Eur J Cardiothorac Surg 2006;30:597-603
© 2006 Elsevier Science NL
Evaluation of myocardial metabolism with microdialysis during bypass surgery with cold blood- or Calafiore cardioplegia
Jochen Pölinga,d,*,
Wolfgang Reesa,d,
Vittorio Mantovanie,
Stephan Klausc,
Ludger Bahlmannc,
Virgilius Ziaukasa,
Norbert Hübnerb,
Henning Warneckea,d
a Department of Cardiac Surgery, Schüchtermann-Klinik Bad Rothenfelde, Ulmenallee 11, 49214 Bad Rothenfelde, Germany
b Department of Anesthesiology, Schüchtermann-Klinik Bad Rothenfelde, Germany
c Department of Anesthesiology, Medical University of Lübeck, Germany
d Institut für klinische und molekulare Herz-Kreislaufforschung der Universität Witten-Herdecke, Dortmund, Germany
e Department of Cardiac Surgery, University of Insubria-Varese, Germany
Received 25 December 2005;
received in revised form 7 June 2006;
accepted 26 June 2006.
* Corresponding author. Address: Department of Cardiac Surgery, Schüchtermann-Klinik Bad Rothenfelde, Ulmenallee 11, 49214 Bad Rothenfelde, Germany. Tel.: +49 5424 64130070. (Email: jochen.poeling{at}freenet.de).
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Abstract
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Background: For the first time, microdialysis was used to investigate in vivo and online the myocardial metabolism during and after cardiac surgery in patients treated with two different methods of myocardial protection. Methods: Thirty patients underwent standard CABG with one of two different methods of myocardial protection. The patients were randomised to receive either cold blood (COLD group) or warm modified Calafiore cardioplegia (WARM group). Microdialysis probes were implanted into the myocardium of left ventricular apical region of the heart. Cardioplegia was given antegrade only. Microdialysis measurements were performed at time intervals before, during and 24 h after cardiopulmonary bypass and analysed for glucose, lactate, pyruvate and glycerol. Results: Myocardial lactate concentrations were significantly higher in the WARM group compared with that of the COLD group, while serum lactate was comparable. Glycerol was significantly higher at the end of the clamping time in the WARM group. At the same time the glucose–lactate ratio as a marker of nutritional disorder had significantly lower levels in the WARM group. The cumulative CK-MB release over 24 h was significantly higher in those hearts protected with warm blood. Conclusions: The oxidative stress measured was significantly higher in patients undergoing CABG using modified Calafiore cardioplegia, whereas the cold cardioplegia minimised the effects of aortic clamping. The results indicate that cold cardioplegia offers superior protection of the heart, in terms of more rapid normalisation of myocardial metabolism. In elective myocardial revascularisation, intermittent antegrade warm blood cardioplegia is a comparable safe method of myocardial protection. However, in patients referring to a long clamping time, advantages of cold cardioplegia for myocardial revascularisation may be magnified.
Key Words: Cardiovascular surgery • Cardioplegia • Energy metabolism • Glycolysis • Ischaemia
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1. Introduction
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Despite of improvements in surgical and myocardial protection techniques, postoperative ventricular dysfunction after cardiac surgery is clinically not uncommon and well observed experimentally [1,2]. Insufficient cardioplegia results in anaerobic metabolism during cardiac arrest with subsequent heart failure. However, a more detailed knowledge is required about myocardial regulation processes in concentration of nutrients and information about interstitial fluid shifts due to perfusion of cardioplegic solutions. Numerous investigations on the effect of different cardioplegic solutions were published, but up to now, monitoring of the postischaemic human myocardium is focussed only on global myocardial function, systemic haemodynamics and on indirect criteria to assess oxidative stress in the clinical setting [3,4]. Reason for this lack of information was the inability to monitor in vivo cell metabolism in the human myocardium. Currently used animal models and histologic examinations only reflect partial complexity of myocardial metabolism and are not able to describe dynamics of this process [5]. Therefore, results of these investigations can only be considered as superficial and leave essential questions unanswered.
