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Eur J Cardiothorac Surg 2002;22:402-409
© 2002 Elsevier Science NL

Warm retrograde blood cardioplegia saves more ischemic myocardium but may cause a functional impairment compared to cold crystalloid

Odd Petter Elvenesa*, Christian Korvalda, Reidar Myklebustb, Dag Sørliea

a Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine, University of Tromsø, N-9038 Tromso, Norway
b Department of Pathology and Anatomy, Faculty of Medicine, University of Tromsø, N-9038 Tromso, Norway

Received 27 September 2001; received in revised form 30 April 2002; accepted 2 May 2002.

* Corresponding author. Tel.: +47-77-62-67-08; fax: +47-77-62-82-98
e-mail: odd.petter.elvenes{at}unn.no


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Comments
 References
 
Objectives: Ongoing ischemia, or even ischemia in progress, is regularly encountered in today's patients amenable to cardiac surgery. We set out to assess the effect of ‘active resuscitation’ during cardioplegia with warm continuous retrograde blood cardioplegia (WB) in a protocol simulating a clinical situation. Methods: After 60 min with a regional ischemic injury to the left ventricle, 21 pigs were randomized to receive no treatment (control), cold retrograde intermittent crystalloid cardioplegia (CC) or WB. All animals were put on cardiopulmonary bypass. After 1 h of cardioplegia and 1 h of reperfusion the perfused left ventricle was colored with methylene blue. After excision of the hearts a standard planimetri technique was used to determine the area at risk and amount of necrosis (triphenyltetrazolium). Heart rate, mean arterial pressure (MAP), cardiac output and myocardial blood flow were recorded as well as myocardial oxygen consumption, plasma levels of free fatty acids, glucose, lactate and Troponin T from the coronary sinus. Results: The area at risk of the left ventricle was 13.6±1.2%. We found 71±2, 61±3 and 30±2% necrosis of the area at risk in the controls, CC and WB, respectively (P<0.001, CC versus control and P<0.0001, WB against CC and control). Troponin T release was highest in the CC group in the reperfusion period. Glucose levels increased significantly after ischemia in the controls and WB. In accordance with the amount of saved myocardium in the WB group which also had a normal coronary sinus lactate level as opposed to the fourfold increase in the CC group after ischemia. After standstill cardiac output and MAP were significantly lower than baseline values in the WB group only (P<0.05). Conclusions: CC did reduce the size of the infarction by about 10% compared to control animals, whereas WB reduced the infarction by more than 50% of that seen after CC. Both modalities are, however, associated with a functional reduction during the first 60 min of reperfusion, WB being the worst.

Key Words: Regional ischemia • Retrograde blood cardioplegia • Resuscitation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Comments
 References
 
Cardiac surgery today is performed with safety and efficacy with current myocardial protection. Cold crystalloid cardioplegia (CC) usually offers good protection of the heart and optimal working conditions for the surgeon provided we stick to good risk patients and ischemic times less than 90 min [1]. However, an aging, sicker population even with ongoing ischemia, requiring difficult, repeat and longer operative procedures increase the demands on myocardial protection. Warm retrograde continuous blood cardioplegia (WB) has been suggested for myocardial protection, particularly in acute myocardial ischemia because of its theoretical ability to arrest the heart without ischemia and to perfuse tissues behind coronary occlusions [2].

Occasionally, an acute occlusion occurs in a major coronary vessel that cannot be safely and properly dealt with without immediate surgical revascularization in order to reduce ischemic injury. Several studies involving retrograde blood cardioplegia and acute cardiac ischemia conclude that this cardioprotective regimen is superior to the antegrade approach [2–5]. Other similar studies have drawn less clear conclusions [6–8]. Many of these studies are also rather far from the clinical situation in their setup.

The number of studies addressing the ability to resuscitate ischemic myocardium perioperatively [4–7] is limited. The present study was performed to assess the effect of ‘active resuscitation’ during cardioplegia with WB in a protocol simulating a clinical situation. We compared this technique with the widely used cold retrograde crystalloid cardioplegia and also against the spontaneous course of the untreated ischemia.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Comments
 References
 
2.1. Animal care
All animals were treated in compliance with the ‘European Convention on the Care and Management of Laboratory Animals’. The Animal Welfare Committee of the University of Tromsø, Norway approved the experimental protocol. The animals were fasted overnight, but had free access to water prior to surgery.

