Interventions on arterial pressure and perfusion flow rate during cardiopulmonary bypass : effects on global fluid shifts, cerebral metabolic and structural markers in a porcine model

Global and regional organ perfusion during cardiopulmonary bypass (CPB) depends on hemodynamic parameters as mean arterial pressure (MAP) and perfusion flow rate. These parameters may also exert influence on the load of micro-emboli delivered to the central nervous system (Sungurtekin et al., 1999), to the operating conditions (Cartwright & Mangano, 1998) and to the degree of extravascular fluid accumulation during CPB (Paper III). The present thesis focus on some specific consequences of different MAP and perfusion flow rate values during CPB. Two particular endpoints have been addressed: A. Net fluid balance and fluid extravasation rate during CPB (Paper I - III) B. Cerebral biochemical changes associated with energy metabolism and ultrastructural integrity (Paper IV – V) Paper I compares a group of animals with lowered MAP (LP-group, n=7) by use of nitroprusside and a historical control group (C-group, n=7)) with respect to fluid shifts. Paper II compares groups with elevated MAP by norepinephrine (HP-group, n=8)) and lowered MAP by phentolamine (LP-group, n=8)), also with respect to fluid shifts. Paper III determines fluid shifts in groups with two different CPB perfusion flow rates (LFgroup, n=8 and HF-group, n=8). Paper IV assesses cerebral biochemical markers in groups with elevated MAP by norepinephrine (HP-group, n=6) and lowered MAP by nitroprusside (LP-group, n=6). Paper V assesses the same cerebral markers as well as mitochondrial ultrastructure by electron microscopy in animals with elevated MAP by norepinephrine (HP-group, n=8) and lowered MAP by phentolamine (LP-group, n=8). Methods: Young pigs aged 10-12 weeks were given general anesthesia and underwent 60 minutes of normothermic CPB (38°C) followed by 90 minutes of hypothermic CPB (28°C). Acetated Ringer’s solution was given with 5 ml/kg/h i.v. and as CPB prime. Extra acetated Ringer’s solution was added to the CPB venous reservoir whenever necessary, to maintain a constant level. In paper I, II, IV and V infusions of vasoactive agents were given during the whole CPB period. MAP was kept between 60 – 80 mmHg in the animals with elevated arterial pressure and at 40 – 45 mmHg in the animals with reduced arterial pressure. The two groups of animals in paper III had CPB perfusion flow rate set to 80 ml/kg/min and 110 ml/kg/min, respectively. Colloid osmotic pressure in plasma and interstitial fluid (wick method) was measured in addition to acid base parameters and blood chemistry. Plasma volume was determined by the carbon-monoxide method and subsequent changes were calculated based on new values of hematocrit and the measured amount of bleeding. Fluid extravasation rate was calculated as net fluid balance minus the change in plasma volume over a defined period of time. Intracranial pressure was monitored. Cerebral glucose, lactate, pyruvate and glycerol were measured by microdialysis. After each experiment, total tissue water content was determined in relevant organs. In paper V, cerebral tissue from cortex and thalamus in two animals from each group, were examined by electron microscopy. Results: Paper I: Net fluid balance was higher in the LP-group as compared with the C-group after 30 min of CPB. Fluid extravasation rate tended to be higher in the LP-group. The animals of the LPgroup did have higher tissue water content in the myocardium, skin and gastrointestinal tract as compared with the control group. Paper II: Plasma volume was higher in the LP-group as compared with the HP-group after 60 minutes of CPB. Net fluid balance and fluid extravasation rate did not differ between the two study groups. Left myocardial tissue water content was slightly higher in the LP-group compared with the HP-group. Paper III: Plasma volume was higher in the HF-group compared with the LF-group after 60 minutes of CPB. During the initial phase of CPB, fluid extravasation rate was significantly higher in the HF-group. The average net fluid balance during CPB was higher and the average fluid extravasation rate tended strongly to be higher in the HF-group as compared with the LF group (P=0.07). Total tissue water content of the kidneys were higher in the HF-group and tended to be higher in most other organs as compared with the LF-group. Paper IV: Intracranial pressure increased in both groups during CPB. Intracerebral glucose decreased while lactate-pyruvate ratio and cerebral glycerol increased significantly during CPB in the LP-group as compared with pre-bypass values. The values remained stable and within normal range in the HP-group. Paper V: Cerebral lactate was higher in LP-group as compared with HP-group during normothermic CPB. Compared to baseline, cerebral glucose decreased and cerebral lactate, lactate-pyruvate ratio and glycerol increased in the LP-group during normothermic CPB. The values remained unchanged in the HP-group. Electron microscopy of cortical and thalamic tissue, showed a higher frequency of altered mitochondria in the LP-group as compared with the HP-group. Conclusion: Paper I-II suggest that different levels of MAP by use of nitroprusside, phentolamine or norepinephrine have essentially no influence on fluid extravasation rate. An impact on net fluid balance was found in paper I. Paper III demonstrate that elevation of CPB flow rate to 110 ml/kg/min, may lead to higher positive net fluid balance and probably higher fluid extravasation rate as compared with a CPB flow rate of 80 ml/kg/min. Plasma volume was affected by the use of these vasoactive agents and was significantly higher in the study groups receiving phentolamine as compared with norepinephrine. Indeed, plasma volume was also affected by CPB flow rate, resulting in higher values in the experimental group with higher CPB flow rate. In paper IV and V we found that a reduction of MAP to about 40 mmHg during CPB by nitroprusside or phentolamine was associated with changes in cerebral markers of metabolism and membrane integrity compatible with cerebral ischemia and membrane degradation. Electron microscopic examination of cortical and thalamic tissue demonstrated a high frequency of mitochondrial alterations in two animals with reduced MAP by phentolamine in paper V