Effect of postinjury intravenous or intrathecal methylprednisolone on spinal cord excitatory amino-acid release, nitric oxide generation, PGE2 synthesis, and myeloperoxidase content in a pig model of acute spinal cord injury.

STUDY DESIGN: Prospective, randomized, in vivo acute spinal cord injury in pigs. SETTING: Department of Anesthesiology, University of Washington, Seattle, WA, USA. OBJECTIVES: To determine whether postinjury methylprednisolone could reduce the generation of known mediators of secondary neurological injury. METHODS: Intrathecal microdialysis probes were used to sample cerebrospinal fluid (CSF) for measurement of PGE(2), glutamate, and citrulline (a byproduct of nitric oxide generation), before and after spinal cord injury in anesthetized pigs. The spinal cord was removed at the end of the study for measurement of myeloperoxidase and methylprednisolone concentrations. Animals were randomly allocated to receive intravenous methylprednisolone (30 mg/kg bolus then 3.4 mg/kg/h), intrathecal methylprednisolone (5 mg bolus then 5 mg/h), or saline, beginning 30 min after the spinal cord was injured by using a modification of the Allen weight drop technique. RESULTS: Spinal cord injury significantly increased the amount of glutamate, PGE(2), myeloperoxidase, and citrulline, recovered from the CSF dialysates. However, neither intravenous nor intrathecal methylprednisolone administered after injury had any effect on the magnitude of the increase in any of the measured biochemicals. Intrathecal methylprednisolone administration produced a spinal cord methylprednisolone concentration that was eight times greater, and a plasma concentration that was 32 times less, than that achieved with intravenous administration. CONCLUSIONS: Contrary to earlier animal studies in which methylprednisolone was administered either before or immediately after spinal cord injury, we found no effect of intravenous or intrathecal methylprednisolone on any of the parameters measured when administered 30 min postinjury.

Cyclosporine-A-mediated inhibition of p-glycoprotein increases methylprednisolone entry into the central nervous system.

STUDY DESIGN: Prospective, randomized, pharmacokinetic study. OBJECTIVE: To determine if cyclosporine-A-mediated inhibition of p-glycoprotein would increase methylprednisolone entry into the central nervous system thereby permitting a reduction in the systemic methylprednisolone dose. SETTING: Department of Anesthesiology, University of Washington, Seattle, USA. METHODS: Microdialysis probes were used to obtain cerebrospinal fluid and gluteal muscle extracellular fluid samples for measurement of methylprednisolone concentration in pigs. At time zero, a methylprednisolone bolus was given and an infusion started. At 210 min, after reaching a stable methylprednisolone concentration, a cyclosporine-A bolus was given (either 10 or 30 mg/kg) and microdialysis samples collected until 420 min. Plasma samples were collected at 10, 30 min and then every 30 min until the study's end. RESULTS: Cyclosporine-A bolus produced a dose-dependant increase in methylprednisolone concentration in plasma, muscle and cerebrospinal fluid. Importantly, the magnitude of the increase in cerebrospinal fluid was significantly greater than the increase in plasma and muscle. CONCLUSIONS: The relatively greater increase in cerebrospinal fluid concentrations of methylprednisolone is consistent with increased penetration of the blood-brain barrier secondary to cyclosporine-mediated p-glycoprotein inhibition. Theoretically, increased methylprednisolone entry into the central nervous system should allow a reduction in the systemic methylprednisolone dose and a consequent decrease in glucocorticoid-mediated side effects.

Effect of clonidine on lidocaine clearance in vivo: a microdialysis study in humans.

BACKGROUND: The addition of clonidine to local anesthetics has been shown to prolong both peripheral and central neuraxial local anesthetic blocks. Whether clonidine prolongs local anesthetic block by a pharmacokinetic effect or a pharmacodynamic effect is unclear. By directly measuring lidocaine tissue concentrations at the site of injection in the presence and absence of clonidine, this study was designed to address this question. METHODS: Microdialysis probes were placed adjacent to the superficial peroneal nerve in both feet of seven volunteers. Plain lidocaine (1%) was injected along one nerve, and lidocaine with clonidine (10 microg/ml) was injected along the other nerve in a double-blind, randomized manner. The extracellular fluid was then sampled for lidocaine concentration at 5-min intervals using microdialysis, cutaneous blood flow was assessed by laser Doppler at 10-min intervals, and sensory block was assessed every 10 min until resolution. RESULTS: Consistent with previous studies, clonidine prolonged lidocaine sensory block. Blood flow increased in both groups but was significantly lower in the clonidine group, especially during the first 60 min. Consistent with the lower blood flow, the area under the lidocaine concentration-versus-time curve was significantly greater in the clonidine group during the first 60 min. CONCLUSION: When added to lidocaine, clonidine prolonged peripheral nerve block. The pharmacokinetic data suggest that the mechanism of prolongation is at least in part pharmacokinetic.

