The Effect of Altered Cerebral Blood Flow on the Cerebral Kinetics of Thiopental and Propofol in Sheep

Background: Thiopental and propofol are highly lipid-soluble, and their entry into the brain often is assumed to be limited by cerebral blood flow rather than by a diffusion barrier. However, there is little direct experimental evidence for this assumption.

Methods: The cerebral kinetics of thiopental and propofol were examined over a range of cerebral blood flows using five and six chronically instrumented sheep, respectively. Using anesthesia (2.0% halothane), three steady state levels of cerebral blood flow (low, medium, and high) were achieved in random order by altering arterial carbon dioxide tension. For each flow state, 250 mg thiopental or 100 mg propofol was infused intravenously over 2 min. To quantify cerebral kinetics, arterial and sagittal sinus blood was sampled rapidly for 20 min from the start of the infusion, and 1.5 h was allowed between consecutive infusions. Various models of cerebral kinetics were examined for their ability to account for the data.

Results: The mean baseline cerebral blood flows for the "high" flow state were over threefold greater than those for the low. For the high-flow state the normalized arteriovenous concentration difference across the brain was smaller than for the low-flow state, for both drugs. The data were better described by a model with partial membrane limitation than those with only flow limitation or dispersion.     

Minimum Cerebral Blood Flow and Metabolism During Craniotomy. Effect of Thiopental Loading

Cerebral blood flow and metabolism were measured repeatedly during surgery for cerebral tumours by a modification of the classical Kety & Schmidt method using ¹³³Xe infusion intravenously. Our standard procedure for neuroanaesthesia (pentobarbitone-fentanyl induction, halothane-nitrous oxide maintenance) reduced blood flow from 47.1 to 24.2 ml.100 g . ml^-1 and metabolism from 3.30 to 1.83 ml O₂ . 100 g^-1 . ml^-1. PacO₂ was reduced by hyperventilation from 5.3 to 3.6 kPa. Additional thiopental loading and maintenance using 4 + 4 mg.kg^-1 (n=5) or 8 + 8 mgkg^-1 (n = 5) reduced cerebral metabolism by an additional 15% ( P <0.0) and blood flow by 16.5% ( P <0.01), while mean arterial blood pressure fell from 11.0 to 9.9 kPa ( P <0.05). Paco₂ remained unchanged. This additional reduction in cerebral metabolism and blood flow is small, but we nevertheless conclude that it may well be of clinical interest to the problem of protecting the brain in case of episodes of focal cerebral ischaemia which may arise peroperatively during intracramal surgery.     

The Comparative Amnestic Effects of Midazolam, Propofol, Thiopental, and Fentanyl at Equisedative Concentrations

Background: The authors evaluated the effects of midazolam, propofol, thiopental, and fentanyl on volunteer participants' memory for words and pictures at equisedative concentrations.

Methods: Sixty-seven healthy volunteers were randomized to receive intravenous infusions of midazolam (n = 11), propofol (n = 11), thiopental (n = 10), fentanyl with ondansetron pretreatment (n = 11), ondansetron alone (n = 8), or placebo (n = 16) in a double-blind design. Three increasing and then two decreasing sedative concentrations were achieved by computer-controlled infusion in each volunteer. Measures of sedation, memory, and drug concentration were obtained at each target concentration. Drug concentrations were normalized to equisedative effects using both Emax and logistic regression methods of pharmacodynamic modeling. The serum concentrations at 50% memory effect (Cp50s) were determined using four different memory end points. The relative potencies compared with midazolam for memory impairment were determined.

Results: Equisedative concentrations were midazolam, 64.5 +/- 9.4 ng/ml; propofol, 0.7 +/- 0.2 micro gram/ml; thiopental, 2.9 +/- 1.0 micro gram/ml; and fentanyl, 0.9 +/- 0.2 ng/ml. The Cp50s for 50% loss of memory for words were midazolam, 56 +/- 4 ng/ml; propofol, 0.62 +/- 0.04 micro gram/ml; thiopental, 4.5 +/- 0.3 micro gram/ml; and fentanyl, 3.2 +/- 0.4 ng/ml. Compared with midazolam, relative potencies (with 95% confidence intervals) were propofol, 0.96 (0.44-1.78); thiopental, 0.76 (0.52-0.94); and fentanyl, 0.34 (0.05-0.76). Large effects on memory were only produced by propofol and midazolam.     

