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Interact CardioVasc Thorac Surg 2009;8:647-653. doi:10.1510/icvts.2008.200048
© 2009 European Association of Cardio-Thoracic Surgery
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Institutional report - Experimental

Selective antegrade cerebral perfusion at two different temperatures compared to hypothermic circulatory arrest – an experimental study in the pig with microdialysis{star} ,{star}{star}

Ove Jonssona,*, Gunnar Myrdala, Vitas Zemgulisa, Johann Valtyssona, Lars Hilleredb and Stefan Thelina

a Department of Surgical Sciences, Thoracic Surgery, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
b Department of Neuroscience, Neurosurgery, Uppsala University Hospital, Uppsala University, Uppsala, Sweden

Received 2 December 2008; received in revised form 5 March 2009; accepted 6 March 2009

{star} The abstract has been orally presented at the SATS (Scandinavian Society of Thoracic Surgery) meeting in Copenhagen, August 21–23, 2008. Back

{star}{star} Foundings: Swedish Heart-Lung Foundation.

*Corresponding author. Department Thoracic Surgery and Anaesthesia, Uppsala University, SE-751 85 Uppsala, Sweden. Tel.: +46 18 6110000 (operator); fax: +46 18 506143.

E-mail address: ove_jonsson{at}spray.se (O. Jonsson).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
Hypothermic arrest and selective antegrade cerebral perfusion (SACP) is widely used during aortic arch surgery. The microdialysis technique monitors biomarkers of cellular metabolism and cellular integrity over time. In this study, the cerebral changes during hypothermic circulatory arrest (HCA) at 20 °C and HCA with SACP at two different temperatures, 20 and 28 °C, were monitored. Twenty-three pigs were divided into three groups. A microdialysis probe was fixated into the forebrain. Circulatory arrest started at a brain and body temperature of 20 °C or 28 °C. Arrest with/without cerebral perfusion (flow 10 ml/kg, max carotid artery pressure 70 mmHg) lasted for 80 min followed by reperfusion and rewarming during 40 min and an observation period of 120 min. The microdialysis markers were registered at six time-points. The lactate/pyruvate ratio (L/P ratio) and the lactate/glucose ratio (L/G ratio) increased significantly (P<0.05), during arrest, in the HCA group. The largest increase of glycerol was found in the group with tepid cerebral perfusion (28 °C) and the HCA group (P<0.05). This study supports the use of SACP over arrest. It also suggests that cerebral metabolism and cellular membrane integrity may be better preserved with SACP at 20 °C compared to 28 °C.

Key Words: Aortic surgery; Hypothermic circulatory arrest; Selective antegrade cerebral perfusion; Cerebral protection; Pig model; Microdialysis


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
Cerebral injury is a threat during complex aortic arch surgery [1] and optimal cerebral protection is of crucial importance. Reducing the metabolism by cooling is the mainstay of cerebral protection and is used alone with hypothermic circulatory arrest (HCA) or in conjunction with cerebral perfusion [2].

Selective antegrade cerebral perfusion (SACP) is widely used and there are clinical and experimental [3] evidence of its superiority to HCA alone.

The microdialysis technique is an established clinical experimental method to monitor cellular metabolism [4] and is often used in neurointensive care after neurosurgery, trauma and stroke.

In this experimental study we used a porcine model including cardiopulmonary bypass (CPB), HCA and SACP.

The aim of the study was to explore the changes in cerebral energy metabolism and cellular integrity biomarkers by microdialysis during HCA (20 °C) alone and HCA with SACP at two different temperatures, 20 and 28 °C.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
2.1. Study design

The study involved experiments on 23 domestic pigs (31.2±2.5 kg) divided into three separate groups. In the first group (HCA, n=7) cerebral protection was achieved with HCA alone, at 20 °C. In the second group (SACP20, n=7) body temperature and cerebral perfusion temperature was 20 °C, and in the third group (SACP28, n=9) body temperature and cerebral perfusion temperature was 28 °C.

This project was approved by the Animal Research Ethical Committee of Uppsala University (C 284/05) and the animals were treated in compliance with the European Convention on Animal Care.

