Epidural Blockade Modifies Perioperative Glucose Production without Affecting Protein Catabolism

Background: Epidural blockade with local anesthetic has been shown to blunt the increase in plasma glucose concentration during and after abdominal surgery. The aim of the study was to test the hypothesis that epidural blockade inhibits this hyperglycemic response by attenuating endogenous glucose production. The authors further examined if the modification of glucose production by epidural blockade has an impact on perioperative protein catabolism.

Methods: Sixteen patients undergoing colorectal surgery received either general anesthesia and epidural blockade with local anesthetic (n = 8) or general anesthesia alone (control, n = 8). Glucose and protein kinetics were assessed by stable isotope tracer technique ([6,6-2H2]glucose, L-[1-13C]leucine) during and 2 h after surgery. Plasma concentrations of glucose, lactate, free fatty acids (FFA), cortisol, glucagon, and insulin were also determined.

Results: Epidural blockade blunted the perioperative increase in the plasma concentration of glucose, cortisol, and glucagon when compared with the control group (P < 0.05). Plasma concentrations of lactate, FFA, and insulin did not change. Intra- and postoperative glucose production was lower in patients with epidural blockade than in control subjects (intraoperative, epidural blockade 8.2 +/- 1.9 vs. control 10.7 +/- 1.4 [mu]mol[middle dot]kg-1[middle dot]min-1, P < 0.05; postoperative, epidural blockade 8.5 +/- 1.8 vs. control 10.5 +/- 1.2 [mu]mol[middle dot]kg-1[middle dot]min-1, P < 0.05), whereas glucose clearance decreased to a comparable extent in both groups (P < 0.05). Protein breakdown (P < 0.05), protein synthesis (P < 0.05), and amino acid oxidation (P > 0.05) decreased with both anesthetic techniques.     

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).     

Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

Background: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia.

Methods: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 [mu]g [middle dot]kg-1 [middle dot]min-1 (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 [mu]g [middle dot] kg-1 [middle dot] min-1 until skin closure and then 2 [mu]g [middle dot]kg-1 [middle dot]min-1 for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h.

Results: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects.     

Critical Oxygen Delivery in Conscious Humans Is Less Than 7.3 ml O2 · kg-1 · min-1

Background: The "critical" level of oxygen delivery (DO2) is the value below which DO2 fails to satisfy the metabolic need for oxygen. No prospective data in healthy, conscious humans define this value. The authors reduced DO2 in healthy volunteers in an attempt to determine the critical DO2.

Methods: With Institutional Review Board approval and informed consent, the authors studied eight healthy, conscious volunteers, aged 19-25 yr. Hemodynamic measurements were obtained at steady state before and after profound acute isovolemic hemodilution with 5% albumin and autologous plasma, and again at the reduced hemoglobin concentration after additional reduction of DO2 by an infusion of a [beta]-adrenergic antagonist, esmolol.

Results: Reduction of hemoglobin from 12.5 +/- 0.8 g/dl to 4.8 +/- 0.2 g/dl (mean +/- SD) increased heart rate, stroke volume index, and cardiac index, and reduced DO2 (14.0 +/- 2.9 to 9.9 +/- 2.0 ml O2 [middle dot] kg-1 [middle dot] min-1; all P < 0.001). Oxygen consumption (VO2; 3.0 +/- 0.5 to 3.4 +/- 0.6 ml O2 [middle dot] kg-1 [middle dot] min-1;P < 0.05) and plasma lactate concentration (0.50 +/- 0.10 to 0.62 +/- 0.16 mM;P < 0.05; n = 7) increased slightly. Esmolol decreased heart rate, stroke volume index, and cardiac index, and further decreased DO2 (to 7.3 +/- 1.4 ml O2 [middle dot] kg-1 [middle dot] min-1; all P < 0.01 vs. before esmolol). VO2 (3.2 +/- 0.6 ml O2 [middle dot] kg-1 [middle dot] min-1;P > 0.05) and plasma lactate (0.66 +/- 0.14 mM;P > 0.05) did not change further. No value of plasma lactate exceeded the normal range.     

