Hypercarbia depresses cerebral oxygen consumption during cardiopulmonary bypass

No human studies have systematically examined the relations among PaCO2, cerebral blood flow, and the cerebral metabolic rate for oxygen during hypothermic cardiopulmonary bypass. We varied PaCO2 during hypothermic (26-28 degrees C) cardiopulmonary bypass and estimated the cerebral metabolic rate for oxygen by multiplying cerebral blood flow (measured using xenon-133 clearance) by the cerebral arteriovenous difference in oxygen contents. Patients were randomly assigned to either of two methods of managing PaCO2 (uncorrected for body temperature). In group 1 (PACO2 32-48 mm Hg, n = 13) the mean +/- SD cerebral metabolic rate for oxygen was 0.40 +/- 0.11 ml O2 X 100 g-1 X min-1 at a mean +/- SD PaCO2 of 36 +/- 2.0 mm Hg and 0.40 +/- 0.14 ml O2 X 100 g-1 X min-1 at a mean +/- SD PaCO2 of 45 +/- 2 mm Hg. and 49-72 mm Hg, n = 12) the mean +/- SD cerebral metabolic rate for oxygen was 0.31 +/- 0.09 ml O2 X 100 g-1 X min-1 at a mean +/- SD PaCO2 of 55 +/- 3 mm Hg and 0.21 +/- 0.07 ml O2 X 100 g-1 X min-1 at a mean +/- SD PaCO2 of 68 +/- 2 mm Hg. Group 2 values differed significantly from those in Group 1 (p less than 0.05). In both groups, cerebral blood flow increased as PaCO2 increased. During cardiopulmonary bypass, increasing PaCO2 increases cerebral blood flow and decreases the cerebral metabolic rate for oxygen.     

The effect of combined hypoxemia and cephalic hypotension on fetal cerebral blood flow and metabolism

The effect of hypoxemia and cephalic hypotension, alone and in combination, on hemispherical CBF and metabolism was examined in seven chronically catheterized fetal sheep. Hypoxemia was induced by lowering the maternal inspired oxygen fraction and cephalic hypotension was generated by partial occlusion of the fetal brachiocephalic artery. CBF was measured with radionuclide-labeled microspheres. During control, the arterial blood oxygen content (CaO2) was 3.2 +/- 1.0 (SD) mM and CBF averaged 131 +/- 21 (SD) ml min-1 100 g-1. The cephalic perfusion pressure (PP, mean cephalic arterial-sagittal venous) was 40 +/- 4 mm Hg and cerebral vascular resistance (CVR, PP/CBF) was 0.31 +/- 0.06 mm Hg ml-1 min 100 g. During induced hypoxemia, CaO2 was 1.4 +/- 0.7 mM and CBF was elevated to 223 +/- 60 ml min-1 100 g-1. PP was not different from control and CVR was lower at 0.19 +/- 0.04 mm Hg ml-1 min 100 g, reflecting cerebral vasodilation. With cephalic hypotension alone (PP = 21 +/- 4 mm Hg; CaO2 = 3.4 +/- 0.9 mM), CBF fell to 83 +/- 23 ml min-1 100 g-1 and there was no significant change in CVR (0.26 +/- 0.05 mm Hg ml-1 min 100 g). During combined hypoxemia and hypotension (CaO2 = 1.5 +/- 0.8 mM and PP = 18 +/- 4 mm Hg), CBF was significantly greater than during hypotension alone (100 +/- 6 ml min-1 100 g). CVR was 0.19 +/- 0.05 mm Hg ml-1 min 100 g, identical to that measured in normotensive hypoxemia and significantly less than found during hypotension alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of midazolam on cerebral hemodynamics and cerebral vasomotor responsiveness to carbon dioxide

