Epidural morphine in children: pharmacokinetics and CO2 sensitivity

The effects of epidural morphine (50 micrograms X kg-1) after abdominal and urologic surgery were studied in 20 children ranging in age from 2 to 15 yr and weighing between 9 and 54 kg. The onset and the duration of analgesia were 30 +/- 12 min and 19.5 +/- 8 h, respectively (mean +/- SD). Side effects were pruritus (4/20), nausea and vomiting (8/20), and urinary retention (4/14). No apnea was observed. Ventilation control was studied in seven children. No significant change in resting respiratory variables occurred after both surgery and epidural morphine injection. However, the slope of the ventilatory response to CO2 was significantly (P less than 0.05) decreased after surgery but before morphine, as compared with its preoperative control value (0.84 +/- 0.44 versus 1.51 +/- 0.72 l X min-1 X mmHg-1), and remained low for 22 h after epidural morphine (0.90 +/- 0.57 l X min-1 X mmHg-1). Sixty minutes after morphine injection, the plasma morphine concentration was always less than 12 ng X ml-1 in the seven children studied. Pharmacokinetic parameters were similar to those observed after epidural injection of morphine in adults, except for a shorter terminal half-life (73.8 +/- 41.6 min) attributed to a greater total body clearance of morphine in the children (28.3 +/- 3.4 ml X min-1 X kg-1). It is concluded that epidural morphine provides effective and prolonged analgesia in children after abdominal and urologic surgery and that it is associated with prolonged respiratory depression that requires close monitoring for at least 24 h.     

Ventilatory response to CO2 following axillary blockade with bupivacaine

The systemic effect of bupivacaine on the control of ventilation was studied in eight ASA I (six male, two female) unpremedicated healthy subjects aged 30-55 yr (mean 43.5 yr) and weighing 59-82 kg (mean 69 kg) after axillary blockade with bupivacaine 0.5% without epinephrine, 3 mg/kg. The slope of the ventilatory response to CO2 was significantly increased (P less than 0.05) from its control value (1.77 +/- 1.03 l X min-1 X mmHg-1 [mean +/- SD]) 30 min (+19 +/- 32%) and 60 min (+32 +/- 37%) after axillary blockade, while plasma bupivacaine levels were 1.65 +/- 0.82 and 1.40 +/- 0.60 micrograms/ml, respectively. The correlation between individual plasma bupivacaine levels and the changes in the slope of the ventilatory response to CO2 was significant (r = 0.57, n = 16, P less than 0.05). Resting minute ventilation and end-tidal CO2 values did not change significantly. These results suggest that bupivacaine has a systemic stimulating effect on the ventilatory control mechanisms.     

Ventilatory response to CO2 following intravenous and epidural lidocaine

The authors determined the effects of intravenous infusion and epidural administration of lidocaine on the control of ventilation in two groups of eight healthy unpremedicated subjects. In the intravenous group, an injection of 1.5 mg/kg lidocaine was followed by an infusion at a rate of 60 micrograms X kg-1 X min-1 for 30 min. The slope of the ventilatory response to CO2 was significantly increased (P less than 0.05) from its control value (2.65 +/- 1.22 1 X min-1 X mmHg-1 [mean +/- SD]) at the end of the infusion (58%), while plasma lidocaine level was at 3.14 +/- 0.82 microgram/ml. The correlation between individual plasma lidocaine levels and the changes in the slope of the ventilatory response to CO2 was significant (r = 0.58, n = 24, P less than 0.01). In the epidural group, after the administration of 5 mg/kg of lidocaine, the slope of the ventilatory response to CO2 increased significantly (P less than 0.05) from its control value (1.52 +/- 0.75 1 X min-1 X mmHg-1) at 15 (+22%) and 25 min (+42%), while plasma lidocaine levels were at 1.79 +/- 0.42 and 2.22 +/- 0.47 microgram/ml, respectively. In both groups, resting minute ventilation and end-tidal CO2 values remained unchanged. These results suggest that epidural lidocaine has a stimulating effect on the ventilatory control mechanisms that results from the systemic effect of the drug.     

