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.     

Human Chest Wall Function while Awake and during Halothane Anesthesia: II. Carbon Dioxide Rebreathing

Background: Changes in the distribution of respiratory drive to different respiratory muscles may contribute to respiratory depression produced by halothane. The aim of this study was to examine factors that are responsible for halothane-induced depression of the ventilatory response to carbon dioxide rebreathing.

Methods: In six human subjects, respiratory muscle activity in the parasternal intercostal, abdominal, and diaphragm muscles was measured using fine-wire electromyography electrodes. Chest wall motion was determined by respiratory impedance plethysmography. Electromyography activities and chest wall motion were measured during hyperpnea produced by carbon dioxide rebreathing while the subjects were awake and during 1 MAC halothane anesthesia.

Results: Halothane anesthesia significantly reduced the slope of the response of expiratory minute ventilation to carbon dioxide (from 2.88 plus/minus 0.73 (mean plus/minus SE) to 2.01 plus/minus 0.45 l *symbol* min sup -1 *symbol* mmHg sup -1). During the rebreathing period, breathing frequency significantly increased while awake (from 10.3 plus/minus 1.4 to 19.7 plus/minus 2.6 min sup -1, P < 0.05) and significantly decreased while anesthetized (from 28.8 plus/minus 3.9 to 21.7 plus/minus 1.9 min sup -1, P < 0.05). Increases in respiratory drive to the phrenic motoneurons produced by rebreathing, as estimated by the diaphragm electromyogram, were enhanced by anesthesia. Anesthesia attenuated the response of parasternal electromyography and accentuated the response of the transversus abdominis electromyography to rebreathing. The compartmental response of the ribcage to rebreathing was significantly decreased by anesthesia (from 1.83 plus/minus 0.58 to 0.48 plus/minus 0.13 l *symbol* min sup -1 *symbol* mmHg sup -1), and marked phase shifts between ribcage and abdominal motion developed in some subjects. However, at comparable tidal volumes, the ribcage contribution to ventilation was similar while awake and anesthetized in four of the six subjects.     

Myocardial Effects of Propofol in Hamsters with Hypertrophic Cardiomyopathy

Background: Propofol is a short-acting intravenous induction agent that induces cardiovascular depression but without significant effect no intrinsic myocardial contractility in various species. However, its effects on diseased myocardium remain unknown.

Methods: The effects of propofol (1, 3, and 10 micro gram *symbol* ml sup -1) on the intrinsic contractility of left ventricular papillary muscles from normal hamsters and those with hypertrophic cardiomyopathy (strain BIO 14.6, aged 6 months) were investigated in vitro (Krebs-Henseleit solution, 29 degrees Celsius, pH 7.40, Calcium sup +1 2.5 mmol *symbol* l [1], stimulation frequency 3/min).

Results: Cardiac hypertrophy (143 plus/minus 13%, P < 0.001) was observed in cardiomyopathic hamsters. The contractility of papillary muscles from hamsters with cardiomyopathy was less than that of controls, as shown by the decrease in maximum shortening velocity (29%, P < 0.03) and active isometric force (-51%, P < 0.03) and active isometric force (-51%, P < 0.001). Propofol did not induce any significant effect on contraction, relaxation, and contraction-relaxation coupling under low and high loads in normal hamsters. The effects of propofol were not significantly different between normal hamsters and those with cardiomyopathy. A slight but significant increase in maximum unloaded shortening velocity was observed in cardiomyopathic hamsters at 3 micro gram *symbol* ml sup -1 (4 plus/minus 6%, P < 0.05) and 10 micro gram *symbol* ml sup -1 (7 plus/minus 6%, P < 0.05).     

pH-Stat Management Reduces the Cerebral Metabolic Rate for Oxygen during Profound Hypothermia (17 degrees Celsius): A Study during Cardiopulmonary Bypass in Rabbits

Background: Greater cerebral metabolic suppression may increase the brain's tolerance to ischemia. Previous studies examining the magnitude of metabolic suppression afforded by profound hypothermia suggest that the greater arterial carbon dioxide tension of pH-stat management may increase metabolic suppression when compared with alpha-stat management.

