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.     

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).     

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).     

Ventilatory Response to Hypoxia in Humans: Influences of Subanesthetic Desflurane

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

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

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

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.     

Methohexital Impairs Osmoregulation: Studies in Conscious and Anesthetized Volume-expanded Dogs

Background: Anesthetic agents influence central regulations. This study investigated the effects of methohexital anesthesia on renal and hormonal responses to acute sodium and water loading in dogs in the absence of surgical stress.

Methods: Fourteen experiments (two in each dog) were performed in seven well-trained, chronically tracheotomized beagle dogs kept in highly standardized environmental and dietary conditions (2.5 mmol sodium and 91 ml water/kg body weight daily). Experiments lasted 3 h, while the dogs were conscious (7 experiments) or, after 1 h control, while they were anesthetized (7 experiments) with methohexital (initial dose 6.6 mg/kg body weight and maintenance infusion 0.34 mg *symbol* min sup -1 *symbol* kg sup -1 body weight) over a period of 2 h. In both experiments, extracellular volume expansion was performed by intravenous infusion of a balanced isoosmolar electrolyte solution (0.5 ml *symbol* min sup -1 *symbol* kg sup -1 body weight). Normal arterial blood gases were maintained by controlled mechanical ventilation. In another five dogs the same protocol was used, and vasopressin (0.05 mU *symbol* min sup -1 *symbol* kg sup -1 body weight) was infused intravenously during methohexital anesthesia.

Results: Values are given as means. During methohexital anesthesia, mean arterial pressure decreased from 108 to 101 mmHg, and heart rate increased from 95 to 146 beats/min. Renal sodium excretion decreased; urine volume increased; and urine osmolarity decreased from 233 to 155 mosm/l, whereas plasma osmolarity increased from 301 to 312 mosm/l because of an increase in plasma sodium concentration from 148 to 154 mmol/l. Plasma renin activity, plasma aldosterone concentration, plasma atrial natriuretic peptide, and plasma antidiuretic hormone concentrations (range 1.8-2.8 pg/ml) did not change in either protocol. In the presence of exogenous vasopressin (antidiuretic hormone 3.3 pg/ml), water diuresis did not occur, and neither plasma osmolarity nor the plasma concentration of sodium changed.     

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.     

Tourniquet-induced Exsanguination in Patients Requiring Lower Limb Surgery: An Ischemia-Reperfusion Model of Oxidant and Antioxidant Metabolism

Background: Surgically induced ischemia and reperfusion is frequently accompanied by local and remote organ injury. It was hypothesized that this procedure may produce injurious oxidants such as hydrogen peroxide (H2 O2), which, if unscavenged, will generate the highly toxic hydroxyl radical (*symbol* OH). Accordingly, it was proposed that tourniquet-induced exsanguination for limb surgery may be a useful ischemia-reperfusion model to investigate the presence of oxidants, particularly H2 O2.

Methods: In ten patients undergoing knee surgery, catheters were placed in the femoral vein of the limb operated on for collection of local blood and in a vein of the arm for sampling of systemic blood. Tourniquet-induced limb exsanguination was induced for about 2 h. After tourniquet release (reperfusion), blood samples were collected during a 2-h period for measurement of H2 O2, xanthine oxidase activity, xanthine, uric acid (UA), glutathione, and glutathione disulfide.

