Effects of propofol on cerebral blood flow and the metabolic rate of oxygen in humans

BACKGROUND: Effects of propofol on human cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and blood flow-metabolism coupling have not been fully evaluated. We therefore assessed the effects of propofol on total-CBF and CMRO2 in patients without noxious stimuli and neurologic disorders. METHODS: General anesthesia was induced with midazolam (0.2 mg/kg) and fentanyl (5 microg/kg) in 10 patients (ASA physical status I) undergoing knee joint endoscopic surgery. Epidural anesthesia was also performed to avoid noxious stimuli during surgery. Cerebral blood flow (CBF) and cerebral arteriovenous oxygen content difference (a-vDO2) was measured using the Kety-Schmidt method with 15% N2O as a tracer before and after propofol infusion (6 mg/kg/h for 40 min), and the CMRO2 was also calculated. RESULTS: CBF decreased following propofol infusion from 34.4 ml/100 g/min (range 28.4-52.0) to 30.0 ml/100 g/min (range 20.2-42.4) (P=0.04). Although there was no significant change in a-vDO2, CMRO2 decreased following propofol infusion from 2.7 ml/100 g/min (range 2.2-4.3) to 2.2 ml/100 g/min (range 1.4-3.0) (P=0.04). There was a strong linear correlation between CBF and CMRO2 (r=0.90). CONCLUSION: Propofol proportionally decreased CBF and CMRO2 without affecting a-vDO2 in humans, suggesting that normal cerebral circulation and metabolism are maintained.     

The effects of propofol on cerebral blood flow in correlation to cerebral blood flow velocity in dogs

This study correlates the effects of propofol on cerebral blood flow (CBF) and middle cerebral artery blood flow velocity in dogs. CBF was measured using radioactive microspheres. Cerebral oxygen consumption (CMRO2) was measured with each CBF determination. Blood flow velocity was measured through a transtemporal window using a pulsed 8 MHz transcranial Doppler ultrasound system (TCD). Electroencephalogram (EEG) was continuously recorded over both cerebral hemispheres. Cardiac output (CO) was measured using an electromagnetic flow probe placed on the pulmonary artery. Baseline measures were made in all dogs (n = 11) with 0.7% isoflurane end tidal and 50% N2O in O2. There were two treatment groups. In group 1 (n = 6), propofol (0.8 mg/kg/min) was infused and a second measurement made at induction of EEG burst suppression (12 +/- 2 min). CBF and CMRO2 decreased by 70% and mean blood flow velocity decreased by 60%. Blood pressure, heart rate, and CO did not change. Propofol infusion was discontinued and all parameters were measured following recovery of EEG to baseline activity (48 +/- 9 min). CBF and blood flow velocity increased 35 and 25%, respectively, and CMRO2 increased by 32% during this period. A second propofol infusion (0.8 mg/kg/min) was started and all cerebral and systemic hemodynamic parameters were again determined at induction of EEG burst suppression (12 +/- 2 min). CBF decreased 35% and blood flow velocity decreased 25% to levels seen during the first propofol infusion. Over the entire study, changes in CBF correlated with changes in blood flow velocity (r = 0.86, p < 0.05). In group 2 (n = 5), four control measures were made at the same time intervals as in group 1. Baseline CBF and blood flow velocity were lower in group 2 compared to group 1 but these measures did not change over time. Our results show that propofol produces marked decreases in CBF in dogs and that these changes are closely correlated with CBF velocity.     

No influence of the endothelin receptor antagonist bosentan on basal and indomethacin-induced reduction of cerebral blood flow in pigs