Metformin normalizes nonoxidative glucose metabolism in insulin-resistant normoglycemic first-degree relatives of patients with NIDDM.

Many first-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) are characterized by insulin resistance. Because metformin improves peripheral insulin sensitivity, we examined the acute effect of metformin and placebo on glucose and lipid metabolism in nine insulin-resistant first-degree relatives of NIDDM patients with the euglycemic insulin-clamp technique combined with indirect calorimetry and infusion of [3-3H]glucose. Either placebo or 500 mg metformin was taken in random order twice the day before and once 1 h before the clamp. Nine healthy individuals without family history of diabetes served as control subjects. Basal plasma glucose was normal and did not differ between the metformin and the placebo study (4.8 +/- 0.2 vs. 5.0 +/- 0.2 mM) and neither did basal hepatic glucose production (10.59 +/- 0.54 vs. 10.21 +/- 0.80 mumol.kg-1.min-1). Insulin-stimulated glucose disposal was significantly increased by 25% after metformin compared with placebo (26.67 +/- 2.87 vs. 21.31 +/- 1.73 mumol.kg-1.min-1, P less than 0.05). The enhancement in glucose utilization was primarily due to normalization of nonoxidative glucose disposal (from 8.02 +/- 1.35 to 15.07 +/- 2.69 mumol.kg-1.min-1, P less than 0.01, vs. 15.65 +/- 2.72 mumol.kg-1.min-1 in control subjects). In contrast, glucose oxidation during the clamp was slightly lower after metformin compared with both placebo (11.59 +/- 0.83 vs. 13.30 +/- 1.00 mumol.kg-1.min-1, P = 0.06) and healthy control subjects (15.68 +/- 1.38 mumol.kg-1.min-1, P less than 0.05). We conclude that acutely administered metformin improves peripheral insulin sensitivity in insulin-resistant normoglycemic individuals primarily by stimulating the nonoxidative pathway of glucose metabolism.     

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).     

Epinephrine Increases the Extracellular Lidocaine Concentration in the Brain: A Possible Mechanism for Increased Central Nervous System Toxicity

Background: Local anesthetics exert central nervous system (CNS) toxicity by inhibiting intracerebral neuronal activity, while epinephrine augments the CNS toxicity of intravenously administered local anesthetics. Viewed together, increases of extracellular concentrations of local anesthetics in the brain may be directly associated with increased CNS toxicity. The authors examined the hypothesis that epinephrine enhances the CNS toxicity of lidocaine by increasing the extracellular concentration in the brain.

Methods: An awake, spontaneously breathing rat model was used. Twenty male Sprague-Dawley rats received an intravenous infusion of lidocaine (3 mg [middle dot] kg-1 [middle dot] min-1; group C) or lidocaine with epinephrine (3 mg [middle dot] kg-1 [middle dot] min-1 and 2 [mu]g [middle dot] kg-1 [middle dot] min-1, respectively; group E) for 10 min (n = 10 in each group). Effects of epinephrine on the convulsive dose and concentrations of total (protein-bound and unbound) and unbound lidocaine in plasma were examined. Concentrations of extracellular lidocaine in the cerebral nucleus accumbens were quantitatively determined by a microdialysis method.

Results: The convulsive dose of lidocaine was significantly lower in group E than in group C (22.4 +/- 5.5 vs. 27.9 +/- 3.1 mg/kg, respectively; P < 0.05). Overall concentrations and area under the plasma concentration-versus-time curve of unbound lidocaine in group E were significantly higher than those in group C. Concentrations of extracellular lidocaine in the nucleus accumbens in group E were comparable to those of unbound fraction in plasma and were also significantly higher than those in group C.     

Sex Differences in Morphine-induced Ventilatory Depression Reside within the Peripheral Chemoreflex Loop

Background: This study gathers information in humans on the sites of sex-related differences in ventilatory depression caused by the [micro sign]-opioid receptor agonist morphine.

