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.     

Sevoflurane-induced Reduction of Hypoxic Drive Is Sex-independent

Background: Although the [micro sign]-opioid agonist morphine affects ventilatory control in men and women in different ways, no data exist regarding the influence of sex on the ventilatory effects of inhalational anesthetics. The authors compared the effect of sevoflurane on the ventilatory response to isocapnic hypoxia in healthy young men and women.

Methods: Breath-to-breath ventilatory responses to hypoxic steps (number of hypoxic steps, four-six, duration, 3 min; end-tidal oxygen tension, [approximate] 50 mmHg; end-tidal carbon dioxide tension clamped at [approximate] 4 mmHg above resting values) were assessed in nine men and nine women without and with low-dose sevoflurane (end-tidal concentration, 0.25%). The bispectral index of the electroencephalogram was measured concomitantly.

Results: Sevoflurane reduced the hypoxic ventilatory sensitivity significantly in both sexes (men: control, 0.62 +/- 0.17 vs. sevoflurane, 0.38 +/- 0.19 1 [middle dot] min-1 [middle dot] %-1; women: control, 0.52 +/- 0.30 vs. sevoflurane, 0.34 +/- 0.15 1 [middle dot] min-1 [middle dot] %-1). Sevoflurane-induced reductions of the hypoxic responses were not different in the men and women. During sevoflurane inhalation, the bispectral index values decreased equally in men and women.     

Effect of Flumazenil on Ventilatory Drive during Sedation with Midazolam and Alfentanil

Background: Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine-induced depression of ventilatory drive in the presence of an opioid.

Methods: Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and "study drug" (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2-6 weeks later to receive the alternate study drug.

Results: Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 l [dot] min sup -1 [dot] mmHg sup -1 (x +/- SE, P < 0.05), and decreased the minute ventilation at PET CO2 = 50 mmHg (V with dotE 50) from 19.7 +/- 1.2 to 14.8 +/- 0.9 l [dot] min sup -1 (P < 0.05). Midazolam further reduced these variables to 0.87 +/- 0.17 l [dot] min sup -1 [dot] mmHg sup -1 (P < 0.05) and 11.7 +/- 0.8 l [dot] min sup -1 (P <0.05), respectively. With addition of flumazenil, slope and V with dot sub E 50 increased to 1.47 +/- 0.37 l [dot] min sup -1 [dot] mmHg sup -1 (P < 0.05) and 16.4 +/- 2.0 l [dot] min sup -1 (P < 0.05); after placebo, the respective values of 1.02 +/- 0.19 l [dot] min sup -1 [dot] mmHg sup -1 and 12.5 +/- 1.2 l [dot] min sup -1 did not differ significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P < 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at PET CO2 = 46 +/- 1 mmHg, were affected similarly, with flumazenil showing a significant improvement compared to placebo.     

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 mu-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 microg/kg, followed by 30 microg x kg(-1) x 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 x min(-1) x mmHg(-1) (P < 0.05) without affecting Gp (control, 0.41 +/- 0.16 and morphine, 0.49 +/- 0.12 l x min(-1) x mmHg(-1), not significant). In carbon dioxide studies in women, morphine reduced Gc, from 1.51 +/- 0.74 to 1.17 +/- 0.52 l x min(-1) x mmHg(-1) (P < 0.05), and Gp, from 0.54 +/- 0.19 to 0.39 +/- 0.22 l x min(-1) x 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 x min(-1) x %(-1), respectively; P < 0.05). The ventilatory response to sustained hypoxia (i/e., 15 min) did not differ between men and women. CONCLUSIONS: The data indicate the existence of sex differences in morphine-induced depression of responses mediated via the peripheral chemoreflex pathway, with more depression in women, but not of responses mediated via the central chemoreflex pathway. In men and women, morphine did not change the translation of the initial hyperventilatory response to short-term hypoxia into the secondary decrease in inspired minute ventilation (Vi) caused by sustained hypoxia.     

Comparison of Remifentanil and Fentanyl in Patients Undergoing Craniotomy for Supratentorial Space-occupying Lesions

Background: Remifentanil hydrochloride is an ultra-short-acting, esterase-metabolized micro-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions.