BACKGROUND: The mechanism behind indomethacin-induced cerebral vasoconstriction is incompletely understood. We tested the hypothesis that the mixed endothelin-1 receptor antagonist bosentan would modify or prevent indomethacin-induced reduction of CBF in the anaesthetized pig. Furthermore, we investigated the effect of bosentan on resting CBF and CMRO2. METHODS: Twelve pigs were randomized in two groups of six, and received either bosentan and indomethacin (group 1), or placebo and indomethacin (group 2). Anaesthesia was induced with ketamine and midazolam and maintained with fentanyl, nitrous oxide and pancuronium. Baseline measurements of CBF and CMRO2 were performed before intravenous bolus injection of bosentan (10 mg/kg) or placebo (0.9% NaCl). The second CBF and CMRO2 measurement was performed 30 min after administration of bosentan/placebo. A 40-min infusion of indomethacin (0.05 mg/kg/min) was administered and the third CBF and CMRO2 measurement was performed 80 min after administration of bosentan/placebo. Independently, pharmacokinetic data of bosentan were generated in four pigs. RESULTS: In group 1, baseline CBF was 55 +/- 7 ml/100 cm3/min. Administration of bosentan i.v. did not change CBF significantly. Indomethacin decreased CBF to 41 +/- 5 ml/100 cm3/min (P < 0.002). In group 2, baseline CBF was 54 +/- 10 ml/100 cm3/min. Placebo did not change CBF while indomethacin decreased CBF significantly to 41 +/- 5 ml/100 cm3/min (P < 0.002). No significant changes in CMRO2 were observed. In group 2, a significant increase in MABP was observed after administration of indomethacin. No change in MABP was observed in the bosentan-treated animals. Total plasma concentrations of bosentan at the time of the first and the second PET measurement were 3.9 and 1.4 microg/ml, respectively. The corresponding values for the pharmacologically active metabolite Ro 48-5033 were 1.2 and 0.4 microg/ml. CONCLUSION: These findings indicate that endothelin receptor stimulation is not involved in indomethacin-induced cerebral vasoconstriction or maintenance of cerebrovascular tone in the anaesthetized pig. However, our results suggest that the increase in MABP is mediated through endothelin receptors.     

Electroencephalogram, cerebral metabolic, and vascular responses to propofol anesthesia in dogs

Previous studies on the cerebral effects of propofol report conflicting results regarding the cerebral metabolic rate for oxygen (CMRO2), cerebral blood flow (CBF), autoregulation of CBF, intracranial pressure, and cerebral perfusion pressure (CPP). The present studies were designed to examine these issues as well as propofol effects on the CBF responses to hypocapnia and on the electroencephalogram (EEG) in a well-known canine model that permits continuous determination of EEG activity, CMRO2, CBF, and cerebrospinal fluid (CSF) pressure. Dogs were studied at normocapnia (n = 6) and at hypocapnia (n = 6) during three doses of propofol (12, 24, and 48 mg kg(-1) h(-1)) and during a combination of propofol and elevated (20-25 mm Hg) CSF pressure. In both groups propofol caused dose-related decreases of EEG power and number of waveforms, CMRO2 (by 25-30%), and CBF (by 73-76%). The cerebral vasoconstrictor response to hypocapnia was preserved at all three doses of propofol. Autoregulation of CBF was preserved at the low and moderate doses of propofol but was impaired at the high dose of propofol (where CPP decreased significantly to approximately 41 +/- 13 mm Hg) and at the high dose of propofol combined with elevated CSF pressure (where CPP decreased significantly to approximately 32 +/- 12 mm Hg). Cerebrospinal fluid pressure decreased (by 33-42%) when the continuous infusion of propofol was begun, but returned to prepropofol values as infusion of propofol continued. The authors conclude that low and moderate doses of propofol decrease EEG activity and CMRO2, causing an associated decrease of CBF and CSF pressure. Autoregulation of CBF and cerebral vascular CO2 reactivity are preserved at these propofol doses. In contrast, high dose propofol significantly decreases CPP, resulting in impaired autoregulation of CBF.     

Cerebral metabolic depression and brain protection produced by midazolam and etomidate in the rat

Midazolam and etomidate have been shown to depress cerebral metabolism and may protect the brain during ischemia. However, it has been reported that etomidate may produce EEG spiking activity and seizures, which could adversely affect outcome. We compared the effects of midazolam and etomidate on EEG, cerebral blood flow (CBF), and cerebral cortical oxygen consumption (CMRO2) as well as neurologic outcome following incomplete cerebral ischemia in the rat. CBF was measured with radioactive microspheres and cortical CMRO2 was calculated by multiplying cortical CBF by the arterial-sagittal sinus oxygen content. Incomplete ischemia was produced by unilateral carotid artery occlusion combined with hemorrhagic hypotension. In low doses (0.02 mg/kg/min i.v.), both midazolam and etomidate depressed EEG, decreased CMRO2, and improved outcome from ischemia compared to nitrous oxide control rats. At a higher dose (0.2 mg/kg/min i.v.), midazolam further depressed EEG and CMRO2 and again improved outcome compared to N2O controls. In contrast, high dose etomidate (0.2 mg/kg/min) produced spiking EEG activity without further depression of CMRO2 and a worsening of outcome following cerebral ischemia. These results support previous reports that midazolam and etomidate may protect the brain from incomplete cerebral ischemia but suggest that EEG spiking activity associated with high dose etomidate may be associated with a worse outcome.     