Analgesia and ventilatory response to carbon dioxide after intramuscular and epidural alfentanil

The analgesic and ventilatory depressant effects of epidural and intramuscular alfentanil (15 micrograms/kg) were compared in two groups of seven healthy unpremedicated subjects. Fifteen minutes after IM injection, the slope of the ventilatory response to CO2 decreased significantly (from 2.72 +/- 0.34 to 1.8 +/- 0.20 L.min-1.mmHg-1) while assessment of periosteal analgesia showed no change. After epidural injection, the slope of the ventilatory response to CO2 decreased significantly (from 2.32 +/- 0.42 to 1.61 +/- 0.29, 1.51 +/- 0.29, and 1.53 +/- 0.21 L.min-1.mm Hg-1) at 15, 45, and 90 minutes (x +/- SD, P less than 0.05), and there was significant periosteal analgesia of the tibia (15 and 30 minutes after injection) and of the radius (30 to 90 minutes after injection). Throughout the study, plasma alfentanil levels were similar after intramuscular and epidural injection. These results suggest that epidural alfentanil induces ventilatory depression due to the rostral spread of the drug rather than to systemic absorption.     

Ventilatory response to CO2 following intravenous ketamine in children

The effects of intravenous ketamine (bolus of 2 mg.kg-1 followed by a continuous infusion at a rate of 40 micrograms.kg-1.min-1) on ventilatory response to carbon dioxide were studied in nine children ranging in age from 6 to 10 yr and in weight from 20 to 48 kg. Ketamine did not affect resting respiratory rate, tidal volume, end-tidal CO2 tension (PETCO2), or minute ventilation. Five minutes after the ketamine bolus, the slope VE/PETCO2 decreased significantly (P less than 0.05) from 1.71 +/- 0.47 to 1.05 +/- 0.23 1.min-1.mmHg-1 (mean +/- SD). After 30 min of continuous iv ketamine infusion, the slope returned to 1.65 +/- 0.44 1.min-1.mmHg-1, a significantly higher value (P less than 0.05) compared with the nadir and not significantly different from control. The minute ventilation at a PETCO2 of 60 mmHg decreased from 824 +/- 98 to 626 +/- 26 ml.kg-1.min-1 5 min after iv ketamine, and remained depressed (640 +/- 125 ml.kg-1.min-1 P less than 0.05) throughout the 30-min ketamine infusion. In addition, the slope VT/PETCO2 and the VT 60 did not change during the study; nonetheless, the slope f/PETCO2 and the f 60 decreased significantly following iv bolus ketamine, and the f 60 remained significantly decreased following ketamine infusion. The authors conclude that clinically useful doses of iv ketamine significantly alter ventilatory control in children.     

Comparison of the ventilatory effects of etomidate and methohexital

Using a dual-isohypercapnic technique, the authors determined the effect of equipotent doses of methohexital (1.5 mg/kg) and etomidate (0.3 mg/kg) on the ventilatory response to CO2 (VERCO2) in six healthy volunteers. Speed of induction and duration of hypnosis did not differ significantly between the two drugs. Within 2 min after injection, the slope of VERCO2 decreased significantly after both methohexital (from 2.52 to a minimum of 0.15 l . min-1 . mmHg-1, P less than 0.05) and etomidate (from 2.56 to a minimum of 0.62 l . min-1 . mmHg-1, P less than 0.05); the magnitude of this depression did not differ significantly between the drugs. Methohexital also caused a significant decrease in minute ventilation at end-tidal PCO2 of 46 mmHg (VE 46) from 14.6 to 4.3 l . min-1 within 60 s after injection (P less than 0.05). In contrast, after etomidate VE 46 gradually increased from 17.9 1 . min-1 to a maximum of 31.6 l . min-1 at 3.5 min after injection (P less than 0.05); respiratory rate increased significantly, while changes in tidal volume were not significant. Effects of etomidate and methohexital on VE 46 differed significantly (P less than 0.001). These data indicate that, while etomidate and methohexital similarly depress the medullary centers that modify ventilatory drive in response to changing CO2 tensions, ventilation at any given CO2 tension is greater after etomidate than after methohexital. This indicates that etomidate may cause a CO2-independent stimulation of ventilation, suggesting its use for induction of anesthesia in cases where maintenance of spontaneous ventilation is desirable.     