2.2. Anesthesia

Induction by intramuscular injection of 6 mg/kg tiletamine/zolazepam (Zoletil®; Reading Laboratories, Carros, France) and xylazine/atropine (Rompum®; Bayer AG, Leverkusen, Germany) 2.2 mg/kg and 0.04 mg/kg, respectively, followed by intravenous 5–10 µg/kg Fentanyl (Fentanyl® 50 µg/ml, Pharmalink, Pharmaceuticals Ltd, Roscrea, Ireland). After intubation artificial ventilation was instituted using a Servo I ventilator (Siemens Electromedical Group, Danvers, MA). Tidal volume was 10 ml/kg, FiO2 50% and respiratory frequency adjusted to an end-tidal carbon dioxide tension between 5.2 and 5.6 kPa. Ventilation was reduced to 5 ml/min during CPB cooling and reperfusion and disconnected during HCA/SACP.

An infusion of 7.5 ml/kg/h glucos (Rehydrex, Fresenius Kabi, Sweden, glucos 25 g, Na+ 70 mmol, Cl– 45 mmol, Ac– 25 mmol) with 4 g ketamin (Ketalar® 50 mg/ml, Pfeizer), 40 mg pancuronium bromide (Pavulon® 2 mg/ml, Organon Teknika) and 0.5 mg fentanyl in every 1000 ml was used. Body temperature was measured rectally, in the brain and in the main pulmonary artery.

2.3. Perioperative management

Arterial and central venous catheters were used in the femoral and carotid arteries and the jugular vein for pressure monitoring, blood sampling and cardiac output measurement. The skull was prepared with two parallel burr holes. The microdialysis probe was placed in the first burr hole (see section 2.5.). The second was used for the temperature probe.

Ringer's solution (Ringer-acetate®; Fresenius Kabi, Sweden; Na+ 131 mmol, K+ 4 mmol, Ca2+ 2 mmol, Mg2+ 1 mmol, Ac– 30 mmol, Cl– 110 mmol) (6 ml/kg/h) and colloid (Voluven® 60 mg/ml, Fresenius Kabi, Sweden) was infused.

2.4. Surgical preparation and CPB

After sternotomy heparin (Heparin® 5000 IU/ml; Løvens Kemiske Fabrik, Denmark) 400 U/kg was given to ACT over 400 s. The ascending aorta was cannulated with a 16 F arterial cannula and separate venous cannulaes were used (28 F).

Priming of the CPB circuit was done with Ringer-acetate solution (600 ml), mannitol (200 ml) and 2500 U of heparin.

Non-pulsatile CPB (Jostra Heart-Lung Machine HL-15Ts, Sweden), using alpha-stat pH management, was initiated at a flow rate of 70–100 ml/kg/min and the flow was adjusted to a perfusion pressure not exceeding 70 mmHg. After cooling to a brain temperature of 20 °C or 28 °C, SACP was instituted by redirection of flow to the brachiocephalic artery from where both carotid arteries originate [3]. The right subclavian artery was snared.

Cardiac arrest was induced by infusion of cardioplegia (Cardioplegic St Thomas type I solution, Ringer-acetate 1000 ml, K+ 16 mmol, Mg2+ 16 mmol, procainum 1 mmol, Cl– 49 mmol, tribonate 10 ml) at a minimum of 15 ml/kg.

After declamping the aorta, rewarming was started. The temperature difference between blood and water was always below 10 °C.

After weaning epinephrine (Adrenalin®, NM Pharma; Stockholm, Sweden) and fenylefrin hydrochloride (Fenylefrin-hydroklorid® 10 mg/ml, Apoteksbolaget, Umeå, Sweden), were used as required.

2.5. Microdialysis

The microdialysis probe was inserted obliquely into the superficial area of the forebrain. The microdialysis probe (CMA-70 brain MD probe with 10 mm polyamide membrane; CMA/Microdialysis, Stockholm, Sweden) was perfused with artificial cerebrospinal fluid (containing Na+ 148 mM. Ca2+ 1.2 mM, Mg2+ 0.9 mM, K+ 2.7 mM and Cl– 155 mM) by a micro injection pump (CMA 107 MD pump, CMA/Microdialysis) at a rate of 2 µl/min. A 30-min period of calibration was followed by three 20-min periods of basal level measurement before start of CPB. The microdialysate samples were collected in 20-min fractions and stored in a freezer.

The interstitial concentrations of brain tissue glucose, lactate, pyruvate, glycerol and glutamate were analyzed enzymatically (CMA 600 Microdialysis Analyzer, Microdialysis, CMA/Microdialysis).

The analyzer was automatically calibrated and quality controlled according to the manufacturers instructions.

The lactate/pyruvate ratio (L/P ratio) and lactate/glucose ratio (L/G ratio) were calculated.