Cerebral functional, metabolic, and hemodynamic effects of etomidate in dogs

The effects of a continuous infusion of etomidate on cerebral function, metabolism, and hemodynamics and on the systemic circulation were examined in six dogs. The infusion rate of etomidate was progressively increased at 20-min intervals from 0.02 to 0.4 mg X kg-1 X min-1 for 2 h. Cerebral oxygen consumption (CMRO2) decreased until there was cessation of neuronal function as reflected by the onset of an isoelectric EEG. This occurred during an infusion of 0.3 mg X kg-1 X min-1 etomidate when the animals had received a total of 10.7 mg X kg-1 over 91 min. At this time the CMRO2 was 2.6 ml X min-1 X 100 g-1, 48% of control. Thereafter, despite continued administration of etomidate to a total dose of 21.4 mg X kg-1, CMRO2 did not decrease further. Cerebral blood flow (CBF) decreased in association with a marked increase in cerebrovascular resistance but was independent of changes in CMRO2. CBF decreased precipitously from 145 +/- 23 to 72 +/- 6 ml X min-1 X 100 g-1 during the lowest infusion rate of 0.02 mg X kg-1 X min-1 etomidate and stabilized at 34-36 ml X min-1 X 100 g-1 during an infusion rate of 0.1 mg X kg-1 X min-1. CBF remained at this level despite the continued administration of etomidate and a further decrease in CMRO2. Etomidate produced physiologically minor but statistically significant changes in the systemic hemodynamic variables. Assays of cerebral metabolites taken at the end of the infusion revealed a normal energy state and a very mild but significant increase in cerebral lactate to 1.49 mumol X g-1. We conclude that etomidate is a potent, direct cerebral vasoconstrictor that appears to be independent of its effect on CMRO2 and that the cerebral metabolic effects of etomidate are secondary to its effect on neuronal function, with little if any direct or toxic effects on metabolic pathways.     

Midazolam-ethanol interactions and reversal with a benzodiazepine antagonist

The purpose of these experiments was to analyze the cerebrovascular and cerebral metabolic effects of midazolam, a short-acting water-soluble benzodiazepine, and to investigate its interaction with alcohol in rats. A benzodiazepine antagonist, 3-carbo-t-butoxy-beta-carboline (beta-CCT), was used to test the role of the benzodiazepine receptor in midazolam-alcohol effects. Experiments were carried out under 70% N2O, 30% O2 anesthesia. Rats were tested with intraperitoneal injections of 0.75-5 mg/g ethanol, intravenous infusions of 0.57, 5.75 mg/kg midazolam, and 1.15 mg/kg beta-CCT separately and in combination. Cortical cerebral blood flow (CBF) was measured with radioactive microspheres, and cerebral oxygen consumption (CMRO2) was determined from cortical CBF and arterial-sagittal sinus blood samples 20 min after ethanol treatment and/or after a 15-min drug infusion. Alcohol alone produced dose-related increases in plasma ethanol concentrations but no depression in CMRO2 except at the highest dose (5 mg/g). Midazolam infusions alone decreased cortical CBF and CMRO2 35-40%, while 2.5 mg/g alcohol (which did not depress CMRO2 alone) combined with midazolam produced a 70% depression of cortical CBF and metabolism. An infusion of beta-CCT given alone increased CMRO2 alone and reversed the depression in both cortical CBF and CMRO2 produced by midazolam plus alcohol. These results indicate that the ability of alcohol to potentiate benzodiazepine-induced sedation is not simply an additive effect but may be related to the facilitation by alcohol of benzodiazepine receptor binding. The fact that beta-CCT reversed midazolam-ethanol-induced depression suggests that the effect may be mediated through the benzodiazepine receptor.     