The microdialysis technique is a new and feasible technique for online and in vivo measuring of drug concentrations, markers of cell injury and metabolites in the interstitial fluid of nearly every organ and also in the beating heart. Interstitial fluid component changes reflect intracellular disorder. Habicht et al. [6] introduced this technique to human cardiac surgery, inserting a microdialysis probe into the interventricular septum of the heart in 1994. For the first time, using this method of metabolic monitoring enables to reveal real-time and continuous information of occurring pathophysiological processes of target organs. Up to now, only animal and isolated perfused heart experiments have been used to monitor the different steps in the development of acute ischaemic injury on a cellular level [7,8].
In this study, myocardial microdialysis was used to investigate the metabolism during and after cardiac surgery in patients treated with two different methods of myocardial protection. Modified Calafiore warm blood cardioplegia and modified cold blood cardioplegia are widely used due to the limited cost, but in contrast to Buckberg blood cardioplegia not well investigated.
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2. Material and methods
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Thirty patients gave their informed consent to participate in the study, which was approved by the local ethics committee. They were randomly allocated to one of two groups: group 1 (COLD, n
= 15) received intermittent antegrade cold cardioplegia and group 2 (WARM, n
= 15) received intermittent antegrade warm blood cardioplegia.
2.1 Anaesthesia
Anaesthesia was induced with etomidate (0.3–0.5 mg g–1) and sufentanyl (0.5–1 g kg–1) and maintained with continuous infusions of propofol (5–8 mg kg–1
h–1) and sufentanyl (0.5–1 g kg–1
h–1). Muscle relaxation was achieved by pancuroniumbromide (0.1 mg kg–1). All patients were equipped with a radial arterial line, a central venous catheter and a standard pulmonary artery catheter. Fluid management was adjusted to achieve and maintain a central venous pressure (CVP) between 8 and 12 mmHg. Volume replacement was performed with cristalloids only.
2.2 Operative technique
After median sternotomy and pericardotomy, the myocardial microdialysis probe was inserted into the anterior wall of the left ventricle, followed by the preparation of the LIMA. Routine cardiopulmonary bypass was performed in normothermia. Standard graft anastomosing technique was used in all cases. The volume and temperature of the cardioplegia solution and the rate of infusion were recorded. Cardiopulmonary bypass time, cross-clamp time, need for inotropic support, number of trials necessary to separate the patient from the extracorporeal circuit, and the number of electric shocks required to achieve ventricular defibrillation were registered. Epinephrine was infused, if the heart was clinically hypocontractile, if cardiac index was below 2.0 l m2 despite of adequate filling or if the systolic blood pressures was lower than 60 mmHg despite an adequate preload.
2.3 Microdialysis procedure
Microdialysis imitates natural blood capillary function. Before preparation of the LIMA, a thin (double lumen catheter (CMA 70, CMA/Microdialysis AB, Sweden) with a superficial dialysis membrane diameter: 0.6 mm) at its end was inserted in the myocardium of the left ventricular apical region of the beating heart. Therefore, a venous cannula was tangentially inserted through the myocardial wall. The tip of the microdialysis catheter then was inserted into the distal end of the cannula and by retracting the cannula the catheter tip was finally placed into the myocardium and sutured with 5/0 prolene. A miniaturised battery driven pump (CMA 107 pump, CMA Microdialysis Solna, Sweden) which is connected to the catheter and is placed outside the body perfuses the interior lumen of the catheter with lactate-free Ringer's solution at a flow rate of 2 µl min–1. This fluid equilibrates with the myocardial interstitial fluid surrounding the microdialysis membrane at the tip of the catheter. The equilibration takes place by diffusion of markers across the dialysis membrane without the need to remove any fluid from the body. Substances from the interstitial fluid diffuse across the membrane into the perfusion fluid inside the catheter. The microdialysis catheters used had a membrane length of 10 mm and a molecular cut off of 20 kD. Interstitial fluid was sampled via the outlet in microvials, and stored at –75 °C for later analysis.
Microvials were changed directly before cardiopulmonary bypass (CPB), before aortic cross-clamping, at the end of each 10 min cardioplegia period, directly before aortic declamping (cross-clamp 1–3) and at the end of the CPB procedure. Further measurements were performed every 5 min until 20 min after CPB (post-CPB 1–4), then every second postoperative hour up to 24 h. Haemodynamic measurements were performed correspondingly before, during and 24 h after CPB. Artificial dislocation of catheter immediately could be detected due to irregular metabolite levels.
