Histopathologic consequences of hyperglycemic cerebral ischemia during hypothermic cardiopulmonary bypass in pigs.

BACKGROUND: This study examined whether 34 degrees C or 31 degrees C hypothermia during global cerebral ischemia with hyperglycemic cardiopulmonary bypass (CPB) in surviving pigs improves electroencephalographic (EEG) recovery and histopathologic scores when compared with normothermic animals. METHODS: Anesthetized pigs were placed on CPB and randomly assigned to 37 degrees C (n = 9), 34 degrees C (n = 10), or 31 degrees C (n = 8) management. After increasing serum glucose to 300 mg/dL, animals underwent 15 minutes of global cerebral ischemia by temporarily occluding the innominate and left subclavian arteries. Following reperfusion, rewarming, and termination of CPB, animals were recovered for 24 (37 degrees C animals) or 72 hours (34 degrees C and 31 degrees C animals). Daily EEG signals were recorded, and brain histopathology from cortical, hippocampal, and cerebellar regions was graded by an independent observer. RESULTS: Before ischemia, serum glucose concentrations were similar in the 37 degrees C (307+/-9 mg/dL), 34 degrees C (311+/-14 mg/dL), and 31 degrees C (310+/-15) groups. By the first postoperative day, EEG scores in 31 degrees C animals (4.2+/-0.6) had returned to baseline and were greater than those in the 34 degrees C (3.4+/-0.5) and 37 degrees C (2.5+/-0.4) groups (p < 0.05, respectively, between groups). Cooling to 34 degrees C showed selective improvement over 37 degrees C in hippocampal, temporal cortical, and cerebellar regions, but the greatest improvement in all regions occurred with 31 degrees C. Cumulative neuropathology scores in 31 degrees C animals (13.5+/-2.2) exceeded 34 degrees C (6.8+/-2.2) and 37 degrees C (1.9+/-2.1) animals (p < 0.05, respectively, between groups). CONCLUSIONS: Hypothermia during CPB significantly reduced the morphologic consequences of severe, temporary cerebral ischemia under hyperglycemic conditions, with the greatest protection at 31 degrees C.

Intraischemic mild hypothermia increases hippocampal CA1 blood flow during forebrain ischemia.

The hippocampal CA1 sector is selectively vulnerable to forebrain ischemia but protected by mild hypothermia. However, the consequence of intraischemic hypothermia on CA1 blood flow during the insult has not been adequately characterized. The effects of mild intraischemic hypothermia on relative changes in regional hippocampal CA1 blood flow were recorded continuously using laser Doppler flowmetry (LDF) during and 30 min after 6 min of forebrain ischemia. Six experimental groups (n=6/group) of fasted male Wistar rats were compared. Groups 1, 3 and 5 consisted of normothermic rats that underwent either 6 (for CBF measurements) and 6 or 10 (for 7 day survival-CA1 neuronal death measurements) min of transient forebrain ischemia using bilateral carotid clamping and hemorrhagic hypotension. Groups 2, 4 and 6 rats were subjected to mild hypothermia (34 degrees C) before, during, and 30 min after 6 (for CBF measurements) and 6 or 10 (for 7 day survival-CA1 neuronal death measurements) min of transient forebrain ischemia. CA1 blood flow and electroencephalogram (EEG) were continuously recorded. During the ischemic insult there were intergroup differences in the magnitude of CBF decreases in the CA1 region. In both groups 1 and 2, CBF returned to preischemic values within 1 min of reperfusion but hypothermic rats had more sustained hyperemia. Hypothermic rats had a quicker recovery of EEG activity and less delayed CA1 neuronal death (group 2 versus 4). These data suggest ischemic blood flow to the CA1 sector was altered by intraischemic mild hypothermia which may contribute to the greater benefit of intraischemic hypothermic neuroprotection.

Technique of controlled reperfusion of the transplanted lung in humans.