Methods: Sixty-three adults gave written informed consent for this prospective, randomized, double-blind, multiple-center trial. Anesthesia was induced with thiopental, pancuronium, nitrous oxide/oxygen, and fentanyl (n = 32; 2 micro gram [center dot] kg [center dot] sup -1 min sup -1) or remifentanil (n = 31; 1 micro [center dot] kg sup -1 [center dot] min sup -1). After tracheal intubation, infusion rates were reduced to 0.03 micro gram [center dot] kg sup -1 [center dot] min sup -1 (fentanyl) or 0.2 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil) and then adjusted to maintain anesthesia and stable hemodynamics. Isoflurane was given only after specified infusion rate increases had occurred. At the time of the first burr hole, intracranial pressure was measured in a subset of patients. At bone flap replacement either saline (fentanyl group) or remifentanil ([nearly equal] 0.2 micro gram [center dot] kg sup -1 [center dot] min sup -1) were infused until dressing completion. Hemodynamics and time to recovery were monitored for 60 min. Analgesic requirements and nausea and vomiting were observed for 24 h. Neurological examinations were performed before operation and on postoperative days 1 and 7.

Results: Induction hemodynamics were similar. Systolic blood pressure was greater in the patients receiving fentanyl after tracheal intubation (fentanyl = 127 +/- 18 mmHg; remifentanil = 113 +/- 18 mmHg; P = 0.004). Intracranial pressure (fentanyl = 14 +/- 13 mmHg; remifentanil = 13 +/- 10 mmHg) and cerebral perfusion pressure (fentanyl = 76 +/- 19 mmHg; remifentanil = 78 +/- 14 mmHg) were similar. Isoflurane use was greater in the patients who received fentanyl. Median time to tracheal extubation was similar (fentanyl = 4 min: range = -1 to 40 min; remifentanil = 5 min: range = 1 to 15 min). Seven patients receiving fentanyl and none receiving remifentanil required naloxone. Postoperative systolic blood pressure was greater (fentanyl = 134 +/- 16 mmHg; remifentanil = 147 +/- 15 mmHg; P = 0.001) and analgesics were required earlier in patients receiving remifentanil. Incidences of nausea and vomiting were similar.     

Lack of Analgesic Activity of Morphine-6-glucuronide after Short-term Intravenous Administration in Healthy Volunteers

Background: The analgesic activity of morphine-6-glucuronide (M-6-G) is well recognized for its contribution to the effects of morphine and its possible use as an opioid analgesic with a wider therapeutic range than morphine. The present study attempted to quantify the relative contribution of M-6-G to analgesia observed after systemic administration of morphine.

Methods: In a placebo-controlled, sixfold crossover study in 20 healthy men, the effects of M-6-G were assessed at steady-state plasma concentrations of M-6-G identical to and two and three times higher than those measured after administration of morphine. Morphine and M-6-G were administered as an intravenous bolus followed by infusion over 4 h. Dosage A was M-6-G-bolus of 0.015 mg/kg plus infusion of 0.0072 mg [center dot] kg sup -1 [center dot] h sup -1. Dosage B was M-6-G-bolus of 0.029 mg/kg plus infusion of 0.014 mg [center dot] kg sup -1 [center dot] h sup -1. Dosage C was M-6-G-bolus of 0.044 mg/kg plus infusion of 0.022 mg [center dot] kg sup -1 [center dot] h sup -1. Dosage D was a morphine bolus of 0.14 mg/kg plus infusion of 0.05 mg [center dot] kg sup -1 [center dot] h sup -1 for 4 h. Dosage E was M-6-G combined with morphine (doses A + D). Dosage F was a placebo. The analgesic effects of M-6-G and morphine were measured before administration of the bolus and after 3.5 h using an experimental pain model based on pain-related cortical potentials and pain ratings after specific stimulation of the nasal nociceptor with short pulses of gaseous carbon dioxide.

Results: Morphine significantly reduced subjective and objective pain correlates compared with placebo. In contrast, M-6-G produced no statistically significant effects. The addition of M-6-G to morphine did not increase the effects of morphine. Morphine produced significantly more side effects than M-6-G.     