Cerebral Blood Flow Affects Dose Requirements of Intracarotid Propofol for Electrocerebral Silence

Background: The authors hypothesized that cerebral blood flow (CBF) changes will affect the dose of intracarotid propofol required to produce electrocerebral silence.

Methods: The authors tested their hypothesis on New Zealand White rabbits. The first group of 9 animals received intracarotid propofol during (1) normoventilation, (2) hyperventilation, and (3) hypoventilation. The second group of 14 animals received intracarotid propofol with or without concurrent intraarterial verapamil, a potent cerebral vasodilator. The third group of 8 animals received bolus injection of propofol during normotension, during severe cerebral hypoperfusion, and after hemodynamic recovery.

Results: In the first group, there was a linear correlation between the dose of intracarotid propofol and percent change (%[DELTA]) in CBF from the baseline due to changes in the minute ventilation, Total Dose (y) = 0.17 + 0.012 * %[DELTA] CBF (x), n = 27, r = 0.76. In the second group, the dose of propofol was also a function of CBF change after verapamil, Total Dose (y) = 0.98 + 0.1 * %[DELTA] CBF (x), n = 14, r = 0.75. In the third group, the duration of electrocerebral silence after intracarotid propofol (3 mg) was significantly increased with concurrent cerebral hypoperfusion compared with prehypoperfusion and posthypoperfusion values (141 +/- 38 vs. 19 +/- 24 and 16 +/- 12 s, respectively, P < 0.0001).     

Effects of Sevoflurane, Propofol, and Adjunct Nitrous Oxide on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans

Background: Anesthetic agents, especially volatile anesthetics and nitrous oxide (N2O), are suspected to perturb cerebral homeostasis and vascular reactivity. The authors quantified the effects of sevoflurane and propofol as sole anesthetics and in combination with N2O on regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV) in the living human brain using positron emission tomography.

Methods: 15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine rCBF, rCMRO2 and rCBV, respectively, in eight healthy male subjects during the awake state (baseline) and at four different anesthetic regimens: (1) sevoflurane alone, (2) sevoflurane plus 70% N2O (S+N), (3) propofol alone, and (4) propofol plus 70% N2O (P+N). Sevoflurane and propofol were titrated to keep a constant hypnotic depth (Bispectral Index 40) throughout anesthesia. End-tidal carbon dioxide was strictly kept at preinduction level.

Results: The mean +/- SD end-tidal concentration of sevoflurane was 1.5 +/- 0.3% during sevoflurane alone and 1.2 +/- 0.3% during S+N (P < 0.001). The measured propofol concentration was 3.7 +/- 0.7 [mu]g/ml during propofol alone and 3.5 +/- 0.7 [mu]g/ml during P+N (not significant). Sevoflurane alone decreased rCBF in some (to 73-80% of baseline, P < 0.01), and propofol in all brain structures (to 53-70%, P < 0.001). Only propofol reduced also rCBV (in the cortex and cerebellum to 83-86% of baseline, P < 0.05). Both sevoflurane and propofol similarly reduced rCMRO2 in all brain areas to 56-70% and 50-68% of baseline, respectively (P < 0.05). The adjunct N2O counteracted some of the rCMRO2 and rCBF reductions caused by drugs alone, and especially during S+N, a widespread reduction (P < 0.05 for all cortex and cerebellum vs. awake) in the oxygen extraction fraction was seen. Adding of N2O did not alter the rCBV effects of sevoflurane and propofol alone.     