Methods: Experiments were performed in healthy young men (n = 9) and women (n = 7). Dynamic ventilatory responses to square-wave changes in end-tidal carbon dioxide tension (7.5-15 mmHg) and step decreases in end-tidal oxygen tension (step from 110 to 50 mmHg, duration of hypoxia 15 min) were obtained before and during morphine infusion (intravenous bolus dose 100 [micro sign]g/kg, followed by 30 [micro sign]g [middle dot] kg-1 [middle dot] h-1). Each hypercapnic response was separated into a fast peripheral and slow central component, which yield central (Gc) and peripheral (Gp) carbon dioxide sensitivities. Values are mean +/- SD.

Results: In carbon dioxide studies in men, morphine reduced Gc from 1.61 +/- 0.33 to 1.23 +/- 0.12 l [middle dot] mmHg-1 (P < 0.05) without affecting Gp (control, 0.41 +/- 0.16 and morphine, 0.49 +/- 0.12 l [middle dot] [middle dot] min-1 [middle dot] mmHg-1, not significant). In carbon dioxide studies in women, morphine reduced Gc, from 1.51 +/- 0.74 to 1.17 +/- 0.52 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05), and Gp, from 0.54 +/- 0.19 to 0.39 +/- 0.22 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05). Morphine-induced changes in Gc were equal in men and women; changes in Gp were greater in women. In hypoxic studies, morphine depressed the hyperventilatory response at the initiation of hypoxia more in women than in men (0.54 +/- 0.23 vs. 0.26 +/- 0.34 l [middle dot] min-1 [middle dot] %-1, respectively; P < 0.05). The ventilatory response to sustained hypoxia (i.e., 15 min) did not differ between men and women.     

Effects of Mild Hypothermia on Blood-Brain Barrier Disruption during Isoflurane or Pentobarbital Anesthesia

Background: This study was performed to determine whether mild hypothermia (32[degrees]C) could attenuate the degree of blood-brain barrier (BBB) disruption caused by a hyperosmolar solution and whether the degree of disruption would vary depending on anesthetic agents.

Methods: Rats were assigned to one of four groups: normothermic isoflurane, normothermic pentobarbital, hypothermic isoflurane, and hypothermic pentobarbital. During isoflurane (1.4%; normothermic or hypothermic) or pentobarbital (50 mg/kg administered intraperitoneally; normothermic or hypothermic) anesthesia, the external carotid artery and the femoral artery and vein were catheterized. Body temperature was maintained at 37 and 32[degrees]C for the normothermic and hypothermic groups, respectively. To open the BBB, 25% mannitol was infused through the right carotid artery at the rate of 0.25 ml [middle dot] kg-1 [middle dot] s-1 for 30 s. The transfer coefficient of 14C-[alpha]-aminoisobutyric acid was determined.

Results: Blood pressure was similar among the four groups of animals. The degree of the BBB disruption by hyperosmolar mannitol was less with isoflurane than pentobarbital anesthesia in the normothermic groups (transfer coefficient: 29.9 +/- 17.1 and 50.4 +/- 17.5 [mu]l [middle dot] g-1 [middle dot] min-1 for normothermic isoflurane and pentobarbital, respectively;P < 0.05). Mild hypothermia decreased the BBB disruption during anesthesia with both anesthetic agents (hypothermic isoflurane: 9.8 +/- 8.3 [mu]l [middle dot] g-1 [middle dot] min-1, P < 0.05 vs. normothermic isoflurane; hypothermic pentobarbital: 30.2 +/- 13.9 [mu]l [middle dot] g-1 [middle dot] min-1, P < 0.05 vs. normothermic pentobarbital), but the disruption was less during isoflurane anesthesia (hypothermic isoflurane vs. hypothermic pentobarbital, P < 0.005). In the contralateral cortex, there were no significant differences among these four experimental groups.     

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).     

Comparison of Adenosine and Remifentanil Infusions as Adjuvants to Desflurane Anesthesia

Background: Because adenosine has been alleged to produce both anesthetic and analgesic sparing effects, a randomized, double-blinded study was designed to compare the perioperative effects of adenosine and remifentanil when administered as intravenous adjuvants during general anesthesia for major gynecologic procedures.