Cerebral effects of high-dose midazolam and subsequent reversal with Ro 15-1788 in dogs

The effects of a continuous high-dose infusion of midazolam on cerebral function, metabolism, and hemodynamics were studied in nine dogs receiving a spinal anesthetic and breathing 65% nitrogen/35% oxygen. In five dogs, the effects of 65% nitrous oxide (N2O) inspired and the benzodiazepine antagonist Ro 15-1788 were also examined. Midazolam was infused at a rate of 0.66 mg.kg-1.min-1 for 60 min for a total dose of 40 mg.kg-1. Cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) (measured by venous outflow technique) both decreased until a plateau level was reached at approximately 75% of control values (4.0 +/- 0.2 ml.min-1.100 g-1 and 49 +/- 3 ml.min-1.100 g-1, respectively, mean +/- SEM). This occurred after 6-10 mg.kg-1 of midazolam, corresponding to serum midazolam levels between 18.4 +/- 3.8 and 31.2 +/- 3.3 micrograms.ml-1. Serum midazolam levels increased throughout the midazolam infusion, reaching a mean value of 53 +/- 5.5 micrograms.ml-1 by the end of the midazolam infusion. A similar plateau was seen for changes in the electroencephalogram (EEG), which never developed burst suppression. Five dogs inspired 65% nitrous oxide/35% oxygen during minutes 30-45 of the midazolam infusion, rather than 65% nitrogen/35% oxygen. Nitrous oxide had no effect upon CMRO2, but significantly increased CBF when compared to dogs receiving nitrogen. Ro 15-1788, 1.0 mg.kg-1 caused a return of CMRO2 and EEG activity to control levels. CBF and intracranial pressure (ICP) increased markedly, to greater than control levels immediately following Ro 15-1788.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of sufentanil on cerebral metabolism and circulation in the rat

The authors examined the effects of large intravenous doses of sufentanil (5-160 micrograms/kg) on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) in rats. CBF and CMRO2 were measured by a modified Kety-Schmidt technique using 133Xenon washout. Progressive decreases in CBF and CMRO2 occurred in animals receiving sufentanil. The maximum decrease was 53% and 40% for CBF and CMRO2 respectively, at a dose of 80 micrograms/kg. The values for CBF and CMRO2 in this group were 105 +/- 10 ml X 100 g-1 X min-1 (mean +/- SEM) and 6.5 +/- 0.5 ml X 100 g-1 X min-1, respectively, compared with 226 +/- 28 ml X 100 g-1 X min-1 and 10.9 +/- 1 ml X 100 g-1 X min-1 in the control group, which received N2O 70% in oxygen. Larger doses of sufentanil did not cause further significant changes in CBF and CMRO2. Sharp waves appeared on the electroencephalogram (EEG) of all the animals following sufentanil injection, and some animals had EEG changes develop consistent with seizure activity. This seizure-like activity appeared to consist of a single episode of short duration in the groups receiving 5, 10, and 20 micrograms/kg sufentanil. The incidence and frequency of seizure activity increased in the groups receiving higher doses of sufentanil, although the duration of seizures was still short. The results of this study indicate that sufentanil causes a significant decrease in CBF and CMRO2 similar to that previously reported for fentanyl, and high doses of sufentanil may cause frequent seizure-like patterns appearing on EEG.     

Propofol anaesthesia via target controlled infusion or manually controlled infusion: effects on the bispectral index as a measure of anaesthetic depth.

Target controlled infusions (TCI) of propofol allow anaesthetists to target constant blood concentrations and respond promptly to signs of inappropriate anaesthetic depth. Studies comparing propofol TCI with manually controlled infusion (MCI) reported similar control of anaesthesia, but did not use an objective measure of anaesthetic depth. We therefore tested whether the Bispectral Index (BIS), an electroencephalographic (EEG) variable, is more stable during propofol TCI or MCI. Forty patients received midazolam and fentanyl before induction and were randomized to TCI or MCI. Target propofol concentrations in the TCI group were 3 to 8 microg/ml. The MCI group received propofol bolus (approximately 2 mg/kg) and infusion (3 to 10 mg/kg/h). Neuromuscular blockade was achieved with rocuronium. Following endotracheal intubation, nitrous oxide (66%) in oxygen was delivered and propofol infusion and fentanyl boluses were titrated against clinical signs. Blood pressure, heart rate and EEG were recorded, although the anaesthetist was blind to BIS values. The ideal BIS for general anaesthesia was defined as 50. Performance error, absolute performance error, wobble and divergence of BIS, and maximum changes in blood pressure and heart rate were compared using two-sample t-tests or rank-sum tests where appropriate. There was no difference in absolute performance errors during maintenance of anaesthesia with propofol TCI or MCI (23 +/- 11% vs 23 +/- 9%; P=0.97). The two groups did not differ significantly in performance error, wobble, divergence on haemodynamic changes. We conclude that TCI and MCI result in similar depth of anaesthesia and haemodynamic stability when titrated against traditional clinical signs.     