Although it is known that hypercarbia increases and benzodiazepines decrease cerebral blood flow (CBF), the effects of benzodiazepines on CBF responsiveness to CO2 are not well documented. The influence on CBF and CBF-CO2 sensitivity of placebo or midazolam, which is a new water-soluble benzodiazepine, was measured in eight healthy volunteers using the noninvasive 133Xe inhalation method for CBF determination. Under normocarbia, midazolam decreased CBF from 40.6 +/- 3.2 to 27.0 +/- 5.0 ml 100 g-1 min-1 (means +/- SD). At a later session under hypercarbia, CBF was 58.8 +/- 4.4 ml 100 g-1 min-1 after administration of placebo, and 49.1 +/- 10.2 ml 100 g-1 min-1 after midazolam. The mean of the slopes correlating PaCO2 and CBF was significantly steeper with midazolam (2.5 +/- 1.2 ml 100 g-1 min-1 mm Hg-1) than with placebo (1.5 +/- 0.4 ml 100 g-1 min-1 mm Hg-1). Our results suggest that midazolam may be a safe agent to use in patients with intracranial hypertension, since it decreases CBF and thus cerebral blood volume; however, it should be administered with caution in nonventilated patients with increased intracranial pressure, since its beneficial effects on cerebrovascular tone can be readily counteracted by the increase in arterial CO2 tension induced by this drug.     

Cerebral blood flow in rats during physiological and humoral stimuli

The technique for estimating cerebral blood flow (CBF) in anesthetized rats by injecting 133Xe into the internal carotid artery represents a potentially useful and inexpensive model for screening cerebral vascular responses to pathophysiological and pharmacological stimuli. We have examined associated neuropathology, the validity and the reproducibility of the method, and made comparisons of initial slope estimates of CBF with those obtained by stochastic analysis. Initial slope estimates (CBF = 1.62 +/- 0.04 ml min-1g-1, X +/- SE, N = 38) were linearly related to stochastic measurements (CBF = 1.42 +/- 0.09 ml min-1g-1, N = 6), and overestimated mean CBF by about 15%. A reactivity to CO2 of 0.05 ml min-1g-1 per mm Hg, and an auto-regulation range of 70 to 180 mm Hg were found. CBF responses to the intra-arterial infusion of aminergic drugs were determined before and after opening of the blood-brain barrier with hypertonic urea. Serotonin reduced CBF after, but not before, the administration of urea. Acetylcholine increased CBF when the barrier was intact, the effect being augmented when the barrier was disrupted; these responses were reduced by atropine. Histamine increased CBF only after barrier opening, and this response was attenuated by the H2-receptor antagonist, metiamide. These studies indicate that initial slope estimates of CBF derived in rats from intracarotid 133Xe injection, which represents an inexpensive and simplified approach for screening cerebral circulatory adjustments, may facilitate the characterization of stimuli affecting CBF.     

Effects of endothelium-derived nitric oxide on cerebral circulation during normoxia and hypoxia in the rat.

The aim of this study was to determine the effects of endogenous nitric oxide (NO) on cerebral blood flow (CBF) and cerebrovascular resistance (CVR) under conditions of normoxia and hypoxia. Experiments were performed on anesthetized, mechanically ventilated Wistar rats. CBF was measured using the intracarotid 133Xe injection technique. NO formation was inhibited by NG-monomethyl-L-arginine (L-NMMA). Administration of L-NMMA (100 mg kg-1 i.v.) during normoxia resulted in an increase in mean arterial blood pressure from 113 +/- 4 to 145 +/- 4 mm Hg (p less than 0.001), a decrease in CBF of 21% (from 91 +/- 4 to 75 +/- 5 ml 100 g-1 min-1, p less than 0.001), and an increase in CVR of 53% (from 1.3 +/- 0.1 to 2.0 +/- 0.2 mm Hg ml-1 100 g min, p less than 0.001). These effects were reversed by i.v. administration of 300 mg kg-1 of L-arginine but not D-arginine. Moreover, the administration of L-NMMA abolished the enhancement of CBF and the diminution in CVR observed during intracarotid infusion of acetylcholine (ACh). The increase in CBF and decrease in CVR during hypoxia in the group of rats that received L-NMMA were similar to that in the control group, although CBF and CVR levels attained during hypoxia in both groups were different. The results show that NO is involved in the maintenance of basal CBF and CVR, and is responsible for the ACh-elicited increase in CBF and the decrease in CVR in rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral blood flow reactivity to changes in carbon dioxide calculated using end-tidal versus arterial tensions