BACKGROUND: Reperfusion injury remains a significant and sometimes fatal problem in clinical lung transplantation. Controlled reperfusion of the transplanted lung using white cell-filtered, nutrient-enriched blood has been shown recently to significantly ameliorate reperfusion damage in a porcine model. We modified this experimental technique and applied it to human lung transplantation. METHODS: Approximately 1,500 mL of arterial blood was slowly collected in a cardiotomy reservoir during the lung implant, and mixed to make a 4:1 solution of blood:modified Buckberg perfusate. This solution was passed through a leukocyte filter and into the transplant pulmonary artery for 10 minutes, at a controlled rate (200 mL/min) and pressure (less than 20 mm Hg), immediately before removal of the vascular clamp. RESULTS: Five patients underwent lung transplantation (1 bilateral, 4 single lung) using this technique. All patients were ventilated on a 40% fraction of inspired oxygen within a few hours and extubated on or before the first postoperative day. CONCLUSIONS: Controlled reperfusion of the transplanted lung with white cell-filtered, nutrient-enriched blood has given excellent functional results in our small initial clinical series.

Transient electroencephalographic suppression with initiation of cardiopulmonary bypass in pigs: blood versus nonblood priming.

Electroencephalographic (EEG) changes have been reported with cardiopulmonary bypass (CPB). We tested whether the type of priming solution (blood versus nonblood) affected the EEG. Twenty-six anesthetized pigs (29.5+/-1.6 kg) were cannulated for CPB primed with 1 liter plasmalyte and 500 ml 6% hetastarch (nonblood prime). EEG signals were recorded during the initiation of normothermic CPB. Three minutes later, animals were weaned from CPB and allowed to stabilize. CPB was reinstituted using the animals' hemodiluted blood as prime. We found that with nonblood prime, abrupt and marked EEG suppression lasting 12.6+/-0.7 s was found in all animals, followed by gradual resumption of baseline EEG activity. In contrast, CPB with blood prime caused no detectable EEG changes. We conclude that severe reductions in EEG activity occur after initiating CPB with nonblood prime; these reductions are not seen when using blood prime. The cause of EEG suppression is unknown, but may represent transient impairment of oxygen delivery to the brain caused by nonblood perfusion.

Lamotrigine attenuates cortical glutamate release during global cerebral ischemia in pigs on cardiopulmonary bypass.

BACKGROUND: The dose-response effects of pretreatment with lamotrigine (a phenyltriazine derivative that inhibits neuronal glutamate release) in a porcine cerebral ischemia model during cardiopulmonary bypass were studied. METHODS: Sagittal sinus catheters and cortical microdialysis catheters were inserted into anesthetized pigs. Animals undergoing normothermic cardiopulmonary bypass were pretreated with lamotrigine 0, 10, 25, or 50 mg/kg (n = 10 per group). Fifteen minutes of global cerebral ischemia was produced, followed by 40 min of reperfusion and discontinuation of cardiopulmonary bypass. Cerebral oxygen metabolism was calculated using cerebral blood flow (radioactive microspheres) and arterial-venous oxygen content gradients. Concentrations of microdialysate glutamate and aspartate were quantified; electroencephalographic signals were recorded. After cardiopulmonary bypass, blood and cerebrospinal fluid were sampled for S-100B protein, and a biopsy was performed on the cerebral cortex for metabolic profile. RESULTS: Lamotrigine caused dose-dependent reductions in systemic vascular resistance so that additional fluid was required to maintain venous return. Concentrations of glutamate and aspartate did not change during reperfusion after 50 mg/kg lamotrigine in contrast to fivefold and twofold increases, respectively, with lower doses. There were no intergroup differences in cerebral metabolism, electroencephalographic scores, cortical metabolites, brain lactate, or S-100B protein concentrations in the cerebrospinal fluid and blood. CONCLUSIONS: Lamotrigine 50 mg/kg significantly attenuated excitatory neurotransmitter release during normothermic cerebral ischemia during cardiopulmonary bypass without improving other neurologic parameters. Lamotrigine caused arterial and venous dilation, which limits its clinical usefulness.

Combined therapy affects outcomes differentially after mild traumatic brain injury and secondary forebrain ischemia in rats.

