Dexmedetomidine increases the cocaine seizure threshold in rats

BACKGROUND: Central alpha adrenoceptors have been demonstrated to play an important role in the control of seizure activity; moreover, alpha adrenoceptors have been linked to electroencephalogram changes associated with cocaine. The purpose of this study was to determine if dexmedetomidine, a highly selective alpha -adrenoceptor agonist, alters the threshold for cocaine-induced seizure activity in rats. METHODS: Sprague-Dawley rats received a cocaine infusion (1.25 mg x kg(-1) x min(-1)) followed 15 min later by the coinfusion of either dexmedetomidine (20-microg/kg intravenous bolus followed by an infusion of 1 microg x kg(-1) x min(-1), CD group, n = 8) or an equal volume of saline (CS group, n = 8). Dexmedetomidine or saline were coinfused with cocaine until the onset of cocaine-induced seizures. Dopamine concentrations in the nucleus accumbens were measured by microdialysis paired with chromatography. To determine if changes in extracellular dopamine were related to the seizures, dopamine (1 microm) was continuously delivered to the nucleus accumbens in a separate group (DACD group, n = 6) retrograde microdialysis. These rats then received an intravenous cocaine infusion followed by dexmedetomidine in the same manner as the CD group. RESULTS: Dexmedetomidine significantly increased the dose of cocaine necessary to produce seizures. Seizures occurred at 25.0 +/- 7.7 and 49.3 +/- 14.8 min in CS and CD, respectively (P < 0.001). The ratio of the percent increase in accumbal dopamine to the cocaine dose at the onset of seizure activity was significantly lower in CD, 39.9 +/- 16.5, compared to CS, 82.2 +/- 46.5 (P = 0.04). Intraaccumbal administration of dopamine prevented the effects of dexmedetomidine on the cocaine seizure threshold. CONCLUSIONS: These data suggest that dexmedetomidine increases the cocaine-induced seizure threshold possibly a mechanism related to the attenuation of the extracellular dopaminergic neurotransmitter response to cocaine.     

Effects of Different Catecholamines on the Dynamics of Volume Expansion of Crystalloid Infusion

Background: The authors studied the influence of [alpha], [beta], and dopaminergic catecholamines on blood volume expansion in conscious normovolemic sheep before, during, and after a bolus infusion of a crystalloid.

Methods: A 0.9% NaCl bolus (24 ml/kg in 20 min) was infused in four paired experiments each: no drug, dopamine infusion (50 [mu]g [middle dot] kg-1 [middle dot] min-1), isoproterenol infusion (0.1 [mu]g [middle dot] kg-1 [middle dot] min-1), and phenylephrine infusion (3 [mu]g [middle dot] kg-1 [middle dot] min-1). Blood volume expansion was calculated by the dilution of blood hemoglobin concentration.

Results: Dopamine had little effect on peak blood volume expansion (12.7 +/- 0.9 ml/kg) compared with 0.9% NaCl (13.0 +/- 2.7 ml/kg); in contrast, isoproterenol augmented blood volume expansion (18.5 +/- 1.8 ml/kg), and phenylephrine reduced blood volume expansion (8.9 +/- 1.4 ml/kg). Two hours after the 0.9% NaCl bolus, sustained blood volume expansion was greatest in the isoproterenol protocol (12.2 ml/kg), whereas the dopamine protocol (6.8 ml/kg) remained similar to the control protocol (4.1 ml/kg), and the phenylephrine protocol had a net volume loss (-1.9 ml/kg). Some blood volume expansion differences were attributed to changes in renal function as phenylephrine infusion increased urinary output, whereas isoproterenol was associated with antidiuresis. However, dopamine caused diuresis and sustained augmentation of blood volume.     

Pharmacokinetics of Dopamine in Healthy Male Subjects

Background: Dopamine is an agonist of [alpha], [beta], and dopaminergic receptors with varying hemodynamic effects depending on the dose of drug being administered. The purpose of this study was to measure plasma concentrations of dopamine in a homogeneous group of healthy male subjects to develop a pharmacokinetic model for the drug. Our hypothesis was that dopamine concentrations can be predicted from the infusion dose using a population-based pharmacokinetic model.