2.2. Anesthesia
Twenty-three locally bred domestic pigs of either sex weighing 53.4±16.2 kg (SD) were sedated with intramuscular injections of 1000 mg ketamine (Ketalar®, Parke-Davis, NJ, USA) and 2 mg atropine (Atropine®, Hydro Pharma, Norway). Anesthesia was maintained with continuous infusion of pentobarbital 4 mg kg-1 h-1 (Pentobarbital®, Nycomed Pharma, Oslo, Norway), fentanyl 0.020 mg kg-1 h-1 (Leptanal®, Janssen-Cilag, Beerse, Belgium) and midazolam 0.3 mg kg-1 h-1 (Dormicum®, Roche, Basel, Switzerland) into the external jugular vein using a venous catheter (Secalon Seldy, Ohmeda, Denmark). The animals were tracheostomized and mechanically ventilated (Servo 900, Elema-Schønander, Stockholm, Sweden) with 0.5 FiO2 and a respiratory of 20 breaths min-1. Tidal volume was adjusted by means of repeated arterial blood gas analyses (Rapidlab, ChironDiagnostics Corp., MA, USA) to achieve pCO2 and pH within normal ranges (3.5–5.7 mmHg and 7.34–7.47, respectively). Sodium chloride (0.9%) enriched with glucose (1.25 g glucose 1000 ml-1 sodium chloride) was given for basal fluid replacement (10 mg kg-1 h-1). Depth of anesthesia was regularly checked by testing the ciliary reflex and reaction to pain in the nasal cartilage.

2.3. Experimental setup
The experimental protocol is outlined in Fig. 1 . The heart was exposed through a mid sternotomy. The left hemiazygos vein was ligated. Flow was measured with ultrasonic transit-time probes (Cardio-Med, Medistim, Oslo, Norway); cardiac output (CO) with a probe around the pulmonary artery and the myocardial blood flow (MBF) with probes around the proximal part of the left anterior descending and circumflex arteries and on the main stem of the right coronary artery. Cardiopulmonary bypass (CPB) was initiated with a transatrial two-staged venous cannula and a left axillary arterial cannulation with flow rates sufficient to give a systemic pressure of 59.4±2.7 mmHg. A large-bore catheter was placed in the main trunk of the pulmonary artery during crossclamping to decompress the right ventricle.



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  		Fig. 1. Outline of the study protocol. Twenty-one pigs randomized into three groups of seven animals each; controls, CC (cold retrograde intermittent crystalloid) and WB (warm retrograde continuous blood cardioplegia). Blood samples were obtained 15 min before each filled circle.

 
The blood was oxygenated using a membrane oxygenator along with a reservoir (Avecor Cardiovacular Ltd®, Bellshill, Scotland). The extracorporeal circuit was primed with homologous fresh blood from a cross-matched donor pig. The pigs were randomized into three groups. In the control group myocardial ischemia was maintained for 3 h before terminating the protocol. The two other groups of animals received either CC or WB. Blood for the cardioplegia groups was drawn from the arterial line of the CPB circuit and a ‘mini’plegi solution was made from 20 ml ampoules containing 16 mequiv potassium chloride and 6 mequiv magnesium chloride per ampoule in distilled water [9]. This mixture was added directly into the blood-cardioplegia line, using a syringe infusion pump. When the ascending aorta was cross-clamped, cardioplegic perfusion was initiated through a retrograde double lumen perfusion cannula (Research Medical, Inc, UT, USA), without an automatic inflatable balloon (see subsequently). A quiescent heart was achieved by manually injecting 20 ml of ‘mini’plegi through the sideport of the retrograde perfusion cannula during the first 30 s after applying the aortic cross-clamp and starting the cardioplegic perfusion. The flow rate was adjusted until we had a pressure of 45±3 mmHg in the coronary sinus corresponding to 150–200 ml min-1. The ‘mini’plegi solution was administered with a speed rate of the infusion pump at 45 ml h-1. If we observed recurrence of electromechanical activity, a boost was given. Cardiac arrest was achieved within 1 min of aortic cross-clamping in both the crystalloid and the blood group. In the cold crystalloid group 600 ml of St. Thomas solution number 2 with a temperature of 4°C was infused followed by 200 ml cold crystalloid into the coronary sinus at a pressure of 40–60 mmHg every 20 min.