2.4 Cardioplegia
Two different types of modified Calafiore blood cardioplegia were used (Table 1
):
Group 1 (WARM): Blood was taken directly from the oxygenator and was infused at 37 °C into the aortic root by means of a roller pump. A syringe pump was connected to add potassium solution. The syringe contained 50 ml of a solution with 1 mmol ml–1 of potassium. The first dose lasted 2 min at a flow rate of 200–300 ml min–1. The syringe pump rapidly pushed 2 ml of the potassium solution in about 20 s, and then the blood flow rate was adjusted at 150 ml min–1 for a final concentration of about 20 mmol l–1. After each distal anastomosis, a second dose was repeated, at a flow rate of 200–300 ml min–1 (blood) and 120 ml h–1 (potassium) for 2 min.
Group 2 (COLD): This type of cardoplegia was a mixture of blood, Ringer solution, sodium bicarbonate and potassium. Cardiac arrest was achieved with initial warm blood cardioplegia with a flow rate of 200–300 ml min–1 for 2 min and for further 2 min with cold blood cardioplegia (4–8 °C) where the perfusion pressure did not exceed 40 mmHg. After each distal anastomosis, a second cold dose was administered at a flow rate of 200–300 ml min–1 (blood) and 120 ml h–1 (potassium) for 2 min through the aorta. Before cross-clamp release, warm (37 °C) blood solution was infused at a flow rate of 200–300 ml min–1 for 3 min.
2.5 Experimental design
The study was designed to monitor myocardial glucose, lactate, pyruvate and glycerol concentrations. Therefore, an enzymatic assay on a CMA 600 analyzer (CMA Mikrodialysis, Solna, Sweden) was used. The lactate–pyruvate ratio (LPR) – as a marker of the myocardial redox state – and the glucose–lactate ratio (GLR) – as a marker of nutritional disorder – were calculated. The myocardial metabolites‘ concentrations were correlated with the systemic haemodynamics and clinical course. Arterial blood was drawn from the radial line and venous blood from the central venous catheter simultaneously. In addition, blood samples were analysed for glucose, lactate concentrations and blood gases in plasma in our lab. Furthermore the release of the MB isoenzyme of creatine kinase (CK) was measured. Sequential CK-MB measurements were performed 6, 12, 18, and 24 h after cross-clamp removal. Acute occurrence of new Q-waves in two or more contiguous electrocardiographic leads, poor R-wave progression, a myocardial-specific isoenzyme of the total creatine kinase (CK/CKMB ratio) of more than 10% and new wall segment irregularity detected by echo was defined as perioperative myocardial infarction. Serial postoperative standard neurologic investigations were performed beginning at ICU to detect perioperative stroke. When clinical investigation shows irregularity, cranial CT was performed.
2.6 Statistical analysis
Data are presented as mean ± standard deviation. Statistical comparison of parameters in both groups and were analysed using the Mann–Whitney U-test. For baseline versus end-experiment values a Wilcoxon Signed Rank test were used. A p
< 0.05 was considered to be statistically significant. Statistical analysis was performed with the SPSS (version 12.0) software package (SPSS Inc., Chicago, IL, USA).
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3. Results
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Demographic data revealed no significant differences between the WARM and the COLD groups (Table 2
); preoperative left ventricular ejection fraction was lower in the COLD group, but number of patients with severe reduced LV-function was not different. No patient required inotropic support before institution of CPB. The norepinephrine doses applied during CPB were not different between the groups. All patients were immediately and successfully weaned from cardiopulmonary bypass. No intraaortic balloon pump implantation was necessary. The number of intraoperative defibrillations was significantly higher in the COLD group.