S-Ketamine Anesthesia Increases Cerebral Blood Flow in Excess of the Metabolic Needs in Humans

Background: Animal studies have demonstrated neuroprotective properties of S-ketamine, but its effects on cerebral blood flow (CBF), metabolic rate of oxygen (CMRO2), and glucose metabolic rate (GMR) have not been comprehensively studied in humans.

Methods: Positron emission tomography was used to quantify CBF and CMRO2 in eight healthy male volunteers awake and during S-ketamine infusion targeted to subanesthetic (150 ng/ml) and anesthetic (1,500-2,000 ng/ml) concentrations. In addition, subjects' GMRs were assessed awake and during anesthesia. Whole brain estimates for cerebral blood volume were obtained using kinetic modeling.

Results: The mean +/- SD serum S-ketamine concentration was 159 +/- 21 ng/ml at the subanesthetic and 1,959 +/- 442 ng/ml at the anesthetic levels. The total S-ketamine dose was 10.4 mg/kg. S-ketamine increased heart rate (maximally by 43.5%) and mean blood pressure (maximally by 27.0%) in a concentration-dependent manner (P = 0.001 for both). Subanesthetic S-ketamine increased whole brain CBF by 13.7% (P = 0.035). The greatest regional CBF increase was detected in the anterior cingulate (31.6%; P = 0.010). No changes were detected in CMRO2. Anesthetic S-ketamine increased whole brain CBF by 36.4% (P = 0.006) but had no effect on whole brain CMRO2 or GMR. Regionally, CBF was increased in nearly all brain structures studied (greatest increase in the insula 86.5%; P < 0.001), whereas CMRO2 increased only in the frontal cortex (by 15.7%; P = 0.007) and GMR increased only in the thalamus (by 11.7%; P = 0.010). Cerebral blood volume was increased by 51.9% (P = 0.011) during anesthesia.     

Effect of labetalol on cerebral blood flow, oxygen metabolism and autoregulation in healthy humans

We have studied the effects of labetalol on cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2) in eight healthy volunteers. CBF was measured by single photon emission computerized tomography before and during infusion of labetalol. CMRO2 was calculated as CBF x cerebral arteriovenous oxygen content difference (CaO2-CvO2). CBF autoregulation was tested during infusion of labetalol by changing arterial pressure and estimating relative changes in global CBF from changes in (CaO2-CvO2). CBF before and during infusion of labetalol was 67 and 65 ml/100 g min-1, respectively (P > 0.05). CMRO2 was 2.9 and 2.8 ml/100 g min-1, respectively (P > 0.05). CBF autoregulation was preserved in all subjects. The lower limit of CBF autoregulation was 88 mm Hg (94% of baseline mean arterial pressure). We conclude that labetalol did not influence global or regional CBF, or CMRO2, and CBF autoregulation was preserved.      