The ostium where the coronary sinus enters the right ventricle in the porcine heart is wide. During cardiac arrest this ostium was snared with a stitch around the coronary sinus and the retrograde cardioplegia catheter. Care was taken to avoid obstructing the veins draining the right ventricle [2,10]. The activated clotting time (ACT, Hemochrom 400, Techidyne-Corp, Edison, NJ, USA) was kept above 500 s at all times. Systemic temperature in the control and the warm group along with the temperature in the blood cardioplegia circuit were held at 37°C during the whole CPB period. In the cold group the systemic temperature was allowed to drift down to 32°C. Prior to declamping the temperature was gradually risen to 37°C. After 20 min of reperfusion following aortic declamping the pigs were tried off bypass without use of any supportive drugs. A second attempt was done after an additional 20 min if the first one did not succeed. If unsuccessful the pigs were kept on CPB until the termination of the protocol.

Mean arterial pressure (MAP) and pressure in the cardioplegic line were measured in the femoral artery and in the coronary sinus with calibrated transducers (Transpac 3, Abbot Critical Care systems, Chicago, IL, USA). All pressure transducers were connected to an amplifier (Gould ES 2000, Valley View, OH, USA), digitized (LABview, National Instruments, Austin, TX, USA) and stored. The automatized sampling rates for all channels were 0.25 Hz.

Blood samples were taken from the arterial and venous lines at timepoints depicted in Fig. 1. These samples were drawn simultaneously from all cites and were immediately cooled on ice and centrifuged at 4°C with 14.000 rpm. The plasma was divided in several aliquots and stored at -70°C for later determination of plasma metabolite levels.

2.4. Area at risk/infarcted area
One hour before CPB was started the second and third diagonals from the left anterior descending artery were snared. In order to mimic the clinical situation of high serum concentrations of free fatty acid (FFA) during ischemia in man [11] an infusion of Intralipid® 200 mg ml-1, 1 ml kg-1 h-1 (Pharmacia & Upjohn, Stockholm, Sweden) was given intravenously at the initiation of ischemia and a serum concentration of 876 nmol/l±37 was achieved. This infusion continued throughout the whole protocol. After 60 min of ischemia CPB and cardiac arrest with retrograde techniques were started, except in the control group in which the hearts were similarly unloaded by the CPB, but continued to beat all through the protocol with the snares on. The cardiac arrest lasted for 60 min followed by release of snares on the diagonals and then 60 min reperfusion (CC and WB). Then the hearts were excised and examined. Immediately before excision the snares on the diagonals on the left anterior descending artery were reapplied and within seconds the aortic root and the right coronary ostium were clamped while simultaneously methylene blue was injected into the aortic root and potassium chloride into the left ventricle. This procedure colored the left ventricle except the area at risk. The hearts were then cut into 1 cm thick slices from the apex of the heart to the level of the coronary sinus in a fixed randomized fashion. The slices were then immersed in a triphenyltetrazolium chloride (TTC) 1% bath for 30 min. Viable myocytes were colored red and dead myocardium remained uncolored. The colorpattern of the slices were copied onto a transparent paper for later analyses. Combining histochemical staining with TCC and the Cavalieri principle we determined the area at risk and necrosis (more precisely volume rather than area) [12]. This part of the study was done by one of the authors (R.M.), irrespective of the experimental groups that each heart belonged to.

2.5. Chemical analyses
Plasma concentrations of glucose, lactate and FFA were determined enzymatically using a semiautomatic analyzer (Cobas, Fara II, Roche, Basel, Switzerland). The standard reagents for glucose and lactate analyses were purchased from Boehringer Mannheim, Germany and for FFA analyses from Wako Chemicals, Germany. Oxygen saturation was determined in blood samples from all the sample lines (Rapidlab, ChironDiagnostics Corp, MA, USA).