Methods: New Zealand White rabbits, anesthetized with fentanyl and diazepam, were maintained during cardiopulmonary bypass (CPB) at a brain temperature of 17 degrees Celsius with alpha-stat (group A, n = 9) or pH-stat (group B, n = 9) management. Measurements of brain temperature, systemic hemodynamics, arterial and cerebral venous blood gases and oxygen content, cerebral blood flow (CBF) (radiolabeled microspheres), and cerebral metabolic rate for oxygen (CMRO2) (Fick) were made in each animal at 65 and 95 min of CPB. To control for arterial pressure and CBF differences between techniques, additional rabbits underwent CPB at 17 degrees Celsius. In group C (alpha-stat, n = 8), arterial pressure was decreased with nitroglycerin to values observed with pH-stat management. In group D (pH-stat, n = 8), arterial pressure was increased with angiotensin II to values observed with alpha-stat management. In groups C and D, CBF and CMRO2 were determined before (65 min of CPB) and after (95 min of CPB) arterial pressure manipulation.

Results: In groups A (alpha-stat) and B (pH-stat), arterial pressure; hemispheric CBF (44 plus/minus 17 vs. 21 plus/minus 4 ml *symbol* 100 g sup -1 *symbol* min sup -1 [median plus/minus quartile deviation]; P = 0.017); and CMRO2 (0.54 plus/minus 0.13 vs. 0.32 plus/minus 0.10 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min sup -1; P = 0.0015) were greater in alpha-stat than in pH-stat animals, respectively. As a result of arterial pressure manipulation, in groups C (alpha-stat) and D (pH-stat) neither arterial pressure (75 plus/minus 2 vs. 78 plus/minus 2 mm Hg) nor hemispheric CBF (40 plus/minus 10 vs. 48 plus/minus 6 ml *symbol* 100 g sup -1 *symbol* min sup -1; P = 0.21) differed between alpha-stat and pH-stat management, respectively. Nevertheless, CMRO2 was greater in alpha-stat than in pH-stat animals (0.71 plus/minus 0.10 vs. 0.45 plus/minus 0.10 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min sup -1, respectively; P = 0.002).     

Effect of Halothane Anesthesia on Glucose Utilization and Production in Adolescents

Background: It should be possible to avoid variations in plasma glucose concentration during anesthesia by adjusting glucose infusion rate to whole-body glucose uptake. To study this hypothesis, we measured glucose utilization and production, before and during halothane anesthesia.

Methods: After an overnight fast, six adolescents between 12 and 17 yr of age were infused with tracer doses of [6,6-sup 2 H2]glucose for 2 h before undergoing anesthesia, and the infusion was continued after induction, until the beginning of surgery. Plasma glucose concentration was monitored throughout, and free fatty acids, lactate, insulin, and glucagon concentrations were measured before and during anesthesia.

Results: Despite the use of a glucose-free maintenance solution, plasma glucose concentration increased slightly but significantly 5 min after induction (5.3 plus/minus 0.4 vs. 4.5 plus/minus 0.4 mmol *symbol* 1 sup -1 , P < 0.05). This early increase corresponded to a significant increase in endogenous glucose production over basal conditions (4.1 plus/minus 0.4 vs. 3.6 plus/minus 0.2 mg *symbol* kg sup -1 *symbol* min sup -1, P < 0.05), with no concomitant change in peripheral glucose utilization. Fifteen minutes after induction, both glucose utilization and production rates decreased steadily and were 20% less than basal values by 35 min after induction (2.9 plus/minus 0.3 vs. 3.6 plus/minus 0.2 mg *symbol* kg sup -1 *symbol* min sup -1, P < 0.05). Similarly, glucose metabolic clearance rate decreased by 25% after 35 min. Despite the increase in blood glucose concentration, anesthesia resulted in a significant decrease in plasma insulin concentration.     

The Relation between Cerebral Metabolic Rate and Ischemic Depolarization: A Comparison of the Effects of Hypothermia, Pentobarbital, and Isoflurane

Background: Reductions in cerebral metabolic rate may increase the brain's tolerance of ischemia. However, outcome studies suggest that reductions in cerebral metabolic rate produced by anesthetics and by hypothermia may not be equally efficacious. To examine this question, we measured the effects of hypothermia, pentobarbital, and isoflurane on the cerebral metabolic rate for glucose (CMRG) and on the time to the loss of normal membrane ion gradients (terminal ischemic depolarization) of the cortex during complete global ischemia.