Methods: Nine healthy male volunteers aged 23 to 45 yr were studied in a clinical research facility within our academic medical center. After placement of venous and arterial catheters, dopamine was infused at 10 [mu]g [middle dot] kg-1 [middle dot] min-1 for 10 min, followed by a 30-min washout period. Subsequently, dopamine was infused at 3 [mu]g [middle dot] kg-1 [middle dot] min-1 for 90 min, followed by another 30-min washout period. Timed arterial blood samples were centrifuged, and the plasma was analyzed by high-performance liquid chromatography. Mixed-effects pharmacokinetic models using NONMEM software (NONMEM Project Group, University of California, San Francisco, CA) were used to determine the optimal compartmental pharmacokinetic model for dopamine.

Results: Plasma concentrations of dopamine varied from 12,300 to 201,500 ng/l after 10 min of dopamine infusion at 10 [mu]g [middle dot] kg-1 [middle dot] min-1. Similarly, steady-state dopamine concentrations varied from 1,880 to 18,300 ng/l in these same subjects receiving 3-[mu]g [middle dot] kg-1 [middle dot] min-1 infusions for 90 min. A two-compartment model adjusted for body weight was the best model based on the Schwartz-Bayesian criterion.     

Remifentanil versus Morphine Analgesia and Sedation for Mechanically Ventilated Critically Ill Patients: A Randomized Double Blind Study

Background: The rapid onset and offset of action of remifentanil could make it quickly adjustable to the required level of sedation in critically ill patients. The authors hypothesized that the efficacy of a remifentanil-based regimen was greater than that of a morphine-based regimen.

Methods: Forty intent-to-treat patients were randomly allocated to receive a blinded infusion of either remifentanil 0.15 [mu]g[middle dot]kg-1[middle dot]min-1 or morphine 0.75 [mu]g[middle dot]kg-1[middle dot]min-1. The opioid infusion was titrated, in the first intent, to achieve optimal sedation defined as Sedation Agitation scale of 4. A midazolam open-label infusion was started if additional sedation was required.

Results: The mean percentage hours of optimal sedation was significantly longer in the remifentanil group (78.3 +/- 6.2) than in the morphine group (66.5 +/- 8.5). This was achieved with less frequent infusion rate adjustments (0.34 +/- 0.25 changes/h) than in the morphine group (0.42 +/- 0.22 changes/h). The mean duration of mechanical ventilation and extubation time were significantly longer in the morphine group (18.1 +/- 3.4 h, 73 +/- 7 min) than in the remifentanil group (14.1 +/- 2.8 h, 17 +/- 6 min), respectively. Remifentanil mean infusion rate was 0.13 +/- 0.03 [mu]g[middle dot]kg-1[middle dot]min-1, whereas morphine mean infusion rate was 0.68 +/- 0.28 [mu]g[middle dot]kg-1[middle dot]min-1. More subjects in the morphine group (9 of 20) than in the remifentanil group (6 of 20) required midazolam. The incidence of adverse events was low and comparable across the two treatment groups.     

Dexmedetomidine Weakens Dynamic Cerebral Autoregulation as Assessed by Transfer Function Analysis and the Thigh Cuff Method

Background: Dexmedetomidine, which is often used in intensive care units in patients with compromised circulation, might induce further severe decreases in cerebral blood flow (CBF) with temporal decreases in arterial pressure induced by various stimuli if dynamic cerebral autoregulation is not improved. Therefore, the authors hypothesized that dexmedetomidine strengthens dynamic cerebral autoregulation.

Methods: Fourteen healthy male subjects received placebo, low-dose dexmedetomidine (loading, 3 [mu]g [middle dot] kg-1 [middle dot] h-1 for 10 min; maintenance, 0.2 [mu]g [middle dot] kg-1 [middle dot] h-1 for 60 min), and high-dose dexmedetomidine (loading, 6 [mu]g [middle dot] kg-1 [middle dot] h-1 for 10 min; maintenance, 0.4 [mu]g [middle dot] kg-1 [middle dot] h-1 for 60 min) infusions in a randomized, double-blind, crossover study. After 70 min of drug administration, dynamic cerebral autoregulation was estimated by transfer function analysis between arterial pressure variability and CBF velocity variability, and the thigh cuff method.

Results: Compared with placebo, steady state CBF velocity and mean blood pressure significantly decreased during administration of dexmedetomidine. Transfer function gain in the very-low-frequency range increased and phase in the low-frequency range decreased significantly, suggesting alterations in dynamic cerebral autoregulation in lower frequency ranges. Moreover, the dynamic rate of regulation and percentage restoration in CBF velocity significantly decreased when a temporal decrease in arterial pressure was induced by thigh cuff release.     