Results: At 30 s of reperfusion, H2 O2 concentrations increased ([nearly equal] 90%) from 133+/-5 to 248+/-8 nmol *symbol* ml sup -1 (P < 0.05) in local blood samples, but no change was evident in systemic blood. However, in both local and systemic blood, xanthine oxidase activity increased [nearly equal] 90% (1.91+/- 0.07 to 3.93+/-0.41 and 2.19+/-0.07 to 3.57+/- 0.12 nmol UA *symbol* ml sup -1 *symbol* min sup -1, respectively) as did glutathione concentrations (1.27+/-0.04 to 2.69+/-0.14 and 1.27+/-0.03 to 2.43+/-0.13 micro mol *symbol* ml sup -1, respectively). At 5 min reperfusion, in local blood, H2 O2 concentrations and xanthine oxidase activity peaked at 796+/-38 nmol *symbol* ml sup -1 ([nearly equal] 500%) and 11.69+/-1.46 nmol UA *symbol* ml sup -1 *symbol* min sup -1 ([nearly equal] 520%), respectively. In local blood, xanthine and UA increased from 1.49 +/-0.07 to 8.36+/-0.33 nmol *symbol* ml sup -1 and 2.69 +/-0.16 to 3.90+/-0.18 micro mol *symbol* ml sup -1, respectively, whereas glutathione and glutathione disulfide increased to 5.13+/-0.36 micro mol *symbol* ml sup -1 and 0.514+/- 0.092 nmol *symbol* ml sup -1, respectively. In systemic blood, xanthine oxidase activity peaked at 4.75+/-0.20 UA nmol *symbol* ml sup -1 *symbol* min sup -1. At 10 min reperfusion, local blood glutathione and UA peaked at 7.08+/-0.46 micro mol *symbol* ml sup -1 and 4.67 +/-0.26 micro mol *symbol* ml sup -1, respectively, while the other metabolites decreased significantly toward pretourniquet levels. From 20 to 120 min, most metabolites returned to pretourniquet levels; however, local and systemic blood xanthine oxidase activity remained increased 3.76+/-0.29 and 3.57+/-0.37 nmol UA *symbol* ml sup -1 *symbol* min sup -1, respectively. Systemic blood H2 O2 was never increased during the study. During the burst period ([nearly equal] 5-10 min), local blood H2 O2 concentrations and xanthine oxidase activities were highly correlated (r = 0.999).     

Anesthetic Potency of Remifentanil in Dogs

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

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

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

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

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

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

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

Effects of Thiopental on Regional Blood Flows in the Rat

Background: The goal of this investigation was to characterize the effects of thiopental on cardiac output and regional blood flows in the rat. Blood flows influence thiopental pharmacokinetics. Acquisition of these data may ultimately permit evaluation of the contribution of thiopental-induced alterations in regional blood flows to the disposition and hypnotic effect of this drug.

Methods: Chronically instrumented unrestrained Wistar rats (n = 20) aged 3-4 months received either a dose of thiopental sufficient to induce a brief period of unconsciousness (20 mg *symbol* kg sup -1) or a larger dose achieving electroencephalographic burst suppression (45 mg *symbol* kg sup -1). Cardiac output and blood flows to 14 tissues were determined at 4 times in each rat for a period of 420 min using injections of radioactive microspheres (expressed as mean+/-SD). Mean arterial pressure, heart rate, and blood gas tensions were determined at all measurement times. Arterial plasma concentrations we sampled at postinfusion times.

Results: No important changes in systemic cardiovascular measurements were detected after the smaller dose of thiopental. One minute after the larger dose, cardiac output decreased from baseline (123+/-14 to 84+/-11 ml *symbol* min sup -1, P < 0.01), flow to muscle and fat decreased, and muscle and fat resistance increased. At 5 min, compared to baseline, no difference in cardiac output was detected (123+/-14 vs. 119+/-11 ml *symbol* min sup -1), intestinal flows increased, and intestinal resistances decreased. Cardiac output was again depressed at 30, 90, and 180 min. Brain blood flow decreased 25+/-19% (P < 0.01) from baseline for the duration of the study.     

The effects of positive end-expiratory pressure during active compression decompression cardiopulmonary resuscitation with the inspiratory threshold valve