Intracarotid Nitroprusside Does Not Augment Cerebral Blood Flow in Human Subjects

Background: The recent resurgence of interest in the cerebrovascular effects of nitroprusside can be attributed to the possibility of using nitric oxide donors in treating cerebrovascular insufficiency. However, limited human data suggest that intracarotid nitroprusside does not directly affect cerebrovascular resistance. In previous studies, physiologic or pharmacologic reactivity of the preparation was not tested at the time of nitroprusside challenge. The authors hypothesized that if nitric oxide is a potent modulator of human cerebral blood flow (CBF), then intracarotid infusion of nitroprusside will augment CBF.

Methods: Cerebral blood flow was measured (intraarterial 133Xe technique) in sedated human subjects undergoing cerebral angiography during sequential infusions of (1) intracarotid saline, (2) intravenous phenylephrine to induce systemic hypertension, (3) intravenous phenylephrine with intracarotid nitroprusside (0.5 [mu]g [middle dot] kg-1 [middle dot] min-1), and (4) intracarotid verapamil (0.013 mg [middle dot] kg-1 [middle dot] min-1). Data (mean +/- SD) were analyzed by repeated-measures analysis of variance and post hoc Bonferroni-Dunn test.

Results: Intravenous phenylephrine increased systemic mean arterial pressure (from 83 +/- 12 to 98 +/- 6 mmHg; n = 8;P < 0.001), and concurrent infusion of intravenous phenylephrine and intracarotid nitroprusside reversed this effect. However, compared with baseline, CBF did not change with intravenous phenylephrine or with concurrent infusions of intravenous phenylephrine and intracarotid nitroprusside. Intracarotid verapamil increased CBF (43 +/- 9 to 65 +/- 11 ml [middle dot] 100 g-1 [middle dot] min-1;P < 0.05).     

Regional Cerebral Blood Flow Autoregulation in Patients With Fulminant Hepatic Failure

The absence of cerebral blood flow autoregulation in patients with fulminant hepatic failure (FHF) implies that changes in arterial pressure directly influence cerebral perfusion. It is assumed that dilatation of cerebral arterioles is responsible for the impaired autoregulation. Recently, frontal blood flow was reported to be lower compared with other brain regions, indicating greater arteriolar tone and perhaps preserved regional cerebral autoregulation. In patients with severe FHF (6 women, 1 man; median age, 46 years; range, 18 to 55 years), we tested the hypothesis that perfusion in the anterior cerebral artery would be less affected by an increase in mean arterial pressure compared with the brain area supplied by the middle cerebral artery. Relative changes in cerebral perfusion were determined by transcranial Doppler–measured mean flow velocity (V_mean ), and resistance was determined by pulsatility index in the anterior and middle cerebral arteries. Cerebral autoregulation was evaluated by concomitant measurements of mean arterial pressure and V_mean in the anterior and middle cerebral arteries during norepinephrine infusion. Baseline V_mean was lower in the brain area supplied by the anterior cerebral artery compared with the middle cerebral artery (median, 47 cm/s; range, 21 to 62 cm/sv 70 cm/s; range 43 to 119 cm/s, respectively;P < .05). Also, vascular resistance determined by pulsatility index was greater in the anterior than middle cerebral artery (median, 1.02; range 1.00 to 1.37 v 0.87; range 0.75 to 1.48; P < .01). When arterial pressure was increased from 84 mm Hg (range 57 to 95 mm Hg) to 115 mm Hg (range, 73 to 130 mm Hg) during norepinephrine infusion, V_mean remained unchanged in 2 patients in the anterior cerebral artery, whereas it increased in the middle cerebral artery in all 7 patients. In the remaining patients, V_mean increased approximately 25% in both the anterior and middle cerebral arteries. Thus, this study could only partially confirm the hypothesis that autoregulation is preserved in the brain regions supplied by the anterior cerebral artery in patients with FHF. Although the findings of this small study need to be further evaluated, one should consider that autoregulation may be impaired not only in the brain region supplied by the middle cerebral artery, but also in the area corresponding to the anterior cerebral artery. (Liver Transpl 2000;6:795-800.)     