Intravenous Magnesium Sulfate Administration Reduces Propofol Infusion Requirements during Maintenance of Propofol-N2O Anesthesia: Part I: Comparing Propofol Requirements According to Hemodynamic Responses: Part II: Comparing Bispectral Index in Control and Magnesium Groups

Background: The authors investigated whether an intravenous administration of magnesium sulfate reduces propofol infusion requirements during maintenance of propofol-N2O anesthesia.

Methods: Part I study: 54 patients undergoing total abdominal hysterectomy were randomly divided into two groups (n = 27 per group). The patients in the control group received 0.9% sodium chloride solution, whereas the patients in the magnesium group received magnesium (50 mg/kg as a bolus, then 8 mg [middle dot] kg-1 [middle dot] h-1). To maintain mean arterial blood pressure (MAP) and heart rate (HR) at baseline value, the propofol infusion rate was changed when the MAP or the HR changed. The amount of propofol infused excluding the bolus dosage was divided by patient's body weight and total infusion time. Part II study: Another 20 patients were randomly divided into two groups (n = 10 per group). When the MAP and HR had been maintained at baseline value and the propofol infusion rate had been maintained at 80 [mu]g [middle dot] kg-1 [middle dot] min-1 (magnesium group) and 160 [mu]g [middle dot] kg-1 [middle dot] min-1 (control group), bispectral index (BIS) values were measured.

Results: Part I: The mean propofol infusion rate in the magnesium group (81.81 +/- 13.09 [mu]g [middle dot] kg-1 [middle dot] min-1) was significantly less than in the control group (167.57 +/- 47.27). Part II: BIS values in the control group (40.70 +/- 3.89) were significantly less than those in the magnesium group (57.80 +/- 7.32).     

Optimal Adrenergic Support in Septic Shock Due to Peritonitis

Background: The authors evaluated optimal adrenergic support using norepinephrine, dopamine, and dobutamine in a clinically relevant model of septic shock.

Methods: Twenty-eight mature, female, anesthetized sheep (weight, 30.5 +/- 3.6 kg) underwent cecal ligation and perforation and were randomized into four groups of seven animals to be treated with norepinephrine, dopamine-norepinephrine, dobutamine-norepinephrine, or no adrenergic agent. In all groups, lactated Ringer's solution was administered to restore cardiac filling pressures to baseline. In the norepinephrine group, norepinephrine (0.5-5 [mu]g [middle dot] kg-1 [middle dot] min-1) was titrated to maintain mean arterial pressure between 75-85 mmHg. In the dopamine-norepinephrine group, dopamine was given first, and norepinephrine was added only when mean arterial pressure remained below 75 mmHg despite the infusion of 20 [mu]g [middle dot] kg-1 [middle dot] min-1 dopamine. In the dobutamine-norepinephrine group, dobutamine was started at the same time as norepinephrine and titrated up to 20 [mu]g [middle dot] kg-1 [middle dot] min-1 to get a 15% increase in cardiac output.

Results: The dobutamine-norepinephrine group had greater cardiac output; superior mesenteric blood flow, oxygen delivery (Do2), and oxygen consumption ([latin capital V with dot above]o2); and lower blood lactate concentration and partial pressure of carbon dioxide (Pco2) gap than the controls did. Cumulative urine output was significantly higher in the dobutamine-norepinephrine group than in the other groups. Survival time was significantly longer in the dobutamine-norepinephrine (24 +/- 4 h), dopamine- norepinephrine (24 +/- 6 h), and norepinephrine (20 +/- 1 h) groups than the control group (17 +/- 2 h;P < 0.05 vs. other groups), and significantly longer in the combined dopamine-norepinephrine and dobutamine-norepinephrine groups (24 +/- 5 h) than in the norepinephrine alone group (P < 0.05). Histologic examination of lung biopsies revealed less severe lesions in the dobutamine-norepinephrine group than in the control and norepinephrine alone groups. Anatomic alterations in the lung, liver, and small intestine were less severe in the dobutamine-norepinephrine group than in the other groups.     

High-dose Remifentanil Does Not Impair Cerebrovascular Carbon Dioxide Reactivity in Healthy Male Volunteers

Background: Cerebrovascular carbon dioxide reactivity during high-dose remifentanil infusion was investigated in volunteers by measurement of regional cerebral blood flow (rCBF) and mean CBF velocity (CBFv).

