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Eur J Cardiothorac Surg 1999;15:75-83
© 1999 Elsevier Science NL
Cardiac Surgical Research and Cardiothoracic Surgery, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, UK
Received 10 August 1998; received in revised form 2 November 1998; accepted 11 November 1998.
Corresponding author. Tel.: +44-171-261-0157; fax: +44-171-928-0658; e-mail: d.chambers@umds.ac.uk
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Abstract |
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 Top Abstract Introduction
Materials and methods
ResultsDiscussion
Conclusions
References |
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Key Words: Patients • Cardioplegia • Myocardial protection • Function • Arrhythmias • Metabolism
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Introduction |
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TopAbstractIntroduction
Materials and methods
ResultsDiscussion
Conclusions
References |
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Myocardial protection was initially achieved using crystalloid cardioplegic solutions [1]; however, after Buckberg et al. [2] introduced the concept of blood as the basis for cardioplegia, there has been an increase in the use of blood-based cardioplegic solutions, particularly in the US [1] but also in Europe and the UK. Over this period, a number of studies, both experimental [3] [4] [5] and clinical [6] [7] [8] [9] [10], have suggested the superiority of blood cardioplegia over crystalloid cardioplegia. In many of these comparative studies, however, the formulation and/or the administration of the crystalloid cardioplegic solutions have been less than optimal, as was highlighted by Tyers, in the discussion section of a paper by Iverson et al. [8]. They had demonstrated a significant advantage with blood over crystalloid cardioplegia but had selected an `inappropriate crystalloid solution' to compare to blood cardioplegia. Thus, crystalloid solutions have been used that contain zero calcium (which could have led to calcium overload problems during reperfusion [7] [8] [11]), an inappropriate infusion temperature (for example, 27°C [4]) or studies in which too many variables were compared to enable a definite conclusion to be reached. All this makes it hardly surprising that blood cardioplegic solutions have been shown to be more efficacious than crystalloid solutions in most studies, but they fail to provide convincing evidence that blood cardioplegia is significantly more efficacious. There have also been some studies [11] [12] [13] suggesting that blood cardioplegic solutions provide no better myocardial preservation than crystalloid cardioplegic solutions. Despite these factors, there is an increasing tendency in cardiac centres to change to blood cardioplegic solutions.
Although experimental evidence has demonstrated better myocardial protection with St. Thomas' Hospital cardioplegic solution No 2 (Plegisol) [14], commercial cost implications in the UK have meant that St. Thomas' Hospital cardioplegic solution No. 1 (STH1) is used in preference in the majority of centres. In this study, we have investigated the myocardial protective properties of STH1 and compared it to a blood cardioplegic solution that is as similar to STH1 as possible, allowing a true comparison of the protective effect of crystalloid versus blood cardioplegia.
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Materials and methods |
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TopAbstractIntroduction
Materials and methods
ResultsDiscussion
Conclusions
References |
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Cardioplegia
Composition
The crystalloid St. Thomas' Hospital cardioplegic solution No. 1 (STH1) was prepared by addition of an ampoule of STH1 (manufactured by Martindale Pharmaceuticals, Romford, Essex, UK) to a 1 l bag of Ringer's solution. For the blood cardioplegia, a double strength STH1 was prepared by adding 1 ampoule to 500 ml of Ringer's solution, which was then mixed in a ratio of 1:1 with blood drawn from the cardiopulmonary bypass machine (haematocrit of approximately 25%) to give a blood cardioplegic solution with a similar composition to STH1, but with a haematocrit of 10–12% (BSTH1). The composition of the cardioplegic solutions is shown in Table 2.
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Surgical protocol
Non-pulsatile cardiopulmonary bypass was established using a single two-stage right atrial and ascending aortic cannulae, a disposable membrane oxygenator (Bard HF/5707) and arterial line filter (Pall EC3840, 40 µm). The perfusion circuit was primed with 2 l of Hartmann's electrolyte solution (Ringer's lactate solution) and the systemic flow rate was maintained at 2.4 l/min/m2 at a pressure of 50–60 mmHg with a core temperature of 28°C.
Distal anastamoses were constructed on the arrested heart and proximal anastamoses were fashioned following release of the aortic cross-clamp with the heart beating. Additional analgesic, cardioactive and vasoactive drugs were administered according to the individual requirements of each patient.
Electrocardiographic analysis
Patients were assessed for the presence and the severity of arrhythmias during the immediate post-operative period, during the time in the intensive treatment unit (usually 24 h) and on the fifth post-operative day. We identified (1) the incidence of reperfusion-induced ventricular fibrillation, (2) the number of direct-current shocks required to convert to sinus rhythm, (3) the incidence of AV dissociation and (4) the incidence of intraoperative myocardial infarction (as defined by the development of new Q waves).