Methods: As pericranial temperature was varied between 39 and 25 degrees Celsius in normocapnic halothane-anesthetized rats, CMRG (using14 Carbon-deoxyglucose) or the time to depolarization (using a glass microelectrode in the cortex) after a Potassium sup + -induced cardiac arrest was measured. In other studies, CMRG and depolarization times were measured in normothermic animals (37.7 plus/minus 0.2 degree Celsius) anesthetized with high-dose pentobarbital or isoflurane (both producing burst suppression on the electroencephalogram) or in halothane-anesthetized animals whose temperatures were reduced to 27.4 plus/minus 0.3 degree Celsius. These three states were designed to produce equivalent CMRG values.

Results: As temperature was reduced from 39 to 25 degrees Celsius, CMRG decreased from 66 to 21 micro Meter *symbol* 100 g sup -1 *symbol* min1 (Q10 = 2.30), and depolarization times increased from 76 to 326 s. In similarly anesthetized animals at approximately 27 degrees Celsius, CMRG was 32 plus/minus 4 micro Meter *symbol* 100 g sup -1 *symbol* min sup -1 (mean plus/minus SD), whereas in normothermic pentobarbital- and isoflurane-anesthetized rats, CMRG values were 33 plus/minus 3 and 37 plus/minus 4 micro Meter *symbol* 100 g1 *symbol* min sup -1, respectively (P = 0.072 by one-way analysis of variance). Despite these similar metabolic rates, the times to depolarization were markedly different: for hypothermia it was 253 plus/minus 29 s, for pentobarbital 109 plus/minus 24 s, and for isoflurane 130 plus/minus 28 s (P < 0.0001).     

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.     

Consequences of Electroencephalographic-suppressive Doses of Propofol in Conjunction with Deep Hypothermic Circulatory Arrest

Background: Some patients who undergo cerebral aneurysm surgery require cardiopulmonary bypass and deep hypothermic circulatory arrest. During bypass, these patients often are given large doses of a supplemental anesthetic agent in the hope that additional cerebral protection will be provided. Pharmacologic brain protection, however, has been associated with undesirable side effects. These side effects were evaluated in patients who received large doses of propofol.

Methods: Thirteen neurosurgical patients underwent cardiopulmonary bypass and deep hypothermic circulatory arrest to facilitate clip application to a giant or otherwise high-risk cerebral aneurysm. Electroencephalographic burst suppression was established before bypass with an infusion of propofol, and the infusion was continued until the end of surgery. Hemodynamic and echocardiographic measurements were made before and during the prebypass propofol infusion and again after bypass. Emergence time also was determined.

Results: Prebypass propofol at 243 plus/minus 57 micro gram *symbol* kg sup -1 *symbol* min sup -1 decreased vascular resistance from 34 plus/minus 8 to 27 plus/minus 8 units without changing heart rate, arterial or filling pressures, cardiac index, stroke volume, or ejection fraction. Propofol blood concentration was 8 plus/minus 2 micro gram/ml. Myocardial wall motion appeared hyperdynamic at the end of cardiopulmonary bypass, and all patients were weaned therefrom without inotropic support. After bypass, vascular resistance decreased further, and cardiovascular performance was improved compared to baseline values. Nine of the 13 patients emerged from anesthesia and were able to follow commands at 3.1 plus/minus 1.4 h. Three others had strokes and a fourth had cerebral swelling.     

Propofol Linearly Reduces the Vasoconstriction and Shivering Thresholds

Background: Skin temperature is best kept constant when determining response thresholds because both skin and core temperatures contribute to thermoregulatory control. In practice, however, it is difficult to evaluate both warm and cold thresholds while maintaining constant cutaneous temperature. A recent study shows that vasoconstriction and shivering thresholds are a linear function of skin and core temperatures, with skin contributing 20 plus/minus 6% and 19 plus/minus 8%, respectively. (Skin temperature has long been known to contribute [nearly equal] 10% to the control of sweating.) Using these relations, we were able to experimentally manipulate both skin and core temperatures, subsequently compensate for the changes in skin temperature, and finally report the results in terms of calculated core- temperature thresholds at a single designated skin temperature.