The role of drug-lipid interactions on the disposition of liposome-formulated opioid analgesics in vitro and in vivo.

UNLABELLED: Although liposome encapsulation prolongs the duration of action of epidurally administered drugs, little is known about how liposome encapsulation affects opioids differently, or about how lipid content of liposomes alters the bioavailability of epidurally-administered opioids. To address these issues, morphine, alfentanil, fentanyl, and sufentanil were loaded into D-alpha-dipalmitoyl phosphatidylcholine multilamellar liposomes, and incorporation efficiency and in vitro release rates were determined. We then determined epidural morphine and sufentanil liposomes, at two different lipid/opioid ratios, in vivo in a pig model in which epidural and intrathecal spaces were continuously sampled via microdialysis. Liposome encapsulation efficiency was significantly more for sufentanil (100%) than for the other opioids (25%-30%). The in vitro release rate was slowest for morphine, intermediate for fentanyl and alfentanil, and fastest for sufentanil. In vivo, morphine was released more slowly than sufentanil. It is most important to note that increasing the lipid content of morphine liposomes increased the proportion of drug reaching the intrathecal space. In contrast, increasing the lipid content of sufentanil liposomes did not alter intrathecal movement but did decrease movement into plasma. Therefore, increasing drug hydrophobicity and lipid content of the liposomes modulates drug distribution in vivo. IMPLICATIONS: The degree of interaction between opioids and lipid bilayers in liposome-formulated opioids dictates the rates at which epidurally-administered drugs distribute into the intrathecal compartment and blood in potentiating analgesic effects.

Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein.

BACKGROUND: P-glycoprotein is a transmembrane protein expressed by multiple mammalian cell types, including the endothelial cells that comprise the blood-brain-barrier. P-glycoprotein functions to actively pump a diverse array of xenobiotics out of the cells in which it is expressed. The purpose of this study was to determine if P-glycoprotein alters the analgesic efficacy of clinically useful opioids. METHODS: Using a standard hot-plate method, the magnitude and duration of analgesia from morphine, morphine-6-glucuronide, methadone, meperidine, and fentanyl were assessed in wild-type Friends virus B (FVB) mice and in FVB mice lacking P-glycoprotein [mdr1a/b(-/-)]. Analgesia was expressed as the percent maximal possible effect (%MPE) over time, and these data were used to calculate the area under the analgesia versus time curves (AUC) for all opioids studied. In addition, the effect of a P-glycoprotein inhibitor (cyclosporine, 100 mg/kg) on morphine analgesia in both wild-type and mdr knockout mice was also determined. RESULTS: Morphine induced greater analgesia in knockout mice compared with wild-type mice (AUC 6,450 %MPE min vs. 1,610 %MPE min at 3 mg/kg), and morphine brain concentrations were greater in knockout mice. Analgesia was also greater in knockout mice treated with methadone and fentanyl but not meperidine or morphine-6-glucuronide. Cyclosporine pretreatment markedly increased morphine analgesia in wild-type mice but had no effect in knockout mice. CONCLUSIONS: These results suggest that P-glycoprotein acts to limit the entry of some opiates into the brain and that acute administration of P-glycoprotein inhibitors can increase the sensitivity to these opiates.

Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil.