Methods: Thirty-two women were assigned randomly to one of two drug treatment groups. After premedication with 0.04 mg/kg intravenous midazolam, anesthesia was induced with 2 [micro sign]g/kg intravenous fentanyl, 1.5 mg/kg intravenous propofol, and 0.6 mg/kg intravenous rocuronium, and maintained with desflurane, 2%, and nitrous oxide, 65%, in oxygen. Before skin incision, an infusion of either remifentanil (0.02 [micro sign]g [middle dot] kg-1 [middle dot] min-1) or adenosine (25 [micro sign]g [middle dot] kg-1 [middle dot] min-1) was started and subsequently titrated to maintain systolic blood pressure, heart rate, or both within 10-15% of the preincision values.

Results: Adenosine and remifentanil infusions were effective anesthetic adjuvants during lower abdominal surgery. Use of adenosine (mean +/- SEM, 166 +/- 17 [micro sign]g [middle dot] kg-1 [middle dot] min-1) was associated with a significantly greater decrease in systolic blood pressure and higher heart rate values compared with remifentanil (mean +/- SEM, 0.2 +/- 0.03 [micro sign]g [middle dot] kg-1 [middle dot] min-1). Total postoperative opioid analgesic use was 45% and 27% lower in the adenosine group at 0-2 h and 2-24 h after surgery, respectively.     

Acute pain induces insulin resistance in humans

BACKGROUND: Painful trauma results in a disturbed metabolic state with impaired insulin sensitivity, which is related to the magnitude of the trauma. The authors explored whether pain per se influences hepatic and extrahepatic actions of insulin. METHODS: Ten healthy male volunteers underwent two randomly sequenced hyperinsulinemic-euglycemic (insulin infusion rate, 0.6 mU x kg(-1) x min(-1) for 180 min) clamp studies 4 weeks apart. Self-controlled painful electrical stimulation was applied to the abdominal skin for 30 min, to a pain intensity of 8 on a visual analog scale of 0-10, just before the clamp procedure (study P). In the other study, no pain was inflicted (study C). RESULTS: Pain reduced whole-body insulin-stimulated glucose uptake from 6.37+/-1.87 mg x kg(-1) x min(-1) (mean +/- SD) in study C to 4.97+/-1.38 mg x kg(-1) x min(-1) in study P (P < 0.01) because of a decrease in nonoxidative glucose disposal, as determined by indirect calorimetry (2.47+/-0.88 mg x kg(-1) x min(-1) in study P vs. 3.41+/-1.03 mg x kg(-1) x min(-1) in study C; P < 0.05). Differences in glucose oxidation rates were not statistically significant. The suppression of isotopically determined endogenous glucose output during hyperinsulinemia tended to be decreased after pain (1.67+/-0.48 mg x kg(-1) x min(-1) in study P vs. 2.04+/-0.45 mg x kg(-1) x min(-1) in study C; P = 0.06). Pain elicited a twofold to threefold increase in serum cortisol (P < 0.01), plasma epinephrine (P < 0.05), and serum free fatty acids (P < 0.05). Similarly, circulating concentrations of glucagon and growth hormone tended to increase during pain. CONCLUSIONS: Acute severe pain decreases insulin sensitivity, primarily by affecting nonoxidative glucose metabolism. It is conceivable that the counterregulatory hormonal response plays an important role. This may indicate that pain relief in stress states is important for maintenance of normal glucose metabolism.     

Acute Opioid Tolerance: Intraoperative Remifentanil Increases Postoperative Pain and Morphine Requirement

Background: Rapid development of acute opioid tolerance is well established in animals and is more likely to occur with large doses of short-acting drugs. The authors therefore tested the hypothesis that intraoperative remifentanil administration results in acute opioid tolerance that is manifested by increased postoperative pain and opioid requirement.

Methods: Fifty adult patients undergoing major abdominal surgery were randomly assigned to two anesthetic regimens: (1) desflurane was kept constant at 0.5 minimum alveolar concentrations and a remifentanil infusion was titrated to autonomic responses (remifentanil group); or (2) remifentanil at 0.1 [mu]g [middle dot] kg-1 [middle dot] min-1 and desflurane titrated to autonomic responses (desflurane group). All patients were given a bolus of 0.15 mg/kg morphine 40 min before the end of surgery. Morphine was initially titrated to need by postanesthesia care nurses blinded to group assignment. Subsequently, patients-who were also blinded to group assignment-controlled their own morphine administration. Pain scores and morphine consumption were recorded for 24 postoperative h.