Methods: Five volunteers were each studied on 4 days: (1) control; (2) a target blood propofol concentration of 2 micro gram/ml; (3) a target concentration of 4 micro gram/ml; and (4) a target concentration of 8 micro gram/ml. On each day, we increased skin and core temperatures sufficiently to provoke sweating. Skin and core temperatures were subsequently reduced to elicit peripheral vasoconstriction and shivering. We mathematically compensated for changes in skin temperature by using the established linear cutaneous contributions to the control of sweating (10%) and to vasoconstriction and shivering (20%). From these calculated core-temperature thresholds (at a designated skin temperature of 35.7 degrees Celsius), the propofol concentration- response curves for the sweating, vasoconstriction, and shivering thresholds were analyzed using linear regression. We validated this new method by comparing the concentration-dependent effects of propofol with those obtained previously with an established model.

Results: The concentration-response slopes for sweating and vasoconstriction were virtually identical to those reported previously. Propofol significantly decreased the core temperature triggering vasoconstriction (slope = 0.6 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.98 plus/minus 0.02) and shivering (slope = 0.7 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.95 plus/minus 0.05). In contrast, increasing the blood propofol concentration increased the sweating threshold only slightly (slope = 0.1 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.46 plus/minus 0.39).     

Comparative Systemic Toxicity of Ropivacaine and Bupivacaine in Nonpregnant and Pregnant Ewes

Background: Ropivacaine is a new amide local anesthetic, having therapeutic properties similar to those of bupivacaine but with a wider margin of safety. Bupivacaine is probably the most commonly used drug in obstetric epidural analgesia, even though laboratory studies have suggested that pregnancy increases the cardiotoxicity of bupivacaine but not of other local anesthetics. The current study was designed to reevaluate, in a random and blinded fashion, the systemic toxicity of bupivacaine and ropivacaine in nonpregnant and pregnant sheep.

Methods: Chronically prepared nonpregnant and pregnant ewes were randomized to receive an intravenous infusion of ropivacaine or bupivacaine at a constant rate of 0.5 mg *symbol* kg sup -1 *symbol* min sup -1 until circulatory collapse. The investigators were blinded to the identity of local anesthetic. Heart rate, arterial blood pressure, and cardiac rhythm were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations, which appeared in the following sequence: convulsions, hypotension, apnea, and circulatory collapse. Serum drug concentrations and protein binding were determined. Blood pH and gas tensions were measured.

Results: There were no significant differences between nonpregnant and pregnant animals in the doses or serum concentrations of either drug required to elicit toxic manifestations. In nonpregnant animals, similar doses and serum concentrations of ropivacaine and bupivacaine were associated with the onset of convulsions and circulatory collapse. In pregnant ewes, greater doses of ropivacaine as compared to bupivacaine were required to produce convulsions (7.5 plus/minus 0.5 vs. 5.0 plus/minus 0.6 mg *symbol* kg sup -1) and circulatory collapse (12.9 plus/minus 0.8 vs. 8.5 plus/minus 1.2 mg *symbol* kg sup -1). The corresponding serum concentrations of ropivacaine were similar to those of bupivacaine. Pregnancy did not affect the serum protein binding of either drug. The proportion of animals manifesting a malignant ventricular arrhythmia as the terminal event was similar among all groups.     

Pulsatile Versus Nonpulsatile Flow: No Difference in Cerebral Blood Flow or Metabolism during Normothermic Cardiopulmonary Bypass in Rabbits

Background: Although pulsatile and nonpulsatile cardiopulmonary bypass (CPB) do not differentially affect cerebral blood flow (CBF) or metabolism during hypothermia, studies suggest pulsatile CPB may result in greater CBF than nonpulsatile CPB under normothermic conditions. Consequently, nonpulsatile flow may contribute to poorer neurologic outcome observed in some studies of normothermic CPB. This study compared CBF and cerebral metabolic rate for oxygen (CMRO2) between pulsatile and nonpulsatile CPB at 37 degrees Celsius.

