Propofol Fails to Attenuate the Cardiovascular Response to Rapid Increases in Desflurane Concentration

Background: A rapid increase in desflurane concentration to greater than 1 MAC transiently increases heart rate, arterial blood pressure, and circulating catecholamine concentration. Because propofol decreases sympathetic outflow, it was hypothesized that propofol would blunt these responses.

Methods: To test this hypothesis, five healthy male volunteers were studied three times. After induction of anesthesia with 2 mg *symbol* kg sup -1 propofol, anesthesia was maintained with 4% end-tidal desflurane in oxygen (0.55 MAC) via an endotracheal tube for 32 min. On separate occasions, in random order, either no propofol or 2 mg *symbol* kg sup -1 propofol was administered either 2 or 5 min before increasing end-tidal desflurane concentration from 4% to 8%.

Results: Without propofol pretreatment, the increase to 8% desflurane transiently increased heart rate (from 63+/-3 beats/min to 108 +/-5 beats/min, mean+/-SEM; P < 0.01), mean arterial pressure (from 73+/-1 mmHg to 118+/-6 mmHg; P < 0.01), and epinephrine concentration (from 14+/-1 pg *symbol* ml sup -1 to 279+/-51 pg *symbol* ml sup -1; P < 0.05). There was no significant change in norepinephrine concentration (from 198+/-37 pg *symbol* ml sup -1 to 277+/-46 pg *symbol* ml sup -1). The peak plasma epinephrine concentration was attenuated by each propofol pretreatment (158+/-35 pg *symbol* ml sup -1, propofol given 2 min before, and 146 + 41 pg *symbol* ml sup -1, propofol given 5 min before; P < 0.05), but neither propofol pretreatment modified the cardiovascular or norepinephrine responses.     

Oral Clonidine Premedication Blunts the Heart Rate Response to Intravenous Atropine in Awake Children

Background: Clonidine, which is known to have analgesic and sedative properties, has recently been shown to be an effective preanesthetic medication in children. The drug may cause side effects, including bradycardia and hypotension. This study was conducted to evaluate the ability of intravenous atropine to increase the heart rate (HR) in awake children receiving clonidine preanesthetic medication.

Methods: We studied 96 otherwise healthy children, 8-13 yr old, undergoing minor surgery. They received, at random, oral clonidine 2 or 4 micro gram *symbol* kg sup -1 or placebo 105 min before scheduled induction of anesthesia. Part I (n = 48, 16 per group): When hemodynamic parameters after insertion of a venous catheter had been confirmed to be stable, atropine was administered in incremental doses of 2.5, 2.5, and 5 micro gram *symbol* kg sup -1 every 2 min. The HR and blond pressure were recorded at 1-min intervals. Part II (n = 48, 16 per group): After the recording of baseline hemodynamic values, successive doses of atropine (5 micro gram *symbol* kg sup -1 every 2 min, to 40 micro gram *symbol* kg sup -1), were administered until HR increased by 20 beats *symbol* min sup -1. The HR and blood pressure were recorded at 1-min intervals.

Results: Part I: The increases in HR in response to a cumulative dose of atropine 10 micro gram *symbol* kg sup -1 were 33 plus/minus 3%, 16 plus/minus 3%, and 8 plus/minus 2% (mean plus/minus SEM) in children receiving placebo, clonidine 2 micro gram *symbol* kg sup -1, and clonidine 4 micro gram *symbol* kg sup -1, respectively (P < 0.05). Part II: The HR in the control group increased by more than 20 beats *symbol* min sup -1 in response to atropine 20 micro gram *symbol* kg sup -1 or less. In two patients in the clonidine 4 micro gram *symbol* kg sup -1 group, HR did not increase by 20 beats *symbol* min sup -1 even after 40 micro gram *symbol* kg sup -1 of atropine.     

Ventilatory Response to Hypoxia in Humans: Influences of Subanesthetic Desflurane

Background: At low dose, the halogenated anesthetic agents halothane, isoflurane, and enflurane depress the ventilatory response to isocapnic hypoxia in humans. In the current study, the influence of subanesthetic desflurane (0.1 minimum alveolar concentration [MAC]) on the isocapnic hypoxic ventilatory response was assessed in healthy volunteers during normocapnia and hypercapnia.

Methods: A single hypoxic ventilatory response was obtained at each of 4 target end-tidal partial pressure of oxygen concentrations: 75, 53, 44, and 38 mmHg, before and during 0.1 MAC desflurane administration. Fourteen subjects were tested at a normal end-tidal partial pressure of carbon dioxide (43 mmHg), with 9 subjects tested at an end-tidal carbon dioxide concentration of 49 mmHg (hypercapnia). The hypoxic sensitivity (S) was computed as the slope of the linear regression of inspired minute ventilation (VI) on (100 - SP O2). Values are mean +/-SE.

