Comparison of Intracarotid and Intravenous Propofol for Electrocerebral Silence in Rabbits

Background: The high lipid solubility that permits rapid transfer across the blood-brain barrier makes propofol attractive for intracarotid injection. The authors hypothesized that intracarotid injection produces electrocerebral silence at a fraction of the intravenous dose and with less adverse systemic and cerebrovascular side effects.

Methods: The authors compared the systemic and cerebrovascular effects of intracarotid and intravenous propofol during transient (10 s) and sustained (1 h) electrocerebral silence in anesthetized New Zealand White rabbits. Hemispheric electrocerebral activity, mean arterial blood pressure, ipsilateral and contralateral cerebral blood flow, tympanic temperature, and end-tidal carbon dioxide were continuously monitored in these animals. Changes in outcome variables were analyzed at four time points: at baseline, during electrical silence, during burst suppression, and after recovery of electrocerebral activity. Propofol (1%) was injected as intracarotid (0.1 ml) or intravenous (0.5 ml) boluses.

Results: Intracarotid propofol produced electrocerebral silence at one fifth (sustained silence) to one tenth (transient silence) of the intravenous dose. Compared with baseline values, the mean arterial pressure and ipsilateral cerebral blood flow remained unchanged or decreased transiently during electrocerebral silence with intracarotid propofol. In contrast, intravenous propofol resulted in systemic hypotension and a decrease in ipsilateral cerebral blood flow.     

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).     

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.     

Intracarotid Infusion of the Nitric Oxide Synthase Inhibitor, l-NMMA, Modestly Decreases Cerebral Blood Flow in Human Subjects

Background: The authors hypothesized that if nitric oxide (NO) was a determinant of background cerebrovascular tone, intracarotid infusion of NG-monomethyl-l-arginine (l-NMMA), a NO synthase (NOS) inhibitor, would decrease cerebral blood flow (CBF) and intracarotid l-arginine would reverse its effect.

Methods: In angiographically normal cerebral hemispheres, after the initial dose-escalation studies (protocol 1), the authors determined the effect of intracarotid l-NMMA (50 mg/min for 5 min) on CBF and mean arterial pressure (MAP) over time (protocol 2). Changes in CBF and MAP were then determined at baseline, during l-NMMA infusion, and after l-NMMA during l-arginine infusion (protocol 3). To investigate effects of higher arterial blood concentrations of l-NMMA, changes in CBF and MAP were assessed at baseline and after a bolus dose of l-NMMA (250 mg/1 min), and vascular reactivity was tested by intracarotid verapamil (1 mg/min, protocol 4). CBF changes were also assessed during induced hypertension with intravenous phenylephrine (protocol 5).

Results: Infusion of l-NMMA (50 mg/min for 5 min, n = 7, protocol 2) increased MAP by 17% (86 +/- 8 to 100 +/- 11 mmHg;P < 0.0001) and decreased CBF by 20% (45 +/- 8 to 36 +/- 6 ml [middle dot] 100 g-1 [middle dot] min-1;P < 0.005) for 10 min. Intracarotid l-arginine infusion after l-NMMA (protocol 3) reversed the effect of l-NMMA. Bolus l-NMMA (protocol 4) increased MAP by 20% (80 +/- 11 to 96+/-13 mmHg;P < 0.005), but there was no significant decrease in CBF. Intracarotid verapamil increased CBF by 41% (44+/- 8 to 62 +/- 9 ml [middle dot] 100 g-1 [middle dot] min-1;P < 0.005). Phenylephrine-induced hypertension increased MAP by 20% (79 +/- 9 to 95 +/- 6 mmHg;P = 0.001) but did not affect CBF.     

Propofol and Thiopental Do Not Interfere with Regional Cerebral Blood Flow Response at Sedative Concentrations

Background: Anesthetics may affect the regional cerebral blood flow (rCBF) response associated with increased brain activity in humans. rCBF was measured as auditory stimulus rate was increased during propofol and thiopental administration.

Methods: After informed consent, 10 right-handed male volunteer participants (aged 33.5 +/- 10.4 yr, weighing 74.5 +/- 8.4 kg) received thiopental (n = 4) or propofol (n = 6) intravenously at stepwise target concentrations of propofol 1.2 and 2.5-3, or thiopental 4 and 7-9 [mu]g/ml, representing sedative and hypnotic drug concentrations. The latter made volunteers unresponsive to voice or mild stimulation. Quantitative positron emission tomographic brain images were obtained at 0, 20, and 40 auditory words per minute at each drug concentration. Using SPM99 analysis, 10-mm spherical regions of interest were identified by peak covariation of word rate with rCBF across all conditions and drug concentrations. Individual mean rCBF responses in these and primary auditory cortex (Heschl's gyri) were obtained.