Diphenhydramine Increases Ventilatory Drive during Alfentanil Infusion

Background: Diphenhydramine is used as an antipruritic and antiemetic in patients receiving opioids. Whether it might exacerbate opioid-induced ventilatory depression has not been determined.

Methods: The ventilatory response to carbon dioxide during hyperoxia and the ventilatory response to hypoxia during hypercapnia (end-tidal pressure of carbon dioxide [PETCO2] [almost equal to] 54 mmHg) were determined in eight healthy volunteers. Ventilatory responses to carbon dioxide and hypoxia were calculated at baseline and during an alfentanil infusion (estimated blood levels [almost equal to] 10 ng/ml) before and after diphenhydramine 0.7 mg/kg.

Results: The slope of the ventilatory response to carbon dioxide decreased from 1.08 +/- 0.38 to 0.79 +/- 0.36 l [middle dot] min-1 [middle dot] mmHg-1 (x +/- SD, P < 0.05) during alfentanil infusion; after diphenhydramine, the slope increased to 1.17 +/- 0.28 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05). The minute ventilation (VE) at PETCO2 [almost equal to] 46 mmHg (VE 46) decreased from 12.1 +/- 3.7 to 9.7 +/- 3.6 l/min (P < 0.05) and the VE at 54 mmHg (V (E) 54) decreased from 21.3 +/- 4.8 to 16.6 +/- 4.7 l/min during alfentanil (P < 0.05). After diphenhydramine, VE 46 did not change significantly, remaining lower than baseline at 9.9 +/- 2.9 l/min (P < 0.05), whereas VE 54 increased significantly to 20.5 +/- 3.0 l/min. During hypoxia, VE at Sp O2 = 90% (VE 90) decreased from 30.5 +/- 9.7 to 23.1 +/- 6.9 l/min during alfentanil (P < 0.05). After diphenhydramine, the increase in VE 90 to 27.2 +/- 9.2 l/min was not significant (P = 0.06).     

Respiratory Sites of Action of Propofol: Absence of Depression of Peripheral Chemoreflex Loop by Low-dose Propofol

Background: Propofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol.

Methods: In 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 [mu]g/ml (Plow), and two studies at a target propofol concentration of 1.5 [mu]g/ml (Phigh) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, carbon dioxide sensitivity, and apneic threshold. Values are mean +/- SD.

Results: Plasma propofol concentrations were approximately 0.5 [mu]g/ml for Plow and approximately 1.3 mg/ml for Phigh. Propofol reduced the central carbon dioxide sensitivity from 1.5 +/- 0.4 to 1.2 +/- 0.3 (Plow;P < 0.01 vs. control) and 0.9 +/- 0.1 l [middle dot] min-1 [middle dot] mmHg-1 (Phigh;P < 0.001 vs. control). The peripheral carbon dioxide sensitivity remained unaffected by propofol (control, 0.5 +/- 0.3; Plow, 0.5 +/- 0.2; Phigh, 0.5 +/- 0.2 l [middle dot] min-1 [middle dot] mmHg-1). The apneic threshold was reduced from 36.3 +/- 2.7 (control) to 35.0 +/- 2.1 (Plow;P < 0.01 vs. control) and to 34.6 +/- 1.9 mmHg (Phigh;P < 0.01 vs. control).     

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

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

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

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

Sevoflurane-induced reduction of hypoxic drive is sex-independent.

BACKGROUND: Although the mu-opioid agonist morphine affects ventilatory control in men and women in different ways, no data exist regarding the influence of sex on the ventilatory effects of inhalational anesthetics. The authors compared the effect of sevoflurane on the ventilatory response to isocapnic hypoxia in healthy young men and women. METHODS: Breath-to-breath ventilatory responses to hypoxic steps (number of hypoxic steps, four-six; duration, 3 min; end-tidal oxygen tension, approximately 50 mmHg; end-tidal carbon dioxide tension clamped at approximately 4 mmHg above resting values) were assessed in nine men and nine women without and with low-dose sevoflurane (end-tidal concentration, 0.25%). The bispectral index of the electroencephalogram was measured concomitantly. RESULTS: Sevoflurane reduced the hypoxic ventilatory sensitivity significantly in both sexes (men: control, 0.62 +/- 0.17 vs. sevoflurane, 0.38 +/- 0.19 l x min(-1) x %(-1); women: control, 0.52 +/- 0.30 vs. sevoflurane, 0.34 +/- 0.15 l x min(-1) x %(-1)). Sevoflurane-induced reductions of the hypoxic responses were not different in the men and women. During sevoflurane inhalation, the bispectral index values decreased equally in men and women. CONCLUSION: In contrast to morphine, the influence of a low dose of the inhalational anesthetic sevoflurane on the ventilatory response to hypoxia is independent of sex.     