Results: Sensitivity was unaffected by desflurane during normocapnia (control: S = 0.45+/-0.071 *symbol* min *symbol* sup -1 *symbol* % sup -1 vs. 0.1 MAC desflurane: S = 0.43+/-0.09 1 *symbol* min sup -1 *symbol* % sup -1). With hypercapnia S decreased by 30% during desflurane inhalation (control: S = 0.74+/-0.091 *symbol* min sup -1 *symbol* %1 vs. 0.1 MAC desflurane: S = 0.53+/-0.06 1 *symbol* min sup -1 *symbol* % sup -1; P < 0.05).     

Effect of Vasoconstrictive Agents Added to Lidocaine on Intravenous Lidocaine-induced Convulsions in Rats

Background: Epinephrine is reported to decrease the threshold of intravenous lidocaine-induced convulsions. However, the mechanism underlying this effect is not clear. Therefore, we carried out a study to examine the role of vasopressor-induced hypertension.

Methods: Fifty-six awake Wistar rats were assigned to seven groups of eight. All groups received a continuous intravenous infusion of lidocaine at a rate of 4 mg *symbol* kg sup -1 *symbol* min sup -1 until generalized convulsions occurred. The control group (group C) received plain lidocaine. The acute hypertensive groups received lidocaine with epinephrine (group E), norepinephrine (group N), or phenylephrine (group P) to increase mean arterial blood pressure (MAP) to 150 plus/minus 5 mm Hg. Sodium nitroprusside (SNP) was added to prevent an increase in mean arterial pressure in the remaining three groups (vasopressor-SNP groups).

Results: The acute hypertensive groups required significantly smaller cumulative doses of lidocaine to produce convulsions compared with control (C - 41.5 plus/minus 2.9 > E - 24.1 plus/minus 2.7, N = 27.1 plus/minus 2.8, P = 26.7 plus/minus 2.5 mg *symbol* kg sup -1; values are mean plus/minus SD, P < 0.01) In addition, plasma lidocaine concentrations (C = 11.0 plus/minus 0.7 > E = 7.4 plus/minus 0.5, N = 7.9 plus/minus 0.6, P = 8.1 plus/minus 0.8 micro gram *symbol* ml sup -1, P < 0.01) and brain lidocaine concentrations (C = 50.9 plus/minus 4.5 > E = 32.6 plus/minus 4.2, N - 34.5 plus/minus 4.8, P - 37.1 plus/minus 4.5 micro gram *symbol* g sup -1, P < 0.01) were less in the acute hypertensive groups at the onset of convulsions. In the vasopressor-SNP groups, the plasma and brain lidocaine concentrations at the onset of convulsions returned to the control values, although epinephrine and norepinephrine, but not phenylephrine, still decreased cumulative convulsant doses of lidocaine significantly (P < 0.01) compared with control (E + SNP = 30.8 plus/minus 2.9 < N + SNP = 34.8 plus/minus 2.8, P < 0.01) < P + SNP = 40.2 plus/minus 3.0 mg *symbol* kg sup -1, P < 0.01). The brain/plasma concentration ratios were similar for the seven groups.     

Anesthetic Potency of Remifentanil in Dogs

Background: Remifentanil is an opioid that is rapidly inactivated by esterases in blood and tissues. This study examined the anesthetic potency and efficacy of remifentanil in terms of its reduction of enflurane minimum alveolar concentration (MAC) in dogs.

Methods: Twenty-five dogs were anesthetized with enflurane. One group received incremental infusion rates of remifentanil from 0.055 to 5.5 micro gram *symbol* kg sup -1 *symbol* min sup -1. A second group received constant rate infusions of remifentanil of 1.0 micro gram *symbol* kg sup -1 *symbol* min sup -1 for 6-8 h. Enflurane MAC was measured before, hourly during remifentanil infusion, and at the end of the experiment after naloxone administration. A third group received alternating infusions of 0.5 and 1.0 micro gram *symbol* kg sup -1 *symbol* min sup -1 with MAC determinations made 30 min after each change in the infusion rate. Heart rate, mean arterial pressure, and remifentanil blood concentrations were measured during MAC determinations.

Results: Enflurane MAC was reduced up to a maximum of 63.0+/- 10.4% (mean+/-SD) in a dose-dependent manner by remifentanil infusion. The dose producing a 50% reduction in the enflurane MAC was calculated as 0.72 micro gram *symbol* kg sup -1 *symbol* min sup -1 and the corresponding blood concentration was calculated as 9.2 ng/ml. Enflurane MAC reduction remained stable during continuous, constant rate infusions for periods of 6-8 h without any signs of tolerance. Recovery of enflurane MAC to baseline occurred in 30 min (earliest measurement) after stopping the remifentanil infusion.     

Derivation and Cross-validation of Pharmacokinetic Parameters for Computer-controlled Infusion of Lidocaine in Pain Therapy

Background: Lidocaine administered intravenously is efficacious in treating neuropathic pain at doses that do not cause sedation or other side effects. Using a computer-controlled infusion pump (CCIP), it is possible to maintain the plasma lidocaine concentration to allow drug equilibration between the plasma and the site of drug effect. Pharmacokinetic parameters were derived for CCIP administration of lidocaine in patients with chronic pain.