We retrospectively examined arerial and end-tidal estimations of CO2 tension used to calculate cerebrovascular reactivity in 68 anesthetized patients. CBF was measured using the intravenous 133Xe technique at mean +/- SD PaCO2 values of 28.2 +/- 5.2 and 38.8 +/- 4.8 mm Hg. The correlation between all PaCO2 and end-tidal PCO2 (PetCO2) values was y = 0.85x - 0.49 (r = 0.93, p = 0.0001). There was a moderate correlation between age and the difference between PaCO2 and PetCO2 (y = 0.11x + 0.79; r = 0.73, p = 0.0001). Cerebrovascular reactivity to changes in CO2 (ml 100 g-1 min-1 mm Hg-1) was similar (p = 0.358) when calculated by using either PaCO2 (1.9 +/- 0.8) or PetCO2 (1.8 +/- 0.8) and highly correlated (y = 0.86x + 0.23; r = 0.91, p = 0.0001). The CBF response to changes in CO2 tension can be reliably estimated from noninvasive measurement of PetCO2.     

Cerebral blood flow response to increases in arterial CO2 tension during alfentanil anesthesia in the rabbit.

The stability of cerebral function and blood flow (CBF), and the CBF response to changes in arterial carbon dioxide tension (CBF reactivity) during alfentanil anesthesia were examined in rabbits. This model was first shown to provide stable anesthesia, cortical function, and CBF for 4 h. CBF increased significantly to 159% [of baseline] in the left hemisphere and to 167% in the right within 5 min of an exposure to 5% CO2 (p = 0.009 on the left and p = 0.003 on the right), but then decreased to 123% on the left and to 137% on the right (not significantly different from baseline, p = 0.11 on the left and p = 0.07 on the right) while PaCO2 was still rising. Steady state reactivity levels (0.8 ml 100 g-1/min-1/mm Hg-1 CO2 on the left and 0.65 ml 100 g-1/min-1/mm Hg-1 CO2 on the right) were consistent with previous work and were reached at 20 min. These results suggest that mechanisms other than perivascular hydrogen ion concentration mediate the CBF response to changes in arterial CO2 tension during alfentanil anesthesia.     

The influence of a cryogenic brain injury on the cerebrovascular response to isoflurane in the rabbit

To determine if an acute neurologic injury alters the cerebrovascular response to isoflurane, rabbits were anesthetized with morphine/N2O, mechanically ventilated, surgically instrumented, and assigned to one of three groups. Group 1 animals (n = 8) served as controls and received no injury. In Groups 2 (n = 9) and 3 (n = 8), a 30-s cryogenic injury was produced in the left parietal region using liquid N2 poured into a funnel affixed to the surface of the skull. Regional CBF was measured using microspheres. In Groups 2 and 3, flow was determined before and then 30 and 90 min after injury or at equivalent times in Group 1. After the 90-min data were collected, 1% [approximately 0.5 minimal alveolar concentration (MAC)] and then 2% (approximately 1.0 MAC) isoflurane was administered to uninjured rabbits in Groups 1 and to lesioned rabbits in Group 3. A mean arterial pressure of greater than or equal to 80 mm Hg was maintained during isoflurane administration by an infusion of angiotensin II. In uninjured rabbits (Group 1), 2% isoflurane produced bilaterally symmetrical increases in hemispheric CBF, from 76 +/- 21 (mean +/- SD) to 150 +/- 48 ml 100 g-1 min-1. CBF in the hindbrain increased from 91 +/- 25 to 248 +/- 102 ml 100 g-1 min-1. By contrast, in the lesioned rabbits of Group 3, 2% isoflurane resulted in CBF in the lesioned hemisphere changing from 56 to only 77 ml 100 g-1 min-1 (NS), while in the contralateral hemisphere, CBF rose from 68 to 97 ml 100 g-1 min-1 (also NS). These results indicate that a cryogenic injury attenuates the normal CBF response to a volatile anesthetic, both in the damaged hemisphere as well as in apparently uninjured regions distant from the injury focus. In a separate group of animals, a similar cryogenic injury abolished the CBF response to changing PaCO2 in the injured hemisphere, but not in either the contralateral hemisphere or the cerebellum. It is possible that the CBF effects of isoflurane may be mediated via some intermediary neurogenic and/or biochemical process.     