Information Loss over Time Defines the Memory Defect of Propofol: A Comparative Response with Thiopental and Dexmedetomidine

Background: Sedative-hypnotic drugs impair memory, but details regarding the nature of this effect are unknown. The influences of propofol, thiopental, and dexmedetomidine on the performance of a task that isolates specific components of episodic memory function were measured.

Methods: Working (1 intervening item, 6 s) and long-term memory (10 intervening items, 33 s) were tested using auditory words in a continuous recognition task before and during drug administration. Eighty-three volunteer participants were randomly assigned to receive a constant target concentration of drug or placebo, producing sedative effects from imperceptible to unresponsiveness. Responsive participants were categorized as high or low performers, using a median split of long-term memory performance during drug administration. Recognition of words at the end of the study day was assessed.

Results: High performers had acquisition of material into long-term memory when drug was present at the same level as placebo. Retention of this material at 225 min was significantly less for propofol (39 +/- 23% loss of material) than for other drugs (17-23% loss; P < 0.01). Greater sedation in low performers was evident in multiple measures. Memory for words presented before drug was no different from that associated with placebo for all groups.     

Influence of Fluid Infusion Associated with High-volume Blood Loss on Plasma Propofol Concentrations

Background: It is common clinical practice to use fluid infusion to manage high-volume blood loss until a blood transfusion is performed. The authors investigated the influence of fluid infusion associated with blood loss on the pseudo-steady state propofol concentration.

Methods: Twenty-seven swine were assigned to a lactated Ringer's solution group, a hydroxyethyl starch group, or a threefold lactated Ringer's solution group (n = 9 in each group). After 180 min of steady state infusion of propofol at a rate of 2 mg [middle dot] kg-1 [middle dot] h-1, hemorrhage and infusion were induced by stepwise bleeding followed by fluid infusion every 30 min. In each of the first two steps, 400 ml blood was collected; thereafter, 200 ml was collected at each step. Just after each bleeding step, fluid infusion was rapidly performed using a volume of lactated Ringer's solution or hydroxyethyl starch equivalent to the blood withdrawn, or a threefold volume of lactated Ringer's solution. Hemodynamic parameters and the plasma propofol concentration were recorded at each step.

Results: Although the plasma propofol concentration in the lactated Ringer's solution group increased with hemorrhage and infusion, it decreased in both the hydroxyethyl starch and the threefold lactated Ringer's solution groups. The propofol concentration in the hydroxyethyl starch group could be expressed by the following equation: Plasma Propofol Concentration Decrease (%) = 0.80 x Hematocrit Decrease (%) (r2 = 0.83, P < 0.0001).     

异丙酚不同给药方法辅助硬膜外阻滞时的血浆浓度与镇静作用

目的：探讨异丙酚最适给药方法，在４２例硬外麻醉下行上腹部手术的患者研究了三种给药法的血浆浓度和临床效应。方法：组１异丙酚负荷量１．５ｍｇ／ｋｇ，３ｍｉｎ后开始维持量３．７５ｍｇ．ｋｇ＾－１．ｈ＾－１，组２负荷量０．７５ｍｇ／ｋｇ，随之接与组１相同的维持量，组３以０．１５ｍｇ．ｋｇ＾－１．ｍｉｎ＾－１，６ｍｉｎ为负荷１ｍｉｎ内注入异丙酚１５ｍｇ并将维持量增加０．７５ｍｇ．ｋｇ＾－１．ｈ＾－１。结果．     

Regional Cerebral Blood Flow and Vertebral Angiography at Rest and in Connection with Arm Work in Patients with the “Subclavian Steal Phenomenon”