Muscarinic and NMDA receptors contribute to post-traumatic hypersensitivity to secondary ischemia. However, the effect of these receptor antagonists on behavior and CA1 neuronal death after traumatic brain injury (TBI) with acute (1 h after TBI) forebrain ischemia has not been systematically assessed. We examined cognitive and motor dysfunction and the relationship of behavior deficits to neuronal death in this model using muscarinic and NMDA antagonists. Three behavioral groups (n=10/group) of Wistar rats were subjected to mild TBI and 6 min of forebrain ischemia imposed 1 h after TBI with 45 days survival. Motor and spatial memory performance were assessed using the rotarod task and Morris water maze. Seven additional groups (n=6/group) were evaluated only for CA1 death after 7 days survival following sham, individual or combined injury with and without drug treatments. Rats were given 0.3 mg/kg MK-801 (M) and 1.0 mg/kg scopolamine (S) alone or combined (M-S) before or 45 min after TBI. Rotarod performance was tested at days 1-5 and maze performance on days 11-15 and 40-44 after M-S treatment. The 7-day studies showed M-S treatment (p<0.01) reduced CA1 neuronal death better than either S or M alone. Behavioral groups had inadvertent post-ischemic hypothermia that decreased CA1 death and likely influenced behavioral morbidity. M-S given before TBI (p<0.01) decreased memory deficits on day 15, while M-S treatment given after TBI was ineffective. Unexpectedly, M-S treatment before or after TBI produced transient motor deficits (p<0. 01). Memory improvement occurred independent of CA1 death.

Hypothermic modulation of cerebral ischemic injury during cardiopulmonary bypass in pigs.

BACKGROUND: The aim of this study was to determine whether progressive levels of hypothermia (37, 34, 31, or 28 degrees C) during cardiopulmonary bypass (CPB) in pigs reduce the physiologic and metabolic consequences of global cerebral ischemia. METHODS: Sagittal sinus and cortical microdialysis catheters were inserted into anesthetized pigs. Animals were placed on CPB and randomly assigned to 37 degrees C (n = 10), 34 degrees C (n = 10), 31 degrees C (n = 11), or 28 degrees C (n = 10) management. Next 20 min of global cerebral ischemia was produced by temporarily ligating the innominate and left subclavian arteries, followed by reperfusion, rewarming, and termination of CPB. Cerebral oxygen metabolism (CMRO2) was calculated by cerebral blood flow (radioactive microspheres) and arteriovenous oxygen content gradient. Cortical excitatory amino acids (EAA) by microdialysis were measured using high-performance liquid chromatography. Electroencephalographic (EEG) signals were graded by observers blinded to the protocol. After CPB, cerebrospinal fluid was sampled to test for S-100 protein and the cerebral cortex was biopsied. RESULTS: Cerebral oxygen metabolism increased after rewarming from 28 degrees C, 31 degrees C, and 34 degrees C CPB but not in the 37 degrees animals; CMRO2 remained lower with 37 degrees C (1.8 +/- 0.2 ml x min[-1] x 100 g[-1]) than with 28 degrees C (3.1 +/- 0.1 ml x min[-1] x 100 g[-1]; P < 0.05). The EEG scores after CPB were depressed in all groups and remained significantly lower in the 37 degrees C animals. With 28 degrees C and 31 degrees C CPB, EAA concentrations did not change. In contrast, glutamate increased by sixfold during ischemia at 37 degrees C and remained significantly greater during reperfusion in the 34 degrees C and 37 degrees C groups. Cortical biopsy specimens showed no intergroup differences in energy metabolites except two to three times greater brain lactate in the 37 degrees C animals. S-100 protein in cerebrospinal fluid was greater in the 37 degrees C (6 +/- 0.9 microg/l) and 34 degrees C (3.5 +/- 0.5 microg/l) groups than the 31 degrees C (1.9 +/- 0.1 microg/l) and 28 degrees C (1.7 +/- 0.2 microg/l) animals. CONCLUSIONS: Hypothermia to 28 degrees C and 31 degrees C provides significant cerebral recovery from 20 min of global ischemia during CPB in terms of EAA release, EEG and cerebral metabolic recovery, and S-100 protein release without greater advantage from cooling to 28 degrees C compared with 31 degrees C. In contrast, ischemia during 34 degrees C and particularly 37 degrees C CPB showed greater EAA release and evidence of neurologic morbidity. Cooling to 31 degrees C was necessary to improve acute recovery during global cerebral ischemia on CPB.

A dynamic model of ventricular interaction and pericardial influence.