Results: The mean remifentanil infusion rate was 0.3 +/- 0.2 [mu]g [middle dot] kg-1 [middle dot] min-1 in the remifentanil group, which was significantly greater than in the desflurane group. Intraoperative hemodynamic responses were similar in each group. Postoperative pain scores were significantly greater in the remifentanil group. These patients required morphine significantly earlier than those in the desflurane group and needed nearly twice as much morphine in the first 24 postoperative h: 59 mg (25-75% interquartile range, 43-71) versus 32 mg (25-75% interquartile range, 19-59;P < 0.01).     

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).     

Effect of Dobutamine on Splanchnic Carbohydrate Metabolism and Amino Acid Balance after Cardiac Surgery

Background: As a predominant [beta]-adrenergic agonist, dobutamine may modify blood flow distribution and increase metabolic demands. The authors investigated the effect of a dobutamine-induced increase in cardiac output on splanchnic and femoral blood flow and metabolism in patients after cardiac surgery.

Methods: Seventeen stable patients were randomized to receive dobutamine or placebo (n = 8 per group, one dropout). After baseline measurement for systemic, splanchnic, and femoral blood flow (by dye dilution); oxygen consumption; gastric mucosal pressure of carbon dioxide (PCO2); total and splanchnic glucose production (by stable isotope tracer dilution); and regional lactate and amino acid balance, patients received either dobutamine, at a dosage (6 [mu]g [middle dot] kg-1min-1) sufficient to increase cardiac index by at least 25%, or placebo. A second set of measurements was performed 60 min after the start of dobutamine or placebo infusion.

Results: Dobutamine increased cardiac index (3.0 +/- 0.6 to 4.4 +/- 1.0 l [middle dot] min-1m-2, mean +/- SD;P< 0.05), splanchnic blood flow (from 0.8 +/- 0.2 to 1.0 +/- 0.2 l [middle dot] min-1m-2;P< 0.05), femoral blood flow (from 0.2 +/- 0.1 to 0.3 +/- 0.1 l [middle dot] min-1m-2;P< 0.05), and the arterial-gastric mucosal PCO2 gap (from 11.4 +/- 9.5 to 11.9 +/- 8.0 mmHg;P< 0.05). Dobutamine increased systemic oxygen consumption (from 132 +/- 14 to 146 +/- 13 ml [middle dot] min-1 [middle dot] m-2;P< 0.05) but not splanchnic or femoral oxygen consumption. Splanchnic glucose production and lactate and amino acid balance did not change.     

Early Effects of Acid-Base Management during Hypothermia on Cerebral Infarct Volume, Edema, and Cerebral Blood Flow in Acute Focal Cerebral Ischemia in Rats

Background: Although the frequency for the use of moderate hypothermia in acute ischemic stroke is increasing, the optimal acid-base management during hypothermia remains unclear. This study investigates the effect of pH- and [alpha]-stat acid-base management on cerebral blood flow (CBF), infarct volume, and cerebral edema in a model of transient focal cerebral ischemia in rats.

Methods: Twenty Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h during normothermic conditions followed by 5 h of reperfusion during hypothermia (33[degrees]C). Animals were artificially ventilated with either [alpha]- (n = 10) or pH-stat management (n = 10). CBF was analyzed 7 h after induction of MCAO by iodo[14C]antipyrine autoradiography. Cerebral infarct volume and cerebral edema were measured by high-contrast silver infarct staining (SIS).