Clinical function assessment
Clinical data were recorded before, during and after operation in all patients. Haemodynamic data were obtained using the thermodilution technique (Explorer, Baxter Healthcare Ltd.); this involves the use of a Swan-Ganz catheter inserted into the pulmonary artery and incorporates a fast-response temperature probe. A 10 ml bolus of iced saline solution was injected (within 3 s) into the right atrium and the change in blood temperature is measured over time in the pulmonary artery, and cardiac output and other variables are derived from these data.
Measurements were determined in rapid succession, and three values in close agreement were averaged; values judged to be outside the range of close agreement were excluded. Measurements were made during the pre-operative phase (after onset of general anaesthesia), during the operative phase (when the chest had been opened), and at 0.5, 1, 2, 4, 6, 8 and 24 h after ischaemia. Absolute values of mean aortic pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO), systemic vascular resistance (SVR), left ventricular stroke work index (LVSWI), right ventricular stroke work index (RVSWI), right ventricular ejection fraction (REF) and cardiac index (CI) and a number of other variables were obtained for all patients. There was, however, a wide variation in values obtained in this randomised sample of patients and so the preoperative baseline value for each patient was normalised to 100% and all other values were expressed as a percentage of this baseline value.
High-energy phosphate compounds
Three full thickness left ventricular needle biopsies (1.5 mm TruCut biopsy needle; Baxter Healthcare Ltd., Newbury, Berks, UK) were taken from the apex of the left ventricle (1) immediately before application of the aortic cross-clamp (control), (2) at the end of the ischaemic arrest period (ischaemia) and (3) after 10 min of supportive bypass (reperfusion). Biopsy samples were prepared for high performance liquid chromatography (HPLC) measurement of high-energy phosphate compounds and their metabolites according to the method described by Smolenski et al.
[15]. Briefly, this involved immediate washing of the biopsy in an ice-cold isotonic buffer solution before freezing in liquid nitrogen (within 15 s from the time of collection). Samples were stored under liquid nitrogen for later analysis; they were then freeze-dried and tissue was extracted, centrifuged and neutralised and samples were analysed using a Merck-Hitachi LiChrograph HPLC system.
Statistical analysis
Data are expressed as the mean±SEM. Univariate analyses were conducted using 
2-analysis or the Fisher's exact test where appropriate. Between group analysis was conducted with a repeated-measures analysis of variance (incorporating the Bonferroni correction for multiple comparisons) and an unpaired t-test when appropriate. On non-normally distributed continuous data, the Mann–Whitney U-test for non-parametric data was performed. Data were analysed using Abacus Concepts StatView statistical software (Abacus Concepts, Berkeley, CA) on an Apple Macintosh computer. A P value of less than 0.05 was considered significant.
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Results |
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TopAbstractIntroduction
Materials and methods
ResultsDiscussion
Conclusions
References |
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Electrocardiographic results
Electrocardiographic data are shown in Table 3. There was a significant (P=0.002) increase in the incidence of spontaneous sinus rhythm in the BSTH1 group (24/25: 96%) compared to the STH1 group (16/25: 64%) and this was associated with a significant (P=0.023) decrease in the incidence of DC shocks required to convert to sinus rhythm in the BSTH1 group compared to the STH1 group; only one DC shock was needed in all patients requiring cardioversion. The incidence of post-ischaemic AV dissociation and of transient pacing were slightly higher in the STH1 group but were not significantly different from the BSTH1 group. There were no significant differences in the incidence of post-operative arrhythmias, either at 1 day or 5 days post-operatively.
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Representative data for cardiac index (CI), left ventricular stroke work index (LVSWI) and right ventricular stroke work index (RVSWI) are shown in Fig. 1 , together with the percent change when the pre-operative value was normalised to a baseline value of 100%. CI was relatively low in both groups of patients before and during the operation, but had increased considerably by 0.5 h after ischaemia; however, in the control (STH1) patients, CI was depressed at 1 h post-ischaemia and remained at a lower value until 8 h. In contrast, in the BSTH1 group, there was less of a depression of CI and this recovered more rapidly to a stable level by 4 h ( Fig. 1A,B). All post-operative values of CI in both groups of patients were higher than the pre-operative and peri-operative values. LVSWI was also depressed at 0.5 h post-operatively in both groups of patients and remained depressed at 1 h, but subsequently gradually recovered in the STH1 group of patients and was back to the pre-operative value by 24 h; in the BSTH1 group of patients, LVSWI had recovered to the pre-operative value by 2 h, was maintained at this level to 6 h, but then further improved to above pre-operative values at 8 and 24 h ( Fig. 2 A). These changes are shown more clearly in Fig. 2B, where the values were expressed as a percentage of the pre-operative value (normalised to 100%); this indicates that there was a significant (P=0.043) difference in LVSWI in the BSTH1 group of patients, recovering significantly faster than the STH1 group of patients at 2 h (P=0.045) and 4 h (P=0.026) post-ischaemia.