Cerebral blood flow during dihydralazine-induced hypotension in hypertensive rats

The cerebrovascular effects of graded, controlled dihydralazine-induced hypotension were studied in rats with renal hypertension (RHR) and spontaneous hypertension (SHR). Repeated measurements of cerebral blood flow (CBF) were made using the intraarterial 133Xenon injection technique in anaesthetised normocapnic animals. Dihydralazine was administered in single increasing i.v. doses (0.1 to 2 mg/kg), and CBF measured after each dose when a stable blood pressure had been reached. From a resting level of 145 +/- 7 mm Hg in RHR and 138 +/- 11 mm Hg in SHR, mean arterial pressure (MAP) fell stepwise to a minimum of around 50 mm Hg. CBF was preserved during dihydralazine induced hypotension, and remained at the resting level of 79 +/- 13 ml/100 g . min in RHR and 88 +/- 16 ml/100 g . min in SHR. Following 2 hours hypotension at the lowest pressure reached, the rats were sacrificed by perfusion fixation and the brains processed for light microscopy. Evidence of regional ischaemic brain damage was found in 4 of 11 animals: in 2 cases the damage appeared to be accentuated in the arterial boundary zones. Although the lower limit of CBF autoregulation in these rats is around 100 mm Hg during haemorrhagic hypotension, dihydralazine brought MAP to around 50 mm Hg without any concomitant fall in CBF. This was interpreted as being due to direct dilatation of cerebral resistance vessels. The combination of low pressure and direct dilatation may have resulted in uneven perfusion, thus accounting for the regional ischaemic lesions.     

The role of adenosine in the vascular adaptation of neonatal cerebral blood flow during hypotension

This study investigated the potential role of adenosine in cerebral blood flow (CBF) regulation in the neonate during moderate and severe hypotension. Experiments were done in anesthetized, 1- to 3-day-old piglets. Regional CBF (determined by radiolabeled microsphere technique) and cerebral metabolic rate for O2 (CMRO2) were measured (a) during normotension and (b) during a 3-min period of moderate (58 +/- 9 mm Hg) or severe (36 +/- 7 mm Hg) hypotension produced by the inflation of a balloon catheter placed in the aortic root. Measurements of CBF and CMRO2 were performed successively after intracerebroventricular (i.c.v.) injections of vehicle (n = 17), the adenosine receptor blocker 8-phenyltheophylline (8-PT, 10 micrograms, n = 14), and the A2-receptor agonist 5'-N-(ethylcarboxamide)adenosine (NECA, 2 ng, n = 8). After i.c.v. administration of vehicle, none of the parameters studied was significantly altered by moderate hypotension, but severe hypotension decreased the total CBF (mean +/- SD) from 86 +/- 24 to 40 +/- 15 ml min-1 100 g-1 and CMRO2 from 3.2 +/- 0.8 to 1.8 +/- 1.0 ml min-1 100 g-1 (p less than 0.05). Administration of 8-PT did not alter these parameters during normotension, but significantly decreased CBF during moderate hypotension compared to postvehicle values (53 +/- 11 versus 81 +/- 12 ml min-1 100 g-1, p less than 0.05). This loss of autoregulation was completely reversed by NECA. During severe hypotension, 8-PT altered the CBF redistribution towards the brainstem.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic hyperglycemic diabetes in the rat is associated with a selective impairment of cerebral vasodilatory responses