BACKGROUND: Despite widespread use, little is known about the comparative pharmacokinetics of intrathecally administered opioids. The present study was designed to characterize the rate and extent of opioid distribution within cerebrospinal fluid, spinal cord, epidural space, and systemic circulation after intrathecal injection. METHODS: Equal doses of morphine and alfentanil, fentanyl, or sufentanil were administered intrathecally (L3) to anesthetized pigs. Microdialysis probes were used to sample cerebrospinal fluid at L2, T11, T7, T3, and the epidural space at L2 every 5-10 min for 4 h. At the end of the experiment, spinal cord and epidural fat tissue were sampled, and each probe's recovery was determined in vitro. Using SAAM II pharmacokinetic modeling software (SAAM Institute, University of Washington, Seattle, WA), the data were fit to a 16-compartment model that was divided into four spinal levels, each of which consisted of a caternary arrangement of four compartments representing the spinal cord, cerebrospinal fluid, epidural space, and epidural fat. RESULTS: Model simulations revealed that the integral exposure (area under the curve divided by dose) of the spinal cord (i.e., effect compartment) to the opioids was highest for morphine because of its low spinal cord distribution volume and slow clearance into plasma The integral exposure of the spinal cord to the other opioids was relatively low, but for different reasons: alfentanil has a high clearance from spinal cord into plasma, fentanyl distributes rapidly into the epidural space and fat, and sufentanil has a high spinal cord volume of distribution. CONCLUSIONS: The four opioids studied demonstrate markedly different pharmacokinetic behavior, which correlates well with their pharmacodynamic behavior.

Spinal cord bioavailability of methylprednisolone after intravenous and intrathecal administration: the role of P-glycoprotein.

BACKGROUND: High-dose intravenously administered methylprednisolone has been shown to improve outcome after spinal cord injury. The resultant glucocorticoid-induced immunosuppression, however, results in multiple complications including sepsis, pneumonia, and wound infection. These complications could be reduced by techniques that increase the spinal bioavailability of intravenously administered methylprednisolone while simultaneously decreasing plasma bioavailability. This study aimed to characterize the spinal and plasma bioavailability of methylprednisolone after intravenous and intrathecal administration and to identify barriers to the distribution of methylprednisolone from plasma into spinal cord. METHODS: The spinal and plasma pharmacokinetics of intravenous (30-mg/kg bolus dose plus 5.4 mg x kg(-1) x h(-1)) and intrathecal (1-mg/kg bolus dose plus 1 mg x kg(-1) x h(-1)) methylprednisolone infusions were compared in pigs. In addition, wild-type mice and P-glycoprotein knockout mice were used to determine the role of P-glycoprotein in limiting spinal bioavailability of methylprednisolone. RESULTS: Despite the greater intravenous dose, concentrations of methylprednisolone in pig spinal cord were far higher and plasma concentrations much lower after intrathecal administration. After intraperitoneal administration in the mouse, the concentrations of methylprednisolone in muscle were not different between mice expressing P-glycoprotein (2.39 +/- 1.79 microg/g) and those lacking P-glycoprotein (2.83 +/- 0.46 microg/g). In contrast, methylprednisolone was undetectable in spinal cords of wild-type mice, whereas concentrations in spinal cords of P-glycoprotein-deficient mice were similar to those in skeletal muscle (2.83 +/- 0.27 microg/g). CONCLUSIONS: These pig studies demonstrate that the spinal cord bioavailability of methylprednisolone is poor after intravenous administration. The studies in knockout mice suggest that this poor bioavailability results from P-glycoprotein-mediated exclusion of methylprednisolone from the spinal cord.

Effect of epinephrine on lidocaine clearance in vivo: a microdialysis study in humans.

BACKGROUND: Local anesthetic nerve block prolonged by epinephrine is thought to result from local vasoconstriction and consequent decreased local anesthetic clearance from the injection site. However, no study has yet confirmed this directly in humans by measuring tissue concentrations of local anesthetic over time. In addition, recent studies have shown that the alpha2-adrenergic receptor agonist, clonidine, also prolongs nerve block without altering local anesthetic clearance. Because epinephrine is also an alpha2-adrenergic receptor agonist, it is possible that epinephrine prolongs local anesthetic block by a pharmacodynamic mechanism and not a pharmacokinetic one. This study was designed to address this issue. METHODS: Microdialysis probes were placed adjacent to the superficial peroneal nerve in both feet of eight volunteers. Plain lidocaine (1%) was injected along one peroneal nerve and lidocaine with epinephrine (2.5 microg/ml) was injected along the other nerve in a double-blinded, randomized manner. The concentration of lidocaine in tissue was measured at 5-min intervals, and sensory block and cutaneous blood flow were assessed by laser Doppler at 10-min intervals for 5 h. The resulting data for lidocaine concentration versus time were fit to a two-compartment model using modeling software. RESULTS: Epinephrine prolonged sensory block by decreasing local blood flow and slowing clearance. There was no evidence of a pharmacodynamic effect of epinephrine. CONCLUSION: Although epinephrine activates alpha2-adrenergic receptors, its mechanism for prolonging the duration of local anesthetic block rests on its ability to decrease local anesthetic clearance and not on a pharmacodynamically mediated potentiation of local anesthetic effect.