Methods: In experiment A, 16 anesthetized New Zealand white rabbits were randomized to one of two pulsatile CPB groups based on pump systolic ejection period (100 and 140 ms, respectively). Each animal was perfused at 37 degrees Celsius for 30 min at each of two pulse rates (150 and 250 pulse/min, respectively). This scheme created four different arterial pressure waveforms. At the end of each perfusion period, arterial pressure waveform, arterial and cerebral venous oxygen content, CBF (microspheres), and CMRO2 (Fick) were measured. In experiment B, 22 rabbits were randomized to pulsatile (100-ms ejection period, 250 pulse/min) or nonpulsatile CPB at 37 degrees Celsius. At 30 and 60 min of CPB, physiologic measurements were made as before.

Results: In experiment A, CBF and CMRO2 were independent of ejection period and pulse rate. Thus, all four waveforms were physiologically equivalent. In experiment B, CBF did not differ between pulsatile and nonpulsatile CPB (72 plus/minus 6 vs. 77 plus/minus 9 ml *symbol* 100 g sup -1 *symbol* min1, respectively (median plus/minus quartile deviation)). CMRO2 did not differ between pulsatile and nonpulsatile CPB (4.7 plus/minus 0.5 vs. 4.1 plus/minus 0.6 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min1, respectively) and decreased slightly (0.4 plus/minus 0.4 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min1) between measurements.     

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).     

Positive End-Expiratory Pressure Ventilation Elicits Increases in Endogenously Formed Nitric Oxide as Detected in Air Exhaled by Rabbits

Background: Nitric oxide (NO) formed from L-arginine is exhaled by mammals and regulates pulmonary vascular tone. Little is known about how its formation is stimulated.

Methods: The concentration of NO in exhaled air was monitored by chemiluminescence in pentobarbital-anesthetized rabbits receiving mechanical ventilation by tracheostomy with graded positive end-expiratory pressure (PEEP).

Results: Introduction of PEEP (2.5-15 cmH2 O) elicited dose-dependent and reproducible increments in exhaled NO and in arterial oxygen tension (PaO2). The increase in exhaled NO exhibited a biphasic pattern, with an initial peak followed by a partial reversal during the 4-min period at each level of PEEP. Thus, at a PEEP of 10 cmH sub 2 O, exhaled NO initially increased from 19 plus/minus 4 to 30 plus/minus 5 parts per billion (ppb) (P < 0.001, n = 9) and then decreased to 27 plus/minus 5 ppb (P < 0.005) at the end of the 4-min observation period. Simultaneously, PaO2 increased from 75 plus/minus 12 mmHg in the control situation to 105 plus/minus 11 mmHg (P < 0.05) at a PEEP of 10 cmH2 O. After bilateral vagotomy, including bilateral transection of the depressor nerves, the increase in exhaled NO in response to PEEP was significantly reduced (P < 0.01). Thus, after vagotomy, a PEEP of 10 cmH2 O elicited an increase in the concentration of exhaled NO from 13 plus/minus 3 to 17 plus/minus 3 ppb (n = 7). Vagotomy did not affect the baseline concentration of NO in exhaled air. The PEEP-induced increments in PaO2 were not affected by the NO synthase inhibitor L-Nomega-arginine-methylester (30 mg *symbol* kg sup -1 intravenously). In open-chest experiments, PEEP (10 cmH2 O) induced a reduction in cardiac output from 317 plus/minus 36 to 235 plus/minus 30 ml *symbol* min sup -1 and an increase in exhaled NO from 23 plus/minus 6 to 30 plus/minus 7 ppb (P < 0.05, n = 5). Reduction in cardiac output from 300 plus/minus 67 to 223 plus/minus 52 ml *symbol* min sup -1 by partial obstruction of the pulmonary artery did not significantly increase exhaled NO (from 23 plus/minus 7 to 25 plus/minus 6, difference not significant; n = 3).     

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.     

Multicenter Study of Target-Controlled Infusion of Propofol-Sufentanil or Sufentanil-Midazolam for Coronary Artery Bypass Graft Surgery

Background: The use of target-controlled infusions of anesthetics for coronary artery bypass graft surgery has not been studied in detail. The effects of target-controlled infusions of propofol or sufentanil, supplemented by infusions of sufentanil or midazolam, respectively, were evaluated and compared.