Methods: Ten healthy male volunteers with a laryngeal mask for artificial ventilation received remifentanil at an infusion rate of 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 under normocapnia, hypocapnia, and hypercapnia. Stable xenon-enhanced computed tomography and transcranial Doppler ultrasonography of the left middle cerebral artery were used to assess rCBF and mean CBFv, respectively. If required, blood pressure was maintained within baseline values with intravenous phenylephrine to avoid confounding effects of altered hemodynamics.

Results: Hemodynamic parameters were maintained constant over time. Remifentanil infusion at 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 significantly decreased rCBF and mean CBFv. Both rCBF and mean CBFv increased as the arterial carbon dioxide tension increased from hypocapnia to hypercapnia, indicating that cerebrovascular reactivity remained intact. The average slopes of rCBF reactivity were 0.56 +/- 0.27 and 0.49 +/- 0.28 ml [middle dot] 100 g-1 [middle dot] min-1 [middle dot] mmHg-1 for 2 and 4 [mu]g[middle dot]kg-1[middle dot]min-1 remifentanil, respectively (relative change in percent/mmHg: 1.9 +/- 0.8 and 1.6 +/- 0.5, respectively). The average slopes for mean CBFv reactivity were 1.61 +/- 0.95 and 1.54 +/- 0.83 cm [middle dot] s-1 [middle dot] mmHg-1 for 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil, respectively (relative change in percent/mmHg: 1.86 +/- 0.59 and 1.79 +/- 0.59, respectively). Preanesthesia and postanesthesia values of rCBF and mean CBFv did not differ.     

Dose-Response Relationship and Infusion Requirement of Cisatracurium Besylate in Infants and Children during Nitrous Oxide-Narcotic Anesthesia

Background: To determine the effect of age on the dose-response relation and infusion requirement of cisatracurium besylate in pediatric patients, 32 infants (mean age, 0.7 yr; range, 0.3-1.0 yr) and 32 children (mean age, 4.9 yr; range, 3.1-9.6 yr) were studied during thiopentone-nitrous oxide-oxygen-narcotic anesthesia.

Methods: Potency was determined using a single-dose (20, 26, 33, or 40 [mu]g/kg) technique. Neuromuscular block was assessed by monitoring the electromyographic response of the adductor pollicis to supramaximal train-of-four stimulation of the ulnar nerve at 2 Hz.

Results: Least-squares linear regression analysis of the log-probit transformation of dose and maximal response yielded median effective dose (ED50) and 95% effective dose (ED95) values for infants (29 +/- 3 [mu]g/kg and 43 +/- 9 [mu]g/kg, respectively) that were similar to those for children (29 +/- 2 [mu]g/kg and 47 +/- 7 [mu]g/kg, respectively). The mean infusion rate necessary to maintain 90-99% neuromuscular block during the first hour in infants (1.9 +/- 0.4 [mu]g [middle dot] kg-1 [middle dot] min-1; range: 1.3-2.5 [mu]g [middle dot] kg-1 [middle dot] min-1) was similar to that in children (2.0 +/- 0.5 [mu]g [middle dot] kg-1 [middle dot] min-1; range: 1.3-2.9 [mu]g [middle dot] kg-1 [middle dot] min-1).     

Dopamine and Intraocular Pressure in Critically Ill Patients

Background: A recently released dopamine-1 receptor agonist, fenoldopam, increases intraocular pressure (IOP) in both healthy volunteers and patients with chronic ocular hypertension. Dopamine, a potent agonist at both dopamine-1 and -2 receptors, is frequently infused in critically ill patients for its inotropic, renal vasodilatory, and natriuretic effects. The authors hypothesized that low doses of dopamine would significantly increase IOP.

Methods: Patients in the intensive care unit who were currently receiving dopamine infusions of less than 5 [mu]g [middle dot] kg-1 [middle dot] min-1 were studied. After local ocular anesthesia was obtained, baseline IOP was measured in each eye with a hand-held tonometer. IOP was then determined after dopamine was discontinued.