Permissive Hypercapnia with and without Expiratory Washout in Patients with Severe Acute Respiratory Distress Syndrome

Background: Permissive hypercapnia is a ventilatory strategy aimed at avoiding lung volutrauma in patients with severe acute respiratory distress syndrome (ARDS). Expiratory washout (EWO) is a modality of tracheal gas insufflation that enhances carbon dioxide removal during mechanical ventilation by reducing dead space. The goal of this prospective study was to determine the efficacy of EWO in reducing the partial pressure of carbon dioxide (PaCO2) in patients with severe ARDS treated using permissive hypercapnia.

Methods: Seven critically ill patients with severe ARDS (lung injury severity score, 3.1 +/- 0.3) and no contraindications for permissive hypercapnia were studied. On the first day, hemodynamic and respiratory parameters were measured and the extent of lung hyperdensities was assessed using computed tomography. A positive end-expiratory pressure equal to the opening pressure identified on the pressure-volume curve was applied. Tidal volume was reduced until a plateau airway pressure of 25 cm H2 O was reached. On the second day, after implementation of permissive hypercapnia, EWO was instituted at a flow of 15 l/min administered during the entire expiratory phase into the trachea through the proximal channel of an endotracheal tube using a ventilator equipped with a special flow generator. Cardiorespiratory parameters were studied under three conditions: permissive hypercapnia, permissive hypercapnia with EWO, and permissive hypercapnia.

Results: During permissive hypercapnia, EWO decreased PaCO2 from 76 +/- 4 mmHg to 53 +/- 3 mmHg (-30%; P < 0.0001), increased pH from 7.20 +/- 0.03 to 7.34 +/- 0.04 (P < 0.0001), and increased PaO2 from 205 +/- 28 to 296 +/- 38 mmHg (P < 0.05). The reduction in PaCO sub 2 was accompanied by an increase in end-inspiratory plateau pressure from 26 +/- 1 to 32 +/- 2 cm H2 O (P = 0.001). Expiratory washout also decreased cardiac index from 4.6 +/- 0.4 to 3.7 +/- 0.3 l [center dot] min sup -1 [center dot] m sup -2 (P < 0.01), mean pulmonary arterial pressure from 28 +/- 2 to 25 +/- 2 mmHg (P < 0.01), and true pulmonary shunt from 47 +/- 2 to 36 +/- 3% (P < 0.01).     

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).     

The Pharmacodynamic Effect of a Remifentanil Bolus on Ventilatory Control

Background: In doses typically administered during conscious sedation, remifentanil may be associated with ventilatory depression. However, the time course of ventilatory depression after an initial dose of remifentanil has not been determined previously.

Methods: In eight healthy volunteers, the authors determined the time course of the ventilatory response to carbon dioxide using the dual isohypercapnic technique. Subjects breathed via mask from a to-and-fro circuit with variable carbon dioxide absorption, allowing the authors to maintain end-tidal pressure of carbon dioxide (PETCO2) at approximately 46 or 56 mmHg (alternate subjects). After 6 min of equilibration, subjects received 0.5 [mu]g/kg remifentanil over 5 s, and minute ventilation ([latin capital V with dot above]E) was recorded during the next 20 min. Two hours later, the study was repeated using the other carbon dioxide tension (56 or 46 mmHg). The [latin capital V with dot above]E data were used to construct two-point carbon dioxide response curves at 30-s intervals after remifentanil administration. Using published pharmacokinetic values for remifentanil and the method of collapsing hysteresis loops, the authors estimated the effect-site equilibration rate constant (keo), the effect-site concentration producing 50% respiratory depression (EC50), and the shape parameter of the concentration-response curve ([gamma]).