S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans

BACKGROUND: Animal studies have demonstrated neuroprotective properties of S-ketamine, but its effects on cerebral blood flow (CBF), metabolic rate of oxygen (CMRO2), and glucose metabolic rate (GMR) have not been comprehensively studied in humans. METHODS: Positron emission tomography was used to quantify CBF and CMRO2 in eight healthy male volunteers awake and during S-ketamine infusion targeted to subanesthetic (150 ng/ml) and anesthetic (1,500-2,000 ng/ml) concentrations. In addition, subjects' GMRs were assessed awake and during anesthesia. Whole brain estimates for cerebral blood volume were obtained using kinetic modeling. RESULTS: The mean +/- SD serum S-ketamine concentration was 159 +/- 21 ng/ml at the subanesthetic and 1,959 +/- 442 ng/ml at the anesthetic levels. The total S-ketamine dose was 10.4 mg/kg. S-ketamine increased heart rate (maximally by 43.5%) and mean blood pressure (maximally by 27.0%) in a concentration-dependent manner (P = 0.001 for both). Subanesthetic S-ketamine increased whole brain CBF by 13.7% (P = 0.035). The greatest regional CBF increase was detected in the anterior cingulate (31.6%; P = 0.010). No changes were detected in CMRO2. Anesthetic S-ketamine increased whole brain CBF by 36.4% (P = 0.006) but had no effect on whole brain CMRO2 or GMR. Regionally, CBF was increased in nearly all brain structures studied (greatest increase in the insula 86.5%; P < 0.001), whereas CMRO2 increased only in the frontal cortex (by 15.7%; P = 0.007) and GMR increased only in the thalamus (by 11.7%; P = 0.010). Cerebral blood volume was increased by 51.9% (P = 0.011) during anesthesia. CONCLUSIONS: S-ketamine-induced CBF increases exceeded the minor changes in CMRO2 and GMR during anesthesia.     

The use of propofol infusions in paediatric anaesthesia: a practical guide.

Children require higher infusion rates of propofol than adults to maintain clinical anaesthesia. We aimed to produce a manual infusion regimen capable of maintaining a steady-state blood concentration of 3 microg ml(-1) in children aged 3-11 years. Pharmacokinetic parameter estimates were taken from published studies of infusion data in children and used in a pharmacokinetic simulation programme to predict likely propofol blood concentrations during infusions. A variability of 5% was allowed about the target concentration of 3 microg ml(-1). A loading dose of 2.5 mg x kg(-1) followed by an infusion rate of 15 mg x kg(-1) x h(-1) for the first 15 min, 13 mg x kg(-1) x h(-1) from 15 to 30 min, 11 mg x kg(-1) x h(-1) from 30 to 60 min, 10 mg x kg(-1) x h(-1) from 1 to 2 h and 9 mg x kg(-1) x h(-1) from 2 to 4 h resulted in a pseudo-steady state target concentration of 3 microg x ml(-1) in children 3-11 years. We were unable to predict similar rates by applying size models to adult data. The context sensitive half-time in children was longer than in adults, rising from 10.4 min at 1 h to 19.6 min at 4 h compared to adult estimates of 6.7 min and 9.5 min, respectively. Children require higher infusion rates than adults to maintain steady state concentrations of 3 microg x ml(-1) and have longer context sensitive half-times than adults. These differences can be attributed to altered pharmacokinetics in this age group.     

Responses of EEG, cerebral oxygen consumption and blood flow to peripheral nerve stimulation during thiopentone anaesthesia in the dog

The effects of sciatic nerve stimulation on the electroencephalogram (EEG), cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) were investigated during thiopentone anaesthesia in dogs. Anaesthetic levels at 15, 35, 65, 95 and 125 minutes after the start of thiopentone infusion (23 mg X kg-1 X hr-1) were designated levels I, II, III, IV and V, respectively. The effects of stimulation for 5 min were tested at each level. At level I (plasma thiopentone concentration; 15 +/- 2 micrograms X ml-1), the EEG was activated with stimulation and CMRO2 and CBF increased by a maximum of 16 and 15 per cent, respectively. The increase in CMRO2 and CBF was significant for five and four minutes, respectively, though the increase became less with time. At level II (27 +/- 3 micrograms X ml-1), the CMRO2 and CBF increased at one minute by eight and nine per cent, the increase being accompanied by transient EEG activation. At the three deepest levels III, IV and V (37 +/- 6, 42 +/- 6, 49 +/- 6 micrograms X ml-1), the EEG, CMRO2 and CBF remained unchanged with stimulation. The results suggest the existence of the tight coupling between the EEG, CMRO2 and CBF and of a threshold level of thiopentone to block the response to peripheral stimulation during thiopentone anaesthesia.     