Respiratory effects of epidural sufentanil after cesarean section.

The ventilatory response to CO2 was measured to evaluate the degree of respiratory depression after epidural sufentanil. After cesarean section performed with bupivacaine epidural anesthesia, 14 patients received either 30 micrograms (n = 7) or 50 micrograms (n = 7) of epidural sufentanil. Respiratory measurements were made before and 15, 45, and 120 min after sufentanil injection. The presence and severity of sedation and other nonrespiratory side effects were evaluated throughout the study. Plasma sufentanil assays were performed on blood samples obtained at frequent intervals during the first 2 h. Although changes in resting ventilation did not occur, both sufentanil doses depressed the ventilatory response to CO2. After sufentanil 30 micrograms, the slope of the CO2 response curve decreased significantly at 45 and 120 min (control value, 2.33 +/- 0.3 L.min-1.mm Hg-1 [mean +/- SEM] vs 1.61 +/- 0.24 and 1.72 +/- 0.15, respectively, P less than 0.05). After sufentanil 50 micrograms, significant decreases occurred at 15 and 45 min (control value, 2.84 +/- 0.71 vs 1.81 +/- 0.48 and 1.48 +/- 0.31 L.min-1.mm Hg-1, respectively). The mean maximal decrease in the slope occurred at 45 min and was more pronounced after 50 micrograms (-42.3% +/- 7.4%) than after 30 micrograms (-27.4% +/- 9.9%). Analgesia was similar in both groups. Side effects, particularly sedation, were more severe with the 50-micrograms dose. We conclude that 30 micrograms of epidural sufentanil is preferable to the higher dose with regard to both respiratory and nonrespiratory side effects. Even with the lower dose, monitoring of ventilation is advisable for a minimum of 2 h.     

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.     

Sufentanil does not increase cerebral blood flow in healthy human volunteers

The effect of sufentanil on human cerebral blood flow (CBF) was studied in seven unpremedicated, healthy volunteers 31 +/- 3.5 yr of age (mean +/- SD) and either sex. CBF (ml.100 g-1.min-1) was measured noninvasively with the 133Xe clearance technique and a scintillation camera before and after sufentanil 0.5 micrograms/kg administered intravenously. This technique provides values for global blood flow and for gray and white matter blood flow, and from 13 preselected regions in one hemisphere. After the administration of sufentanil, the volunteers were stimulated verbally in order to prevent their loss of consciousness and hypercarbia. Heart rate (HR), arterial pressure, oxyhemoglobin saturation, and end-tidal CO2 (ETCO2 were recorded during the measurements. Neither global CBF (46.1 +/- 1.6 control and 43 +/- 1.9 after sufentanil, mean +/- SEM) nor gray (76.5 +/- 3.2 and 70.9 +/- 6.1) or white (22.7 +/- 1.5 and 24.2 +/- 1.6) matter blood flow changed significantly after sufentanil administration. As well, no significant differences in HR (72 +/- 4 control and 79 +/- 4 beats per min after sufentanil) and ETCO2 (39.8 +/- 1.4 and 41.1 +/- 1.1 mmHg) were observed. It is concluded that sufentanil has no significant effect on CBF in healthy human volunteers.     