Results: Significant increases in rCBF with auditory word rate occurred in temporal lobes bilaterally at baseline (significance, T = 4.95). There was no change in this response during sedation (T = 5.60). During unresponsiveness seven of 10 participants had a diminished response in the left temporal lobe (T = 3.18). Global CBF, corrected for changes in Pco2 (3% [middle dot]mmHg Pco2-1), was reduced 15% by sedation and 27% during unresponsiveness.     

Relation between Initial Blood Distribution Volume and Propofol Induction Dose Requirement

Background: Propofol induction dose is variable and depends on many factors, including initial volume of distribution and early disposition. The authors hypothesized that preadministration blood distribution volumes, cardiac output (CO), and hepatic blood flow (HBF) could be examined to establish a propofol induction dose.

Methods: Propofol dose required to reach loss of consciousness, when infused at infusion rate per lean body mass (LBM) of 40 mg [middle dot] kg-1 [middle dot] h-1, was determined in 75 patients aged 11-85 yr. CO, blood volume (BV), central blood volume (CBV), and HBF were measured with indocyanine green pulse spectrophotometry. Univariate least squares linear regression analysis was used to individually analyze the relation between propofol induction dose and patient characteristics, including LBM, baseline distribution volumes, CO, and HBF. Stepwise multiple linear regression models were used to select important predictors of induction dose.

Results: Although there was a significant correlation between the induction dose and each of the eight variables of age, sex, LBM, hemoglobin, CO, BV, CBV, and HBF, only factors of age (partial r = -0.655), LBM (partial r = 0.325), CBV (partial r = 0.540), and HBF (partial r = 0.357) were independently associated with the induction dose (R2 = 0.85) when all variables were included in a multivariate model.     

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.     

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.     

Controlled Hypotension with Sodium Nitroprusside: Effects on Cerebral Blood Flow and Cerebral Venous Blood Gases in Patients Operated for Cerebral Aneurysms

The effect on cerebral haemodynamics of arterial hypotension induced by sodium nitroprusside infusion was studied in nine patients at the end of operations for intracranial aneurysms under N2O-O2-halothane anaesthesia. Cerebral blood flow (CBF), using the intraarterial 133Xe injection method, and cerebral jugular venous blood gases were monitored before, during and after the induced hypotension. CBF and jugular venous oxygen tension (PvO2) remained constant during the hypotensive period. Following its termination, a 13% increase in CBF occurred (P less than 0.05) and PvO2 showed the same trend, a 5% increase (P less than 0.30). Regional CBF recordings (rCBF) in 16 small areas within the cerebral hemisphere were obtained at each measurement. In four of the patients, rCBF abnormalities were present in the form of hyperaemic regions, probably induced by the operation or the disease itself. The focal abnormalities were not accentuated during hypotension nor were ischaemic regions disclosed. It is concluded that sodium nitroprusside has only a minor influence on cerebral haemodynamics in the anaesthetized state.     

Influence of Enflurane on Cerebral Blood Flow in Man

Cerebral blood flow was measured by means of a 10-channel cerebrograph in anesthe-tised patients before and during 2% enfluranc. This investigation was carried out after carotid angiography; 2 3 mCi Xe¹³³ was injected into the internal carotid artery. The clearance curves of Xe^l33 were captured by 10 scintillation counters. In addition to regional cerebral blood flow (rCBF), arterial blood pressure, heart rate, stroke volume, cardiac output and arterial blood gases were measured in seven adult patients.
During 2% enflurane, a small, and in two regions a significant decrease in rCBF was observed. Mean arterial pressure and heart rate decreased significantly, but cardiac output did not. The decrease in PaCo2 was not significant.     

Nitroprusside-Hypotension: Cerebral Blood Flow and Cerebral Oxygen Consumption in Neurosurgical Patients

The effects of nitroprusside-induced hypotension on cerebral blood flow and cerebral oxygen consumption were investigated in nine patients scheduled for cerebral arterial aneurysm surgery. Anesthesia was maintained with nitrous oxide/oxygen and fentanyl; muscle relaxation was achieved with pancuronium; Paco₂ was maintained at 4.79-5.32 kPa. Mean arterial pressure was reduced to 50 mm Hg by nitroprusside infusion after opening of the dura. Measurements were recorded and blood samples were taken 15 min before induction of hypotension, during stable hypotension and 15 min after termination of nitroprusside infusion. Measurements included: cerebral blood flow, using the argon-washin technique, cardiac output (thermodilution), mean arterial pressure and heart rate. Cerebral blood flow averaged 56 ± 6 ml/min. 100 g before hypotension. Nitroprusside produced hypotension but did not significantly alter cerebral blood flow (61 ± 7 ml/min · 100 g). Cerebral blood flow remained virtually at preinfusion values upon cessation of infusion (53 ± 6 ml/min · 100 g). Cerebral oxygen uptake averaged 3 ± 0.2 ml/min · 100 g before hypotension and did not change significantly during hypotension (3.3 ± 0.3 ml/min · 100 g) and after termination of hypotension (2.7 ± 0.3 ml/min · 100 g). In two patients nitroprusside produced a 17 and 20% increase, respectively, in cerebral blood flow with no change in cerebral oxygen consumption, together with a marked increase in cardiac output and heart rate.     