2.6. Experimental protocol

The animals were cooled during 40 min to a brain and body temperature of 20 °C or 28 °C. Arrest or SACP lasted for 80 min. Reperfusion continued during 40 min (37 °C). After termination of CPB the animals were observed for 2 h. The microdialysis samples were recorded at six timepoints; at baseline, end of cooling, end of HCA/SACP, end of rewarming and in the middle and end of the observation time.

2.7. Statistics

The data were entered in an Excel spreadsheet and analyzed using SPSS 15.0.

Microdialysis values, hemodynamic values, hematocrit, pH, pCO2, and temperature are expressed as mean±S.D.

The statistical analysis for the microdialysis results were performed on their relative changes.

Significance between groups at selected time-points were analyzed with the Kruskal–Wallis test. If significance between groups existed the Mann–Whitney test was used to compare significance between two groups at each time-point.

A difference of P<0.05 was considered to be statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 5. Limitations
 6. Conclusion
 References
 
3.1. Comparability of experimental groups

Baseline values for temperature, hemodynamics, respiratory parameters and acid-base data were without significant differences between the groups (see Table 1).


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  		Table 1 Temperature, hemodynamic variables, and blood gases

 
One animal in the SACP28 group died of hemmorhage and was replaced.

3.2. Microdialysis

The analyzed microdialysis samples showed the following significant differences.

Glucose was higher in group SACP28 compared to SACP20 after CPB cooling (1030±620 vs. 517±330 µmol/l) and at the end of cerebral perfusion/arrest (1610±1660 vs. 352±314 µmol/l) (Fig. 1a).


Figure 1
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  		Fig. 1. Energy metabolites and their ratios shown as mean values±S.D. Number of asterisks show group. White asterisks indicate significance (P<0.05) compared to black asterisks. *, HCA; **, SACP20; ***, SACP28.

 
A difference was also registered at the end of CPB warming between SACP28 and HCA (1956±1900 vs. 410±462 µmol/l) (Fig. 1a).

Lactate showed an increase in all groups during the experiment. This was most pronounced in SACP28 with a difference compared to SACP20 at the end of cerebral perfusion/arrest (1880±1214 vs. 720±180 µmol/l) (Fig. 1b).

Pyruvate had the most pronounced increase in SACP28 (Fig. 1c).

Compared to SACP20 there was a difference at end of cooling (46±32 vs. 17±17 µmol/l) and compared to HCA there were differences both at end of cooling (46±32 vs. 32±14 µmol/l) and at end of cerebral perfusion (73±51 vs. 8.4±8 µmol/l).

L/P ratio showed a peak at the end of arrest in HCA (430±480) which was different from both SACP20 (25±5) and SACP28 (25±11).

However, there was also a difference between SACP20 and SACP28 at this timepoint (Fig. 1d).

L/G ratio showed a peak at the end of arrest in group HCA (409±470) with a difference from both SACP20 (4.7±6) and SACP28 (1.6±1). At the end of CPB warming a difference was seen between HCA and SACP20 (7.8±7 vs. 1.7±2). At the end of the experiment these changes were normalized (Fig. 1e).

Glycerol showed an increase in both group HCA and SACP28 (Fig. 2a). There were differences between HCA and SACP20 at end of perfusion/arrest (22.5±7 vs. 6.5±4 µmol/l) but also at end of CPB warming (37±21 vs. 11±6 µmol/l). There was also a difference between SACP28 and SACP20 at end of perfusion (62±65 vs. 6.5±4 µmol/l) and at end of CPB warming (74±74 vs. 11±6 µmol/l).


Figure 2
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  		Fig. 2. Time course of cerebral, cell membrane and cell integrity, metabolites shown as mean values±S.D. Number of asterisks show group. White asterisks indicate significance compared to black asterisks. *, HCA; **, SACP20; ***, SACP28.

 
Glutamate was without differences between the groups. However, a tendency to a peak was noted at the end of CPB warming in group SACP28 (Fig. 2b).

3.2.1. Individual microdialysis results from group SACP28 animals
The microdialysis results in SACP28 showed great heterogeneity dividing this group into two subgroups. Glucose, lactate, pyruvate, glycerol and glutamate showed almost no increase in half of the animals but a considerable peak in the other subgroup (Fig. 3).


Figure 3
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  		Fig. 3. Time course of individual microdialysis results from group SACP28. The group is divided into two subgroups. Half of the animals show almost no increase of the microdialysis biomarkers but the other half show a considerable increase.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
5. Limitations
 6. Conclusion
 References
 
The main findings of this study support the hypothesis that cerebral energy metabolism in pigs is best preserved with SACP compared to HCA alone. It also may support the notion that SACP with colder perfusate (20 °C) could be superior to tepid perfusate (28 °C) regarding cellular integrity.