Effects of different anesthetic techniques on antidiuretic hormone secretion during laparoscopic cholecystectomy

BACKGROUND: With the advent of minimally invasive surgery, laparoscopic cholecystectomy has become the standard treatment for symptomatic gallbladder disease. This study aimed to evaluate the effects of using high- versus low-pressure pneumoperitoneum with different anesthetic techniques on hemodynamics and antidiuretic hormone (ADH) secretion. METHODS: For this prospective study, 60 patients scheduled for elective laparoscopic cholecystectomy were randomly recruited. They were classified into four equal groups: group 1 received general anesthesia with low insufflation pressure (7-9 mmHg); group 2 received general anesthesia with high insufflation pressure (13-15 mmHg); group 3 received general anesthesia in addition to epidural analgesia with low insufflation pressure; and group 4 received general anesthesia in addition to epidural analgesia with high insufflation pressure. Routine intraoperative monitoring was done. The study parameters included heart rate per minute, mean blood pressure (mmHg), and ADH levels (via blood samples) before anesthesia, after induction, 30 and 45 min after abdominal insufflation, and finally, 2 h postoperatively. RESULTS: The heart rate showed significant increases after pneumoperitoneum in group 2, as compared with the other three groups. Significant differences in mean blood pressure were observed between the study groups. In groups 1 and 4, mean arterial pressure (MAP) significantly decreased after 15 min, and this decrease persisted until the end of the study. In group 2, MAP significantly increased after 15, 30, 45, and 60 min and after 60 min postoperatively. In group 3, MAP significantly decreased after 30 min, and this decrease persisted 1 h after surgery. There were no significant differences in ADH levels before and after induction of anesthesia among any of the study groups. In groups 1 and 4, no statistically significant changes in ADH levels were observed throughout the study period except a mild increase in ADH levels 30 and 45 min after abdominal insufflation. In group 2, after pneumoperitoneum, there was statistically significant increase in ADH levels from the baseline value of 6.422 +/- 0.551 pmol/l to 7.749 +/- 0.635 pmol/l at 30 min and to 6.457 +/- 0.450 pmol/l at 45 min. In group 3, there was a statistically significant decrease in ADH levels from the baseline value of 6.551 +/- 0.356 pmol/l to 6.125 +/- 0.618 pmol/l at 30 min, to 6.118 +/- 0.491 pmol/l at 45 min, and to 6.169 +/- 0.676 pmol/l at 2 h after abdominal insufflation. CONCLUSION: Pneumoperitoneum can affect several homeostatic systems, leading to hemodynamic and hormonal stress responses. The use of general anesthesia plus epidural analgesia with low insufflation pressure, general anesthesia with low insufflation pressure, or general anesthesia plus epidural analgesia with high insufflation pressure is safe and effective in attenuating these responses.     

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).     

Time course of ventilatory depression following induction doses of propofol and thiopental.

To improve our understanding of the respiratory pharmacology of intravenous induction agents, the authors compared the acute effects of intravenous (iv) propofol 2.5 mg.kg-1 and iv thiopental 4.0 mg.kg-1 on the ventilatory response to CO2 (VeRCO2) of eight healthy volunteers. The slope of VeRCO2 decreased from 1.75 +/- 0.23 to a minimum of 0.77 +/- 0.14 1.min-1.mmHg-1 (mean +/- standard error) 90 s after propofol; similarly, the slope of VeRCO2 decreased from 1.79 +/- 0.22 to a minimum of 0.78 +/- 0.23 l.min-1.mmHg-1 30 s after thiopental. For both drugs, the slope was less than control in the 0.5-5-min period after injection (P less than 0.05). The slope returned to baseline within 6 min after thiopental; in contrast, after propofol, the slope remained less than control for the entire 20-min follow-up period (P less than 0.05 at 6-10, 11-15, and 16-20 min after injection). Also, from 6-10, 11-15, and 16-20 min after injection, the slope was less after propofol than at corresponding times after thiopental (P less than 0.05). Recovery of consciousness was approximately 4 min slower after propofol than after thiopental; nonetheless, awareness scores returned to baseline within 14 min after both drugs. The authors conclude that propofol 2.5 mg.kg-1 iv produces longer-lasting depression of VeRCO2 than a 4.0 mg.kg-1 iv dose of thiopental; after propofol, ventilatory depression may persist despite apparently complete recovery of consciousness.     