Effects of Xenon on Cerebral Blood Flow and Cerebral Glucose Utilization in Rats

Background: The effects of xenon inhalation on mean and local cerebral blood flow (CBF) and mean and local cerebral glucose utilization (CGU) were investigated using iodo-[14C]antipyrine and [14C]deoxyglucose autoradiography.

Methods: Rats were randomly assigned to the following groups: conscious controls (n = 12); 30% (n = 12) or 70% xenon (n = 12) for 45 min for the measurement of local CBF and CGU; or 70% xenon for 2 min (n = 6) or 5 min (n = 6) for the measurement of local CBF only.

Results: Compared with conscious controls, steady state inhalation of 30 or 70% xenon did not result in changes of either local or mean CBF. However, mean CBF increased by 48 and 37% after 2 and 5 min of 70% xenon short inhalation, which was entirely caused by an increased local CBF in cortical brain regions. Mean CGU determined during steady state 30 or 70% xenon inhalation remained unchanged, although local CGU decreased in 7 (30% xenon) and 18 (70% xenon) of the 40 examined brain regions. The correlation between CBF and CGU in 40 local brain structures was maintained during steady state inhalation of both 30 and 70% xenon inhalation, although at an increased slope at 70% xenon.     

Despite In Vitro Increase in Cyclic Guanosine Monophosphate Concentrations, Intracarotid Nitroprusside Fails to Augment Cerebral Blood Flow of Healthy Baboons

Background: During cerebral angiography, intracarotid infusion of sodium nitroprusside (SNP), an endothelium-independent nitric oxide donor, fails to increase cerebral blood flow (CBF) of human subjects. A confounding effect of intracranial pathology or that of radiocontrast could not be ruled out in these experiments. The authors hypothesized that, if nitric oxide was a significant regulator of CBF of primates, then intracarotid SNP will augment CBF of baboons.

Methods: In in vivo studies, CBF (intraarterial 133Xe technique) was measured in healthy baboons during isoflurane anesthesia at (1) baseline and during (2) induced hypertension with intravenous phenylephrine, (3) concurrent infusions of intravenous phenylephrine and intracarotid SNP, and (4) intracarotid verapamil (positive control drug). In in vitro studies, the authors measured tissue cyclic guanosine monophosphate (cGMP) by radioimmunoassay after incubating vascular rings obtained from freshly killed baboons (1) with increasing concentrations of SNP and (2) after SNP exposure following preincubation with the radiocontrast agent, iohexhol.

Results: In the in vivo studies, coinfusion of intravenous phenylephrine and intracarotid SNP did not increase CBF. However, intracarotid verapamil significantly increased CBF (from 26 +/- 7 to 43 +/- 11 ml [middle dot] 100 g-1 [middle dot] min-1;P < 0.0001) without a change in mean arterial pressure. In the in vitro studies, incubation of intracranial arterial rings in SNP resulted in dose-dependent increases in cGMP concentrations. A similar increase in cGMP content was evident despite iohexhol preincubation.     

Bedside Assessment of Cerebral Blood Flow by Double-indicator Dilution Technique

Background: Currently, quantitative measurement of global cerebral blood flow (CBF) at bedside is not widely performed. The aim of the present study was to evaluate a newly developed method for bedside measurement of CBF based on thermodilution in a clinical setting.

Methods: The investigation was performed in 14 anesthetized patients before coronary bypass surgery. CBF was altered by hypocapnia, normocapnia, and hypercapnia. CBF was measured simultaneously by the Kety-Schmidt inert-gas technique with argon and a newly developed transcerebral double-indicator dilution technique (TCID). For TCID, bolus injections of ice-cold indocyanine green were performed via a central venous line, and the resulting thermo-dye dilution curves were recorded simultaneously in the aorta and the jugular bulb using combined fiberoptic thermistor catheters. CBF was calculated from the mean transit times of the indicators through the brain.

Results: Both methods of measurement of CBF indicate a decrease during hypocapnia and an increase during hypercapnia, whereas cerebral metabolic rate remained unchanged. Bias between CBFTCID and CBFargon was -7.1 +/- 2.2 (SEM) ml [middle dot] min-1 [middle dot] 100 g-1; precision (+/- 2 [middle dot] SD of differences) between methods was 26.6 ml [middle dot] min-1 [middle dot] 100 g-1.