Methods: Thirteen patients (mean age 45 yr, mean weight 66 kg) were studied. Eight subjects received a computer-controlled infusion, targeting four increasing lidocaine concentrations (1-7 micro gram *symbol* ml sup -1) for 30 min each, based on published kinetic parameters in which venous samples were obtained infrequently after bolus administration. From the observations in these eight patients, new lidocaine pharmacokinetic parameters were estimated. These were prospectively tested in five additional patients. From the complete data set (13 patients), final structural parameters were estimated using a pooled analysis approach. The interindividual variability was determined with a mixed-effects model, with the structural model parameters fixed at the values obtained from the pooled analysis. Internal cross-validation was used to estimate the residual error in the final pharmacokinetic model.

Results: The lidocaine administration based on the published parameters consistently produced higher concentrations than desired, resulting in acute lidocaine toxicity in most of the first eight patients. The highest measured plasma concentration was 15.3 micro gram *symbol* ml sup -1. The pharmacokinetic parameters estimated from these eight patients differed from the initial estimates and included a central volume one-sixth of the initial estimate. In the subsequent prospective test in five subjects, the new parameters resulted in concentrations evenly distributed around the target concentration. None of the second group of subjects had evidence of acute lidocaine toxicity. The final parameters (+/-population variability expressed as %CV) were estimated as follows: V1 0.101+/-53% 1 *symbol* kg sup -1, V2 0.452 +/-33% l *symbol* kg sup -1, Cl1 0.0215+/-25% l *symbol* kg sup -1 *symbol* min sup -1, and Cl2 0.0589+/-35% l *symbol* kg sup -1 *symbol* min sup -1. The median error measured by internal cross-validation was +1.9%, and the median absolute error was 14%.     

Effects of Oral Clonidine Premedication on Plasma Glucose and Lipid Homeostasis Associated with Exogenous Glucose Infusion in Children

Background: Oral clonidine may influence plasma glucose and lipid homeostasis by modulating endocrinologic responses to surgical stress. The effect of oral clonidine premedication on plasma glucose and lipid homeostasis associated with exogenous glucose infusion were investigated in children undergoing minor surgery.

Methods: Otherwise healthy children (n, 120; aged 3-13 yr) were assigned randomly to six groups according to the glucose concentration of the intravenous solution (0%, 2%, or 5%, at a rate of 6 ml [center dot] kg sup -1 [center dot] h sup -1) and the preoperative medications (4 micro gram/kg clonidine or placebo given 100 min before anesthesia) they were to receive. The plasma concentrations of glucose, nonesterified fatty acid, ketone bodies, epinephrine, norepinephrine, and cortisol were determined.

Results: Infusion of 5% glucose caused hyperglycemia (mean glucose concentration > 200 mg/dl) in six children receiving placebo and two receiving clonidine. Although the mean plasma glucose concentration increased in three placebo groups, it was unchanged and the plasma concentrations of total ketone bodies and nonesterified fatty acid were increased in children receiving clonidine and glucose-free solution. The plasma epinephrine, norepinephrine, and cortisol levels in children receiving placebo increased in response to surgery. Clonidine attenuated the increase in catecholamines and cortisol.     

Sympatholytic and Minimum Anesthetic Concentration-sparing Responses are Preserved in Rats Rendered Tolerant to the Hypnotic and Analgesic Action of Dexmedetomidine, a Selective alpha sub 2 -adrenergic Agonist

Background: The development of tolerance to the sympatholytic and anesthetic-reducing effects of alpha2 agonists after prolonged administration of dexmedetomidine and how the number of available alpha sub 2 adrenoceptors affects these dexmedetomidine-induced responses was studied.

Methods: The sympatholytic action of acute and chronic (3 and 10 micro gram *symbol* kg sup -1 *symbol* h sup -1 for 7 days) dexmedetomidine, was assessed by the decrease in norepinephrine turnover in the locus coeruleus and hippocampus. The anesthetic-reducing effect of chronic (7 days) dexmedetomidine (5 and 10 micro gram *symbol* kg sup -1 *symbol* h sup -1) was studied by determining the minimum alveolar concentration (MAC) for halothane that prevented rats from responding to a supramaximal noxious stimulus of dexmedetomidine (10 or 30 micro gram *symbol* kg sup -1), doses in the steep part of the dose-response curve.

The receptor reserve for the norepinephrine turnover and anesthetic-sparing responses to dexmedetomidine was delineated with 0.3-1.0 mg *symbol* kg sup -1 N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible alkylating agent.

Results: After chronic administration of dexmedetomidine at both doses, acute dexmedetomidine significantly decreased norepinephrine turnover in the hippocampus and locus coeruleus. The baseline minimum anesthetic concentration (MAC) and the MAC-sparing effect to acutely administered dexmedetomidine were preserved after chronic dexmedetomidine treatment. In the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline experiments, the dexmedetomidine-induced norepinephrine turnover effect required less than 20% and greater than 4% alpha2 adrenoceptor availability in the locus coeruleus and the dexmedetomidine induced MAC-sparing effect required less than 40% and greater than 20% alpha2 adrenoceptor availability in the locus coeruleus.     