Results: Twenty-three patients received a mean dopamine infusion of 2.6 +/- 0.2 [mu]g [middle dot] kg-1 [middle dot] min-1. Twelve of the 23 patients were receiving mechanical ventilation during the study. Mean IOPs in nonventilated patients (n = 11) off dopamine were 13.1 +/- 0.9 mmHg (left eye) and 12.6 +/- 0.9 mmHg (right eye). Mean IOPs for the same patients receiving dopamine were significantly higher at 16.1 +/- 0.9 mmHg (left eye) and 15.9 +/- 1.1 mmHg (right eye). Mean IOPs in intubated patients (n = 12) off dopamine were 12.3 +/- 0.7 mmHg (left eye) and 12.5 +/- 1.2 mmHg (right eye). Mean IOPs for the same patients while receiving dopamine were significantly higher in intubated patients at 17.8 +/- 1.3 mmHg (left eye) and 17.3 +/- 1.3 mmHg (right eye). The average mean elevation in IOP in patients while receiving dopamine was significantly higher in intubated patients as compared with nonintubated patients (5.2 +/- 0.9 mmHg vs. 3.1 +/- 0.6 mmHg).     

Sole Use of Dexmedetomidine Has Limited Utility for Conscious Sedation during Outpatient Colonoscopy

Background: This study evaluated the ability of dexmedetomidine to provide analgesia and sedation for outpatient colonoscopy, examining outcomes including cardiorespiratory variables, side effects, and discharge readiness.

Methods: Sixty-four patients were randomly assigned to one of three treatment regimens. In group D, patients received 1 [mu]g/kg dexmedetomidine over 15 min followed by an infusion of 0.2 [mu]g [middle dot] kg-1 [middle dot] h-1. Group P received meperidine (1 mg/kg) with midazolam (0.05 mg/kg), and group F received fentanyl (0.1-0.2 mg intravenous) on demand. The assessment included measurements of heart rate, blood pressure, oxygen saturation, respiratory rate, quality of sedation/analgesia, and an evaluation of the recovery time.

Results: The study was terminated before the planned 90 patients had been recruited because of adverse events in group D. In all groups, negligible hemoglobin oxygen saturation and respiratory rate variations were observed. In group D, there was a significantly larger decrease in heart rate (to approximately 40 beats/min in 2 of 19 cases) and blood pressure (to less than 50% of the initial value in 4 of 19 patients). Supplemental fentanyl was required in 47% of patients receiving dexmedetomidine to achieve a satisfactory level of analgesia (vs. 42.8% of patients in group P and 79.2% of patients in group F). Vertigo (5 patients), nausea/vomiting (5 patients), and ventricular bigeminy (1 patient) were observed only in group D. Time to home readiness was longest in group D (85 +/- 74, 39 +/- 21, and 32 +/- 13 min in groups D, P and F, respectively; P = 0.007).     

Remifentanil Requirements during Sevoflurane Administration to Block Somatic and Cardiovascular Responses to Skin Incision in Children and Adults

Background: The authors found no studies comparing intraoperative requirements of opioids between children and adults, so they determined the infusion rate of remifentanil to block somatic (IR50) and autonomic response (IRBAR50) to skin incision in children and adults.

Methods: Forty-one adults (aged 20-60 yr) and 24 children (aged 2-10 yr) undergoing lower abdominal surgery were studied. In adults, anesthesia induction was with sevoflurane during remifentanil infusion, whereas in children remifentanil administration was started after induction with sevoflurane. After intubation, sevoflurane was administered in 100% O2 and was adjusted to an ET% of 1 MAC-awake corrected for age at least 15 min before surgery. Patients were randomized to receive remifentanil at a rate ranging from 0.05 to 0.35 [mu]g [middle dot] kg-1 [middle dot] min-1 for at least 20 min before surgery. At the beginning of surgery, only the skin incision was performed, and the somatic and autonomic responses were observed. The somatic response was defined as positive with any gross movement of extremity, and the autonomic response was deemed positive with any increase in heart rate or mean arterial pressure equal to or more than 10% of preincision values. Using logistic regression, the IR50 and IRBAR50 were determined in both groups of patients and compared with unpaired Student t test. A P value less than 0.05 was considered significant.

Results: The IR50 +/- SD was 0.10 +/- 0.02 [mu]g [middle dot] kg-1 [middle dot] min-1 in adults and 0.22 +/- 0.03 [mu]g [middle dot] kg-1 [middle dot] min-1 in children (P < 0.001). The IRBAR50 +/- SD was 0.11 +/- 0.02 [mu]g [middle dot] kg-1 [middle dot] min-1 in adults and 0.27 +/- 0.06 [mu]g [middle dot] kg-1 [middle dot] min-1 in children (P < 0.001).     