Methods: At 14 clinical sites, 329 patients were given a target-controlled infusion of propofol (n = 165) to produce effect-site concentration (Ce) of greater or equal to 3-micro gram/ml or a target-controlled infusion of sufentanil (n = 164). Sufentanil or midazolam, respectively, also were infused. Systolic hypertension, hypotension, tachycardia, and bradycardia were assessed by measuring heart rate and blood pressure every minute during operation. Myocardial ischemia was assessed perioperatively by monitoring ST segment deviation via continuous three-lead Holter electrocardiography, and it was evaluated during operation by monitoring left ventricular wall motion abnormality via transesophageal echocardiography.

Results: The measured cardiovascular parameters were satisfactory and usually similar for the patients receiving propofol-sufentanil or sufentanil-midazolam. The primary endpoint of the percentage of patients with intraoperative ST segment deviation (23 plus/minus 6% vs. 24 plus/minus 6%, P = 0.86) did not differ significantly between the two groups. The incidence of left ventricular wall motion abnormality shown on transesophageal echocardiography before (19 plus/minus 4% vs. 26 plus/minus 4%, P = 0.25) and after (23 plus/minus 4% vs. 31 plus/minus 5%, P = 0.32) cardiopulmonary bypass also did not differ significantly for the two groups. Changes in intraoperative target concentration were more frequent with propofol-sufentanil anesthetic than with sufentanil-midazolam (11.7 plus/minus 7.1 vs. 7.3 plus/minus 3.6, P <0.001). The incidence of intraoperative hypotension (77% vs. 55%, P <0.001), the use of inotropic/vasopressor medications (93% vs. 84%, P = 0.01), and the administration of crystalloids (2.8 plus/minus 1.4 L vs. 2.4 plus/minus 1.2 L, P < 0.001) were significantly greater in the propofol-sufentanil group. Conversely, the incidence of intraoperative hypertension (43% vs. 54%, P = 0.05) and the use of antihypertensive/vasodilator medications (70% vs. 90%, P < 0.001) were significantly less in the propofol-sufentanil group.     

Clonidine Modulation of Hemodynamic and Catecholamine Responses Associated with Hypoxia or Hypercapnia in Dogs

Background: Hypoxia or hypercapnia elicits cardiovascular responses associated with increased plasma catecholamine concentrations, whereas clonidine, an alpha2 -adrenergic agonist, decreases plasma catecholamine concentrations. The authors examined whether systemic clonidine administration would alter the hemodynamic and catecholamine responses to hypoxia or hypercapnia in anesthetized dogs.

Methods: Pentobarbital-anesthetized dogs whose lungs were mechanically ventilated were instrumented for measurement of mean arterial pressure, heart rate, mean pulmonary artery pressure, right atrial pressure, cardiac output, left ventricular end-diastolic pressure, and the peak of first derivative of left ventricular pressure. The dogs were randomly assigned to receive an intravenous bolus injection of 10 micro gram/kg clonidine followed by continuous infusion at a rate of 1 micro gram *symbol* kg sup -1 *symbol* min sup -1 (clonidine-10 group, n = 7), an intravenous bolus injection of 5 micro gram/kg clonidine followed by continuous infusion at a rate of 0.5 micro gram *symbol* kg sup -1 *symbol* min sup -1 (clonidine-5 group, n = 7), or an equivalent volume of 0.9% saline (control group, n = 7). Each dog underwent random challenges of hypoxia (PaO2 30, 40, and 50 mmHg) and hypercapnia (PaCO sub 2 60, 80, and 120 mmHg). Measurements of hemodynamic and plasma norepinephrine and epinephrine concentrations were made during each period of hypoxia or hypercapnia, and measurements of plasma clonidine concentrations were made after the loading dose of clonidine and the first and the second exposure of hypoxia or hypercapnia.

Results: Although significant increases from prehypoxic values in mean arterial pressure (39+/-10 mmHg) and plasma norepinephrine (291+/-66 pg/ml) and epinephrine (45+/-22 pg/ml) concentrations were noted during hypoxia of PaO2 30 mmHg in the control group (P < 0.05), such changes were absent in both clonidine groups. During hypercapnia of PaCO2, 120 mmHg, changes from prehypercapnic values in mean arterial pressure, mean pulmonary artery pressure, the peak of first derivative of left ventricular pressure, and plasma norepinephrine and epinephrine concentrations in the clonidine-10 and clonidine-5 groups were significantly less than those in the control group. Plasma clonidine concentrations in the clonidine-10 and clonidine-5 groups were 16.8+/-1.7 and 8.9+/-1.0, 42.5+/- 2.9 and 21.5+/-1.5, and 51.1+/-3.2 and 26.7+/- 1.0 ng/ml after the loading dose of clonidine and the first and the second exposure of hypoxia or hypercapnia, respectively.     