Cerebral metabolism is dependent on substrate delivery from the blood but also on cellular mitochondrial function and membrane integrity. The microdialysis technique measures local metabolic changes and typical patterns of biomarkers are identified in the interstitial fluid if the energy metabolism or cellular integrity is altered.

The ratios of the energy substrates (L/P ratio, L/G ratio) are less susceptible to changes in probe recovery than the actual values of the substrates themselves. This makes them more accurate markers and quantitative measures of changes in energy metabolism over time [5]. These ratios are especially used to identify cellular anaerobic metabolism (mitochondrial dysfunction) and to follow the substrate (glucose) delivery status. A parallel increase in lactate and pyruvate with a normal L/P ratio is considered to reflect a situation of increased glycolysis in response to an increased energy demand [6].

If the cellular integrity is disturbed there will be an increase in interstitial glycerol and glutamate. Glycerol has become a tool for monitoring membrane lipolysis and it is used in clinical and experimental settings as a marker for cellular disruption and degradation [7]. Glycerol in the brain has also been implicated as a biomarker of increased free radical activity/oxidative stress in acute brain injury [8].

Glutamate is increased as a consequence of disturbed glutamatergic neurotransmission, reflecting increased glutamate release and/or deficient function of the glutamate/glutamine cycle activity, owing to insufficient energy (ATP) production.

In this study, we compared three groups, HCA alone and SACP at two different temperatures. The relatively long time of arrest, which was beyond what is used clinically, was necessary to produce a considerable cerebral trauma.

4.1. Energy metabolism and cell damage during HCA and SACP

Microdialysis findings in the HCA group indicated anaerobic metabolism compared to SACP. In group SACP28 lactate was significantly higher compared to the SACP20 group but the L/P ratio was unaffected. This can be explained with a preserved oxidative phosphorylation in which lactate and pyruvate both will increase as a consequence of increased glycolysis.

In group SACP20, the L/P ratio was increased compared to the group SACP28. The increase was significant but very low compared to the L/P ratio in the HCA group which had overt ischemia. This may be explained by a reduction of pyruvate due to reduced metabolism with colder perfusate.

Our results are supported by other microdialysis markers of ischemia [9, 10].

Experimental studies on piglets from Schultz et al. [11, 12], concluded worse cerebral metabolism with HCA (18 °C) alone compared to intermittent low-flow CPB (20 ml/kg/min). A recent microdialysis study [13] compared HCA followed by different CPB flows and confirmed the same metabolic results as above.

The increase of glycerol in HCA is most probably of ischemic origin. In contrast, the peak of glycerol in group SACP28 could be by another mechanism as the ischemic trauma was less severe (see below).

4.2. SACP at moderate temperatures

The results in the group SACP28 split the group into two subgroups with two separate biochemical patterns (Fig. 3). One possible explanation of this is that SACP with 28 °C, in this experiment, is close to the border of unsafe protection and that the cellular response is of the type on/off reaction. The combination of hyperglycolysis and disturbed cellular integrity could reflect a situation of augmented oxidative stress that may lead to permanent cell damage.

These results could give further support to the observation that tepid SACP could be insufficient.

There are, to our knowledge, no microdialysis studies comparing metabolic effects of different perfusate temperatures. However, there are experimental studies supporting cold perfusate as cellular damage decreases, and psychometrical tests are better performed at follow-up [14, 15].


   5. Limitations
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Limitations
6. Conclusion
 References
 
The microdialysis method reflects metabolism in a focal brain area surrounding the catheter membrane. However, we assume that the interventions used in this study have a global impact on cerebral metabolism suggesting that our results are representative for the whole brain.

Serum values of glucose, lactate and glycerol were not taken together with the microdialysis samples and it is unknown how the plasma levels relate to interstitial values in the present study.

There were no true randomizations but the experiments were mixed during the study period.