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Discussion |
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TopAbstractIntroduction
Materials and methods
ResultsDiscussion
Conclusions
References |
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Recovery of function (represented by CI, LVSWI and RVSWI) was not significantly different by 24 h post-operatively; significant differences were observed, however, in the rate at which recovery occurred, with patients in the BSTH1 group demonstrating significantly more rapid recovery at 2 and 4 h post-operatively than patients in the STH1 group. There were no differences in the two groups between patients requiring inotropic support for intra-operative myocardial infarction (with two patients in each group) but, in the STH1 group, this support was required for considerable durations. No other patients required inotropic support for low cardiac output. Extubation times were not different between the two groups of patients, either in incidence of early or late extubation or in the duration of late extubation. The cross-clamp durations in this series of patients undergoing elective surgery were not different between the two groups of patients and were relatively short; longer periods of ischaemic cross-clamp may have exacerbated any differences observed between the cardioplegia techniques. Mean ITU stay and mean hospital stay were slightly reduced in the BSTH1 group of patients; however, the number of patients in this study are too small to make any conclusive statement regarding these differences.
A comprehensive analysis of myocardial metabolism, comparing high-energy phosphate compounds and their catabolites, together with metabolic co-factors, revealed no significant differences between the two groups except for a significant increase in creatine phosphate at the end of ischaemia in the BSTH1 group of patients. This would suggest improved myocardial protection during ischaemia as creatine phosphate is utilised in preference to ATP during ischaemia and usually declines rapidly in the ischaemic myocardium.
Myocardial arrhythmias
Few studies have examined the effect of crystalloid or blood cardioplegic solutions on the incidence of post-operative arrhythmias. Mullen et al.
[16] demonstrated that blood cardioplegia was associated with a lower incidence of post-operative supraventricular arrhythmias than a crystalloid cardioplegia, whereas there were no differences in post-operative ventricular arrhythmias. However, the crystalloid cardioplegic solution had low-sodium (27 mmol/l) and zero-calcium concentrations; this was potentially less protective than the blood cardioplegia and could account for the higher incidence of arrhythmias. A significantly lower incidence of conduction disturbances has previously been demonstrated by Rousou et al.
[17] in patients arrested with blood cardioplegia than in patients arrested with a crystalloid solution. In contrast, Gundry et al.
[18] observed the reverse, with a significantly higher incidence of conduction disturbances with blood cardioplegia than with crystalloid cardioplegia; however, potassium concentrations were higher (30–35 mmol/l) in the crystalloid solution than the blood solution (18 mmol/l).
One of the components of STH1 is procaine, included at a concentration of 1 mmol/l, which is thought to have membrane stabilising effects. Recently, Sellevold et al. [19] investigated the effect of adding 1 mmol/l procaine to the St. Thomas' Hospital cardioplegic solution No. 2 (Plegisol; Abbott) and demonstrated a significant reduction in reperfusion-induced ventricular fibrillation (VF) requiring DC cardioversion together with a reduced level of myocardial enzyme release on the first post-operative day. In a previous study [20], we demonstrated a relatively high incidence of VF in patients arrested with STH1 that was significantly attenuated when 10 mmol/l creatine phosphate was used as an additive. In the present study, the incidence of VF was lower than in this earlier study but was further significantly reduced when BSTH1 was used, supporting the conclusions of Mullen and Rousou's groups [16] [17].
Myocardial function
Crystalloid potassium-based cardioplegia was introduced into clinical practice in the mid-70's
[21], and the concept of cold intermittent blood cardioplegia followed soon after
[2]. Blood cardioplegia has subsequently become the most widely used solution in the US
[1] and is being used increasingly in both Europe and the UK.
There have been many experimental and clinical studies comparing the efficacy of crystalloid and blood cardioplegic solutions. Most experimental studies have demonstrated superiority of blood over crystalloid cardioplegia, but the majority of these studies have tended to use conditions and/or formulations that favoured blood cardioplegia. Thus, comparisons were made between blood and crystalloid cardioplegia during ischaemia at 27°C in studies by Bing et al. [3] and by Feindel et al. [4], with hearts protected by blood cardioplegia showing improved protection or reduced necrosis, respectively. It is well known that crystalloid cardioplegia should be used at lower temperatures than the moderate hypothermia (27°C) used in the above studies. This was demonstrated by Magovern et al. [12] who showed that a similar degree of protection was achieved when dog hearts were infused with either crystalloid or blood cardioplegia at 4 and 20°C, respectively; however, reduced recovery was observed with blood cardioplegia at 4°C or crystalloid cardioplegia at 20°C. Axford-Gatley et al. [22] observed no differences in terms of necrosis between dog hearts protected at 4°C with crystalloid cardioplegia, and blood cardioplegia at either 4 or 27°C. All hearts were successfully weaned from bypass suggesting no differences in the protective properties of these solutions at the different temperatures; interestingly, the effect of crystalloid cardioplegia at 27°C was not examined. In the present study, both crystalloid and blood solutions were infused at 4°C, with the hearts being maintained during ischaemia at around 15°C.