Results: The slope of the carbon dioxide response decreased from 0.99 [95% confidence limits 0.72 to 1.26] to a nadir of 0.27 l [middle dot] min-1 [middle dot] mmHg-1 [-0.12 to 0.66] 2 min after remifentanil (P < 0.001); within 5 min, it recovered to approximately 0.6l [middle dot] min-1 [middle dot] mmHg-1, and within 15 min of injection, slope returned to baseline. The computed ventilation at PET = 50 mmHg ([latin capital V with dot above]E50) decreased from 12.9 [9.8 to 15.9] to 6.1 l/min [4.8 to 7.4] 2.5 min after remifentanil injection (P < 0.001). This was caused primarily by a decrease in tidal volume rather than in respiratory rate. Estimated pharmacodynamic parameters based on computed mean values of [latin capital V with dot above]E50 included keo = 0.24 min-1 (T1/2 = 2.9 min), EC50 = 1.12 ng/ml, and [gamma] = 1.74.     

Alterations in Canine Left Ventricular-arterial Coupling and Mechanical Efficiency Produced by Propofol

Background: Propofol reduces blood pressure by decreasing left ventricular (LV) afterload and myocardial contractility. This investigation tested the hypothesis that propofol preserves LV-arterial coupling and mechanical efficiency because of these simultaneous hemodynamic actions.

Methods: Experiments were conducted in open-chest dogs (n = 8) instrumented for measurement of aortic and LV pressure, dP/dtmax, and LV volume. Myocardial contractility was assessed with the slope (E sub es) of the LV end systolic pressure-volume relationship. Effective arterial elastance (Ea; the ratio of end systolic arterial pressure to stroke volume), stroke work (SW), and pressure-volume area (PVA) were determined from the LV pressure-volume relationships. Dogs were studied 30 min after instrumentation and after 15-min intravenous infusions of propofol at 5, 10, 20, and 40 mg [center dot] kg sup -1 [center dot] h sup -1.

Results: Propofol caused dose-dependent decreases in Ees (4.7 +/- 0.9 during control to 2.7 +/- 0.5 mmHg/ml during the high dosage) and dP/dtmax, indicating a direct negative inotropic effect. Ea increased at the 10 mg [center dot] kg sup -1 [center dot] h sup -1 dose of propofol but decreased at higher dosages. Propofol decreased the ratio of Ees to Ea (0.88 +/- 0.13 during control to 0.56 +/- 0.10 during the high dosage), consistent with impairment of LV-arterial coupling. Propofol also reduced the ratio SW to PVA (0.54 +/- 0.03 during control to 0.45 +/- 0.03 during the 20 mg [center dot] kg sup -1 [center dot] h sup -1), suggesting a decline in LV mechanical efficiency. SW and PVA recovered toward baseline values at the 40 mg [center dot] kg sup -1 [center dot] h sup -1 dose.     

A Comparison of Remifentanil and Morphine Sulfate for Acute Postoperative Analgesia after Total Intravenous Anesthesia with Remifentanil and Propofol

Background: The transition from remifentanil intraoperative anesthesia to postoperative analgesia must be planned carefully due to the short duration of action (3-10 min) of remifentanil hydrochloride, a potent, esterase-metabolized micro-opioid agonist. This study compared the efficacy and safety of transition regimens using remifentanil or morphine sulfate for immediate postoperative pain relief in patients who had surgery under general anesthesia with remifentanil/propofol.

Methods: One hundred fifty patients who had received open-label remifentanil and propofol for intraoperative anesthesia participated in this multicenter, double-blind, double-dummy study and were randomly assigned to either the remifentanil (R) group or the morphine sulfate (M) group. Twenty minutes before the anticipated end of surgery, the propofol infusion was decreased by 50%, and patients received either a placebo bolus (R group) or a bolus of 0.15 mg/kg morphine (M group). At the end of surgery, the propofol and remifentanil maintenance infusions were discontinued and the analgesic infusion was started: either 0.1 micro gram [center dot] kg sup -1 [center dot] min sup -1 remifentanil (R group) or placebo analgesic infusion (M group). During the 25 min after tracheal extubation, remifentanil titrations in increments of 0.025 micro gram [center dot] kg sup -1 [center dot] min sup -1 and placebo boluses (R group), or 2 mg intravenous morphine boluses and placebo rate increases (M group) were administered as necessary at 5-min intervals to control pain. Patients received the 0.075 mg/kg intravenous morphine bolus (R group) or placebo (M group) at 25 and 30 min after extubation, and the analgesic infusion was discontinued at 35 min. From 35 to 65 minutes after extubation, both groups received 2-6 mg open-label morphine analgesia every 5 min as needed.