A mathematical model describing the dynamic interaction between the left and the right ventricle over the complete cardiac cycle is presented. The pericardium-bound left and right ventricles are represented as two coupled chambers consisting of the left and right free walls and the interventricular septum. Time-varying pressure-volume relationships characterize the component compliances, and the interaction of these components produces the globally observed ventricular pump properties (total chamber pressure and volume). The model 1) permits the simulation of passive (diastolic) and active (systolic) ventricular interaction, 2) provides temporal profiles of hemodynamic variables (e.g., ventricular pressures, volumes, and flow) that agree well with reported observations, and 3) can be used to examine the effect of the pericardium on ventricular interaction and ventricular mechanics. It can be reduced to equivalency with models previously reported by invoking simplifying assumptions. Furthermore, model-generated "dynamic interaction gains" are employed to quantify the mode and degree of ventricular interaction. The model also yields qualitative predictions of septal and free wall displacements similar to those detected experimentally via M-mode echocardiography. Such analogies may be extended easily to the study of pathophysiological states via appropriate modifications to 1) the pressure-volume characteristics of the component walls (and/or pericardium) and/or 2) the specific time course of activation of the ventricular free wall or the septum. A limited number of examples are included to demonstrate the utility of the model, which may be used as an adjunct to new experimental investigations into ventricular interaction.

Regional perfusion abnormalities with phenylephrine during normothermic bypass.

BACKGROUND: Hypotension and vasopressors during cardiopulmonary bypass may contribute to splanchnic ischemia. The effect of restoring aortic pressure on visceral organ, brain, and femoral muscle perfusion during cardiopulmonary bypass by increasing pump flow or infusing phenylephrine was examined. METHODS: Twelve anesthetized swine were stabilized on normothermic cardiopulmonary bypass. After baseline measurements, including regional blood flow (radioactive microspheres), aortic pressure was reduced to 40 mm Hg by decreasing the pump flow. Next, aortic pressure was restored to 65 mm Hg either by increasing the pump flow or by titrating phenylephrine. The animals had both interventions in random order. RESULTS: At 40 mm Hg aortic pressure, perfusion to all visceral organs and femoral muscle, but not to the brain, was significantly reduced. Increasing pump flow improved perfusion to the pancreas, colon, and kidneys. In contrast, infusing phenylephrine (2.4 +/- 0.6 micrograms.kg-1.min-1) increased aortic pressure but failed to improve splanchnic perfusion, so that significant perfusion differences existed between the pump flow and phenylephrine intervals. CONCLUSIONS: Increasing systemic pressure during cardiopulmonary bypass with phenylephrine causes significantly lower values of splanchnic blood flow than does increasing the pump flow. Administering vasoconstrictors during normothermic cardiopulmonary bypass may mask substantial hypoperfusion of splanchnic organs despite restoration of perfusion pressure.

Hyperglycemia during hypothermic cardiopulmonary bypass does not alter postbypass vascular endothelial responses in dogs.

BACKGROUND: Hyperglycemia during hypothermic cardiopulmonary bypass (CPB) may alter intrinsic vasomotion by reducing endothelial-dependent vasorelaxation. Using a canine model of hypothermic CPB, this study tested whether hyperglycemia altered the vasodilator response to acetylcholine (ACh) and the vasoconstrictor response to phenylephrine (Phe). METHODS: In 20 anesthetized dogs, the left femoral arteries were excised and placed in gassed (95% O2-5% CO2) cold Krebs's solution. The animals were randomized into two groups undergoing 120 minutes of 28 degrees C CPB using membrane oxygenators. A hyperglycemic group (n = 10) received a continuous infusion of 50% dextrose to maintain blood glucose level greater than 500 mg/dL; a normoglycemic group (n = 10) received 0.9% saline. After rewarming and discontinuing CPB, the right femoral arteries were excised. Vessel rings were placed in a suffusion bath, and changes in isometric tension were measured. Dose-response relationships (ACh: 10(-9) to 10(-6)M; Phe: 3 x 10(-8) to 10(-4)M) and -log ED50 sensitivity to ACh and Phe before and after CPB were compared. RESULTS: Serum glucose during hypothermic CPB was significantly greater in glucose-treated dogs (525 +/- 9 mg/dL) than controls (109 +/- 5 mg/dL; p < 0.05). After CPB, -log ED50 values for ACh changed from 7.7 +/- 0.1 to 7.5 +/- 0.2 (p < 0.05) in normoglycemic dogs and from 7.8 +/- 0.1 to 7.6 +/- 0.1 (p < 0.05) in hyperglycemic animals, indicating similar and significant rightward shifts of the dose-response relationship to ACh after CPB in both groups. Neither hyperglycemia nor CPB altered the vasoconstrictor response to Phe. CONCLUSIONS: The reduction in ACh-mediated vasorelaxation after CPB did not differ between hyperglycemic and normoglycemic animals, indicating that hyperglycemia does not contribute to impaired vasorelaxation after CPB. Because Phe-induced vasoconstriction was unaffected, hyperglycemia during hypothermic CPB does not appear to increase the potential for postbypass vasospasm.