Diabetes has been reported to impair vasodilatory responses in the peripheral vascular tissue. However, little is known about vasodilatory function in the diabetic brain. We therefore studied, in the N2O-sedated, paralyzed, and artificially ventilated rat, the effects of chronic hyperglycemic diabetes on the cerebral blood flow (CBF) responses to 3 acutely imposed vasodilatory stimuli: hypoglycemia (HG) (plasma glucose = 1.6-1.9 mumol ml-1), hypoxia (HX) (PaO2 = 35-38 mm Hg), or hypercarbia HC) (PaCO2 = 75-78 mm Hg). In addition, we evaluated the somatosensory evoked potential (SSEP) and plasma catecholamine changes in rats exposed to acute glycemic reductions. Diabetes was induced via streptozotocin (STZ, 60 mg kg-1 i.p.). All results in diabetic rats were compared to those obtained in age-matched nondiabetic controls. The animals were studied at 6-8 weeks (HG experiments) or 4-6 months (HG, HX, and HC experiments) post-STZ. Values for CBF were obtained for the cortex (CX), subcortex (SC), brainstem (BS), and cerebellum (CE) employing radiolabeled microspheres. Up to three CBF determinations were made in each animal. In 6-8 week diabetics vs. controls, CBF increased to a lesser value in the CX, SC, and BS (p less than 0.05). Thus, in the diabetics, going from chronic hyperglycemia to acute hypoglycemia, CBF values (in ml 100 g-1 min-1 +/- SD) increased (p less than 0.05) from 89 +/- 22 to 221 +/- 57 in the CX, from 82 +/- 21 to 160 +/- 52 in the SC, and from 79 +/- 34 to 237 +/- 125 in the BS. In controls, going from normoglycemia to acute hypoglycemia, the CBF changes (p less than 0.05) were 128 +/- 27 to 350 +/- 219 (CX), 117 +/- 11 to 358 +/- 206 (SC), and 130 +/- 29 to 452 +/- 254 (BS). CBF changes and absolute values in the CE were similar in the two groups. At 4-6 months post-STZ, a complete loss of the hypoglycemic CBF response was found in the CX, SC, and CE. In the BS, a CBF response to hypoglycemia was seen in the diabetic rats, with the CBF increasing from 114 +/- 28 (hyperglycemia) to 270 +/- 204 ml 100 g-1 min-1 (p less than 0.05), compared to a change from 147 +/- 36 (normoglycemia) to 455 +/- 299 ml 100 g-1 min-1 (p less than 0.05) in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Opioids and the prostanoid system in the control of cerebral blood flow in hypotensive piglets

The interaction between opioid and prostanoid mechanisms in the control of cerebral hemodynamics was investigated in the conscious hypotensive piglet. Radiomicrospheres were used to determine regional cerebral blood flow (rCBF) in piglets pretreated with the opioid receptor antagonist, naloxone, or its vehicle, saline, during normotension, hypotension, and after the administration of indomethacin, a cyclooxygenase inhibitor, during hypotension. Hemorrhage (30 ml/kg) decreased systemic arterial pressure from 68 +/- 12 to 40 +/- 10 mm Hg but did not decrease blood flow to any brain region. Indomethacin treatment (5 mg/kg) of hypotensive piglets decreased blood flow to all brain regions within 20 min; this decrease in CBF resulted from increases in cerebral vascular resistance of 65 and 281% at 20 and 40 min after treatment, respectively. In hypotensive piglets, cerebral oxygen consumption was reduced from 2.62 +/- 0.71 to 0.53 +/- 0.27 ml 100 g-1 min-1 and to 0.11 +/- 0.04 ml 100 g-1 min-1 at 20 and 40 min following indomethacin, respectively. Treatment with naloxone (1 mg/kg) had no effect on rCBF, calculated cerebral vascular resistance, or cerebral oxygen consumption of normotensive or hypotensive piglets. However, decreases in CBF and oxygen consumption and increases in cerebral vascular resistance upon treatment of hypotensive piglets with indomethacin were attenuated in animals pretreated with naloxone. These data indicate that the removal of prostanoid modulation of an opioid-mediated constrictor influence on the cerebral circulation is a potential mechanism for the increase in cerebral vascular resistance that follows indomethacin treatment of hypotensive piglets.     