Cerebral blood flow, cerebral metabolic rate of oxygen and relative CO2 reactivity during neurolept anaesthesia in patients subjected to craniotomy for supratentorial cerebral tumours

In 10 patients subjected to craniotomy for supratentorial cerebral tumours in neurolept anaesthesia, cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were measured twice peroperatively by a modification of the Kety & Schmidt technique, using 133Xe. The relative CO2 reactivity was assessed indirectly as the % change of the arteriovenous oxygen difference (AVDO2) per mm change in PaCO2. The patients were premedicated with diazepam 10-15 mg perorally. For induction, thiopentone 4-6 mg/kg, droperidol 0.2 mg/kg and fentanyl 5 micrograms/kg were used, and for maintenance N2O 67% and fentanyl 4 micrograms/kg/h. During the first flow measurement the median and range of CBF was 30 ml/100 g/min (range 17-45), of AVDO2 8.0 vol % (range 4.1-9.5), and of CMRO2 2.28 ml O2/100 g/min (range 1.57-2.84). During the second CBF study, AVDO2 increased to 9.3 vol % (range 3.4-11) (P less than 0.05), and CMRO2 increased to 2.51 ml O2/100 g/min (range 1.88-3.00) P less than 0.05, while CBF was unchanged. The CO2 reactivity was present in all studies, median 1.8%/mmHg (range 0.5-15.1). The correlation coefficients between jugular venous oxygen tension/saturation, respectively, and CBF were high at tensions/saturations exceeding 4.0 kPa and 55%, indicating that hyperperfusion is easily unveiled by venous samples from the jugular vein during this anaesthesia.     

Use of a remifentanil-propofol mixture for pediatric flexible fiberoptic bronchoscopy sedation

BACKGROUND: Flexible fiberoptic bronchoscopy is an important diagnostic tool for pediatric pulmonologists. Because of its favorable respiratory profile, ketamine has become a popular sedative for this procedure, but may be associated with unpleasant emergence reactions in the older child. Remifentanil is a newer, ultra-short acting opioid that has been shown to provide effective sedation and cough suppression for fiberoptic bronchoscopy when combined with intermittent propofol boluses. However, delivery of these agents as a combined, single infusion has not been described. METHODS: Children > or =2 years of age undergoing fiberoptic bronchoscopy were enrolled. Remifentanil was mixed in a single syringe with undiluted propofol giving final drug concentrations of 10 mg x ml(-1) of propofol and 15-20 microg x ml(-1) of remifentanil. Sedation was induced with a bolus of approximately 0.1 ml x kg(-1) of this mixture and maintained by titrating the drip throughout the procedure. Vital signs, sedative effectiveness, recovery patterns, and complications were prospectively recorded. RESULTS: Fifteen patients aged 9.0 +/- 5.3 years were sedated. Sedation was induced with 1.2 +/- 0.4 mg x kg(-1) propofol (2.4 +/- 0.8 microg x kg(-1) remifentanil) and maintained with 4.1 +/- 1.8 mg x kg(-1) x h(-1) propofol (0.13 +/- 0.06 microg x kg(-1) x min(-1) remifentanil). Five patients received low-dose ketamine to augment sedation. The maximal decrease in respiratory rate was 6.1 +/- 5.3 b x min(-1) (27.6 +/- 21%) and no patient became hypoxemic. All procedures were completed easily without significant complication. Patients recovered to baseline 13.3 +/- 8.5 min following infusion discontinuation. CONCLUSIONS: A remifentanil/propofol mixture provided effective sedation and rapid recovery in pediatric patients undergoing fiberoptic bronchoscopy.     

Electroencephalograph variables, drug concentrations and sedation scores in children emerging from propofol infusion anaesthesia