Effects of Ventilation on Hemodynamics and Myocardial Blood Flow during Active Compression-Decompression Resuscitation in Pigs

Background: Active compression-decompression (ACD) improves hemodynamics and vital organ blood flow during cardiopulmonary resuscitation. The effects of intermittent positive pressure ventilation (IPPV) on ACD have not been studied. This study was designed to compare the effects of ACD with and without IPPV on gas exchange, hemodynamics, and myocardial blood flow.

Methods: After 30 s ventricular fibrillation, 14 tracheally intubated pigs were allocated to receive either ACD combined with IPPV (ACD-IPPV) or ACD alone. In animals treated with ACD-IPPV, the lungs were ventilated using a servo ventilator. Animals treated with ACD received 100% oxygen by a reservoir but ventilation was not assisted.

Results: Minute ventilation (median) was 6.5 and 6.1 l/min after 1 and 7 min of ACD-IPPV, and was 4.2 and 1.6 l/min after 1 and 7 min of ACD. In contrast to ACD-IPPV, PaO2 was less and PaCO2 was greater with ACD. Mean arterial (53 and 40 mmHg; P < 0.05) and mean central venous pressure (25 and 14 mmHg; P < 0.01) were greater during ACD-IPPV as compared with ACD. After administration of epinephrine 0.2 mg/kg, myocardial blood flow increased only in ACD-IPPV treated animals, and 5 min after epinephrine administration, myocardial blood flow was greater during ACD-IPPV (33 ml *symbol* min sup -1 *symbol* 100 g sup -1) as compared with ACD (15 ml *symbol* min sup -1 *symbol* 100 g sup -1; P < 0.05). Restoration of spontaneous circulation could be achieved only in animals subjected to ACD-IPPV.     

Protective Effect of Stroma-free Methemoglobin during Cyanide Poisoning in Dogs

Background: During fire exposure, cyanide toxicity can block aerobic metabolism. Oxygen and sodium thiosulfate are accepted therapy. However, nitrite-induced methemoglobinemia, which avidly binds cyanide, decreases oxygen-carrying capacity that is already reduced by the presence of carboxyhemoglobin (inhalation of carbon monoxide in smoke). This study tested whether exogenous stroma-free methemoglobin (SFmetHb) can prevent depression of hemodynamics and metabolism during canine cyanide poisoning.

Methods: In 10 dogs (weighing 18.8 plus/minus 3.5 kg) anesthetized with chloralose-urethane and mechanically ventilated with air, baseline hemodynamic and metabolic measurements were made. Then, 137 plus/minus 31 ml of 12 g% SFmetHb was infused into five dogs (SFmetHb group). Finally, the SFmetHb group and the control group (n = 5, no SFmetHb) received an intravenous potassium cyanide infusion (0.072 mg *symbol* kg sup -1 *symbol* min sup -1) for 20 min. Oxygen consumption (V with dot sub O2) was measured with a Datex Deltatrac (Datex Instruments, Helsinki, Finland) metabolic monitor and cardiac output (Q with dot T) was measured by pulmonary artery thermodilution.

Results: From baseline to cyanide infusion in the control group, Q with dot T decreased significantly (p < 0.05) from 2.9 plus/minus 0.8 to 1.5 plus/minus 0.4 l/min, mixed venous PCO2 (Pv with barCO2) tended to decrease from 35 plus/minus 4 to 23 plus/minus 2 mmHg, Pv with barO2 increased from 43 plus/minus 4 to 62 plus/minus 8 mmHg, V with dotO2 decreased from 93 plus/minus 8 to 64 plus/minus 19 ml/min, and lactate increased from 2.3 plus/minus 0.5 to 7.1 plus/minus 0.7 mM. In the SFmetHb group, cyanide infusion did not significantly change these variables. From baseline to infused cyanide, the increases in blood cyanide (4.8 plus/minus 1.0 to 452 plus/minus 97 micro Meter) and plasma thiocyanate cyanide (18 plus/minus 5 to 65 plus/minus 22 micro Meter) in the SFmetHb group were significantly greater than those increases in the control group. SFmetHb itself caused no physiologic changes, except small decreases in heart rate and Pv with barO2. Peak SFmetHb reached 7.7 plus/minus 1.0% of total hemoglobin.     

