Gels were dried and autoradiographed. Data were analyzed by analysis of variance with adjustment of P values by the t test. Oesophageal temperature during and after CPB was significantly lower in animals operated on under hypothermia than in the other animals. In contrast, myocardial temperature during CPB did not differ significantly between groups, with the exception of that measured before cross-clamping of the aorta Table 1. Heart rate, mean arterial and left and right atrial pressures, cathecolamine support and urine output were not significantly different between groups data not shown.
Lactate levels were lower at the end of CPB in animals operated on under moderate hypothermia than in the other animals 4. Results are representative of four independent experiments in each group. In those operated on under hypothermia, levels of phospho-p38 MAPK were lower during and after CPB than in animals operated on under normothermic conditions.
In the latter animals, levels of phospho-p38 MAPK increased as soon as 30 minutes after CPB was established and reached a peak value just before removal of the aortic clamp 1 hour after ischaemia , and then decreased by 6 hours after CPB. Levels of phospho-c-Jun detected in the nuclear extract paralleled the activation of p38 MAPK in all animals during CPB, but continued to increase after CPB exclusively in those subjected to normothermia.
Lower panel: gel showing the effect of temperature on myocardial expression of phospho-p38 MAPK detected by Western blot. Results are representative of six independent experiments in each group. Band intensities for phospho-c-Jun were normalized for band intensities of actin. Lower panel: gel showing the effect of temperature on expression of phospho-c-Jun in the nuclear extract detected by Western blot. In animals operated on under hypothermia, AP-1 activity was lower during and after CPB than in those operated on under normothermia.
DNA binding activity of AP hypothermia versus normothermia. Its synthesis increased during and after CPB without any difference between groups table 2. The inhibitory effect of hypothermia on p38 MAPK that we report here is supported by experimental work conducted in rat fibroblasts that showed inhibition of Raf [ 24 ], a mitogen-stimulated protein kinase that is an important intermediate to p38 MAPK activation by cold stress [ 25 ].
Via inhibition of Raf, hypothermia suppresses the phosphorylation of p38 MAPK in vitro , thereby inhibiting phosphorylation of c-Jun and AP-1 activation [ 22 ]. Regulation of the activity of AP-1 occurs at two levels, depending on its concentrations and on the level of its phosphorylation [ 26 ].
In the present study, there was no difference in levels of c-Jun in nuclear extract between the groups, but animals operated on in hypothermia exhibited lower phosphorylation of c-Jun and lower DNA binding activity of AP-1 during and after CPB than did those operated on in normothermia. Therefore, we suggest that hypothermia during CPB inhibits phosphorylation of p38 MAPK, which in turn suppresses its nuclear targets, namely phosphorylation of c-Jun and activation of the transcription factor AP High local concentrations of NO related to induction of iNOS are associated with myocardial cell damage and cell death [ 30 ].
The latter is the major promotor element involved in COX-2 expression in cardiomyocytes [ 36 ]. Significant expression of COX-2 has been demonstrated in the myocardium of patients with congestive heart failure and in rat heart after treatment with endotoxin [ 37 , 38 ]. In the present study, animals operated on under hypothermia did not differ from the other animals with respect to haemodynamics, but the fact that they had lower levels of lactate than did the pigs operated on under normothermia indicates that they had better tissue perfusion.
J Thorac Cardiovasc Surg , Article PubMed Google Scholar. J Am Coll Cardiol , Meldrum DR: Tumor necrosis factor in the heart. Am J Physiol , RR Cardiovasc Res , J Mol Cell Cardiol , Mol Cell Biochem , Circulation , II Google Scholar. Circulation , Circulation , III N Engl J Med , Curr Opin Cell Biol , 9: Ono K, Han J: The p38 signal transduction pathway: activation and function.
Chambers London, UK : I wonder whether you could develop from your data some sort of factor whereby you could calculate the right temperature from your nasopharyngeal temperature, if you like. Did you always see the same sort of difference between your jugular bulb temperature and your nasopharyngeal temperature, or was it variable? Dr Kaukuntla : Well, because in the normothermic group, there was hardly any rewarming involved.
The patients would have probably cooled to about So there was only a very short period of rewarming. Once the required temperature was attained, there was no definite relationship between the nasopharynx and the jugular bulb.
This is a very small group to come to any conclusions of what is the statistical relationship between those two temperatures and a bigger study probably might answer that question.
Joubert-Huebner Hamburg, Germany : How did this jugular bulb temperature correspond to the arterial line temperature, the oxygenator? Dr Kaukuntla : The temperature we monitored was arterial return temperature just after the oxygenator. During the rewarming phase or during the cooling phase, the jugular bulb temperatures were a good reflection of the arterial inflow; but they always either lagged behind or lagged in front, if you see, depending upon where in the hypothermic circulatory curve the time point was.
What we found was that in the hypothermic group they tend to even out. But in the normothermic group, towards the end of bypass, the jugular bulb temperature was actually even more than the arterial inflow.
This was a very surprising result for us. We did ponder on the reasons of why the jugular bulb temperature is more than the arterial inflow temperature, and we can only speculate the reasons. We think that one of the reasons is - in normothermia there is no heat debt, if I could use that term. So the brain venous outflow temperature is temperature of the blood going into the brain plus the brain metabolic heat which is generated in normothermia.
So we think that probably is the reason. Philipp Regensburg, Germany : Why didn't you correlate the temperature of the jugular venous blood and the temperature detected with a probe in the typanum?
Tympanic temperature is just easy to monitor, and, as you certainly know, it correlates very exactly with the brain temperature. Dr Kaukuntla : Well, there is conflicting evidence. Some authors have, yes, as you've rightly said, say that it reflects the core brain temperature quite well.
But at the same time, there are some authors who have said that tympanic membrane probably doesn't represent the true temperature at different parts of the brain. Besides this another reason was that when we set up this study, we didn't have the kit to measure tympanic membrane tempearture in the theaters. That will leave our patients a little bit hypothermic, but I think that's the price we have to pay in order to avoid the risks of neurologic sequelae.
Dr Kaukuntla : I entirely agree with you. Because we do not have a definite relationship between the temperature monitoring sites and the core brain temperature, we cannot say it is safe to heat up to this nasopharyngeal temperature or this bladder temperature or this arterial inflow. The safest way is, as you rightly said is to never allow any of the temperatures to go beyond 37, so the likelihood of the brain going much higher than Hassouna Cairo, Egypt : I wanted to know when you have made your correlation between the arterial flow and jugular venous bulb temperatures?
In the graph, we see they cross each other at some points. Did you make a correlation over time or did you make a correlation at a certain time after bypass? Dr Kaukuntla : No, the correlation was done at the point when the jugular bulb temperature reached its peak for each patient. Google Scholar.
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Appendix A Conference discussion. Temperature monitoring during cardiopulmonary bypass—do we undercool or overheat the brain? Hemanth Kaukuntla , Hemanth Kaukuntla.
Oxford Academic. Deborah Harrington. Inderaj Bilkoo. Tom Clutton-Brock. Timothy Jones. Robert S. Revision received:. Select Format Select format. Permissions Icon Permissions. Abstract Objective : Brain cooling is an essential component of aortic surgery requiring circulatory arrest and inadequate cooling may lead to brain injury.
Cardiopulmonary bypass , Temperature monitoring , Hypothermia , Hypothermic circulatory arrest. Open in new tab Download slide.
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