Volume expansion increases right ventricular infarct size in dogs by reducing collateral perfusion.

STUDY OBJECTIVE: Plasma volume expansion is frequently recommended to correct the low output state resulting from right ventricular (RV) infarction. However, any subsequent increase in pericardial and RV filling pressures from volume expansion could impair RV collateral blood flow. We examined whether volume expansion in dogs before right coronary ligation reduced collateral perfusion and worsened the extent of RV necrosis. DESIGN: Randomized experimental study. SETTING: Animal research laboratory in university medical center. PARTICIPANTS: Forty anesthetized, closed-chest dogs were randomly assigned to normovolemic, pericardium opened (n = 10) or intact (n = 10) groups, and hypervolemic, pericardium opened (n = 10) or intact (n = 10) groups. INTERVENTIONS: Hypervolemic animals received 24 mL/kg of 6% hetastarch. All animals underwent 90 min right coronary ligation, followed by 120 min reperfusion. Collateral coronary blood flow (radioactive microspheres) and area of necrosis (An) were determined in the area at risk (Ar). MEASUREMENTS AND RESULTS: Stroke volume decreased in all groups with ischemia but remained 25 to 40% greater in both hypervolemic groups than in normovolemic animals (p < 0.05). In hypervolemic animals with intact pericardium, RV end-diastolic pressure increased to 10.4 +/- 2.1 mm Hg (mean +/- SD), a value that significantly exceeded those of the other three groups. During RV ischemia, collateral perfusion in the Ar was similar in both normovolemic groups and in hypervolemic animals with opened pericardium (mean range, 12.9 +/- 8.8 to 13.8 +/- 7.6 mL/min/100 g; p = NS), and the An/Ar varied from 11.8 +/- 6.3 to 18.6 +/- 17.4% (p = NS). In contrast, in hypervolemic animals with intact pericardium, collateral perfusion decreased to 7.2 +/- 3.5 mL/min/100 g and the An/Ar was increased to 38.2 +/- 18.6% (p < 0.05 compared with other groups, respectively). Overall, An/Ar was inversely related to collateral blood flow in the Ar (r = -0.46; p < 0.05) and correlated positively with RV end-diastolic pressure (r = 0.61; p < 0.05). CONCLUSIONS: Volume expansion preserved stroke volume during RV ischemia, independent of pericardial integrity. However, volume expansion in animals with an intact pericardium increased RV infarct size by twofold to threefold secondary to reduced periischemic collateral perfusion. This detrimental effect of volume expansion on infarct size was prevented by opening the pericardium.

Determinants of cerebral perfusion during cardiopulmonary bypass.

The risk of postoperative neurologic dysfunction in patients undergoing cardiac surgery remains high despite continued improvements in myocardial protective strategies. Part of this neurologic morbidity can be attributed to patients' increased age and underlying pathology, but other factors adversely affecting cerebral blood flow and cerebral metabolism during cardiopulmonary bypass may also contribute. Particulate microembolization during cardiopulmonary bypass appears to be a major cause of postoperative neurologic dysfunction and the pH-stat method of carbon dioxide management during hypothermia may potentiate neurologic damage by allowing a greater embolic load to be delivered to the brain. Echocardiography and transcranial Doppler methods may contribute to reducing the incidence of cerebral embolization by recognizing the timing and number of microemboli. Although hypothermia confers cerebral protection, rewarming may unmask and perhaps potentiate any ischemic damage that occurred with embolization during hypothermia. Both the degree and speed of rewarming may be important factors contributing to the extent of ischemic damage and ultimately neurologic function. In addition, many other factors related to cardiopulmonary bypass can alter cerebral perfusion and metabolism, such as nonpulsatile flow, hemodilution, pressure autoregulation, anesthetic and cerebroprotective drugs, and the neuroimmune response to bypass. In this review, the major factors affecting cerebral blood flow during cardiopulmonary bypass are discussed and their relative importance evaluated with regard to postoperative neurologic function.

Cerebral metabolic consequences of hypotensive challenges in hemodiluted pigs with and without cardiopulmonary bypass.