Effect of salbutamol on regional cerebral oxygen consumption, flow and capillary and arteriolar perfusion

This study quantitatively determined the effect of salbutamol (1 microgram kg-1), a beta 2-adrenoceptor agonist, on the perfusion of the brain microvasculature, cerebral O2 consumption, O2 extraction and cerebral blood flow (CBF) in conscious rat. Indices of arteriolar and capillary structure and the percentage of the total cerebral microvascular volume/mm3 (% Vv) and number/mm2 (% Na) perfused were determined. These parameters were obtained from the perfused microvessels, identified by the presence of fluorescein isothiocyanate (FITC) - dextran, and compared with the entire microvascular bed, identified by alkaline phosphatase stain. Cerebral O2 extraction was determined microspectrophotometrically and CBF was determined using 14[C]iodoantipyrine in another group of salbutamol-treated rats. The acute administration of salbutamol did not alter systemic arterial blood pressure. Significant tachycardia was noted in the salbutamol-treated rats. Salbutamol resulted in a significant increase in the percentage of arterioles perfused. Average percentage perfused capillary Na increased significantly from 46 +/- 2 to 88 +/- 1%; %Vv increased significantly and similarly in the arteriolar and capillary beds in all brain regions examined. Average cerebral O2 consumption increased significantly from 3.0 +/- 0.2 to 7.4 +/- 0.7 ml O2 min-1 100 g-1 with salbutamol, while cerebral O2 extraction was unchanged. Average CBF increased from 50 +/- 2 to 142 +/- 9 ml min-1 100 g-1 with salbutamol. Salbutamol may increase the perfusion of the regional microvasculature by increasing cerebral O2 consumption (metabolic vasodilation) and CBF and microvascular perfusion secondarily, although a direct effect of salbutamol on cerebral microvessels cannot be ruled out.     

The role of electrode size on the incidence of spreading depression and on cortical cerebral blood flow as measured by H2 clearance.

Cerebral blood flow was measured by the H2 clearance method 30 and 60 min after the implantation of 300, 250, 125, or 50 microns diameter platinum-iridium electrodes 2 mm deep into the right parietal cortex of normothermic, normocarbic halothane-anesthetized rats. Another group of animals had 50 microns electrodes inserted 1 mm. In all animals, the presence or absence of a wave of spreading depression (SD) was noted at the time of implantation, with recordings made with glass micropipettes. H2 flow values were compared with those measured in gray matter from the same anatomical region (but from different rats), using [3H]nicotine. The incidence of SD ranged from 60% following insertion of 300 microns electrodes to 0% with 50 microns electrodes. H2 clearance flows also varied with electrode size, from 77 +/- 21 ml 100 g-1 min-1 (mean +/- standard deviation) with 300 microns electrodes to 110 +/- 31 and 111 +/- 16 ml 100 g-1 min-1 with 125 and 50 microns electrodes, respectively (insertion depth of 2 mm). A CBF value of 155 +/- 60 ml 100 g-1 min-1 was obtained with 50 micron electrodes inserted only 1 mm. Cortical gray matter blood flow measured with [3H]nicotine was 154 +/- 35 ml 100 g-1 min-1. When the role of SD in subsequent flow measurements was examined, there was a gradual increase in CBF between 30 and 60 min after electrode insertion in those animals with SD, while no such change was seen in rats without SD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitative measurement of cerebral blood flow and cerebral blood volume after cerebral ischaemia

CBF obtained by the hydrogen clearance technique and cerebral blood volume (CBV) calculated from the [14C]dextran space were measured in three groups of rats subjected to temporary four-vessel occlusion to produce 15 min of ischaemia, followed by 60 min of reperfusion. In the control animals, mean CBF was 93 +/- 6 ml 100 g-1 min-1, which fell to 5.5 +/- 0.5 ml 100 g-1 min-1 during ischaemia. There was a marked early postischaemic hyperaemia (262 +/- 18 ml 100 g-1 min-1), but 1 h after the onset of ischaemia, there was a significant hypoperfusion (51 +/- 3 ml 100 g-1 min-1). Mean cortical dextran space was 1.58 +/- 0.09 ml 100 g-1 prior to ischaemia. Early in reperfusion there was a significant increase in CBV (1.85 +/- 0.24 ml 100 g-1) with a decrease during the period of hypoperfusion (1.33 +/- 0.03 ml 100 g-1). Therefore, following a period of temporary ischaemia, there are commensurate changes in CBF and CBV, and alterations in the permeability-surface area product at this time may be due to variations in surface area and not necessarily permeability.     