Low Doses of Fentanyl Block Central Sensitization in the Rat Spinal Cord In Vivo

Background: [mu]-Opioid receptor agonists are strong analgesics. However, their usefulness for preemptive analgesia is controversial. The authors tested antinociceptive and preemptive properties of fentanyl as a [mu]-opioid receptor agonist in a model of spinal nociception in vivo.

Methods: C fiber-evoked potentials were recorded in the superficial laminae I-II of the rat lumbar spinal cord with glass microelectrodes in response to electrical stimulation of the sciatic nerve. High-frequency stimulation was applied on the sciatic nerve to induce long-term potentiation of C fiber-evoked field potentials, a form of central sensitization. To test the effect of fentanyl on acute nociception, fentanyl was infused intravenously at increasing doses (6-192 [mu]g [middle dot] kg-1 [middle dot] h-1). One hour after start of infusion, high-frequency stimulation was applied to evaluate effects of fentanyl on the induction of long-term potentiation.

Results: In the absence of fentanyl, high-frequency stimulation potentiated C fiber-evoked field potentials to 149 +/- 12% of controls (mean +/- SEM; n = 6) for at least 1 h. Increasing doses of fentanyl led to a significant reduction of C fiber-evoked potentials in a dose-dependent manner. The induction of long-term potentiation was blocked by low doses of fentanyl (infusion 12-48 [mu]g [middle dot] kg-1 [middle dot] h-1). At high doses, fentanyl did not block the induction of long-term potentiation (infusion 96-192 [mu]g [middle dot] kg-1 [middle dot] h-1).     

Effect of the α2-Agonist Dexmedetomidine on Cerebral Neurotransmitter Concentrations during Cerebral Ischemia in Rats

Background: This study investigates whether neuroprotection seen with dexmedetomidine is associated with suppression of peripheral or central sympathetic tone.

Methods: Thirty fasted male Sprague-Dawley rats were intubated and ventilated with isoflurane and N2O/O2 (fraction of inspired oxygen = 0.33). Catheters were inserted into the right femoral artery and vein and into the right jugular vein. Cerebral blood flow was measured using laser Doppler flowmetry. Bilateral microdialysis probes were placed into the cortex and the dorsal hippocampus. At the end of preparation, the administration of isoflurane was replaced by fentanyl (bolus: 10 [mu]g/kg; infusion: 25 [mu]g [middle dot] kg-1 [middle dot] h-1). Animals were randomly assigned to one of the following groups: group 1 (n = 10): control animals; group 2 (n = 10): 100 [mu]g/kg dexmedetomidine administered intraperitoneally 30 min before ischemia; group 3 (n = 10): sham-operated rats. Ischemia (30 min) was produced by unilateral carotid artery occlusion plus hemorrhagic hypotension to a mean arterial blood pressure of 30-35 mmHg to reduce ipsilateral cerebral blood flow by 70%. Pericranial temperature, arterial blood gases, and p H were maintained constant. Cerebral catecholamine and glutamate concentrations and plasma catecholamine concentrations were analyzed using high-performance liquid chromatography.

Results: During ischemia, dexmedetomidine suppressed circulating norepinephrine concentrations by 95% compared with control animals. In contrast, brain norepinephrine and glutamate concentrations were increased irrespective of dexmedetomidine infusion before ischemia.     

The Anabolic Effect of Epidural Blockade Requires Energy and Substrate Supply

Background: The authors examined the hypothesis that continuous thoracic epidural blockade with local anesthetic and opioid, in contrast to patient-controlled intravenous analgesia with morphine, stimulates postoperative whole body protein synthesis during combined provision of energy (4 mg [middle dot] kg-1 [middle dot] min-1 glucose) and amino acids (0.02 ml [middle dot] kg-1 [middle dot] min-1 Travasol(TM) 10%, equivalent to approximately 2.9 g [middle dot] kg-1 [middle dot] day-1).

Methods: Sixteen patients were randomly assigned to undergo a 6-h stable isotope infusion study (3 h fasted, 3 h feeding) on the second day after colorectal surgery performed with or without perioperative epidural blockade. Protein synthesis, breakdown and oxidation, glucose production, and clearance were measured by l-[1-13C]leucine and [6,6-2H2]glucose.