Repeated Doses of Rocuronium Bromide Administered to Cirrhotic and Control Patients Receiving Isoflurane: A Clinical and Pharmacokinetic Study

Background: Steroid muscle relaxants often display pharmacodynamic changes in patients with cirrhosis because of alterations in elimination processes. Rocuronium is a new steroid muscle relaxant possibly eliminated through the liver. This study was designed to compare rocuronium pharmacodynamics and pharmacokinetics in cirrhotic and healthy patients.

Methods: Rocuronium was administered to 26 cirrhotic patients and 24 control subjects anesthetized with isoflurane for an elective procedure. Patients were randomly allocated to receive an initial dose of rocuronium: 120, 180, 250, or 300 micro gram *symbol* kg sup -1. Dose-response curves were established, and ED50 was calculated. Preselected maintenance doses (75, 150, or 225 micro gram *symbol* kg sup -1) were administered at 25% recovery of twitch height to compare clinical duration of action. At the end of the procedure, relaxation was reversed in half of the patients, and the time course of recovery was compared in the two groups. Blood samples drawn during the procedure and after the last maintenance dose allowed pharmacokinetic analysis in six cirrhotic patients and six control subjects.

Results: ED50 of the initial dose was 144 micro gram *symbol* kg sup -1 in cirrhotic patients and 60 micro gram *symbol* kg sup -1 in control subjects, related to a higher initial volume of distribution (cirrhotic 78.5+/-31.7 ml *symbol* kg sup -1, control 29.8 +/-17.3 ml *symbol* kg sup -1). Time from complementary dose to 25% recovery was longer in cirrhotic patients (41.0+/-20.7 min vs. 30.2+/-9.7 min), but time course of action during maintenance was not statistically different in the two groups. In cirrhotic patients receiving five maintenance doses or more, prolongation of the duration of action with successive maintenance doses could be statistically demonstrated. Spontaneous recovery was delayed in cirrhotic patients, because of impaired elimination processes: greater volume of distribution at steady-state (264+/-92 vs. 151+/-59 ml *symbol* kg sup -1); trend toward a lower clearance (189+/-60 vs. 296 +/-169 ml *symbol* min sup -1).     

Urine and Plasma Catecholamine and Cortisol Concentrations after Myocardial Revascularization: Modulation by Continuous Sedation

Background: Cardiopulmonary bypass is associated with substantial release of catecholamines and cortisol for 12 or more h. A technique was assessed that may mitigate the responses with continuous 12-h postoperative sedation using propofol.

Methods: One hundred twenty-one patients having primary elective cardiopulmonary bypass graft (CABG) surgery were enrolled in a double-blind, randomized trial and anesthetized using a standardized sufentanil-midazolam regimen. When arriving at the intensive care unit (ICU), patients were randomly assigned to either group SC (standard care), in which intermittent bolus administration of midazolam and morphine were given as required to keep patients comfortable; or group CP (continuous propofol), in which 12 h of continuous postoperative infusion of propofol was titrated to keep patients deeply sedated. Serial perioperative measurements of plasma and urine cortisol, epinephrine, norepinephrine, and dopamine were obtained; heart rate and blood pressure were recorded continuously, and medication use, including requirements for opioids and vasoactive drugs, was recorded. Repeated-measures analysis was used to assess differences between study groups for plasma catecholamine and cortisol levels at each measurement time.

Results: In the control state-before the initiation of postoperative sedation in the ICU-no significant differences between study groups were observed for urine or plasma catecholamine or cortisol concentrations. During the ICU study period, for the first 6-8 h, significant differences were found between study groups SC and CP in plasma cortisol (SC = 28 +/- 15 mg/dl; CP = 19 +/- 12 mg/dl; estimated mean difference [EMD] = 9 mg/dl; P = 0.0004), plasma epinephrine (SC = 132 +/- 120 micro gram/ml; CP = 77 +/- 122 micro gram/ml; EMD = 69 micro gram/ml; P = 0.009), urine cortisol (SC = 216 +/- 313 micro gram/ml; CP = 93 +/- 129 micro gram/ml; EMD = 127 micro gram/ml; P = 0.007), urine dopamine (SC = 85 +/- 48 micro gram; CP = 52 +/- 43 micro gram; EMD = 32 micro gram; P = 0.002), urine epinephrine (SC = 7 +/- 8 micro gram; CP = 4 +/- 5 micro gram; EMD = 3 micro gram; P = 0.009), and urine norepinephrine (SC = 24 +/- 14 mg; CP = 13 +/- 9 mg; EMD = 11 mg; P = 0.0004). Reductions in urine and plasma catecholamine and cortisol concentrations found for the CP group generally persisted during the 12-h propofol infusion period and then rapidly returned toward control (SC group) values after propofol was discontinued. Postoperative opioid use was reduced in the CP group (SC = 97%; CP = 49%; P = 0.001), as was the incidence of (SC = 79%; CP = 60%; P = 0.04) and hypertension (SC = 58%; CP = 33%; P = 0.01), but the incidence of hypotension was increased (SC = 49%; CP = 81%; P = 0.001).     