2.6. Calculations
Calculation of MVO2 (mLO2 min-1 heart-1) was based on the differences in oxygen content between arterial and coronary sinus samples multiplied by the coronary flow. The oxygen content in blood (mLO2 100 ml blood-1) was calculated according to the formula: HbxSO2x1.34x10-2+0.024pO2, where Hb is the hemoglobin concentration (in g 100 ml-1), SO2 is saturation of hemoglobin with O2 (in%), PO2 partial pressure of oxygen (in kPa), the constant 1.34 is the oxygen binding capacity for hemoglobin (in ml g-1) and 0.024 is the solubility constant of oxygen in blood at 37°C (in ml 100 ml-1 kPa-1).

2.7. Statistics
Values in the tables and the text are given as mean values±standard deviation (SD). Prior to the statistical analysis a Shapiro–Wilks test confirmed that all observations were not abnormally distributed. A general linear model with analyses of variance for repeated measures was used throughout the study to identify between group differences (treatment), and time effects. Statistical significance is reported at the 5% probability level. For the purpose of the statistical analysis, the data were pooled, hence we could identify both the cross-sectional between-subject comparison and the longitudinal within-subject comparison over time. A Wald procedure was used to test for statistical differences. The test statistics uses the full variance–covariance matrix of the data, based on the orthogonal structure of the experiment.

The analyses were performed using the statistical software package SPSS (SPSS 9.0©, SPSS Inc. Chicago, IL, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Comments
 References
 
Pigs completing the protocol without major bleedings leading to anemia or refractory arrhythmias, which could not be converted to sinus rhythm with DC shocks, were included in the study. From 23 experiments two pigs were hence excluded. Six of the remaining 21 included animals could not be weaned from CPB (one in the control group, three in the cold group and two in the warm group). Each group consisted of seven animals.

3.1. Hemodynamics/metabolic parameters
Table 1 shows some hemodynamic variables. Cardiac output and mean arterial pressure were significantly lower than baseline values only in the warm group. Notable are the statistical differences between the cold and the warm groups, compare Table 1.


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  		Table 1. Hemodynamic variables before, during and after 60 min of regional myocardial ischemia with or without treatment in 21 pigsa

 
The plasma values of the most important myocardial fuels and MVO2 are expressed in Table 2. The level of plasma FFA increased significantly after initiation of the Intralipid® infusion and remained elevated throughout the experiment. After ischemia glucose increased significantly both in the controls and in the warm group. Lactate was significantly elevated during ischemia in the two treatment groups and in all groups thereafter. Notable is the fourfold increase in the CC group. Our [K+] values following cardiac arrest were 3.9±0.2 and 4.9±0.3 mmol/l (cold and warm, respectively).


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  		Table 2. Arterial levels of free fatty acid (FFA), glucose, lactate and myocardial oxygen consumption (MVO2) before, during and after 60 min of regional myocardial ischemia with or without treatment in 21 pigsa

 
3.2. Infarcted area/volumes
We found that the area at risk of the left ventricle was 13.6±1.2%. Fig. 2 shows the ratio between infarcted and ischemic areas, while Fig. 3 expresses the serum values of Troponin T in blood from the coronary sinus. The WB reduced necrosis both compared to CC and animals without any active myocardial resuscitation (P<0.0001). Also the treatment with cold retrograde crystalloid cardioplegia significantly reduced the ischemic injury (P<0.001) versus no treatment.



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  		Fig. 2. Plot of area of necrosis against area at risk in 21 pig hearts with regional ischemia exposed to three different protocols. After 60 min of regional myocardial ischemia, experimental animals received either cold retrograde intermittent crystalloid cardioplegia or warm retrograde continuous blood cardioplegia, for 60 min. The cardioplegic periods were followed by 60 min of reperfusion. The third group (control animals) had 180 min of ischemia without any interventions, apart from cardiopulmonary bypass similar to the blood and crystalloid groups. Infract size was determined by triphenyltetrazolium chloride staining after termination of the protocol. Bars are mean±standard error of the mean (n=7 in each group). *P<0.001 versus control, **P<0.0001 versus cold.

 


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  		Fig. 3. Troponin T release in blood samples from coronary sinus before regional left ventricular myocardial ischemia (basal), after 45 min of ischemia and after 45 min of reperfusion. See legend of Fig. 2 for definition of the groups. *P<0.05 versus control. All values during reperfusion were statistically significantly elevated compared to basal values.