We tested the hypothesis that progressive aortic hypotension with bicarotid occlusion produces greater reductions in cerebral blood flow (CBF) and more flow-metabolism mismatching with hemodilution during cardiopulmonary bypass (CPB) than with hemodilution alone. In Yorkshire pigs randomized to hemodilution with CPB (n = 10) or hemodilution without CPB (control; n = 9), the effects of bicarotid ligation and graded hypotension on CBF (microspheres), the electroencephalogram (EEG), and cortical energy metabolites were examined. After bicarotid ligation, systemic flow was reduced for 15-min intervals of 80, 60, and 40 mm Hg aortic pressure, followed by a cortical brain biopsy. At baseline, CBF was lower in CPB (58 +/- 3 mL.100g-1.min-1) than control (90 +/- 3 mL.100 g-1.min-1., P < 0.05) animals, as was cerebral oxygen metabolism (3.1 +/- 0.1 vs 4.2 +/- 0.2 mL.min-1.100g-1; P < 0.05). Although CBF remained 40% lower at each level of hypotension in CPB than control animals (P < 0.05), EEG scores showed no intergroup differences, indicating similar flow-metabolism matching. Brain metabolites were similar between CPB and control groups (adenosine triphosphate, 9.6 +/- 2.4 vs 12.4 +/- 1.9 mumol/g; adenosine diphosphate, 6.0 +/- 0.7 vs 6.3 +/- 0.4 mumol/g; adenosine monophosphate, 4.8 +/- 0.9 vs 3.8 +/- 0.8 mumol/g; creatine phosphate, 8.3 +/- 1.8 vs 7.9 +/- 1.0 mumol/g; and lactate, 178.4 +/- 20.2 vs 150.8 +/- 13.9 mumol/g). Thus, despite significantly lower CBF during hypotension with bicarotid occlusion in hemodiluted animals during normothermic CPB, cortical electrical activity and the balance between flow and metabolism did not differ from those in control animals without CPB.

Systemic gaseous microemboli during left atrial catheterization: a common occurrence?

OBJECTIVE: Gaseous microemboli during cardiac surgery have been implicated as a potential cause of postoperative neurologic injury. Any monitoring technique that exposes the systemic circulation to atmospheric pressure could introduce gaseous microemboli, causing cerebral microembolization. The incidence of carotid artery gaseous microemboli was studied during left atrial catheter insertion. DESIGN: Prospective clinical study. SETTING: Tertiary care university hospital. PARTICIPANTS: Twelve patients undergoing elective cardiac surgery. INTERVENTIONS: Perioperatively, a 5-MHz continuous wave Doppler probe was positioned over the left carotid artery to maximally record blood flow signals. The criteria used for detecting a gaseous microembolus were a sudden increase in the amplitude of the visual signal by 30% and a characteristic audible sound. MEASUREMENTS AND MAIN RESULTS: Numbers of microemboli at three timepoints (before and during left atrial catheter insertion and during catheter flushing) were assessed using the Friedman test. No emboli were detected before left atrial catheter insertion. When compared with the preinsertion time period, statistically (p < 0.05) significant numbers of gaseous microemboli were found in six patients during catheter insertion (3 +/- 1 microemboli; range 1 to 7 microemboli) and in five patients during catheter flushing (5 +/- 2 microemboli; range 1 to 12 microemboli). There was a tendency for patients with lower filling pressures to entrain more microemboli during insertion (r = 0.44; p = 0.149). No patient showed evidence of gross neurologic dysfunction postoperatively, although sensitive neurologic testing was not performed. CONCLUSIONS: Left atrial catheter insertion and flushing can cause systemic gaseous microemboli in more than 50% of patients. Although the number of microemboli introduced is relatively small, extreme care should be used during left atrial catheter insertion.

Increasing organ blood flow during cardiopulmonary bypass in pigs: comparison of dopamine and perfusion pressure.