Results: Compared with the [alpha]-stat regimen, pH-stat management reduced cerebral infarct volume (98.3 +/- 33.2 mm3vs. 53.6 +/- 21.6 mm3;P >= 0.05 mean +/- SD) and cerebral edema (10.6 +/- 4.0%vs. 3.1 +/- 2.4%;P >= 0.05). Global CBF during pH-stat management exceeded that of [alpha]-stat animals (69.5 +/- 12.3 ml [middle dot] 100 g-1 [middle dot] min-1vs. 54.7 +/- 13.3 ml [middle dot] 100 g-1 [middle dot] min-1;P >= 0.05). The regional CBF of the ischemic hemisphere was 62.1 +/- 11.2 ml [middle dot] 100 g-1 [middle dot] min-1 in the pH-stat group versus 48.2 +/- 7.2 ml [middle dot] 100 g-1 [middle dot] min-1 in the [alpha]-stat group (P >= 0.05).     

Underestimation of glucose turnover measured with [6-3H]- and [6,6-2H]- but not [6-14C]glucose during hyperinsulinemia in humans

Recent studies indicate that hydrogen-labeled glucose tracers underestimate glucose turnover in humans under conditions of high flux. The cause of this underestimation is unknown. To determine whether the error is time-, pool-, model-, or insulin-dependent, glucose turnover was measured simultaneously with [6-3H]-, [6,6-2H2]-, and [6-14C]glucose during a 7-h infusion of either insulin (1 mU.kg-1.min-1) or saline. During the insulin infusion, steady-state glucose turnover measured with both [6-3H]glucose (8.0 +/- 0.5 mg.kg-1.min-1) and [6,6-2H2]glucose (7.6 +/- 0.5 mg.kg-1.min-1) was lower (P less than .01) than either the glucose infusion rate required to maintain euglycemia (9.8 +/- 0.7 mg.kg-1.min-1) or glucose turnover determined with [6-14C]glucose and corrected for Cori cycle activity (9.8 +/- 0.7 mg.kg-1.min-1). Consequently "negative" glucose production rates (P less than .01) were obtained with either [6-3H]- or [6,6-2H2]- but not [6-14C]glucose. The difference between turnover estimated with [6-3H]glucose and actual glucose disposal (or 14C glucose flux) did not decrease with time and was not dependent on duration of isotope infusion. During saline infusion, estimates of glucose turnover were similar regardless of the glucose tracer used. High-performance liquid chromatography of the radioactive glucose tracer and plasma revealed the presence of a tritiated nonglucose contaminant. Although the contaminant represented only 1.5% of the radioactivity in the [6-3H]glucose infusate, its clearance was 10-fold less (P less than .001) than that of [6-3H]glucose. This resulted in accumulation in plasma, with the contaminant accounting for 16.6 +/- 2.09 and 10.8 +/- 0.9% of what customarily is assumed to be plasma glucose radioactivity during the insulin or saline infusion, respectively (P less than .01). When corrected for the presence of the contaminant, glucose turnover determined with [6-3H]glucose during insulin infusion (9.5 +/- 0.6 mg.kg-1.min-1) no longer differed from either the glucose infusion rate or that determined with [6-14C]glucose. Therefore, the underestimation of glucose turnover during insulin infusion and negative glucose production rates observed with traditional methods to analyze plasma radioactivity and commercially available tracers is the result of an artifactual increase in [6-3H]glucose specific activity. The etiology of the underestimation of glucose turnover with [6,6-2H2]glucose remains to be determined.     

Effect of Inhaled Prostacyclin in Combination with Almitrine on Ventilation-Perfusion Distributions in Experimental Lung Injury

Background: Inhaled prostacyclin and intravenous almitrine have both been shown to improve pulmonary gas exchange in acute lung injury (ALI). This study was performed to investigate a possible additive effect of prostacyclin and almitrine on pulmonary ventilation-perfusion (a/) ratio in ALI compared with inhaled prostacyclin or intravenous almitrine alone.

Methods: Experimental ALI was established in 24 pigs by repeated lung lavage. Animals were randomly assigned to receive either 25 ng [middle dot] kg-1 [middle dot] min-1 inhaled prostacyclin alone, 1 [mu]g [middle dot] kg-1 [middle dot] min-1 almitrine alone, 25 ng [middle dot] kg-1 [middle dot] min-1 inhaled prostacyclin in combination with 1 [mu]g [middle dot] kg-1 [middle dot] min-1 almitrine, or no specific treatment (controls) for 30 min. For each intervention, pulmonary gas exchange and hemodynamics were analyzed and a/ distributions were calculated using the multiple inert gas elimination technique. The data was analyzed within and between the groups by analysis of variance for repeated measurements, followed by the Student-Newman-Keuls test for multiple comparison when analysis of variance revealed significant differences.