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
References
 
This study supports the use of SACP over HCA, it also may suggest that cerebral metabolism and cellular membrane integrity is better preserved with SACP at 20 °C than with SACP at 28 °C under the given conditions.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 

  1. Khaladj N, Shrestha M, Meck S, Peterss S, Kamiya H, Kallenbach K, Winterhalter M, Hoy L, Haverich A, Hagl C. Hypothermic circulatory arrest with selective antegrade cerebral perfusion in ascending aortic and aortic arch surgery: a risk factor analysis for adverse outcome in 501 patients. J Thorac Cardiovasc Surg 2008;135:908–914.[Abstract/Free Full Text]
  2. Harrington DK, Fragomeni F, Bonser RS. Cerebral perfusion. Ann Thorac Surg 2007;83:S799–804; discussion S824–731.[Abstract/Free Full Text]
  3. Hagl C, Khaladj N, Peterss S, Hoeffler K, Winterhalter M, Karck M, Haverich A. Hypothermic circulatory arrest with and without cold selective antegrade cerebral perfusion: impact on neurological recovery and tissue metabolism in an acute porcine model. Eur J Cardiothorac Surg 2004;26:73–80.[Abstract/Free Full Text]
  4. Plock N, Kloft C. Microdialysis – theoretical background and recent implementation in applied life-sciences. Eur J Pharm Sci 2005;25:1–24.[CrossRef][Medline]
  5. Goodman JC, Valadka AB, Gopinath SP, Uzura M, Robertson CS. Extracellular lactate and glucose alterations in the brain after head injury measured by microdialysis. Crit Care Med 1999;27:1965–1973.[CrossRef][Medline]
  6. Cesarini KG, Enblad P, Ronne-Engstrom E, Marklund N, Salci K, Nilsson P, Hardemark HG, Hillered L, Persson L. Early cerebral hyperglycolysis after subarachnoid haemorrhage correlates with favourable outcome. Acta Neurochir (Wien) 2002;144:1121–1131.[CrossRef][Medline]
  7. Hillered L, Valtysson J, Enblad P, Persson L. Interstitial glycerol as a marker for membrane phospholipid degradation in the acutely injured human brain. J Neurol Neurosurg Psychiatry 1998;64:486–491.[Abstract/Free Full Text]
  8. Merenda A, Gugliotta M, Holloway R, Levasseur JE, Alessandri B, Sun D, Bullock MR. Validation of brain extracellular glycerol as an indicator of cellular membrane damage due to free radical activity after traumatic brain injury. J Neurotrauma 2008;25:527–537.[CrossRef][Medline]
  9. Pastuszko A. Metabolic responses of the dopaminergic system during hypoxia in newborn brain. Biochem Med Metab Biol 1994;51:1–15.[CrossRef][Medline]
  10. Pastuszko A, Lajevardi NS, Huang CC, Tammela O, Delivoria-Papadopoulos M, Wilson DF. Levels of dopamine and its metabolites in the extracellular medium of the striatum of newborn piglets during graded hypoxia. Adv Exp Med Biol 1994;345:587–595.[Medline]
  11. Schultz S, Creed J, Schears G, Zaitseva T, Greeley W, Wilson DF, Pastuszko A. Comparison of low-flow cardiopulmonary bypass and circulatory arrest on brain oxygen and metabolism. Ann Thorac Surg 2004;77:2138–2143.[Abstract/Free Full Text]
  12. Schears G, Zaitseva T, Schultz S, Greeley W, Antoni D, Wilson DF, Pastuszko A. Brain oxygenation and metabolism during selective cerebral perfusion in neonates. Eur J Cardiothorac Surg 2006;29:168–174.[Abstract/Free Full Text]
  13. Pastuszko P, Liu H, Mendoza-Paredes A, Schultz SE, Markowitz SD, Greeley WJ, Wilson DF, Pastuszko A. Brain oxygen and metabolism is dependent on the rate of low-flow cardiopulmonary bypass following circulatory arrest in newborn piglets. Eur J Cardiothorac Surg 2007;31:899–905.[Abstract/Free Full Text]
  14. Khaladj N, Peterss S, Oetjen P, von Wasielewski R, Hauschild G, Karck M, Haverich A, Hagl C. Hypothermic circulatory arrest with moderate, deep or profound hypothermic selective antegrade cerebral perfusion: which temperature provides best brain protection? Eur J Cardiothorac Surg 2006;30:492–498.[Abstract/Free Full Text]
  15. Strauch JT, Spielvogel D, Lauten A, Zhang N, Rinke S, Weisz D, Bodian CA, Griepp RB. Optimal temperature for selective cerebral perfusion. J Thorac Cardiovasc Surg 2005;130:74–82.[Abstract/Free Full Text]

Related Article

eComment: Selective antegrade cerebral perfusion and metabolicsuppression
Nawid Khaladj, Sven Peterss, Axel Haverich, and Christian Hagl
Interactive CardioVascular and Thoracic Surgery 2009 8: 653. [Full Text] [PDF]



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eComment: Selective antegrade cerebral perfusion and metabolicsuppression
Interactive CardioVascular and Thoracic Surgery, June 1, 2009; 8(6): 653 - 653.
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