardium with intermittent warm blood cardioplegia resulted in a reduced left ventricular function measured as PRSW compared to continuous cardioplegia. Diastolic function, however, deteriorated without difference between the treatments. In addition to our study only a few investigators [7,8] have demonstrated detrimental effects of intermittent warm blood cardioplegia with ischaemic intervals of 10 min or less. Although using retrograde cardioplegia, the study of Matsuura et al. is the only study except ours, in which intermittent warm cardioplegia was given as resuscitation after ischaemia [7]. It might be that protocols of intermittent blood cardioplegia used by most investigators provide sufficient protection of the unstressed myocardium, but have limitations in the metabolically deprived heart. Using a model such as ours with global ischaemia before the introduction of cardioplegia has some important implications. (1) The whole heart mimics the region exposed to a sudden coronary occlusion. Global heart function and release of biochemical markers thus indicate what in the clinical situation occurs in the area of regional ischaemia. (2) The sensitivity of our model may be increased since myocardial protection and cardioplegia is not studied in a normal, but in an already ischaemic myocardium. Inducing severe injury in the healthy porcine myocardium will take hours using an ‘optimal’ myocardial protection. (3) Global ischaemia makes it possible to use the relatively load-insensitive PRSW as an index of ventricular contractility. In our study the more load-sensitive and commonly used ejection fraction failed to differentiate between treatments (Table 2).

Intermittent cardioplegia was in our study delivered during 17% of the cross-clamp time, which in this model proved to be inadequate. Although rather large amounts of cardioplegia were delivered in the intermittent group, the total time for ‘catch-up’ reperfusion was evidently too short in relation to the ischaemic insult. Delivery of cardioplegia for 17% of the cross-clamp time is less than in many other studies, but longer than in the study by Calafiore et al. [12] in which 250 coronary bypass patients were given warm antegrade cardioplegia with interruptions for up to 15 min. Despite cardioplegic delivery for only 12% of the cross-clamp time, excellent results are reported in comparison with cold cardioplegia. The Warm Heart Investigators [4] reported in an analysis of 720 patients, that interruptions of cardioplegic delivery exceeding 13 min, but not the cumulative time off cardioplegia, are associated with increased risk for adverse outcome. In our study there were no interruptions exceeding 10 min.

The arrested, normothermic heart requires 75–90% less oxygen than does the normal working heart [24,25]. Although a further reduction in temperature to 22°C only reduces oxygen consumption from 1.1 to 0.3 ml O2/min per 100 g myocardium [25], this still represents a further 70% decrease. Tepid blood cardioplegia (29°C) was recently introduced [26], and perhaps this combines the best of both worlds: intermittent administration and aerobic metabolism. The role of tepid cardioplegia has not yet been defined, however. The real superiority of warm versus optimal regimens of cold cardioplegia has also not yet been conclusively demonstrated. In this study we used a cardioplegic temperature of 34°C, which some surgeons may regard as tepid, whereas classically intermittent warm cardioplegia has a temperature of 37°C [4,12]. We prefer clinically to let the CPB temperature drift to about 34°C, and therefore decided to give cardioplegia at the same temperature. That intermittent cardioplegia was inferior to continuous administration at 34°C, suggests that cardioplegia at 37°C used intermittently, would have been even more harmful.

After 30 min of global ‘unprotected’ ischaemia, cardioplegia was given antegradely with a perfusion pressure of 75–80 mmHg. There is evidence that initial gentle reperfusion at low pressure is important to minimise reperfusion injury [27]. Since the perfusion pressure of cardioplegia would have the same effect in both groups, we did not manipulate with it in order to keep the model as simple as possible.

`Intermittent warm blood cardioplegia' is not a defined entity, but represents a wide range of different regimens in the hands of different investigators. Most investigators use warm blood cardioplegia for 30 to 60% of the cross-clamp time, but others for only about 12% [6,12,14,28]. Obviously the cumulative time off cardioplegia must have an upper safe limit and attention must be paid to ‘catch-up’ perfusion taking place to avoid further ischaemic damage. Warm intermittent cardioplegia will always have lower safety margins than cold techniques and should be demonstrated as being superior, not only safe, if it is to be used. However, a regimen of myocardial protection may provide excellent results in the normal, unstressed myocardium, but be insufficient as resuscitation after ischaemia. The specific method and regimen of warm intermittent cardioplegia should therefore have been tested under stressed conditions in the experimental laboratory before adopting it in the clinic. Our model proved to be beyond the limit of what intermittent warm blood cardioplegia could accomplish after a severe ischaemic insult. A longer ‘catch-up’ period had probably improved the outcome as the continuous cardioplegia actually resuscitated the myocardium with a 96% recovery of global systolic function (PRSW). However, this study defines an outer border of what is ‘too intermittent’ for intermittent warm blood cardioplegia. As a basic rule we believe that warm cardioplegia should conceptually not be intermittent, but continuous with the possibility of intermittent cessation for a few minutes in order to keep the off-periods short and ensuring adequate ‘catch-up’.


   Acknowledgments
 
This study was supported by grants from the Swedish Heart Lung Foundation, from the Swedish Medical Research Council (grant no. 11235), Karolinska Institutet, and from the Karolinska Hospital. For statistical analysis we gratefully acknowledge Ulf Brodin, MSc, statistician at the Institution for HIS/Medical Statistics, Karolinska Institutet. We also acknowledge the invaluable assistance of chief perfusionist Ove Johansson and the perfusionist team at the Department of Thoracic Surgery, Karolinska Hospital.


   Footnotes
 
Results from this study were partly presented at The 47th Annual Meeting of the Scandinavian Association for Thoracic Surgery, Helsinki, Finland, August 21–22, 1998.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 

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Received January 13, 1999; received in revised form April 6, 1999; accepted April 13, 1999.




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