The use of an inspiratory impedance threshold valve (ITV) during active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) improves perfusion pressures, and vital organ blood flow. We evaluated the effects of positive end-expiratory pressure (PEEP) on gas exchange, and coronary perfusion pressure gradients during ACD + ITV CPR in a porcine cardiac arrest model. All animals received pure oxygen intermittent positive pressure ventilation (IPPV) at a 5:1 compression-ventilation ratio during ACD + ITV CPR. After 8 min, pigs were randomized to further IPPV alone (n = 8), or IPPV with increasing levels of PEEP (n = 8) of 2.5, 5.0, 7.5, and 10 cm H(2)O for 4 consecutive min each, respectively. Mean +/- SEM arterial oxygen partial pressure decreased in the IPPV group from 150 +/- 30 at baseline after 8 min of CPR to 110 +/- 25 torr at 24 min, but increased in the PEEP group from 115 +/- 15 to 170 +/- 25 torr with increasing levels of PEEP (P <0.02 for comparisons within groups). Mean +/- SEM diastolic aortic minus diastolic left ventricular pressure gradient was significantly (P < 0.001) higher after the administration of PEEP (24 +/- 0 vs 17 +/- 1 mm Hg with 5 cm H(2)O of PEEP, and 26 +/- 0 vs 17 +/- 1 mm Hg with 10 cm H(2)O of PEEP), whereas the diastolic aortic minus right atrial pressure gradient (coronary perfusion pressure) was comparable between groups. Furthermore, systolic aortic pressures were significantly (P < 0.05) higher with 10 cm H(2)O of PEEP when compared with IPPV alone (68 +/- 0 vs 59 +/- 2 mm Hg). In conclusion, when CPR was performed with devices designed to improve venous return to the chest, increasing PEEP levels improved oxygenation. Moreover, PEEP significantly increased the diastolic aortic minus left ventricular gradient and did not affect the decompression phase aortic minus right atrial pressure gradient. These data suggest that PEEP reduces alveolar collapse during ACD + ITV CPR, thus leading to an increase in indirect myocardial compression. IMPLICATIONS: Inspiratory impedance during active compression-decompression cardiopulmonary resuscitation improves perfusion pressures, and vital organ blood flow during cardiac arrest. Increasing levels of positive end-expiratory pressure during performance of active compression-decompression cardiopulmonary resuscitation with an inspiratory impedance valve improves oxygenation, and increases the diastolic aortic-left ventricular pressure gradient and systolic arterial blood pressure.     

Remifentanil Versus Alfentanil: Comparative Pharmacokinetics and Pharmacodynamics in Healthy Adult Male Volunteers

Background: Remifentanil is an esterase-metabolized opioid with a rapid clearance. The aim of this study was to contrast the pharmacokinetics and pharmacodynamics of remifentanil and alfentanil in healthy, adult male volunteers.

Methods: Ten volunteers received infusions of remifentanil and alfentanil on separate study sessions using a randomized, open-label crossover design. Arterial blood samples were analyzed to determine drug blood concentrations. The electroencephalogram was employed as the measure of drug effect. The pharmacokinetics were characterized using a moment analysis, a nonlinear mixed effects model (NONMEM) population analysis, and context-sensitive half-time computer simulations. After processing the raw electroencephalogram to obtain the spectral edge parameter, the pharmacodynamics were characterized using an effect compartment, inhibitory maximum effect model.

Results: Pharmacokinetically, the two drugs are similar in terms of steady-state distribution volume (VDss), but remifentanil's central clearance (CLc) is substantially greater. The NONMEM analysis population pharmacokinetic parameters for remifentanil include a CLc of 2.9 l *symbol* min sup -1, a VDss of 21.81, and a terminal half-life of 35.1 min. Corresponding NONMEM parameters for alfentanil are 0.36 l *symbol* min sup -1, 34.11, and 94.5 min. Pharmacodynamically, the drugs are similar in terms of the time required for equilibration between blood and the effect-site concentrations, as evidenced by a T12 Ke0 for remifentanil of 1.6 min and 0.96 min for alfentanil. However, remifentanil is 19 times more potent than alfentanil, with an effective concentration for 50% maximal effect of 19.9 ng *symbol* ml sup -1 versus 375.9 ng *symbol* ml sup -1 for alfentanil.     

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.     

Rapid Rewarming Causes an Increase in the Cerebral Metabolic Rate for Oxygen that Is Temporarily Unmatched by Cerebral Blood Flow: A Study during Cardiopulmonary Bypass in Rabbits

Background: Jugular venous hemoglobin desaturation during the rewarming phase of cardiopulmonary bypass is associated with adverse neuropsychologic outcome and may indicate a pathologic mismatch between cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). In some studies, rapid rewarming from hypothermic cardiopulmonary bypass results in greater jugular venous hemoglobin desaturation. The authors wished to determine if rewarming rate influences the temperature dependence of CBF and CMRO2.