Results: Successful analgesia, defined as no or mild pain with adequate respiration (respiratory rate [RR] >or= to 8 breaths/min and pulse oximetry >or= to 90%), was achieved in more patients in the R group than in the M group (58% vs. 33%, respectively) at 25 min after extubation (P < 0.05). The median remifentanil rate for successful analgesia was 0.125 micro gram [center dot] kg sup -1 [center dot] min sup -1 (range, 0.05-0.23 micro gram [center dot] kg sup -1 [center dot] min sup -1), and the median number of 2-mg morphine boluses used was 2 (range, 0-5 boluses). At 35 min after extubation, >or= to 74% of patients in both groups experienced moderate to severe pain. Median recovery times from the end of surgery were similar between groups. Transient respiratory depression, apnea, or both were the most frequent adverse events (14% for the R group vs. 6% for the M group; P > 0.05).     

Effects of a Dobutamine-induced Increase in Splanchnic Blood Flow on Hepatic Metabolic Activity in Patients with Septic Shock

Background: Septic shock leads to increased splanchnic blood flow (Qspl) and oxygen consumption (VO2 spl). The increased Qspl, however, may not match the splanchnic oxygen demand, resulting in hepatic dysfunction. This concept of ongoing tissue hypoxia that can be relieved by increasing splanchnic oxygen delivery (DO2 spl), however, was challenged because most of the elevated VO2 spl was attributed to increased hepatic glucose production (HGP) resulting from increased substrate delivery. Therefore the authors tested the hypothesis that a dobutamine-induced increase in Qspl and DO2 spl leads to increased VO sub 2 spl associated with accelerated HGP in patients with septic shock.

Methods: Twelve patients with hyperdynamic septic shock in whom blood pressure had been stabilized (mean arterial pressure greater or equal to 70 mmHg) with volume resuscitation and norepinephrine received dobutamine to obtain a 20% increase in cardiac index (CI). Qspl, DO2 spl, and VO sub 2 spl were assessed using the steady-state indocyanine green clearance technique with correction for hepatic dye extraction, and HGP was determined from the plasma appearance rate of stable, non-radioactive-labeled glucose using a primed-constant infusion approach.

Results: Although the increase in CI resulted in a similar increase in Qspl (from 0.91 +/- 0.21 to 1.21 +/- 0.34 l [center dot] min sup -1 [center dot] m2; P < 0.001) producing a parallel increase of DO2 spl (from 141 +/- 33 to 182 +/- 44 ml [center dot] min sup -1 [center dot] m2; P < 0.001), there was no effect on VO2 spl (73 +/- 16 and 82 +/- 21 ml [center dot] min sup -1 [center dot] m2, respectively). Hepatic glucose production decreased from 5.1 +/- 1.6 to 3.6 +/- 0.9 mg [center dot] kg sup -1 [center dot] min sup -1 (P < 0.001).     

Epidural Anesthesia and Acutely Increased Intracranial Pressure: Lumbar Epidural Space Hydrodynamics in a Porcine Model

Background: The effects of epidural injection on intracranial pressure (ICP), lumbar epidural pressure, cerebral blood flow (CBF), and spinal cord blood flow (SCBF) were studied after acutely increased ICP in swine.

Methods: Twenty pigs, anesthetized with isoflurane and mechanically ventilated to maintain normocarbia, had two Tuohy needles placed in the lumbar epidural space. The ICP, lumbar epidural pressure, heart rate, mean arterial pressure, and central venous pressure were monitored. All animals had a Fogarty catheter placed in the parietal epidural space. Six pigs were randomized to a normal ICP group (group N) and eight pigs to an increased ICP group by inflation of the Fogarty catheter balloon (group R). Each pig had 0.33 ml [centered dot] kg sup -1 of 2.0% carbonated lidocaine injected over 20 s via an epidural needle placed at L3. The ICP and lumbar epidural pressure were then monitored continuously for 30 min. Pressure-time data were fit to traditional compartmental models. Epidural elastance and resistance were calculated using a derivation of the Windkessel theory. An additional six pigs had ICP elevated as in group R and CBF and SCBF measured using radioactive microspheres at five time periods: baseline, 0-60 s, 100-160 s, 200-260 s, and at 30 min after epidural injection.