OBJECTIVE: To determine whether low-dose dopamine infusion (5 micrograms/kg/min) during cardiopulmonary bypass selectively increases perfusion to the kidney, splanchnic organs, and brain at low (45 mm Hg) as well as high (90 mm Hg) perfusion pressures. DESIGN: Randomized crossover trial. SETTING: Animal research laboratory in a university medical center. SUBJECTS: Ten female Yorkshire pigs (weight 29.9 +/- 1.2 kg). INTERVENTION: Anesthetized pigs were placed on normothermic cardiopulmonary bypass at a 100-mL/kg/min flow rate. After baseline measurements, the animal was subjected, in random sequence, to 15-min periods of low perfusion pressure (45 mm Hg), low perfusion pressure with dopamine (5 micrograms/kg/min), high perfusion pressure (90 mm Hg), and high perfusion pressure with dopamine. Regional perfusion (radioactive microspheres) was measured in tissue samples (2 to 10 g) from the renal cortex (outer two-third and inner one-third segments), stomach, duodenum, jejunum, ileum, colon, pancreas, and cerebral hemispheres. MEASUREMENTS AND MAIN RESULTS: Systemic perfusion pressure was altered by adjusting pump flow rate (r2 = .61; p < .05). In the kidney, cortical perfusion pressure increased from 178 +/- 16 mL/min/100 g at the low perfusion pressure to 399 +/- 23 mL/min/100 g at the high perfusion pressure (p < .05). Perfusion pressure augmentation increased the ratio of outer/inner renal cortical blood flow from 0.9 +/- 0.1 to 1.2 +/- 0.1 (p < .05). At each perfusion pressure, low-dose dopamine had no beneficial effect on renal perfusion or flow distribution. Similar results were found in the splanchnic organs, where regional perfusion was altered by perfusion pressure but not by dopamine. In contrast, neither changing perfusion pressure nor adding low-dose dopamine altered blood flow to the cerebral cortex. CONCLUSIONS: These data indicate that the lower autoregulatory limits of perfusion to the kidneys and splanchnic organs differ from those limits to the brain during normothermic bypass. Selective vasodilation from low-dose dopamine was not found in renal, splanchnic, or cerebral vascular beds. Increasing the perfusion pressure by pump flow, rather than by the addition of low-dose dopamine, enhanced renal and splanchnic but not cerebral blood flows during cardiopulmonary bypass.

Hyperglycemia during hypothermic canine cardiopulmonary bypass increases cerebral lactate.

BACKGROUND: Hyperglycemia frequently occurs during cardiopulmonary bypass (CPB), although its direct effects on cerebral perfusion and metabolism are not known. Using a canine model of hypothermic CPB, we tested whether hyperglycemia alters cerebral blood flow and metabolism and cerebral energy charge. METHODS: Twenty anesthetized dogs were randomized into hyperglycemic (n = 10) and normoglycemic (n = 10) groups. The hyperglycemic group received an infusion of D50W, and the normoglycemic animals received an equal volume of 0.9% NaCl. Both groups underwent 120 min of hypothermic (28 degrees C) CPB using membrane oxygenators, followed by rewarming and termination of CPB. Cerebral blood flow (radioactive microspheres) and the cerebral metabolic rate for oxygen were measured intermittently during the experiment and brain tissue metabolites were obtained after bypass. RESULTS: Before CPB, the glucose-treated animals had higher serum glucose levels (534 +/- 12 mg/dL; mean +/- SE) than controls (103 +/- 4 mg/dL; P < 0.05), and this difference was maintained throughout the study. Cerebral blood flow and metabolism did not differ between groups at any time during the experiment. Sagittal sinus pressure was comparable between groups throughout CPB. Tissue high-energy phosphates and water contents were similar after CPB, although cerebral lactate levels were greater in hyperglycemic (37.2 +/- 5.7 mumol/g) than normoglycemic animals (19.7 +/- 3.7 mumol/g; P < 0.05). After CPB, pH values of cerebrospinal fluid for normoglycemic (7.33 +/- 0.01) and hyperglycemic (7.34 +/- 0.01) groups were similar. CONCLUSIONS: Hyperglycemia during CPB significantly increases cerebral lactate levels without adversely affecting cerebral blood flow and metabolism, cerebrospinal fluid pH, or cerebral energy charge.

Cardiopulmonary bypass impairs vascular endothelial relaxation: effects of gaseous microemboli in dogs.