Methods: Anesthetized New Zealand white rabbits, cooled to 25 degrees Celsius on cardiopulmonary bypass, were randomized to one of two rewarming groups. In the fast group (n = 9), aortic blood temperature was made normothermic over 25 min. Cerebral blood flow (microspheres) and CMRO2 (Fick) were determined at baseline (25 degrees C), and at brain temperatures of 28 degrees, 31 degrees, 34 degrees, and 37 degrees Celsius during rewarming.

Results: Systemic physiologic variables appeared similar between groups. At a brain temperature of 28 degrees C, CMRO2 was 47% greater in the fast rewarming group than in the slow group (2.2 +/-0.5 vs. 1.5+/-0.2 ml O2 *symbol* 100 g sup -1 *symbol* min sup -1, respectively; P = 0.01), whereas CBF did not differ (48+/-18 vs. 49+/-8 ml *symbol* 100 g sup -1 *symbol* min sup -1, respectively; P = 0.47). Throughout rewarming, CBF increased as a function of brain temperature but was indistinguishable between groups. Cerebral metabolic rate for oxygen differences between groups decreased as brain temperatures increased.     

Phenylephrine Increases Cerebral Blood Flow during Low-flow Hypothermic Cardiopulmonary Bypass in Baboons

Background: Although low-flow cardiopulmonary bypass (CPB) has become a preferred technique for the surgical repair of complex cardiac lesions in children, the relative hypotension and decrease in cerebral blood flow (CBF) associated with low flow may contribute to the occurrence of postoperative neurologic injury. Therefore, it was determined whether phenylephrine administered to increase arterial blood pressure during low-flow CPB increases CBF.

Methods: Cardiopulmonary bypass was initiated in seven baboons during fentanyl, midazolam, and isoflurane anesthesia. Animals were cooled at a pump flow rate of 2.5 l *symbol* min-1 *symbol* m-2 until esophageal temperature decreased to 20 degrees C. Cardiopulmonary bypass flow was then reduced to 0.5 l *symbol* min-1 *symbol* m-2 (low flow). During low-flow CPB, arterial partial pressure of carbon dioxide (PCO2) and blood pressure were varied in random sequence to three conditions: (1) PCO2 30-39 mmHg (uncorrected for temperature), control blood pressure; (2) PCO2 50-60 mmHg, control blood pressure; and (3) PCO2 30-39 mmHg, blood pressure raised to twice control by phenylephrine infusion. Thereafter, CPB flow was increased to 2.5 l *symbol* min-1 *symbol* m-2, and baboons were rewarmed to normal temperature. Cerebral blood flow was measured by washout of intraarterial133 Xenon before and during CPB.

Results: Phenylephrine administered to increase mean blood pressure from 23+/-3 to 46+/-3 mmHg during low-flow CPB increased CBF from 14+/-3 to 31+/-9 ml *symbol* min-1 *symbol* 100 g-1, P < 0.05. Changes in arterial PCO2 alone during low flow bypass produced no changes in CBF.     

Influence of Volatile Anesthetics on Left Ventricular Afterload In Vivo: Differences between Desflurane and Sevoflurane

Background: This investigation examined the effects of desflurane and sevoflurane on quantitative indices of left ventricular afterload derived from aortic input impedance (Zin) interpreted using a three-element Windkessel model.

Methods: After Animal Care Committee approval, dogs (n = 8) were chronically instrumented for measurement of systemic hemodynamics including aortic blood pressure and flow. On separate days, aortic pressure and flow waveforms were recorded under steady-state conditions in the conscious state and after equilibration for 30 min at 1.1, 1.3, 1.5, and 1.7 minimum alveolar concentration of desflurane or sevoflurane. Aortic input impedance spectra were obtained via power spectral analysis of aortic pressure and flow waveforms. Characteristic aortic impedance (Z sub c) and total arterial resistance were calculated as the mean of the magnitude of Zin between 2 and 15 Hz and the difference between Zin at zero frequency and Zc, respectively. Total arterial compliance (C) was calculated from aortic pressure and flow waveforms using the Windkessel model.