Results: The animals did not differ with respect to heart rate, central venous pressure, or mean arterial pressure at baseline. The ICP was 10 +/- 2 mmHg in group N, and 24 +/- 2 mmHg after balloon inflation in group R. After epidural injection, peak ICP was significantly greater in group R (76 +/- 22 vs. 54 +/- 17 mmHg) but not different by 30 min (17 +/- 5 vs. 11 +/- 1 mmHg). Epidural elastance in group N was 8.3 +/- 3.1 mmHg [centered dot] ml sup -1 and 12.8 +/- 3.0 mmHg [centered dot] ml sup -1 in group R (P = 0.045). Epidural resistance was 1,330 +/- 590 mmHg [centered dot] s [centered dot] ml sup -1 in group N and 2,220 +/- 600 mmHg [centered dot] s [centered dot] ml sup -1 in group R (P = 0.038). The CBF and SCBF were less than 10% of baseline during the 0- to 60-s time period after epidural injection. Thereafter, CBF and SCBF did not differ from baseline values.     

Remifentanil versus Remifentanil/midazolam for Ambulatory Surgery during Monitored Anesthesia Care

Background: This study was designed to define the appropriate dose of remifentanil hydrochloride alone or combined with midazolam to provide satisfactory comfort and maintain adequate respiration for a monitored anesthesia care setting.

Methods: One hundred fifty-nine patients scheduled for outpatient surgery participated in this multicenter, double-blind study. Patients were randomly assigned to one of two groups: remifentanil, 1 micro gram/kg, given over 30 s followed by a continuous infusion of 0.1 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil); remifentanil, 0.5 micro gram/kg, given over 30 s followed by a continuous infusion of 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil + midazolam). Five minutes after the start of the infusion, patients received a loading dose of saline placebo (remifentanil) or midazolam, 1 mg, (remifentanil + midazolam). If patients were not oversedated, a second dose of placebo or midazolam, 1 mg, was given. Remifentanil was titrated (in increments of 50% from the initial rate) to limit patient discomfort or pain intraoperatively, and the infusion was terminated at the completion of skin closure.

Results: At the time of the local anesthetic, most patients in the remifentanil and remifentanil + midazolam groups experienced no pain (66% and 60%, respectively) and no discomfort (66% and 65%, respectively). The final mean (+/- SD) remifentanil infusion rates were 0.12 +/- 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil) and 0.07 +/- 0.03 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil + midazolam). Fewer patients in the remifentanil + midazolam group experienced nausea compared with the remifentanil group (16% vs. 36%, respectively; P < 0.05). Four patients (5%) in the remifentanil group and two patients (2%) in the remifentanil + midazolam group experienced brief periods of oxygen desaturation (SpO2 < 90%) and hypoventilation (< 8 breaths/min).     

Influence of Acidosis on Cardiotonic Effects of Milrinone

Background: The present study was designed to determine whether augmentation of cardiac performance by milrinone is affected by acidosis in in vivo canine and in vitro guinea pig preparations, and to elucidate a mechanism in relation to the cyclic adenosine monophosphate (cAMP) formation.

Methods: Halothane-anesthetized, ventilated dogs were randomly assigned to a control group (arterial pH [pHa] [nearly =] 7.4, base excess [BE] > -2 mM; n = 7), mild acidosis group (pHa [nearly =] 7.2, BE < -9 mM; n = 7), or severe acidosis group (pHa < 7, BE < -20 mM; n = 6). Arterial blood pressure, left ventricular pressure (including maximum rate of increase, LV dP/dtmax), and pulmonary blood flow (PBF) were measured. Acidosis was induced by transient hypoxia and maintained with hydrogen chloride infusion. Hemodynamic responses to milrinone infusions at 2 and 5 micro gram [center dot] kg sup -1 [center dot] min were then studied. In addition, left atria and right ventricular strips were dissected from guinea pig hearts and suspended in HEPES-Tyrode solution, with pH values adjusted to 7.4, 7, or 6.6. The concentration-response relation of isometric contractions for milrinone (10 sup -7 to 10 sup -4 M) and 8-bromo-cAP (10 sup -4 to 10 sup -3 M) were determined.