Vascular anatomy and haemodynamics of the vertebro-basilar system were investigated by means of vertebral angiography as well as rCBF measurements using the ¹³³Xenon clearance method in 12 patients with occlusive disease of the subclavian artery. Prior to the investigation, the occlusive lesions had been demonstrated by aortocervical angiography, which in 9 out of 12 patients showed reversed vertebral blood flow at rest. All selective vertebral angiographies and rCBF measurements were performed at rest and in connection with graded arm exercise. Patients with the subclavian steal phenomenon were found to have a slightly reduced rCBF. After arm exercise, the intracranial flow velocity of contrast medium in the cerebral vessels remained unchanged, while the velocity of the reversed flow of contrast medium in the vertebral artery was increased. Regional cerebral blood flow in the vertebro-basilar system increased during arm exercise, the average increase being about 16%. The augmentation of flow is probably due to activation of neuronal processes within the brain. The magnitude of these flow alterations in healthy individuals is unknown.     

Effects of Surgical Levels of Propofol and Sevoflurane Anesthesia on Cerebral Blood Flow in Healthy Subjects Studied with Positron Emission Tomography

Background: The authors report a positron emission tomography (PET) study on humans with parallel exploration of the dose-dependent effects of an intravenous (propofol) and a volatile (sevoflurane) anesthetic agent on regional cerebral blood flow (rCBF) using quantitative and relative (Statistical Parametric Mapping [SPM]) analysis.

Methods: Using H215O, rCBF was assessed in 16 healthy (American Society of Anesthesiologists [ASA] physical status I) volunteers awake and at three escalating drug concentrations: 1, 1.5, and 2 MAC/EC50, or specifically, at either 2, 3, and 4% end-tidal sevoflurane (n = 8), or 6, 9, and 12 [mu]g/ml plasma concentration of propofol (n = 8). Rocuronium was used for muscle relaxation.

Results: Both drugs decreased the bispectral index and blood pressure dose-dependently. Comparison between adjacent levels showed that sevoflurane initially (0 vs. 1 MAC) reduced absolute rCBF by 36-53% in all areas, then (1 vs. 1.5 MAC) increased rCBF in the frontal cortex, thalamus, and cerebellum (7-16%), and finally (1.5 vs. 2 MAC) caused a dual effect with a 23% frontal reduction and a 38% cerebellar increase. In the propofol group, flow was also initially reduced by 62-70%, with minor further effects. In the SPM analysis of the "awake to 1 MAC/EC50" step, both anesthetic agents reduced relative rCBF in the cuneus, precuneus, posterior limbic system, and the thalamus or midbrain; additionally, propofol reduced relative rCBF in the parietal and frontal cortices.     

Variability in the Magnitude of the Cerebral Blood Flow Response and the Shape of the Cerebral Blood Flow: Pressure Autoregulation Curve during Hypotension in Normal Rats

Background: The maintenance of constant cerebral blood flow (CBF) as mean cerebral perfusion pressure (CPP) varies is commonly referred to as CBF-pressure autoregulation. The lower limit of autoregulation is the CPP at which the vasodilatory capacity is exhausted and flow falls with pressure. We evaluated variability in the magnitude of percent change in CBF during the hypotensive portion of the autoregulatory curve. We hypothesize that this variability, in normal animals, obeys a Gaussian distribution and characterizes a vasodilatory mechanism that is inherently different from that described by the lower limit.

Methods: Sixty-five male Sprague-Dawley rats were anesthetized with 0.5-1% halothane and 70% nitrous oxide in oxygen. Body temperature was maintained at 37[degrees]C. Using a closed, superfused cranial window, CBF (as % of control) was determined using laser Doppler flowmetry (LDF) through the window with the intracranial pressure set at 10 mmHg. Animals with low vascular reactivity to inhaled carbon dioxide and superfused adenosine diphosphate (ADP) or acetylcholine were excluded. MABP was sequentially lowered by exsanguination to 100, 85, 70, 55, and 40 mmHg. Using the %CBF versus CPP plots for each curve (1) the lower limit of autoregulation was identified; (2) the pattern of autoregulation was classified as "peak" (a rise in LDF flow of at least 15% as arterial pressure was dropped), "classic" (plateau with a fall), or "none" (a fall in LDF flow of greater than 15%); (3) the area under the autoregulatory curve between CPPs of 30 and 90 mmHg was calculated; and (4) the magnitude of the %CBF response to hypotension was assessed by determining the %CBF at a CPP of 60 mmHg (%CBFCPP60).