Effect of Blood Pressure Changes on Air Flow Dynamics in the Upper Airway of the Decerebrate Cat

Background: Previous studies suggest that upper airway neuromuscular activity can be affected by changes in blood pressure via a baroreceptor-mediated mechanism. It was hypothesized that increases in blood pressure would increase upper airway collapsibility predisposing to airway obstruction at a flow-limiting site in the hypopharynx.

Methods: To examine the effect of blood pressure on upper airway function, maximal inspiratory air flow was determined through the isolated feline upper airway before, during, and after intravenous infusion of phenylephrine (10-20 micro gram *symbol* kg sup -1 *symbol* min) in six decerebrate, tracheotomized cats. Inspiratory flow, hypopharyngeal pressure, and pressure at the site of pharyngeal collapse were recorded as hypopharyngeal pressure was rapidly decreased to achieve inspiratory flow limitation in the isolated upper airway. Pressure-flow relationships were used to determine maximal inspiratory air flow and its mechanical determinants, the upper airway critical pressure (a measure of pharyngeal collapsibility), and the nasal resistance upstream to the site of flow limitation.

Results: An increased mean arterial blood pressure of 71+/- 16 mmHg (mean+/-SD) was associated with significant decrease in maximal inspiratory air flow from 147+/-38 ml/s to 115+/- 27 ml *symbol* sec sup -1 (P < 0.01). The decrease in maximal inspiratory air flow was associated with an increase in upper airway critical pressure from -8.1+/-3.8 to -5.7+/-3.7 cmH2 O (p < 0.02), with no significant change in nasal resistance. When blood pressure was decreased to baseline by discontinuing the phenylephrine infusion, maximal inspiratory air flow and upper airway critical pressure returned to their baseline values.     

Intravenous Lidocaine and Bupivacaine Dose-dependently Attenuate Bronchial Hyperreactivity in Awake Volunteers

Background: In standard textbooks, intravenous lidocaine is recommended for intubation of patients with bronchial hyperreactivity. However, whether and to what extent intravenous local anesthetics attenuate bronchial hyperreactivity in humans is unknown. Accordingly, nine awake volunteers with known bronchial hyperreactivity were subjected to an inhalational challenge with acetylcholine before and during intravenous infusion of lidocaine, bupivacaine, or placebo in a randomized, double-blinded fashion.

Methods: Baseline acetylcholine threshold concentrations were determined 3-5 days before initiation of the investigation. The response to the acetylcholine challenge was defined as hyperreactive, if forced expiratory volume in 1 s decreased by at least 20%. In addition, the acetylcholine threshold for a 100% increase in airway resistance was obtained by body plethysmography. On seven different days, the acetylcholine challenge was repeated at the end of a 30-min intravenous infusion period of three doses of lidocaine (1, 3, and 6 mg *symbol* min sup -1) or bupivacaine (0.25, 0.75, and 1.5 mg *symbol* min sup -1), during saline placebo infusion, respectively. Acetylcholine-threshold concentrations were presented with the respective plasma concentrations of the local anesthetic.

Results: The infusion of lidocaine and bupivacaine resulted in plasma concentrations (means+/-SD) of 0.29+/-0.11, 1.14 +/-0.39, and 2.02+/-0.5 micro gram *symbol* ml sup -1 for lidocaine and 0.11+/-0.04, 0.31+/-0.09, and 0.80 +/-0.18 micro gram *symbol* ml sup -1 for bupivacaine, respectively. Compared to baseline, the acetylcholine threshold for a 20% decrease of forced expiratory volume in 1 s as well as the threshold for a 100% increase in total airway resistance increased significantly with increasing plasma concentrations of both local anesthetics. Compared to placebo, acetylcholine threshold was almost quadrupled for lidocaine and tripled for bupivacaine with the highest plasma concentration of each local anesthetic.     

Sympathetic neural activation evoked by mu-receptor blockade in patients addicted to opioids is abolished by intravenous clonidine

BACKGROUND: Mu-opioid receptor blockade by naloxone administered for acute detoxification in patients addicted to opioids markedly increases catecholamine plasma concentrations, muscle sympathetic activity (MSA), and is associated with cardiovascular stimulation despite general anesthesia. The current authors tested the hypothesis that the alpha2-adrenoceptor agonist clonidine (1) attenuates increased MSA during mu-opioid receptor blockade for detoxification, and (2) prevents cardiovascular activation when given before detoxification. METHODS: Fourteen mono-opioid addicted patients received naloxone during propofol anesthesia. Clonidine (10 microg x kg(-1) administered over 5 min + 5 microg x kg(-1) x h(-1) intravenous) was infused either before (n = 6) or after (n = 6) naloxone administration. Two patients without immediate clonidine administration occurring after naloxone administration served as time controls. Muscle sympathetic activity (n = 8) in the peroneal nerve, catecholamine plasma concentrations (n = 14), arterial blood pressure, and heart rate were assessed in awake patients, during propofol anesthesia before and after mu-opioid receptor blockade, and after clonidine administration. RESULTS: Mu-receptor blockade markedly increased MSA from a low activity (burst frequency: from 2 burst/min +/- 1 to 24 +/- 8, means +/- SD). Similarly, norepinephrine (41 pg/ml +/- 37 to 321 +/- 134) and epinephrine plasma concentration (13 pg/ml +/- 6 to 627 +/- 146) significantly increased, and were associated with, increased arterial blood pressure and heart rate. Clonidine immediately abolished both increased MSA (P < 0.001) and catecholamine plasma concentrations (P < 0.001). When clonidine was given before mu-opioid receptor blockade, catecholamine plasma concentrations and hemodynamic variables did not change. CONCLUSIONS: Administration of the alpha2-adrenoceptor agonist clonidine decreases both increased MSA and catecholamine plasma concentrations observed after mu-opioid receptor blockade for detoxification. Furthermore, clonidine pretreatment prevents the increase in catecholamine plasma concentration that otherwise occurs during mu-opioid receptor blockade.     