Effect of Staphylococcus aureus bacteria and bacterial toxins on meningeal permeability in vitro.

BACKGROUND AND OBJECTIVES: Epidural catheterization is associated with a significant bacterial colonization rate and occasionally frank infection. During epidural space infection, decreased analgesia despite increased epidural opioid doses has been described. One possible explanation for this observation is that bacterial infection decreases meningeal permeability. The purpose of the study was to determine whether Staphylococcus aureus bacteria, the most common organism causing epidural space infection, or S. aureus toxins alter meningeal permeability. METHODS: Spinal meninges of M. nemestrina monkeys were mounted in a previously established in vitro diffusion cell model and exposed to S. aureus toxins A, B, and F. Simultaneous transmeningeal fluxes of mannitol and sufentanil were measured before and after toxin exposure and compared to controls. In a second series of experiments, diffusion cells were inoculated with live S. aureus bacteria in suspension and the permeability of sufentanil was investigated. RESULTS: Staphylococcus aureus toxin-A increased the transmeningeal flux of mannitol but not sufentanil. Toxins B and F did not alter the meningeal permeability of either drug. Inoculation with live S. aureus bacteria increased the transmeningeal flux of sufentanil by 115+/-21% (P = .032). CONCLUSIONS: These data demonstrate that S. aureus alpha-toxin and live S. aureus bacteria can increase meningeal permeability. Thus, clinical observations of decreased epidural analgesia in the face of bacterial infection cannot be explained by decreased meningeal permeability.

Cerebral blood flow determinations using fluorescent microspheres: variations on the sedimentation method validated.

We validate a modification of the sedimentation method for measuring fluorescent microspheres (FM) that improves the determination of regional cerebral blood flow (rCBF). Our FM method for rCBF determination is compared to the radioactive microspheres (RM) method for rCBF measurement by simultaneous injection of one radioactive and two fluorescent labeled doses, at two separate time points, into the left ventricle of a pig. The pig was killed, the brain and spinal cord removed, and divided into 92 pieces averaging 0.83 g. Our modifications to FM analysis by sedimentation includes: 2 instead of 1 week of autolysis, pellet washing with 1% Triton X-100 instead of 0.25% Tween 80, phosphate buffer addition during rinse, fluorescent dye extraction using 2-ethoxyethylacetate instead of 2-(2-ethoxyethoxy)ethyl acetate and polypropylene instead of glass tubes. Comparing rCBF using Sc46 RM, to yellow-green and orange FM, yielded mean differences of 0.026 and 0.021 ml/min per piece, respectively. Sn(113) RM compared to blue-green and scarlet FM gave mean differences of -0.010 and 0.137 ml/min per piece, respectively. All RM-FM differences, except those for scarlet FM, are within acceptable limits. This assay provides a reliable method for determining rCBF.

Acetylcholinesterase and butyrylcholinesterase are expressed in the spinal meninges of monkeys and pigs.

BACKGROUND: Acetylcholinesterase inhibition at the spinal level has been shown to produce a potent antinociceptive effect. However, the site of cholinesterase inhibition is unknown. To determine whether the spinal meninges participate in acetylcholine metabolism, the spinal meninges of monkeys and pigs were assayed for cholinesterase activity. METHODS: Spinal cord, dura mater, and arachnoid mater specimens from anesthetized pigs and monkeys were mechanically homogenized and cholinesterase activity was determined quantitatively using a commercially available colorimetric assay. The ability of neostigmine to inhibit cholinesterase activity in vitro was also measured. Finally, the reverse transcriptase polymerase chain reaction (RT-PCR) was used to identify the cholinesterase metabolizing enzymes expressed by the spinal meninges. RESULTS: All spinal cord and meningeal specimens showed cholinesterase activity. In pigs, the dura mater showed less enzyme activity (36 +/- 17.7 U/mg protein) than the arachnoid mater (73.4 +/- 30.3 U/mg protein; P < 0.05), and the arachnoid mater showed less activity than the spinal cord (131.3 +/- 55.2 U/mg protein; P < 0.05). In monkeys, the dura mater again showed less cholinesterase activity (45.8 +/- 20.1 U/mg protein; P < 0.05), whereas cholinesterase activity in the arachnoid mater (90.3 +/- 45.9 U/mg protein) and spinal cord specimens (101.9 +/- 37.5 U/mg protein) were not significantly different. There were no significant species-related differences in cholinesterase activity. Neostigmine inhibited cholinesterase activity in a log-dose-dependent manner. The RT-PCR identified mRNA for acetylcholinesterase and butyrylcholinesterase in monkey pia-arachnoid mater. CONCLUSIONS: These data show that the spinal meninges express acetylcholinesterase and butyrylcholinesterase; for monkeys, although not pigs, the level of cholinesterase activity is comparable with that found in the spinal cord. This finding suggests that the meninges may be an important site for acetylcholine metabolism and may play a role in the analgesic effect produced by intrathecally administered cholinesterase inhibitors.