BACKGROUND: Inadequate sedation or oversedation are common problems in Paediatric Intensive Care because of wide variations in drug response and the lack of objective tests for sedative depth. We undertook a pilot study to try to identify correlates of propofol drug concentration, electroencephalographic (EEG) variables and observed behaviour during a stepwise reduction in propofol infusion after paediatric cardiac surgery. METHODS: This was a prospective pilot study with 10 children (5 months to 8 years) emerging from propofol anaesthesia following cardiac surgery with cardiopulmonary bypass (CPB). Patients underwent a stepped wake-up from propofol anaesthesia during which the propofol infusion rate was decreased from 4 mg.kg(-1).h(-1) in 1 mg.kg(-1).h(-1) steps at 30 min intervals. EEG variables, propofol blood concentrations and clinical sedation scores (COMFORT scale) were recorded during the stepped wakeup. Analgesia was maintained with a standardized continuous infusion of fentanyl. RESULTS: : Mean (SD) whole blood propofol concentrations at arousal varied considerably [973 ng.ml(-1) (SD 523 ng.ml(-1))]. The summed ratio (SR) of high frequency to low frequency bands correlated with both propofol infusion rate (R2 value=0.47) and propofol blood concentrations (R2 value=0.64). The mean SR in deeply sedated patients was significantly different from that in the 5 min prior to wakening (6.84 vs 1.55, P=0.00002). There was no relationship between COMFORT scores and SR. CONCLUSIONS: In this group of patients receiving opioid analgesia and relatively high doses of propofol, sedation scores were unhelpful in predicting arousal. The SR correlated with propofol blood concentrations and clinical arousal and may have potential as a predictive tool for arousal in children.     

Influence of cardiac output on plasma propofol concentrations during constant infusion in swine

BACKGROUND: As propofol is a high-clearance drug, plasma propofol concentrations can be influenced by cardiac output (CO), which can easily change in response to several factors. If propofol is metabolized in the lungs, the difference between pulmonary and arterial propofol concentrations might also be affected by CO. The objective of the current study was to assess how much plasma propofol concentrations are affected by CO and to determine how much the lungs take part in propofol elimination and in concentration changes affected by CO in anesthetized swine. METHODS: Thirteen swine were studied. Propofol was administered via a peripheral vein at a rate of 6 mg x kg(-1) x h(- 1), and blood samples were simultaneously collected from pulmonary and femoral arteries at 0, 2, 3.5, 5, 7, 10, 20, and 30 min and at 20-min intervals up to 270 min. After 90 min of sampling (baseline 1), CO increased in response to a continuous infusion of dobutamine (20 microg x kg(-1) x min(- 1); high-CO state); the infusion was then stopped, and CO was allowed to return to baseline (baseline 2). Finally, CO decreased with the administration of propranolol (2.0-4.0 mg administered intravenously; low-CO state). Each hemodynamic status was maintained for 1 h. RESULTS: As CO increased 36% from baseline 1, plasma propofol concentrations decreased by 18% from baseline 1, and as CO decreased 42% from baseline 1, plasma propofol concentrations increased by 70% from baseline 1. Plasma propofol concentrations can be expressed by the following equation: plasma propofol concentration (micrograms per milliliter) = 6.51/CO (l/min) + 1.11 (r = 0.78, P < 0.0001). No significant differences were observed between plasma propofol concentrations in pulmonary and femoral arteries in any state, and CO caused no apparent differences between pulmonary and arterial propofol concentrations. CONCLUSIONS: An inverse relation was observed between CO and propofol concentrations. The lungs appear to have a minor effect on plasma propofol concentrations during constant infusion in anesthetized swine.     

Cerebral vascular and metabolic effects of fentanyl and midazolam in young and aged rats

Cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2) were measured, and electroencephalogram (EEG) was recorded in young (6-month-old) and aged (28-month-old) rats during ventilation with 70% N2O/30% O2 and following fentanyl or midazolam administration. Cerebral blood flow (CBF) was measured with radioactive microspheres, and cerebral oxygen consumption (CMRO2) was calculated from the arterial-sagittal sinus oxygen content difference and CBF measurements. Fentanyl at the highest dose used (200 micrograms/kg and 400 micrograms.kg-1.h-1) depressed the EEG and decreased CBF 49% and CMRO2 39% in young rats, whereas in old rats, this fentanyl dose decreased CBF 37% and CMRO2 34%, both significantly less than in young rats (P less than 0.05). Midazolam at the highest dose used (5.75 mg/kg) also depressed EEG in both age groups, and decreased CBF 51% and CMRO2 38% in young rats. This depression was significantly less than the 62% decrease in CBF and 59% decrease in CMRO2 produced by midazolam in old rats (P less than 0.05). These results indicate that aging attenuates the cerebrovascular and cerebral metabolic depression produced by fentanyl, but potentiates the same effects produced by midazolam. The enhanced cerebral metabolic depression produced by midazolam in the aged is similar to that seen with phenobarbital, and suggests a similar action of these drugs at the central GABA-benzodiazepine-barbiturate receptor complex.