 

   4. Comments
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Comments
References
 
Our results clearly demonstrate the efficacy of warm retrograde continuous blood cardioplegia to reduce necrosis in an acute ischemic situation (~50%). Cold retrograde crystalloid cardioplegia also reduced the ischemic injury by about 10% compared to our untreated controls. Survival after acute coronary occlusion is determined by the infarct size [13] and the capacity of the adjacent, non-ischemic myocardium to support the systemic circulation [14]. Noteworthy is the significantly lowered mechanical function in both the CC and WB groups compared to controls. Since our study aimed at clarifying whether WB is better in the heart at risk we may hence conclude that, despite the fact that every spared viable myocyte may contribute to a better cardiac function in the long run, it may be too dangerous to use. To what extent our pig hearts would have responded to standard inotropic medication and/or intra-aortic balloon counterpulsation when indicated, we do not know. Standard CC did not turn out to be functionally better than WB and saved only 10% myocytes compared to the spontaneous course.

Our model was designed to mimic a clinical situation with ongoing ischemia, infarction in progress, and we set out to compare the effects of a common cardioplegic modality (CC) with a proposed superior technique (WB) with respect to myocardial necrosis and function. The control group represented the spontaneous course of myocardial ischemia in non-treated animals. Since CPB per se induces considerable changes over time the control animals were also put on extracorporeal circulation. The ischemic time chosen (range from other studies; 10–90 min) leads to significant irreversible myocyte necrosis and 1 h is about as fast as we usually are able to establish CPB after having diagnosed critical myocardial ischemia in a patient. In our study the area at risk (13.6±1.2%) of the left ventricle is in accordance with other published work (range 9–16%) [4–7,15]. This seems to be the largest area tolerable for the pig heart without completely ruining the possibility to have a beating, pharmacologically unsupported heart throughout the protocol. In a previous study from our laboratory we have demonstrated a 40% reduction in left ventricular function after prolonged cardiac arrest with antegrade continuous blood cardioplegia in healthy hearts [16]. In this study we also tried to use conductance catheters to determine left ventricular function more precisely, but were not able to sample enough data due to three causes: non-homogenous function in ventricle with regional ischemia, often dysrhythmias induced by catheters and generally too groggy hearts to stand necessary unloading. However, our reported hemodynamic variables are consistent with results from our previous studies and we believe that the observed hemodynamic deterioration reflects the actual condition of the heart. It is almost impossible to judge pre- and after-load conditions just looking at ‘ordinary’ hemodynamic parameters, but from our reported central venous pressure and systemic vascular resistance no obvious trends could be detected.

A systemic stress impact, e.g. myocardial infarction, leads to an increase in plasma FFA, which the metabolic pathways have to cope with [11]. By intravenous infusion of Intralipid® we mimicked this human situation. In our study we analyzed the release of Troponin T in the myocardial venous blood as an indicator of early myocardial damage [17]. Our measurements indicate better myocardial protection using active resuscitation with warm retrograde blood-cardioplegia. During ischemia and reperfusion we observed that the control animals had the lowest release probably due to a delayed ‘wash out’ of metabolites from the ischemic non-perfused area. The same applies for the low release of lactate in the control hearts. Judged from coronary sinus lactate during reperfusion the WB group seemed to fair better than the CC group concerning myocardial ischemia.

Continuous delivery of K+-cardioplegia is associated with elevated levels of serum potassium following standstill. Since our values are within normal ranges in pigs and not significantly different between groups, it is not likely that [K+] explains the lower mechanical performance in the WB group.