Effects of clonidine on cerebral blood flow and the response to arterial CO2

CBF, as measured by the clearance of 133Xe or 85Kr in the pentobarbital-anesthetized cat, displays a monotonic increase as the PaCO2 is elevated over a range of 20-60 mm Hg (slope Xe, 1.65 +/- 0.14 ml/100g/min/mm Hg; slope Kr, 1.40 +/- 0.11 ml/100 g/min/mm Hg). Clonidine (20 micrograms/kg i.v.), a centrally acting, alpha 2-preferring agonist, reduced the slope of the PaCO2-CBF response functions for Xe and Kr by 70 and 64%, respectively. Clonidine reduced normocarbic CBF-Xe by 36%, but had no effect on normocarbic CBF-Kr. ST-91, a polar structural analog of clonidine that does not cross the blood-brain barrier, did not reproduce the effects of clonidine when administered at an equivalent dose. This indicates that the effects of clonidine observed were secondary to its action on central rather than peripheral sites. In addition to the effects on the clearance of CBF markers, clonidine reduced the increased MABP otherwise evoked by elevated PaCO2. Reduction in the MABP response to PaCO2 did not account for the lowering of CBF during hypercarbia. In separate experiments where MABP was elevated to correspond with the PaCO2-MABP response observed in the absence of clonidine, a comparable reduction in the slope of the PaCO2 response was also observed. In addition, the pressure autoregulatory response was unaltered after clonidine treatment. These observations suggest that the central action of alpha 2-receptors on the CBF-CO2 response cannot be attributed to an altered perfusion pressure.     

Brain luxury perfusion during cardiopulmonary bypass in humans. A study of the cerebral blood flow response to changes in CO2, O2, and blood pressure

CBF and related parameters were studied in 68 patients before, during, and following cardiopulmonary bypass. CBF was measured using the intraarterial 133Xe injection method. The extracorporeal circuit was nonpulsatile with a bubble oxygenator administering 3-5% CO2 in the main group of hypercapnic patients (n = 59) and no CO2 in a second group of hypocapnic patients. In the hypercapnic patients, marked changes in CBF occurred during bypass. Evidence was found of a brain luxury perfusion that could not be related to the effect of CO2 per se. Mean CBF was 29 ml/100 g/min just before bypass, 49 ml/100 g/min at steady-state hypothermia (27 degrees C), reached a maximum of 73 ml/100 g/min during the rewarming phase (32 degrees C), fell to 56 ml/100 g/min at steady-state normothermic bypass (37 degrees C), and was 48 ml/100 g/min shortly after bypass was stopped. Addition of CO2 evoked systemic vasodilation with low blood pressure and a rebound hyperemia. The hypocapnic group responded more physiologically to the induced changes in hematocrit (Htc) and temperature, CBF being 25, 23, 25, 34, and 35 ml/100 g/min, respectively, during the five corresponding periods. Carbon dioxide was an important regulator of CBF during all phases of cardiac surgery, the responsiveness of CBF being approximately 4% for each 1-mm Hg change of PaCO2. The level of MABP was important for the CO2 response. At low blood pressure states, the CBF responsiveness to changes in PaCO2 was almost abolished. An optimal level of PaCO2 during hypothermic bypass of approximately 25 mm Hg (at actual temperature) is recommended. A normal autoregulatory response of CBF to changes in blood pressure was found during and following bypass. The lower limit of autoregulation was at pressure levels of approximately 50-60 mm Hg. CBF autoregulation was almost abolished at PaCO2 levels of greater than 50 mm Hg. The degree of hemodilution neither affected the CO2 response nor impaired CBF autoregulation, although, as would be expected, it influenced CBF: In 33 women CBF was 55 ml/100 g/min at an Htc of 24%, as compared with 42 ml/100 g/min in 35 men (Htc = 28%). High PaO2 was a vasoconstrictor, the autoregulatory plateau being narrowed. The lower limit of autoregulation was shifted to a higher pressure when PaO2 was low.     