Results: All values are expressed as mean +/- SD. In controls, pulmonary gas exchange, hemodynamics, and a/ distribution remained unchanged. With prostacyclin alone and almitrine alone, arterial oxygen partial pressure (Pao2) increased, whereas intrapulmonary shunt (S/T) decreased (P < 0.05). Combined prostacyclin and almitrine also increased Pao2 and decreased S/T (P < 0.05). When compared with either prostacyclin or almitrine alone, the combined application of both drugs revealed no additional effect in gas exchange or a/ distribution.     

Insulin-sensitive and insulin-resistant variants in NIDDM

To define the sequence of events that is involved in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), we studied 16 NIDDM individuals (15 of 16 Black patients) with a mean age of 44 yr who had been near normoglycemic for 2-91 mo while off of antidiabetic medicine. With the euglycemic insulin clamp at 100 microU/ml insulin, we defined two populations, one with normal peripheral insulin sensitivity (glucose disposal 7.51 +/- 0.97 mg.kg-1.min-1) and the other with insulin resistance (glucose disposal 3.35 +/- 0.58 mg.kg-1.min-1; P less than .001). The populations did not differ in age, degree of obesity, fasting plasma glucose, glycosylated hemoglobin, clinical presentation, or clinical course. Basal plasma insulin levels were normal in the sensitive group and significantly elevated in the resistant group. Islet cell cytoplasmic antibodies were absent in all patients. Insulin action on the liver was normal in both groups. Basal hepatic glucose production measured with D-[3-3H]glucose was lower in the insulin-resistant group (1.53 +/- 0.11 mg.kg-1.min-1) than in the insulin-sensitive group (1.88 +/- 0.06 mg.kg-1.min-1) or normal control subjects (1.93 +/- 0.05 mg.kg-1.min-1). The decreased basal hepatic glucose production appeared to be secondary to the twofold higher fasting plasma insulin level seen in the insulin-resistant group. The insulin concentration necessary to suppress basal hepatic glucose production by 50% was 29.6 microU/ml in the insulin-sensitive group and 30.5 microU/ml in the insulin-resistant group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intracarotid Nitroprusside Does Not Augment Cerebral Blood Flow in Human Subjects

Background: The recent resurgence of interest in the cerebrovascular effects of nitroprusside can be attributed to the possibility of using nitric oxide donors in treating cerebrovascular insufficiency. However, limited human data suggest that intracarotid nitroprusside does not directly affect cerebrovascular resistance. In previous studies, physiologic or pharmacologic reactivity of the preparation was not tested at the time of nitroprusside challenge. The authors hypothesized that if nitric oxide is a potent modulator of human cerebral blood flow (CBF), then intracarotid infusion of nitroprusside will augment CBF.

Methods: Cerebral blood flow was measured (intraarterial 133Xe technique) in sedated human subjects undergoing cerebral angiography during sequential infusions of (1) intracarotid saline, (2) intravenous phenylephrine to induce systemic hypertension, (3) intravenous phenylephrine with intracarotid nitroprusside (0.5 [mu]g [middle dot] kg-1 [middle dot] min-1), and (4) intracarotid verapamil (0.013 mg [middle dot] kg-1 [middle dot] min-1). Data (mean +/- SD) were analyzed by repeated-measures analysis of variance and post hoc Bonferroni-Dunn test.

Results: Intravenous phenylephrine increased systemic mean arterial pressure (from 83 +/- 12 to 98 +/- 6 mmHg; n = 8;P < 0.001), and concurrent infusion of intravenous phenylephrine and intracarotid nitroprusside reversed this effect. However, compared with baseline, CBF did not change with intravenous phenylephrine or with concurrent infusions of intravenous phenylephrine and intracarotid nitroprusside. Intracarotid verapamil increased CBF (43 +/- 9 to 65 +/- 11 ml [middle dot] 100 g-1 [middle dot] min-1;P < 0.05).