Effect of chronic cocaine exposure on the hemodynamic response to vasopressors in sheep.

BACKGROUND: The purpose of this study was to determine how chronic cocaine exposure affects the hemodynamic response to epinephrine, dopamine, phenylephrine, and ephedrine in awake sheep. METHODS: The hemodynamic response to dopamine (10 microg/kg), phenylephrine (1.5 microg/kg), and ephedrine (0.15 mg/kg) boluses was determined at baseline before low-dosage cocaine exposure and again after 15 and 18 days of cocaine exposure. The hemodynamic response to epinephrine (0.15 microg/kg), phenylephrine (1.5 microg/kg), and ephedrine (0.15 mg/kg) was determined at baseline before high-dosage cocaine exposure and again after 15 and 18 days of cocaine exposure. RESULTS: Chronic cocaine exposure abolished the mean arterial pressure and heart rate responses to dopamine but did not alter the responses to epinephrine, phenylephrine, or ephedrine. CONCLUSION: In awake sheep, chronic cocaine exposure markedly impairs the hemodynamic response to dopamine but not to epinephrine, phenylephrine, or ephedrine.

Acylcarnitine chain length influences carnitine-enhanced drug flux through the spinal meninges in vitro.

BACKGROUND: Palmitoyl carnitine has been shown to improve the penetration of hydrophilic drugs through the spinal meninges. Naturally occurring acylcarnitines, however, exist as a homologous series of different acyl chain lengths. The purpose of this study was to determine the most effective acylcarnitine chain length to increase meningeal permeability. METHODS: The transmeningeal flux of mannitol, morphine, and sufentanil through monkey spinal meninges was determined before and after adding acylcarnitines with chain lengths of 6 to 18 carbon atoms. Flux was measured using a previously established in vitro diffusion cell model. RESULTS: For mannitol, acylcarnitines generally showed a greater penetration-enhancing effect with increasing chain length, with palmitoyl carnitine (16 carbons) being the most effective compound with an increase of 244 +/- 29% (means +/- SE). Morphine flux was increased most significantly by lauroyl-(12 carbons) and myristoyl-carnitine (14 carbons) with 165 +/- 25% and 188 +/- 44% flux increases, respectively. In contrast, none of the studied acylcarnitines significantly altered the meningeal penetration of the more hydrophobic drug sufentanil. CONCLUSIONS: The results suggest that, to promote hydrophilic drug penetration, acylcarnitines must surpass a critical chain length (10 carbon units) but should not exceed 16 carbon units. The activity of the acylcarnitines at the spinal meninges is reduced on either side of this range. The ability of acylcarnitines to increase the transmeningeal flux of morphine in vitro suggests that lauroyl or myristoyl carnitine may increase the spinal bioavailability of morphine after epidural administration.

Chronic cocaine administration does not modify haemodynamic responses to isoflurane anaesthesia in sheep.