Results: Of the 65 curves, 21 had the peak pattern, 33 the classic pattern, and 11 the none pattern. The %CBFCPP60 and autoregulatory area displayed Gaussian distributions, consistent with normal variability. Although %CBFCPP60, autoregulatory area, and pattern were significantly correlated (r or [rho] > 0.84, P < 0.001), the lower limit correlated weakly with autoregulatory area (r = 0.34, P = 0.012), and not at all with autoregulatory pattern or %CBFCPP60.     

Correlation of Regional Cerebral Blood Flow with Ischemic Electroencephalographic Changes during Sevoflurane-Nitrous Oxide Anesthesia for Carotid Endarterectomy

Background: Carotid endarterectomy necessitates temporary unilateral carotid artery occlusion. Critical regional cerebral blood flow (rCBF) has been defined as the rCBF below which electroencephalographic (EEG) changes of ischemia occur. This study determined the rCBF50, the rCBF value at which 50% of patients will not demonstrate EEG evidence of cerebral ischemia with carotid cross-clamping.

Methods: Fifty-two patients undergoing elective carotid end-arterectomy were administered 0.6-1.2% (0.3-0.6 minimum alveolar concentration) sevoflurane in 50% nitrous oxide (N2 O). A 16-channel EEG was used for monitoring. The washout curves from intracarotid133 Xenon injections were used to calculate rCBF before and at the time of carotid occlusion by the half-time (t1/2) technique. The quality of the EEG with respect to ischemia detection was assessed by an experienced electroencephalographer.

Results: Ischemic EEG changes developed in 5 of 52 patients within 3 min of carotid occlusion at rCBFs of 7, 8, 11, 11, and 13 ml [center dot] 100 g sup -1 [center dot] min sup -1. Logistic regression analysis was used to calculate an rCBF50 of 11.5 +/- 1.4 ml [center dot] 100 g sup -1 [center dot] min sup -1 for sevoflurane. The EEG signal demonstrated the necessary amplitude, frequency, and stability for the accurate detection of cerebral ischemia in all patients within the range of 0.6-1.2% sevoflurane in 50% N2 O.     

Effects of Subanesthetic Doses of Ketamine on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans

Background: Animal experiments have demonstrated neuroprotection by ketamine. However, because of its propensity to increase cerebral blood flow, metabolism, and intracranial pressure, its use in neurosurgery or trauma patients has been questioned.

Methods: 15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine quantitative regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV), respectively, on selected regions of interest of nine healthy male volunteers at baseline and during three escalating concentrations of ketamine (targeted to 30, 100, and 300 ng/ml). In addition, voxel-based analysis for relative changes in rCBF and rCMRO2 was performed using statistical parametric mapping.

Results: The mean +/- SD measured ketamine serum concentrations were 37 +/- 8, 132 +/- 19, and 411 +/- 71 ng/ml. Mean arterial pressure was slightly elevated (maximally by 15.3%, P < 0.001) during ketamine infusion. Ketamine increased rCBF in a concentration-dependent manner. In the region-of-interest analysis, the greatest absolute changes were detected at the highest ketamine concentration level in the anterior cingulate (38.2% increase from baseline, P < 0.001), thalamus (28.5%, P < 0.001), putamen (26.8%, P < 0.001), and frontal cortex (25.4%, P < 0.001). Voxel-based analysis revealed marked relative rCBF increases in the anterior cingulate, frontal cortex, and insula. Although absolute rCMRO2 was not changed in the region-of-interest analysis, subtle relative increases in the frontal, parietal, and occipital cortices and decreases predominantly in the cerebellum were detected in the voxel-based analysis. rCBV increased only in the frontal cortex (4%, P = 0.022).