高渗氯化钠羟乙基淀粉40注射液高容量血液稀释对大鼠肝脏缺血再灌注损伤的影响

目的 探讨高渗氯化钠羟乙基淀粉40注射液高容量血液稀释对大鼠肝脏缺血再灌注损伤的影响.方法 雄性Wistar大鼠30只,体重300～350 g,随机分为3组(n=10):假手术组(S组)、缺血再灌注组(IR组)和高容量血液稀释组(HH组).S组仅开腹,不阻断血管;IR组阻断肝门静脉和左肝动脉30 min,再灌注2 h;HH组30 min内经尾静脉输注高渗氯化钠羟乙基淀粉40注射液10 ml/kg进行高容量血液稀释,输注完毕后15 min,行肝脏缺血再灌注.再灌注2 h时,下腔静脉取血样,测定血清谷丙转氨酶(ALT)和谷草转氨酶(AST)的活性;取左肝叶组织,光镜下观察病理学结果,采用比色法测定丙二醛(MDA)含量,采用黄嘌呤氧化酶法测定超氧化物歧化酶(SOD)活性.结果 与S组比较,IR组和HH组血清ALT和AST的活性、肝组织MDA含量升高,肝组织SOD活性降低(P<0.01),肝组织病理学损伤明显;与IR组比较,HH组血清ALT和AST的活性、肝组织MDA含量降低,肝组织SOD活性升高(P<0.01),肝组织病理学损伤减轻.结论 高渗氯化钠羟乙基淀粉40注射液高容量血液稀释可减轻大鼠肝脏缺血再灌注损伤,可能与氧自由基生成减少有关.     

Anesthetics Affect the Uptake but Not the Depolarization-evoked Release of GABA in Rat Striatal Synaptosomes

Background: Numerous classes of anesthetic agents have been shown to enhance the effects mediated by the postsynaptic gamma-aminobutyric acid A (GABAA) receptor-coupled chloride channel in the mammalian central nervous system. However, presynaptic actions of anesthetics potentially relevant to clinical anesthesia remain to be clarified. Therefore, in this study, the effects of intravenous and volatile anesthetics on both the uptake and the depolarization-evoked release of GABA in the rat stratum were investigated.

Methods: Assay for specific GABA uptake was performed by measuring the radioactivity incorporated in purified striatal synaptosomes incubated with3 H-GABA (20 nM, 5 min, 37 degrees Celsius) and increasing concentrations of anesthetics in either the presence or the absence of nipecotic acid (1 mM, a specific GABA uptake inhibitor). Assay for GABA release consisted of superfusing3 H-GABA preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml *symbol* min sup 1, 37 degrees Celsius) and measuring the radioactivity obtained from 0.5 ml fractions over 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of either KCl alone (9 mM, 15 mM) or with various concentrations of anesthetics (5 min), and finally, with no pharmacologic stimulation (5 min). The following anesthetic agents were tested: propofol, etomidate, thiopental, ketamine, halothane, enflurane, isoflurane, and clonidine.

Results: More than 95% of3 H-GABA uptake was blocked by a 10 sup 3 -M concentration of nipecotic acid. Propofol, etomidate, thiopental, and ketamine induced a dose-related, reversible, noncompetitive, inhibition of3 H-GABA uptake: IC50 = 4.6 plus/minus 0.3 x 105 M, 5.8 plus/minus 0.3 x 10 sup -5 M, 2.1 plus/minus 0.4 x 10 sup -3 M, and 4.9 plus/minus 0.5 x 10 sup -4 M for propofol, etomidate, thiopental, and ketamine, respectively. Volatile agents and clonidine had no significant effect, even when used at concentrations greater than those used clinically. KCl application induced a significant, calcium-dependent, concentration-related, increase from basal3 H-GABA release, +34 + 10% (P < 0.01) and +61 plus/minus 13% (P < 0.001), respectively, for 9 mM and 15 mM KCl. The release of3 H-GABA elicited by KCl was not affected by any of the anesthetic agents tested.