PURPOSE: Cocaine use is epidemic in the developed world, resulting in numerous patients presenting for surgery and anaesthesia with a history of chronic cocaine exposure. The purpose of this study was to determine the effect of chronic cocaine exposure on the cardiovascular response to isoflurane general anaesthesia. METHODS: The changes in mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance (SVR) with increasing concentration of isoflurane (1%, 1.7%, and 2.4% end tidal) were determined at baseline in six sheep. The animals then received a continuous cocaine infusion (0.2 mg.kg-1.hr-1) and twice daily cocaine boluses (4 mg.kg-1) for 17 days followed on day 18 by a cocaine binge consisting of eight cocaine boluses (4 mg.kg-1) administered at one hour intervals. The haemodynamic studies conducted at baseline prior to cocaine exposure were then repeated on days 15 and 18. RESULTS: Increasing concentrations of isoflurane produced the expected dose-dependent cardiovascular depression, but this was not altered by cocaine exposure. CONCLUSION: Although chronic cocaine exposure has been shown to increase isoflurane minimum alveolar concentration by 25% in sheep; chronic cocaine exposure does not result in tolerance of the cardiovascular depression produced by isoflurane.

Ascorbic acid inhibits spinal meningeal catechol-o-methyl transferase in vitro, markedly increasing epinephrine bioavailability.

BACKGROUND: The spinal menings have previously been shown to contain catechol-o-methyl transferase (COMT), the enzyme that metabolizes epinephrine to the inactive metabolite metanephrine. The authors of this study aimed to quantitate the metabolism of epinephrine traversing the spinal meninges and to determine if that metabolism could be inhibited. In addition, they tried to determine the meningeal permeability of epinephrine. METHODS: Macca nemestrina spinal meninges were mounted in a diffusion cell and epinephrine was added to the donor reservoir at time 0. Three hundred minutes later, all buffer in the recipient reservoir was collected and analyzed for epinephrine metabolites. The experiments were conducted with either ascorbic acid (1 mM) or sodium metabisulfite (5.3 mM) added as antioxidants. RESULTS: In the presence of sodium metabisulfite, 60 +/- 6% of the epinephrine traversing the meningeal specimens was metabolized by COMT. In contrast, in the presence of ascorbic acid, less than 3% of the epinephrine traversing the spinal meninges was metabolized by COMT (P = 0.0001). The meningeal permeability coefficient for epinephrine was 0.38 +/- 0.08 cm/min x 10(-3). CONCLUSIONS: Epinephrine permeability through the spinal meninges is low, and meningeal COMT markedly reduces the bioavailability of what little epinephrine can traverse the meninges. However, a clinically relevant concentration of ascorbic acid, a competitive inhibitor of COMT, almost completely blocks epinephrine metabolism and increases the bioavailability of epinephrine.

Intravenous lidocaine decreases but cocaine does not alter the rate of cerebrospinal fluid formation in anesthetized rabbits.

Considering that adrenergic stimulation was reported to decrease the rate of cerebrospinal fluid (CSF) formation (Vf), it was hypothesized that cocaine might exert a similar effect. Accordingly, the present study was designed to examine the effects of low, moderate, and high doses of cocaine on Vf and resistance to reabsorption of CSF (Ra). Because cocaine possesses both adrenergic-stimulating and local anesthetic properties, the present study examined the effects of lidocaine, a local anesthetic without adrenergic-stimulating properties, as a comparison treatment to cocaine. New Zealand white rabbits (n = 17) weighing 3.5-4.3 kg were anesthetized with halothane. A needle was inserted into the left lateral cerebral ventricle and a catheter was inserted into the cisterna magna to permit ventriculocisternal perfusion with mock CSF labeled with blue dextran. A1 each of four experimental conditions, control and three doses of cocaine or lidocaine, fluid volumes and concentrations of blue dextran in timed samples of cisternal outflow were used to determine Vf and the rate of reabsorption of CSF (Va). In turn, Va at normal and elevated CSF pressures (+6 cmH2O) were used to determine Ra. For both the cocaine group (n = 9) and the lidocaine group (n = 8) the three drug doses were 0.5 mg.kg-1 followed by 1.0 microgram.kg-1.min-1, 1.5 mg.kg-1 followed by 3.0 micrograms.kg-1.min-1, and 4.5 mg.kg-1 followed by 9.0 micrograms.kg-1.min-1 i.v. Cocaine caused no significant change of Vf or Ra. In the lidocaine group there was a dose/time-related decrease of Vf (although the slope relating Vf to dose/time was not significantly different from that in the cocaine group), but no significant change of Ra. It is concluded that during halothane anesthesia cocaine does not decrease Vf, a finding not consistent with previous reports that adrenergic stimulation decreases Vf. Decrease of Vf with lidocaine is consistent with previous reports of similar dose-related effects of thiopental, etomidate, midazolam, and fentanyl on Vf.