Four patients in the WARM group and two patients in the COLD group required inotropic support with epinephrine and/or norepinephrine 30 min after CPB (p
< 0.05). Another patient in the COLD group showed perioperative non-Q-wave myocardial infarction. Seven patients in the WARM group and two patients in the COLD group developed an intraoperative supraventricular tachyarrhythmia and were successfully treated by cardioversion. Stay on the intensive care unit (ICU) and in the hospital were not different between the groups. No complications associated with the insertion or removal of the microdialysis probes were observed. No rethoracotomy due to postoperative bleeding was necessary. The rate of myocardial infarction was not different between the two groups. The peak concentration of the systemic myocardial-specific isoenzyme of creatine kinase (Fig. 1
) were higher in the WARM group in absolute value (62 ± 30 IU l–1) than in the COLD (38 ± 11 IU l–1) (p
< 0.05) and in percent of total creatine kinase (8.2 ± 4.1% vs 6.2 ± 2.9%). There was no 30-day mortality. No strokes were found in both groups.
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Fig. 1. Release in absolute values of the myocardial-specific isoenzyme of creatine kinase CK-MB (U l–1) in the WARM and COLD groups after 6, 12, 18 and 24 postoperative hours. Data are expressed as means with standard deviations. CK-MB levels were significantly higher in WARM group compared with that of the COLD group after 12 and 18 h (*
p
< 0.05).
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The metabolite concentrations in the dialysate from both groups followed the same pattern (Figs. 1–4
). Glucose decreased, lactate and glycerol increased during aortic clamping and reached initial values after reperfusion. The pyruvate concentrations of both groups were low before CPB and during the clamping time und started rising after declamping.
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Fig. 2. Myocardial lactate (mmol l–1) levels before, during, and 24 h after CPB. Data are expressed as means with standard deviations. Myocardial lactate was significantly higher in the WARM group compared with the COLD group (*
p
< 0.05).
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Fig. 3. Myocardial glucose–lactate ratio (GLR) before, during, and 24 h after CPB. Data are expressed as means with standard deviations. The GLR of both groups declined from initial values (100%) during the clamping time. The GLR was significantly higher in the COLD group compared with the WARM group (*
p
< 0.05).
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Fig. 4. Myocardial pyruvate (µmol l–1) levels before, during, and 24 h after CPB. Data are expressed as means with standard deviations. Pyruvate levels were comparable in both groups. After aortic declamping a sharp increase (p
< 0.05) of the myocardial pyruvate within 5 min was found in both groups.
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Myocardial lactate concentrations were significantly higher (p
<
0.05) in the WARM group compared with that of the COLD group (Fig. 2). The myocardial lactate of the WARM group showed an immediate increase from 0.5 ± 0.1 µM to 2.1 ± 0.9 µM at the end of CPB and declined to 0.7 ± 0.3 µM after 24 h. The myocardial lactate of the COLD group rose only from 0.6 ± 0.2 µM to 1.2 ± 0.6 µM at the end of CPB. After CPB the myocardial lactate decreased to comparable values of the COLD group at the end of observation. During CPB the patients in the WARM group showed comparable levels of plasma lactate during CPB, increasing from 0.7 ± 0.2 µM to 1.1 ± 0.3 µM in the COLD and from 0.6 ± 0.1 µM to 1.3 ± 0.3 µM in WARM group. The values declined to normal range 24 h after CPB.
The GLR (Fig. 3) of both groups declined during the clamping time. The GLR of the COLD group had significant higher values (26 ± 15% vs 56 ± 17%) at the end of the clamping time. After CPB the GLR of both groups increased to comparable levels before CPB.
Before CPB the pyruvate concentration initially showed low values in both groups with no significant changes during the clamping time (Fig. 4). After aortic declamping a sharp increase (p
< 0.05) of the myocardial pyruvate was found in both groups within 5 min. During the first 24 postoperative hours the pyruvate levels in both groups continued rising. The pyruvate concentrations in the dialysate showed no significant differences between both groups during the observation time. The glycerol concentration increased in both groups during CPB and reached significantly (p
< 0.05) higher levels in the WARM group. Glycerol (Fig. 5
) was significantly higher at end of the clamping time in the WARM group, 146 ± 63 µmol l–1 versus 72 ± 23 µmol l–1 compared with baselines. After CPB the glycerol levels in both groups decreased significantly to initial values (p
< 0.05) during the first 24 h.
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Fig. 5. Myocardial glycerol (mmol l–1) levels before, during, and 24 h after CPB. Data are expressed as means with standard deviations. Myocardial glycerol was significantly higher in the WARM group compared with the COLD group (*
p
< 0.05).