Results: Desflurane and sevoflurane increased heart rate and decreased systolic, diastolic, and mean arterial pressure, left ventricular systolic pressure, left ventricular peak positive rate of increase in left ventricular pressure, percent segment shortening, and stroke volume. Sevoflurane, but not desflurane, decreased cardiac output. Desflurane, but not sevoflurane, decreased systemic vascular resistance. Desflurane decreased R (3,170+/-188 during control to 2441 +/-220 dynes *symbol* second *symbol* centimeter sup -5 at 1.7 minimum alveolar concentration) and did not alter C and Zc. In contrast, sevoflurane increased C (0.57+/-0.05 during control to 0.79+/-0.05 ml/mmHg at 1.7 minimum alveolar concentration) and Z sub c (139+/-10 during control to 194+/-14 dynes *symbol* second *symbol* centimeter sup -5 at 1.7 minimum alveolar concentration) but did not change R.     

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.     

Prediction of Movement during Propofol/Nitrous Oxide Anesthesia: Performance of Concentration, Electroencephalographic, Pupillary, and Hemodynamic Indicators

Background: Movement in response to painful stimulation is the end point classically used to assess the potency of anesthetic agents. In this study, the ability of modeled propofol effect-site concentration to predict movement in volunteers during propofol/nitrous oxide anesthesia was tested, then it was compared with the predictive abilities of the Bispectral Index and 95% spectral edge frequency of the electroencephalogram, pupillary reflex amplitude, and systolic arterial blood pressure. In addition, the relationships between simple end points of loss and recovery of consciousness, and pupillary, hemodynamic, and propofol concentration indicators were studied.

Methods: Ten healthy volunteers were anesthetized with an infusion of propofol, which was increased in three equal steps to 21 mg *symbol* kg lean body mass sup -1 *symbol* h sup -1. After loss of the ability to hold a syringe and of the eyelash reflex, 60% nitrous oxide was introduced and the trachea was intubated without the use of muscle relaxants. The propofol infusion rate then was decreased to 15.4 mg *symbol* kg lean body mass sup -1 *symbol* h sup -1. Ten minutes later, tetanic electrical stimulation was administered to the thigh via needle electrodes: if movement was observed within 1 min, the propofol infusion rate was increased by 1.75 mg *symbol* kg lean body mass sup -1 *symbol* h sup -1 5 min after the stimulus; if not, it was similarly decreased. This 15-min sequence was repeated until volunteers "crossed over" from movement to no movement (or vice versa) four times. The propofol infusion rate then was increased to 21 mg *symbol* kg lean body mass sup -1 *symbol* h sup -1, nitrous oxide was discontinued, the trachea was extubated, and the infusion rate was decreased in five equal steps over 50 min. The times at which the eyelash reflex returned and the birth date was recalled were recorded. The electroencephalogram was monitored continuously (FP1, FP2, ref: nasion, ground: mastoid). Measurements of the pupillary response, arterial blood pressure, and heart rate were recorded during induction and awakening, just before and for 5 min after each stimulation. Arterial blood samples were obtained for propofol assay, and propofol effect-site concentrations were calculated at each time. The predictive value of indicators was compared using a new statistic, the prediction probability (PK).

Results: Loss and return of the eyelash reflex occurred at greater propofol effect-site concentrations than either dropping the syringe or recall of the birthday. The propofol effect-site concentration (in the presence of 60% nitrous oxide) predicted to prevent movement after a supramaximal stimulus in 50% of volunteers was 1.80 micro gram/ml (95% confidence limits: 1.40-2.34 micro gram/ml). The Bispectral Index (PK = 0.86), 95% spectral edge frequency (PK = 0.81), pupillary reflex amplitude (PK = 0.74), and systolic arterial blood pressure (PK = 0.78) did not differ significantly from modeled propofol effect-site concentration (PK = 0.76) in their ability to predict movement.     

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.