In a similar way, the presence of calcium, and oxygenation of the cardioplegic solutions, were shown to be important. Calcium was absent from the crystalloid cardioplegic solutions in the studies of Bing [3] and Feindel [4], and Heitmiller [11] subsequently demonstrated the importance of calcium as a component of crystalloid solutions. Oxygenation of the cardioplegic solution has also been shown to exert a significant additional protection [5] [23], such that oxygenated crystalloid cardioplegic solutions were as efficacious as blood cardioplegia.
Clinical studies have not generally been as conclusive as the experimental studies described above, and few have attempted to compare the composition of the solutions and examine the effect of the blood component alone in a well-established crystalloid solution (as in the present study). A comparison of Plegisol to a blood cardioplegic solution [9], showed fewer patients in the blood cardioplegia group requiring inotropic support to maintain a satisfactory cardiac index (greater than 2 l/min per m2), and a reduced CK-MB leakage, suggesting better myocardial protection. Fremes et al. [7] comparing crystalloid to blood cardioplegia in a clinical study observed similar recovery profiles of CI and LVSWI to those in the present study over the first 24 h post-operatively; there was a depression in CI in both groups which recovered more rapidly in the blood cardioplegia group. However, the crystalloid cardioplegic solution had a zero-calcium, together with a low-sodium, concentration. Similar results were obtained in a study by Iverson et al. [8], using a similarly less-than optimally formulated crystalloid cardioplegic solution; true comparison can only be determined when the crystalloid and blood cardioplegic solutions are as similar as possible (as has been attempted in the present study).
In the present study, we measured both right and left ventricular function; no significant differences were observed between the two groups in right ventricular function, confirming a previous study by Mullen et al. [24], although the crystalloid cardioplegia gave a better systolic performance when the hearts were subjected to volume loading. It was suggested that this may be associated with induction of lower temperatures in the right ventricle with crystalloid cardioplegia.
More recent comparative studies have tended to concentrate on examining selective markers of myocardial injury. Pichon et al. [25] measured release of troponin I in patients randomised to receive either crystalloid or blood cardioplegic solutions (ejection fraction was greater than 55% in each group); the solutions were formulated to be similar but the blood cardioplegic group benefited from a period of warm cardioplegic reperfusion. Cardiac troponin I release was significantly higher in the crystalloid cardioplegia group; the incidence of spontaneous sinus rhythm was significantly higher in the blood cardioplegia group (similar to the results from the present study) and there appeared to be a correlation with a requirement for defibrillation and increase in troponin I. A similar study was conducted by Caputo et al. [13], comparing the crystalloid STH1 to a blood-based STH1 (although made up in a ratio of 4:1) by measurement of both troponin I and troponin T; no differences were observed between the two groups of patients, which were defined as low risk patients with mean ejection fraction greater than 60% in both groups. The patients investigated in the present study were higher risk patients with ejection fraction less than 40%. This may explain why we were able to obtain significant differences in ventricular function in the present study; any benefit would be expected to have a greater effect on patients with poor LV function than on patients with relatively normal LV function.
Myocardial metabolism
Potassium-based cardioplegic solutions are designed to induce rapid arrest and, together with hypothermia, preserve myocardial content of high energy phosphate compounds. In this study, we measured high energy phosphate compounds and their catabolites before bypass, at the end of ischaemia and 10 min after reperfusion. We observed no differences between the two groups except for a significantly higher level of creatine phosphate at the end of ischaemia in the blood cardioplegia group of patients. These results are in general agreement with the limited number of previous studies that have examined myocardial metabolism. Engelman et al.
[26] measured ATP and creatine phosphate in ventricular biopsies taken from pig hearts subjected to arrest with blood or crystalloid cardioplegia. ATP levels were maintained during ischaemia in both groups although the blood cardioplegia group was significantly higher than the crystalloid cardioplegia group; creatine phosphate declined in both groups during ischaemia but remained higher throughout ischaemia in the blood cardioplegia group. The study by Fremes
[7] also demonstrated that creatine phosphate was significantly higher in the blood cardioplegic group of patients at the end of ischaemia and after 30 min of reperfusion than in the crystalloid cardioplegic group.
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Conclusions |
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TopAbstractIntroduction
Materials and methods
ResultsDiscussion
Conclusions
References |
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References |
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TopAbstractIntroduction
Materials and methods
ResultsDiscussion
Conclusions
References |
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