The Effect of Clonidine on Cerebral Blood Flow Velocity, Carbon Dioxide Cerebral Vasoreactivity, and Response to Increased Arterial Pressure in Human Volunteers

Background: Because patients may be taking clonidine chronically or may be receiving it as a premedication before surgery, the authors investigated its effect on cerebral hemodynamics.

Methods: In nine volunteers, middle cerebral artery mean blood flow velocity (Vm) was measured using transcranial Doppler ultrasonography (TCD). CO2 vasoreactivity was measured before clonidine administration (preclonidine), 90 min after clonidine, 5 micro gram/kg yorally, then following restoration of mean arterial pressure (MAP) to the preclonidine level. In addition, Vm was measured after a phenylephrine-induced 30-mmHg increase in MAP.

Results: After clonidine administration, Vm decreased from 62 +/- 9 to 48 +/- 8 cm/s (P < 0.01), and MAP decreased from 86 +/- 10 to 63 +/- 5 mmHg (P < 0.01; mean +/- SD). Clonidine decreased the CO2 vasoreactivity slope from 2.2 +/- 0.4 to 1.2 +/- 0.5 cm [center dot] s sup -1 [center dot] mmHg sup -1 (P < 0.05); restoring MAP to the preclonidine level increased the slope to 1.60 +/- 0.5 cm [center dot] s sup -1 [center dot] mmHg [center dot] sup -1, still less than the preclonidine slope (P < 0.05). CO2 vasoreactivity expressed as a percentage change in Vm, decreased after clonidine, 3.5 +/- 0.8 versus 2.4 +/- 0.8%/mmHg (P < 0.05); this difference disappeared after restoration of MAP, 3.1 +/- 1.2%/mmHg. With a 30-mmHg increase in MAP, Vm increased by 13% before and after clonidine (P < 0.05).     

Pharmacokinetics of Rocuronium in Children Aged 4-11 Years

Background: Rocuronium is a new nondepolarizing muscle relaxant with a rapid onset and intermediate duration of action. Although the pharmacokinetics of rocuronium have been determined in adults and the elderly, similar data are lacking in children. Accordingly, rocuronium's pharmacokinetics were determined in children aged 4-11 yr.

Methods: Rocuronium (600 micro gram/kg) was administered to 20 children aged 4-11 yr anesthetized with nitrous oxide and less or equal to 1% halothane, and four plasma samples were obtained over 4 h to determine rocuronium concentrations. The pharmacokinetics of rocuronium were determined using two sparse-sampling population approaches, mixed- effects modeling, and naive pooled data analysis.

Results: With mixed-effects modeling, weight-normalized plasma clearance varied with weight (P < 0.01), being 79.4 ml *symbol* min sup -1 + 3.13 ml *symbol* kg sup -1 *symbol* min sup -1. Neither weight- normalized distributional clearance (2.67 ml *symbol* kg sup -1 *symbol* min sup -1), weight-normalized central compartment volume (106 ml/kg), nor weight-normalized volume of distribution at steady-state (224 ml/kg) varied with weight, height, or age. Similar results were obtained with the naive pooled data approach.     

Circulatory Effects of Hypoxia, Acute Normovolemic Hemodilution, and Their Combination in Anesthetized Pigs

Background: Because hemodilution decreases the oxygen-carrying capacity of blood, it was hypothesized that severe hemodilution would decrease the tolerance to alveolar hypoxia.

Methods: Hemodynamics, oxygen transport, and blood lactate concentrations were compared in ten pigs with normal hematocrit (33 +/-4%), and ten hemodiluted pigs (hematocrit 11+/-1%; mean+/-SD) anesthetized with ketamine-fentanyl-pancuronium during stepwise decreases in inspired oxygen fraction (FIO2; 1.0, 0.35, 0.21, 0.15, 0.10, 0.05).