Several animal studies, with a great variety of design and clinical relevance involving both canine and pig hearts have demonstrated the value of the retrograde cardioplegic approach on hemodynamic and metabolic parameters [2,3,5,18,19]. However, only few studies have assessed the myocardial necrosis by histochemical staining after regional left ventricular ischemia and the results differ [4–7,15]. Table 3 summarizes some of these studies. Studies using dogs are excluded from the table due to different anatomy of the coronary circulation [19]. Haan et al. [4] showed a 40% reduction of the area of necrosis using retrograde instead of antegrade administration of multidose, potassium, crystalloid cardioplegia after 90 min of regional ischemia. Matsuura et al. [7] compared four cardioplegic modalities after 90 min of regional ischemia; lowest area of necrosis was reported following alternating cold ante-/retrograde continuous blood cardioplegia. A 50% reduction of the area of necrosis was noted compared to their worst group, which had antegrade warm blood. In another study with similar design, but with three cardioplegic groups [6] they experienced 44% less myocardial necrosis with the use of warm retrograde continuous blood instead of warm retrograde intermittent cardioplegia and with intermediate results for the third group receiving alternating cold ante-/retrograde continuous blood cardioplegia. Lazar et al. [5] were able to reduce the necrosis by 75% after 90 min of regional ischemia, using pressure-controlled intermittent coronary sinus occlusion plus blood and L-glutamate instead of no treatment. Finally, Engelman et al. [15] reduced the area of necrosis from 60 (control) to 37% using glutamate and aspartate in the 6 h reperfusion period following 60 min of regional ischemia. Retrograde administration of cardioplegia in all the above series succeeded in reducing the ischemic injury compared to antegrade techniques. The great variety in design of the studies makes it difficult to directly compare them with each other or with a clinical situation in man. Our study strongly supports the assumption that retrograde warm blood can save considerable amounts of myocardium at risk of ischemic damage due to coronary occlusions. The ‘effective’ time window is most likely from 30 to 90 min, with a probably diminishing effect lasting several hours.


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  		Table 3. Review of some reports on myocardial necrosis following regional ischemia in pigs and effects of different cardioplegia on infarcted area as revealed by TCC staining of the hearta

 
We chose to compare the theoretically better retrograde warm blood modality with the spontaneous course and with a common clinical regimen, retrograde, cold crystalloid. Apart from advantages this also renders several limitations to the study; the great assortment of variables in our study design is a consequence of the chosen cardioplegic modalities. The difference in body temperature between the groups, the cardioplegia given only retrograde either in a continuous or intermittent fashion, the different cardioplegic vehicles and different duration of the ischemic injury, all affects our results. This makes a straight interpretation of the results and the mechanisms behind the findings more difficult. Furthermore, our reperfusion time is quite short, and does not allow following the course of the ischemically insulted myocytes for more than 60 min. Hence the present study is unable to reveal to what extent the stunned myocytes and the final amount of necrosis contributes to the final functional result [20].

Retrograde blood cardioplegia, cold or warm, is still not widely used despite its theoretically positive effects [21]. Several authors [22–24] have suggested and proven that the right ventricular myocardium is suboptimally protected during retrograde blood cardioplegia. Mild hypothermic retrograde blood cardioplegia leads to metabolic changes compatible with right ventricular ischemia [8]. At the same time, other reports have demonstrated that tissue levels of high-energy phosphates are well preserved, and that the postoperative course seems to be uneventful in patients after elective coronary surgery exposed to mild hypothermic retrograde blood cardioplegia [25].

Whether tepid or cold blood cardioplegia are as effective as the warm retrograde approach in saving ischemic myocytes remains to be answered. As demonstrated in this study and in others [19], the warm cardioplegic modality is hampered with an ensuing considerable reduction of cardiac contractility [16]. We can only speculate that this functional setback is temporary. Since a direct antegrade revascularisation is possible in acute myocardial infarction (AMI) by angioplasty (PCI), the study also indicates the considerable potential to save ischemic myocardium through primary angioplasty for AMI.

We conclude that it is possible to combine cardioplegia and resuscitation of ischemic areas of the heart through retrograde continuous administration of oxygenated blood. The warm continuous blood cardioplegia saved 57% more of the ischemic left ventricular wall than the commonly used cold retrograde crystalloid cardioplegia. Both cardioplegic modalities, however, induce a significant functional impairment, WB being the worst.

The optimal cardioplegic composition enabling an optimal revitalization of ischemic myocardium both concerning survival and mechanical performance still needs to be announced.


   Acknowledgments
 
This work was supported in part by grants from the Norwegian Council on Cardiovascular Diseases and Odd Berg Research Found, Norway.

The expert assistance from the technical staff at the Research laboratory of the Department of Surgery together with the perfusionists Terje Broks, Knut H. Hansen, Knut R. Hanssen, Ulf Larsen and Jan P. Solbø is gratefully acknowledged.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Comments
 References
 

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