Gaseous microemboli during hypothermic cardiopulmonary bypass (CPB) may injure the vascular endothelium and interfere with intrinsic vasomotion. We tested whether gaseous microemboli reduced the vasodilator response to acetylcholine (ACh, 10(-9)-10(-6) M) and potentiated the vasoconstrictor response to norepinephrine (NE, 3 x 10(-8)-10(-4) M). Arteries from 18 dogs were excised before and after 120 min 28 degrees C CPB using membrane (n = 9) and bubble (n = 9) oxygenators to produce microemboli, which were quantitated by Doppler. Five nonbypassed dogs were controls. In isolated vessel rings, the 50% effective dose (ED50) values for ACh (10(-8) M) and NE (10(-7) M) responses were calculated. Mean microemboli count per minute was 0 +/- 0 in the control group, 1.0 +/- 0.4 in the membrane group (P < 0.05 vs. controls), and 46.9 +/- 8.4 in the bubble group (P < 0.05 vs. control and membrane groups). ACh ED50 values did not change in controls but increased in the membrane group from 4.01 +/- 1.52 to 5.66 +/- 1.39 (P < 0.05) and in the bubble group from 2.32 +/- 0.56 to 7.21 +/- 1.90 (P < 0.05). The change in ED50 was greater for bubble than for membrane animals (P < 0.05) but did not correlate with microemboli number (bubble: r = 0.392, P = 0.297; membrane: r = 0.058, P = 0.802). NE responses were similar in all groups. Hypothermic CPB reduces ACh-induced dilation of the canine femoral artery independent of the incidence of gaseous microemboli.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenylephrine does not reduce cerebral perfusion during canine cardiopulmonary bypass.

Gaseous microemboli during cardiopulmonary bypass (CPB) could injure the blood-brain barrier so that cerebral vasoconstriction would result from infusing alpha-agonist drugs, such as phenylephrine. Cerebral blood flow (radioactive microspheres) and metabolism were measured in seven dogs after rewarming from 150 min hypothermic CPB with bubble oxygenators used to produce gaseous microemboli. Phenylephrine (40 micrograms/min) was infused directly into the brachiocephalic artery so that aortic pressure before (80 +/- 2 mm Hg) and during (79 +/- 3 mm Hg) the infusion did not change. Neither blood flow to the cerebral hemispheres (P = 0.960), cerebellum (P = 0.854), and brainstem (P = 0.694) nor the cerebral metabolic rate for oxygen (P = 0.862) differed when values obtained before and after 30 min of phenylephrine infusion were compared. Cerebral vascular resistance was also unchanged by phenylephrine, being 1.22 +/- 0.10 mm Hg.mL-1.min-1 x 100 g-1 before infusion and 1.25 +/- 0.17 mm Hg.mL-1.min-1 x 100 g-1 during infusion (P = 0.849). Phenylephrine does not cause cerebral vasoconstriction after rewarming from hypothermic CPB, a finding which suggests that the blood-brain barrier is preserved during bypass.

Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion of dogs.

BACKGROUND: It has recently been demonstrated that myocardial ischemia and reperfusion results in a marked decrease in the release of nitric oxide (NO) by the coronary endothelium. NO may possess cardioprotective properties, possibly related to inhibition of neutrophil-related activities. We tested the hypothesis that a cysteine-containing nitric oxide donor compound, SPM-5185, would reduce infarct size and inhibit neutrophil-related activities (adherence to coronary vascular endothelium, accumulation). METHODS AND RESULTS: The effects of intracoronary infusion of SPM-5185 were investigated in a 5.5-hour model of myocardial ischemia (1 hour) and reperfusion (4.5 hours) (MI-R) in anesthetized, open-chest dogs. SPM-5185 (500 nmol/L) or saline vehicle was infused for 4.5 hours into the left anterior descending coronary artery (LAD) at the time of reperfusion after 1 hour of LAD occlusion. MI-R in dogs receiving saline vehicle resulted in severe myocardial injury characterized by dyskinesis, a profound elevation of plasma creatine kinase, marked myocardial necrosis, and high cardiac myeloperoxidase (MPO) activity in the ischemic and necrotic zones. In contrast, treatment with SPM-5185 resulted in a modest restoration of regional function, a reduction of myocardial necrosis expressed as a percentage of the area at risk (12.5 +/- 3.2% versus 41.7 +/- 5.4%, P < .001), and significant reductions of MPO activity in the ischemic zone (0.8 +/- 0.1 versus 2.5 +/- 0.7 U/100 mg tissue, P < .05) and the necrotic zone (1.6 +/- 0.2 versus 3.3 +/- 0.6 U/100 mg tissue, P < .05). In additional studies, SPM-5185 (500 nmol/L) significantly (P < .001) attenuated the adherence of LTB4-stimulated canine neutrophils to autologous segments of coronary artery and attenuated the neutrophil-induced contraction of isolated coronary arterial rings. CONCLUSIONS: SPM-5185 reduces myocardial necrosis and neutrophil accumulation in an acute model of canine myocardial ischemia and reperfusion. This reduction in myocardial cell injury may be partially related to the inhibitory actions of this novel NO donor on neutrophil adherence to the coronary endothelium.