Results: In the control group of dogs, significant increases in LN dP/dtmax (2,674 +/- 822 to 3,999 +/- 1,016 mmHg/s [means +/- SD]) and PBF (2.04 +/- 0.98 to 2.44 +/- 0.96 l/min [means +/- SD]) were seen with a milrinone infusion of 5 micro gram [center dot] kg sup -1 [center dot] min sup -1. In the mild acidosis group, 5 micro gram [center dot] kg sup -1 min sup -1 milrinone also increased LV dP/dtmax and PBF. However, neither LV dP/dtmax nor PBF changed in the severe acidosis group. In in vitro experiments, milrinone exerted a positive inotropic effect in a concentration-dependent manner on the right ventricular preparations at pH 7.4, but not at pH 7 and 6.6, whereas no significant difference was observed in inotropic responses to 8-bromo-cAMP at pH values of 6.6, 7, and 7.4 on the right ventricular strips. In the right ventricular in vitro preparation, 10 sup -4 M milrinone was accompanied by a significant increase in intracellular cAMP content at a pH of 7.4 but not 7.     

The Role of Cytochrome P450 3A4 in Alfentanil Clearance: Implications for Interindividual Variability in Disposition and Perioperative Drug Interactions

Background: There is considerable unexplained variability in alfentanil pharmacokinetics, particularly systemic clearance. Alfentanil is extensively metabolized in vivo, and thus systemic clearance depends on hepatic biotransformation. Cytochrome P450 3A4 was previously shown to be the predominant P450 isoform responsible for human liver microsomal alfentanil metabolism in vitro. This investigation tested the hypothesis that P450 3A4 is responsible for human alfentanil metabolism and clearance in vivo.

Methods: Nine healthy male volunteers who provided institutionally approved written informed consent were studied in a three-way randomized crossover design. Each subject received alfentanil (20 micro gram/kg given intravenously) 30 min after midazolam (1 mg injected intravenously) on three occasions: control; high P450 3A4 activity (rifampin induction); and low P450 3A4 activity (selective inhibition by troleandomycin). Midazolam is a validated selective in vivo probe for P450 3A4 activity. Venous blood was sampled for 24 h and plasma concentrations of midazolam and alfentanil and their primary metabolites 1'-hydroxymidazolam and noralfentanil were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were determined by two-stage analysis using both noncompartmental and three-compartment models.

Results: Plasma alfentanil concentration-time profiles depended significantly on P450 3A4 activity. Alfentanil noncompartmental clearance was 5.3 +/- 2.3, 14.6 +/- 3.8, and 1.1 +/- 0.5 ml kg sup -1 [center dot] min sup -1, and elimination half-life was 58 +/- 13, 35 +/- 7, and 630 +/- 374 min, respectively, in participants with normal (controls), high (rifampin), and low (troleandomycin) P450 3A4 activity (means +/- SD; P <0.05 compared with controls). Multicompartmental modeling suggested a time-dependent inhibition-resynthesis model for troleandomycin effects on P450 3A4 activity, characterized as k10 (t) = k10 [1 - phi e sup -alpha(t-t0)], where k10 (t) is the apparent time-dependent rate constant, k10 is the uninhibited rate constant, phi is the fraction of P450 3A4 inhibited, and alpha is the apparent P450 3A4 reactivation rate. Alfentanil clearance was calculated as V1 [center dot] k10 for controls and men receiving rifampin, and as V1 [center dot] average k10 (t) for men receiving troleandomycin. This clearance was 4.9 +/- 2.1, 13.2 +/- 3.6, and 1.5 +/- 0.8 ml [center dot] kg sup -1 [center dot] min sup -1, respectively, in controls and in men receiving rifampin or troleandomycin. There was a significant correlation (r = 0.97, P < 0.001) between alfentanil systemic clearance and P450 3A4 activity.