Results: Epidural blockade did not affect protein and glucose metabolism in the fasted state. Parenteral alimentation decreased endogenous protein breakdown and glucose production to the same extent in both groups. Administration of glucose and amino acids was associated with an increase in whole body protein synthesis that was modified by the type of analgesia, i.e., protein synthesis increased by 13% in the epidural group (from 93.3 +/- 16.6 to 104.5 +/- 11.1 [mu]mol [middle dot] kg-1 [middle dot] h-1) and by 4% in the patient-controlled analgesia group (from 90.0 +/- 27.1 to 92.9 +/- 14.8 [mu]mol [middle dot] kg-1 [middle dot] h-1;P = 0.054).     

Differential Modulation of Remifentanil-induced Analgesia and Postinfusion Hyperalgesia by S-Ketamine and Clonidine in Humans

Background: Experimental studies and clinical observations suggest a possible role for opioids to induce pain and hyperalgesia on withdrawal. The authors used a new experimental pain model in human skin to determine the time course of analgesic and hyperalgesic effects of the [mu]-receptor agonist remifentanil alone or in combination with the N-methyl-D-aspartate-receptor antagonist S-ketamine or the [alpha]2-receptor agonist clonidine.

Methods: Thirteen volunteers were enrolled in this randomized, double-blind, placebo-controlled study. Transcutaneous electrical stimulation at a high current density (2 Hz, 67.3 +/- 16.8 mA, mean +/- SD) induced acute pain (numerical 11-point rating scale: 5-6 out of 10) and stable areas of mechanical hyperalgesia to punctate stimuli and touch (allodynia). The magnitude of pain and area of hyperalgesia were assessed before, during, and after drug infusion (remifentanil at 0.1 [mu]g [middle dot] kg-1 [middle dot] min-1 and S-ketamine at 5 [mu]g [middle dot] kg-1 [middle dot] min-1 over a period of 30 min, respectively; clonidine infusion at 2 [mu]g/kg for 5 min).

Results: Remifentanil reduced pain and areas of punctate hyperalgesia during infusion. In contrast, postinfusion pain and hyperalgesia were significantly higher than control. During infusion of S-ketamine, pain and hyperalgesia decreased and gradually normalized after infusion. When given in combination, S-ketamine abolished postinfusion increase of punctate hyperalgesia but did not reduce increased pain ratings. Clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings.     

Effect of Dexmedetomidine on Cerebral Blood Flow Velocity, Cerebral Metabolic Rate, and Carbon Dioxide Response in Normal Humans

Background: Dexmedetomidine reduces cerebral blood flow (CBF) in humans and animals. In animal investigations, cerebral metabolic rate (CMR) was unchanged. Therefore, the authors hypothesized that dexmedetomidine would cause a decrease in the CBF/CMR ratio with even further reduction by superimposed hyperventilation. This reduction might be deleterious in patients with neurologic injuries.

Methods: Middle cerebral artery velocity (CBFV) was recorded continuously in six volunteers. CBFV, jugular bulb venous saturation (Sjvo2), CMR equivalent (CMRe), and CBFV/CMRe ratio were determined at six intervals before, during, and after administration of dexmedetomidine: (1) presedation; (2) presedation with hyperventilation; at steady state plasma levels of (3) 0.6 ng/ml and (4) 1.2 ng/ml; (5) 1.2 ng/ml with hyperventilation; and (6) 30 min after discontinuing dexmedetomidine. The slope of the arterial carbon dioxide tension (Paco2)-CBFV relation was determined presedation and at 1.2 ng/ml.

Results: CBFV and CMRe decreased in a dose-related manner. The CBFV/CMRe ratio was unchanged. The CBFV response to carbon dioxide decreased from 1.20 +/- 0.2 cm[middle dot]s-1[middle dot]mm Hg-1 presedation to 0.40 +/- 0.15 cm[middle dot]s-1[middle dot]mm Hg-1 at 1.2 ng/ml. Sjvo2 was statistically unchanged during hyperventilation at 1.2 ng/ml versus presedation (50 +/- 11 vs. 43 +/- 5%). Arousal for hyperventilation at 1.2 ng/ml resulted in increased CBFV (30 +/- 5 to 38 +/- 4) and Bispectral Index (43 +/- 10 to 94 +/- 3).     

Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects

Background: Dexmedetomidine, a selective [alpha]2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating [alpha]2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic [alpha]2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects.

Methods: The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine.

Results: The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, -27% from baseline [95% confidence interval, -31 to -23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate-pressure product (-23% [-28 to -18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (-3% [-12 to +6%] from low dexmedetomidine, P > 0.05; -29% [-39 to -18%] from baseline, P < 0.001) or statistically significantly affect the rate-pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate.     

Narcotrend Monitoring Allows Faster Emergence and a Reduction of Drug Consumption in Propofol-Remifentanil Anesthesia

Background: The Narcotrend is a new electroencephalographic monitor designed to measure depth of anesthesia, based on a six-letter classification from A (awake) to F (increasing burst suppression) including 14 substages. This study was designed to investigate the impact of Narcotrend monitoring on recovery times and propofol consumption in comparison to Bispectral Index(R) (BIS(R)) monitoring or standard anesthetic practice.

Methods: With institutional review board approval and written informed consent, 120 adult patients scheduled to undergo minor orthopedic surgery were randomized to receive a propofol-remifentanil anesthetic controlled by Narcotrend, by BIS(R), or solely by clinical parameters. Anesthesia was induced with 0.4 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil and a propofol target-controlled infusion at 3.5 [mu]g/ml. After intubation, remifentanil was reduced to 0.2 [mu]g [middle dot] kg-1 [middle dot] min-1, whereas the propofol infusion was adjusted according to clinical parameters or to the following target values: during maintenance to D0 (Narcotrend) or 50 (BIS(R)); 15 min before the end of surgery to C1 (Narcotrend) or 60 (BIS(R)). Recovery times were recorded by a blinded investigator, and average normalized propofol consumption was calculated from induction and maintenance doses.

Results: The groups were comparable for demographic data, duration of anesthesia, and mean remifentanil dosages. Compared with standard practice, patients with Narcotrend or BIS(R) monitoring needed significantly less propofol (standard practice, 6.8 +/- 1.2 mg [middle dot] kg-1 [middle dot] h-1vs. Narcotrend, 4.5 +/- 1.1 mg [middle dot] kg-1 [middle dot] h-1 or BIS(R), 4.8 +/- 1.0 mg [middle dot] kg-1 [middle dot] h-1;P < 0.001), opened their eyes earlier (9.3 +/- 5.2 vs. 3.4 +/- 2.2 or 3.5 +/- 2.9 min), and were extubated sooner (9.7 +/- 5.3 vs. 3.7 +/- 2.2 or 4.1 +/- 2.9 min).     

Milrinone Combined with Vasopressin Improves Cardiac Index after Cardiopulmonary Resuscitation in a Pig Model of Myocardial Infarction

Background: Milrinone used for acute cardiac insufficiency could be of interest during cardiopulmonary resuscitation because of its positive inotropic effects. In this study, the combination of milrinone-vasopressin was compared with epinephrine and vasopressin, as well as with the combination of epinephrine-vasopressin, in reference to hemodynamics.

Methods: Thirty-two pigs underwent ligation of the circumflex coronary artery and induction of ventricular fibrillation lasting for 4 min. Cardiopulmonary resuscitation was performed after randomization to one of four groups: epinephrine (30-[mu]g/kg bolus), vasopressin (0.4-U/kg bolus), epinephrine-vasopressin (15-[mu]g/kg epinephrine bolus, 0.2-U/kg vasopressin bolus), or milrinone-vasopressin (0.4-U/kg vasopressin bolus, 50-[mu]g/kg milrinone bolus over 5 min and a continuous infusion of 0.4 [mu]g [middle dot] kg-1 [middle dot] min-1). The hemodynamic variables were measured before cardiopulmonary resuscitation as well as 4, 8, 15, and 30 min after return of spontaneous circulation.

Results: All animals were resuscitated successfully. The animals of the milrinone-vasopressin group displayed significantly (P < 0.05) higher cardiac index values (30 min after return of spontaneous circulation: epinephrine, 65.8 +/- 13.2; vasopressin, 70.7 +/- 18.3; epinephrine-vasopressin, 69.1 +/- 36.2; milrinone-vasopressin, 120.7 +/- 34.8 ml [middle dot] min-1 [middle dot] kg-1) without a decrease in mean arterial pressure or coronary perfusion pressure.