Results: Median systemic oxygen delivery (DO2 SY) became critical (the DO2 SY value when arterial lactate exceeded 2.0 mmol *symbol* l sup -1) at 10.4 ml *symbol* kg sup -1 min sup -1 (range 6.9-16.1) in hemodiluted animals and at 11.8 ml *symbol* kg sup -1 *symbol* min sup -1 (5.9-32.2) in animals with normal hematocrits (NS). The relationship between mixed venous oxygen saturation and arterial lactate values was less consistent and median critical mixed venous oxygen saturation was higher (P < 0.05) in the hemodiluted group (35%, range 21-64), than in animals with normal hematocrits (21%, 7-68%). In animals with normal hematocrit, decreasing FIO2 from 1.0 to 0.10 resulted in a decrease in DO2 SY from 26.3+/-9.1 to 9.3 +/-3.9 ml *symbol* kg sup -1 *symbol* min sup -1 (P < 0.01). Cardiac output did not change, systemic oxygen extraction ratio increased from 0.23+/-0.08 to 0.68+/-0.13 (P < 0.01), and arterial lactate from 0.9+/-0.2 to 3.4+/-3.0 mmol *symbol* l sup -1 (P < 0.05). Cardiac venous blood flow, as measured by retrograde thermodilution, increased from 5.7+/-2.9 to 12.6+/-5.7 ml *symbol* kg sup -1 *symbol* min sup -1 (P < 0.01). When FIO2 was reduced to 0.05, three animals became hypotensive and died. In the second group, hemodilution increased cardiac output and systemic oxygen extraction ratio (P < 0.01). Cardiac venous blood flow increased from 4.1 +/-1.7 to 9.8+/-5.1 ml *symbol* kg sup -1 *symbol* min sup -1 (P < 0.01), and cardiac venous oxygen saturation from 22+/- 5 to 41+/-10% (P < 0.01). During the subsequent hypoxia, cardiac output and DO2 SY were maintained until FIO2 = 0.15 (DO2 SY = 10.1+/-3.3 ml *symbol* kg sup -1 *symbol* min sup -1). Cardiac venous blood flow was then 18.5+/-10.7 ml *symbol* kg sup -1 *symbol* min sup -1 (P < 0.01), but in spite of this, myocardial lactate production occurred. At FIO2 = 0.10 (DO2 SY = 7.7 +/-3.0 ml *symbol* kg sup -1 *symbol* min sup -1), arterial lactate concentration increased to 8.5+/-2.3 mmol *symbol* l sup -1 (P < 0.01), and most animals became hypotensive. All hemodiluted animals died when FIO2 was decreased to 0.05 (P < 0.01 when compared to animals with normal hematocrit).     

Low dose clonidine premedication accentuates the hyperglycemic response to surgery

PURPOSE: To investigate the influence of low dose clonidine premedication on perioperative glucose homeostasis. METHODS: Sixteen patients undergoing abdominal hysterectomy for benign uterine myoma were randomly assigned to receive either iv clonidine (1 microg x kg(-1)) 30 min before induction of general anesthesia (clonidine, n=8) or saline (control, n=8). Plasma concentrations of glucose, insulin, cortisol, epinephrine and norepinephrine were measured before, during and two hours after surgery. At the same time heart rate, mean arterial pressure and cardiac output were recorded. RESULTS: In both groups, glucose concentrations significantly increased during and after surgery. Intraoperative glucose plasma concentration in the clonidine group was higher than in the control group (clonidine: 6.8 +/- 0.6 mmol x L(-1) vs control: 5.7 +/- 0.8 mmol x L(-1), P < 0.05). This was accompanied by a lower insulin plasma concentration (clonidine: 3.9 +/- 1.9 microU x mL(-1) vs control: 6.5 +/- 2.8 microU x mL(-1), P <0.05). Heart rate, mean arterial pressure and cardiac output remained unchanged throughout the study period without any differences between the groups. While norepinephrine plasma concentrations increased in the control group only (P <0.05), the plasma concentrations of epinephrine and cortisol increased in both groups (P <0.05). Clonidine significantly attenuated the cortisol response as reflected by lower intra- and postoperative cortisol plasma concentrations than in the control group (P <0.05). CONCLUSION: Premedication with clonidine 1 microg x kg(-1) accentuates the hyperglycemic response to lower abdominal surgery caused by the decrease in insulin plasma concentrations.     

Pharmacokinetics of Propofol after a Single Dose in Children Aged 1-3 Years with Minor Burns: Comparison of Three Data Analysis Approaches

Background: No complete pharmacokinetic profile of propofol is yet available in children younger than 3 yr, whereas clinical studies have demonstrated that both induction and maintenance doses of propofol are increased with respect to body weight in this age group compared to older children and adults. This study was therefore undertaken to determine the pharmacokinetics of propofol after administration of a single dose in aged children 1-3 yr requiring anesthesia for dressing change.

Methods: This study was performed in 12 children admitted to the burn unit and in whom burn surface area was less than or equal to 12% of total body surface area. Exclusion criteria were: unstable hemodynamic condition, inappropriate fluid loading, associated pulmonary injury, or burn injury older than 2 days. Propofol (4 mg *symbol* kg sup -1) plus fentanyl (2.5 micro gram *symbol* kg sup -1) was administered while the children were bathed and the burn area cleaned during which the children breathed spontaneously a mixture of oxygen and nitrous oxide (50:50). Venous blood samples of 300 micro liter were obtained at 5, 15, 30, 60, 90, and 120 min, and 3, 4, 8, and 12 h after injection; an earlier sample was obtained from 8 of 12 children. The blood concentration curves obtained for individual children were analyzed by three different methods: noncompartmental analysis, mixed-effects population model, and standard two-stage analysis.