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Furthermore, glycerol and lactate levels were significantly higher, if ventricular fibrillation during reperfusion has developed in comparison to regular courses without arrhythmia. Otherwise GLR was significant lower in those cases (Table 3
).
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Table 3. Myocardial glycerol, lactate and GLR values of patients with intraoperative ventricular fibrillation (on CPB) compared with those without arrhythmias 10 min after CPB and 6 postoperative hours
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4. Discussion
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It has recently been shown that it is possible to perform microdialysis measurements safely in the beating heart. As the size and also implantation and removal techniques of microdialysis catheters resemble standard technique of implantation and removal of temporary pacemaker wires during cardiac surgery, complication rate is reported to be the same [9–12]. In our own experience of more than 100 implantation procedures, no complication did arise yet.
No data are available concerning the correlation between myocardial metabolites – determined by the microdialysis technique – and the perioperative course of patients undergoing standard CABG with variations in myocardial protection. With respect to the well-known association between myocardial ischaemia and myocardial dysfunction, we hypothesised that an increase in myocardial metabolites might be accompanied by myocardial dysfunction after CABG and tested this hypothesis by analysing different methods of myocardial protection in patients undergoing standard CABG.
Blood cardioplegia was introduced in the 1970s and provides superior myocardial protection compared with crystalloid cardioplegia [13]. A variety of methods are in use and subject to investigations in terms of delivery, pressure, time, and temperature of the cardioplegic solutions. Different temperatures of the cardioplegic solution during induction were shown to have a significant impact on the metabolic activity of the heart. The optimal temperature is discussed controversially. In the beginning, reducing the metabolic activity of the heart was considered to play a key role in protecting the myocardium from ischaemia. Hypothermic cardioplegia was first introduced in the 1960s. Several studies then appeared suggesting that hypothermic cardioplegia may damage the myocardium and vascular endothelium [14–18]. The reduced myocardial metabolic activity delays functional recovery and may inhibit resuscitation of the acutely ischaemic myocardium. As a result of this, continuous normothermic blood cardioplegia was introduced. Since normothermic blood cardioplegia has often been used with normothermic body perfusion, this modality may expose the patients to a higher risk of the neurologic complications of open-heart surgery [19,20].
Postoperative haemodynamic stability, the course of cardiac enzymes, and the clinical outcome are considered to be the indicators reflecting the efficiency of myocardial protection. The present study clearly demonstrated how cardioplegic temperature can affect cardiac metabolism. Although the clinical course was uneventful, our data suggest that oxidative stress and anaerobic metabolism were significantly higher in patients undergoing CABG using warm cardioplegia, while the cold cardioplegia minimised the effects of aortic clamping. Myocardial lactate concentrations were significantly higher in the WARM group compared with the COLD group, whereas serum lactate was comparable during this time. Glycerol was significantly higher at the end of the clamping time in the WARM group and the GLR as a marker of nutritional disorder of the COLD group had significantly better values (56 ± 17% vs 26 ± 15%) at this point. The cumulative CK-MB release over 24 h was significantly higher in those hearts protected with warm blood. These results indicate that cold blood cardioplegia offers superior protection of the heart, in terms of more rapid normalisation of myocardial metabolism. Due to its main principle, microdialysis sampling requires a time interval less than 3 min. Therefore, measured data always represent only an integral value of the sampling time interval. Exact evaluation of data of a specific point of time is not possible. Due to the high perfusion rate and the length of the catheter membrane of only 1 cm a low recovery rate was achieved (
30%), which explained the relatively low dialysate concentrations of lactate and glucose in comparison to the blood values [9].