Cerebral carbohydrate metabolism during severe ischemia in fetal sheep

The effect of cephalic hypotension on brain metabolism was studied in 10 unanesthetized, normoxic (PaO2 greater than 17 mm Hg), late-gestation fetal lambs. Perfusion pressure (cephalic arterial minus sagittal venous pressure) was 40 +/- 1 mm Hg (SEM) during control and was reduced to 10 +/- 1 by occlusion of the Grachio-cephalic artery. Cerebral blood flow was measured with microspheres, and arterial and sagittal vein blood samples were analyzed for oxygen content, glucose, and lactate. During the occlusion, oxygen consumption decreased from 125 +/- 8 to 95 +/- 4 (p less than 0.05) (all values mumol 100 g-1 min-1), and glucose uptake increased from 20 +/- 3 to 25 +/- 1 (p less than 0.05). During the control period, there was no net lactate flux; during the occlusion, lactate excretion was 5.7 +/- 1.4 (p less than 0.005). The control glucose and oxygen uptakes demonstrated a normal 6:1 molar ratio; however, during the occlusion, 9.4 mumol 100 g-1 glucose min-1 were taken up in excess of expected aerobic glucose metabolism. If all of this glucose were anaerobically metabolized to lactate, three times the measured efflux would be produced. The transport properties of the fetal blood-brain barrier may be important factors in perinatal brain injury.     

Cerebral blood flow and metabolism in soman-induced convulsions

Regional cerebral blood flow (CBF) and regional cerebral glucose utilization (CGU) were studied by quantitative autoradiographic techniques in rats. Animals were treated either with a toxic dose of soman, an irreversible organophosphorus cholinesterase inhibitor, that produced convulsions or with saline as controls. An increased arterial blood pressure (mean increase = 41% of control) always preceded onset of convulsions. Convulsive activity was associated with an increase of plasma glucose concentration and marked increases over controls of CGU [average of all regions: control = 75 +/- 5 mumol.100 g-1.min-1, n = regions/animals (304/8); seizures = 451 +/- 20 mumol.100 g-1.min-1, n = 190/5] and CBF [average of all regions: control = 135 +/- 6 ml.100 g-1.min-1, n = 190/5; seizures = 619 +/- 29 ml.100 g-1.min-1, n = 190/5). Regional distribution of these effects revealed a greater proportional increase of CBF over CGU in cingulate, motor, and occipital cortex and caudate-putamen. In contrast, a lower proportional increase of CBF over CGU in CA3 region of hippocampus, dentate gyrus, medial thalamus, and substantia nigra was observed, implying the existence of a relative ischemia in these brain areas. These findings may be relevant to the pathogenesis of brain lesions associated with soman-induced convulsions.     

Chemical stimulation of the nucleus tractus solitarii decreases cerebral blood flow in anesthetized rats

In anesthetized (chloralose and urethane), paralyzed and artificially ventilated rats, the neurons in the nucleus tractus solitarius (NTS) were chemically stimulated by microinjections of L-glutamate and the cerebral blood flow (CBF) was determined using a combination of labeled microspheres (either 57Co, 113Sn and 46Sc or 141Ce, 85Sr and 46Sc). Unilateral chemical stimulation of the NTS (n = 14) decreased CBF significantly in most brain areas. The decrease in CBF was not due to the decrease in arterial blood pressure (ABP) because the CBF of the whole cerebral cortex during the chemical stimulation of the NTS was significantly smaller (P less than 0.05) than the CBF during controlled hemorrhagic hypotension (n = 10). In another group of rats (n = 6), moderate hypertension was induced by blood transfusion. Unilateral chemical stimulation of the NTS in these rats decreased ABP but it remained within normotensive range. A significant (P less than 0.05) decrease in CBF (from 62 +/- 28 (mean +/- S.D.) to 48 +/- 23 ml.min-1.(100 g)-1) and increase in cerebrovascular resistance (from 1.9 +/- 1.2 to 2.6 +/- 1.2 mm Hg per [ml.min-1.(100 g)-1]) was observed in the whole cerebral cortex of these rats. Chemical stimulation of the NTS did not affect the reactivity of the cerebral vessels to hypercapnea (n = 5). These results suggest that the cell bodies within the NTS may play a role in the control of cerebral circulation.