Results: Using noncompartmental analysis, total clearance of propofol (+/-SD) was 0.053+/-0.013 l *symbol* kg sup -1 *symbol* min sup -1, volume of distribution at steady state 9.5+/-3.7 l *symbol* kg sup -1, and mean residence time 188+/-85 min. Propofol pharmacokinetics were best described by a weight-proportional three-compartmental model in both population and two-stage analysis. Estimated and derived pharmacokinetic parameters were similar using these two pharmacokinetic approaches. Results of population versus two-stage analysis are as follow: systemic clearance 0.049 versus 0.048 l *symbol* kg sup -1 *symbol* min sup -1, volume of central compartment 1.03 versus 0.95 l *symbol* kg sup -1, volume of distribution at steady state 8.09 versus 8.17 l *symbol* kg sup -1.     

Cardiovascular and endocrine effects of clonidine premedication in neurosurgical patients

The present study was conducted to examine the haemodynamic and endocrine effects of clonidine, given as sole preanaesthetic medication, in neurosurgical patients. Nineteen patients of ASA physical status I and II, subjected to craniotomy, randomly received po premedication of either clonidine (300 micrograms, n = 9) or placebo (n = 10). Blood pressure and heart rate were monitored continuously, while arterial blood samples were collected at specific times, from induction of anaesthesia to recovery, for the measurement of plasma concentrations of epinephrine, norepinephrine, cortisol, aldosterone, and glucose. Clonidine treatment led to a decrease in mean arterial blood pressure (MABP), heart rate (HR), and plasma cortisol and aldosterone concentrations throughout the study, compared with placebo (P less than 0.05). Clonidine, however, did not prevent increases in MABP (16 +/- 5 mmHg, mean +/- SE, P less than 0.05) and HR (18 +/- 4 bpm, P less than 0.05) during induction of anaesthesia, which was comparable to the placebo group. Plasma catecholamine concentrations did not differ between the two groups. Plasma glucose concentrations increased in both groups at the end of the study (P less than 0.05), but were lower in clonidine-treated patients (P less than 0.05). Though statistically significant, the observed inhibitory haemodynamic and endocrine effects of clonidine seem to be of minor clinical importance. As the action of clonidine on cerebral blood flow regulation is not well known, we see no advantage in the preanaesthetic administration of clonidine to neurosurgical patients with normal cardiovascular status.     

Plasma Inorganic Fluoride Concentrations after Sevoflurane Anesthesia in Children

Background: Sevoflurane is degraded in vivo in adults yielding plasma concentrations of inorganic fluoride [Fluorine sup -] that, in some patients, approach or exceed the 50-micro Meter theoretical threshold for nephrotoxicity. To determine whether the plasma concentration of inorganic fluoride [Fluorine sup -] after 1-5 MAC *symbol* h sevoflurane approaches a similar concentration in children, the following study in 120 children scheduled for elective surgery was undertaken.

Methods: Children were randomly assigned to one of three treatment groups before induction of anesthesia: group 1 received sevoflurane in air/oxygen 30% (n = 40), group 2 received sevoflurane in 70% N2 O/30% O2 (n = 40), and group 3 received halothane in 70% N2 O/30% O sub 2 (n = 40). Mapleson D or F circuits with fresh gas flows between 3 and 6 l/min were used. Whole blood was collected at induction and termination of anesthesia and at 1, 4, 6, 12, and 18 or 24 h postoperatively for determination of the [Fluorine sup -]. Plasma urea and creatinine concentrations were determined at induction of anesthesia and 18 or 24 h postoperatively.

Results: The mean (+/-SD) duration of sevoflurane anesthesia, 2.7+/-1.6 MAC *symbol* h (range 1.1-8.9 MAC *symbol* h), was similar to that of halothane, 2.5+/-1.1 MAC *symbol* h. The peak [Fluorine sup -] after sevoflurane was recorded at 1 h after termination of the anesthetic in all but three children (whose peak values were recorded between 4 and 6 h postanesthesia). The mean peak [Fluorine sup -] after sevoflurane was 15.8+/-4.6 micro Meter. The [Fluorine sup -] decreased to < 6.2 micro Meter by 24 h postanesthesia. Both the peak [Fluorine sup -] (r2 = 0.50) and the area under the plasma concentration of inorganic fluoride-time curve (r2 = 0.57) increased in parallel with the MAC *symbol* h of sevoflurane. The peak [Fluorine sup -] after halothane, 2.0+/-1.2 micro Meter, was significantly less than that after sevoflurane (P < 0.0001) and did not correlate with the duration of halothane anesthesia (MAC *symbol* h; r2 = 0.007). Plasma urea concentrations decreased 24 h after surgery compared with preoperative values for both anesthetics (P < 0.01), whereas plasma creatinine concentrations did not change significantly with either anesthetic.