The lactate–pyruvate ratio (LP), which describes the myocardial redox state, is widely accepted as a marker of ischaemia [9]. In comparison to other studies, we measured high LPR values in both groups before and after starting CPB despite of low lactate levels. This phenomenon is a consequence of the initially low pyruvate levels (5–10 mmol l–1). Moreover, we found variable determinations of the myocardial pyruvate concentration. For these reasons, no further calculations of the myocardial lactate–pyruvate ratio were performed in our study. Pyruvate concentration developed a twofold increase within 15 min after removal of the cross-clamp. With regard to a decrease of lactate, the increase of pyruvate may characterise the improved myocardial tissue oxygenation during reperfusion. Zemgulis et al. have reported about an animal model of myocardial ischaemia. After CPB they observed a higher increase of the myocardial pyruvate in non-ischaemic versus ischaemic areas [8]. An explanation of this tremendous increase in pyruvate may be that the pyruvate dehydrogenase (PDH) enzyme complex was as inhibited. Fink et al. proposed that systemic inflammation (e.g., ECC) should induce inhibition of the PDH complex [21]. So the increased pyruvate levels after CPB could also be interpreted as a kind of inflammatory response triggered by ischaemia and reperfusion.
If the tissue is exposed to ischaemia, the cells take up as much glucose as possible in order to produce ATP from the anaerobic part of the glycolysis with a subsequent production of lactate. The decrease in glucose delivery from the capillaries, together with the increase in glucose uptake, leads to a fall in the glucose concentration in the dialysate. The outcome of this phenomenon is a decrease of the GLR during the clamping time. Furthermore, the level of glucose is difficult to interpret as it is affected by changes in the glucose supply to the microdialysis catheter. Increased lactate production may be an expression of elevated glycolytic activity or fatty acid oxidation with anaerobic production of high-energy phosphates. The lower CK values in the COLD group suggest less myocardial injury, which contributes to improved ventricular performance. In addition, hearts protected at cold temperatures may have a higher sensitivity to circulating catecholamines, which can enhance left ventricular performance. The relationship between myocardial ischaemia and cardiac dysfunction may also be detected by analysis of venous sinus blood. Interestingly, coronary sinus drainage has been discussed controversy. Von Lüdinghausen [22] has verified a complete drainage of blood of the epicardial veins in only 21% of 300 hearts. The analysis of coronary sinus blood does not necessarily represent the metabolism of all regions of the heart.
Glycerol values were significantly higher at the end of the aortic clamping and kept rising during reperfusion in both groups. The levels were significantly higher at the end of the clamping time in the WARM group. After the ischaemic period the glycerol levels in both areas decreased significantly during the experiment. In the neurosurgical discipline, where microdialysis is used clinically for monitoring traumatic brain damage, glycerol is interpreted as a marker of ischaemic injury, and the increase may correlate to clinical neurologic deficits [23]. The further increase after aortic declamping represents reperfusion injury [24].
The clinical outcome for both groups was similar, but mean cross-clamp time was low in our patients. There were no hospital deaths and no patient required intraaortic balloon pump insertion for low cardiac output. However, patients receiving cold blood cardioplegia experienced a higher frequency of ventricular fibrillation initially after cross-clamp removal. Myocardial lactate and glycerol values as markers of ischaemic induced cell damage rose significantly in those patients with ventricular fibrillation during reperfusion, but declined to normal range in the first postoperative hours (Fig. 4). Hypothermia is known to potentiate ventricular fibrillation after removal of the cross-clamp [25]. Ventricular fibrillation may result in the consumption of high-energy phosphates and is considered undesirable during reperfusion.
Serial measurements of intrapericardial and extracardial fluid were performed in order to identify dislocation of a microdialysis catheter. For identification of postoperative dislocation, urea was used as an internal standard. Urea is not metabolised or affected by ischaemia in the pericardial fluid. In case of catheter dislocation significant increase of microdialytic urea values were found. In this study, no catheter displacement was seen after sternum osteosynthesis.
Microdialysis showed significant deterioration of myocardial cell function in CABG patients during cardioplegic cardiac arrest with warm cardioplegia. We believe that intermittent antegrade cold blood cardioplegia provides superior myocardial protection during elective myocardial revascularisation. Intermittent antegrade warm blood cardioplegia is a comparably safe method of myocardial protection. However, in patients with acute myocardial infarction and procedures requiring a long clamping time, advantages of cold cardioplegia for myocardial revascularisation may be magnified. Further prospective, randomised trials are necessary in order to determine if cold or warm temperatures for blood cardioplegia result in greater myocardial preservation in patients who are at high risk.
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Abstract
1. Introduction