The effect of a lidocaine test dose on analgesia and mobility after an epidural combination of neostigmine and sufentanil in early labor

We previously demonstrated the effectiveness of epidural sufentanil and the cholinesterase inhibitor, neostigmine, to initiate selective labor analgesia. Because the traditional lidocaine plus epinephrine test dose (TD) may alter the effect of subsequent epidural drugs, we undertook this investigation to evaluate the impact of a lidocaine TD on analgesia from a combination of epidural neostigmine plus sufentanil administered in early labor. Eighty healthy parturients were randomly allocated to two groups to receive a 3 mL-TD, either lidocaine 2%-epinephrine (1:200,000) or saline-epinephrine (1:200,000), followed 3 min later by epidural neostigmine 500 microg plus sufentanil 10 microg. Pain scores were recorded for 30 min after injection, as was the time elapsed from initial bolus until request for supplemental analgesia. Thirty minutes after injection, adequacy of motor function was evaluated by the parturient's ability to sit, stand up, bend her knees, and walk. Lidocaine TD hastened the onset (5 min vs 15 min) and increased duration (122 +/- 53 min vs 98 +/- 54 min; P = 0.02) of analgesia from epidural neostigmine plus sufentanil bolus. In contrast, the TD did not significantly impair the ability to sit, stand up, or bend the knees. The ability to ambulate, however, was reduced (57% vs 82%; P = 0.04). In conclusion, a traditional lidocaine TD significantly enhances the analgesic effect from the epidural neostigmine plus sufentanil combination, but affects ambulation in early labor.     

The analgesic effect of sufentanil combined with ropivacaine 0.2% for labor analgesia: a comparison of three sufentanil doses

The combination of opioids with local anesthetics is commonly used for epidural labor analgesia. We examined whether increasing sufentanil in doses of 5, 10, and 15 microg prolonged the duration of labor analgesia produced by ropivacaine. One hundred healthy parturients in the first stage of labor who requested epidural analgesia were enrolled. Parturients were randomized to receive 12 mL ropivacaine 0.2% alone or with sufentanil 5 microg, sufentanil 10 microg, or sufentanil 15 microg. The duration of analgesia, pain score, degree of motor blockade (using a four-point Bromage scale), heart rate, blood pressure, respiratory rate, oxygen saturation, and incidence of nausea and pruritus were recorded. The mean duration of epidural analgesia was 96 +/- 32 min for patients without sufentanil, 134 +/- 27 min for Group 5 (p < 0.01 versus control), 135 +/- 33 min for Group 10 (p < 0.01 versus control), 130 +/- 33 min for Group 15 (p < 0.01 versus control) without differences among sufentanil groups. Between 30 and 90 min, the sufentanil groups (5 microg, 10 microg, and 15 microg) had lower pain scores than the control group (p < 0.01 versus control) but there were no differences among the sufentanil groups. No patient in any group had a Bromage score more than 1. No significant difference was found for opioid-related side effects. We conclude that 5-10 or 15 microg sufentanil induced a similar prolongation of analgesia when combined with ropivacaine 0.2% for initiation of labor analgesia. Implications: We studied the effect of adding one of three possible sufentanil doses to epidural ropivacaine 0.2% for labor analgesia. Adding sufentanil increased the duration of analgesia but there was no advantage in adding more than 5 microg of sufentanil.     

Ventilatory response to carbon dioxide after epidural clonidine injection

The authors studied the effects of epidural clonidine (300 micrograms) on circulation and ventilatory control in seven healthy unpremedicated subjects. After clonidine injection, arterial blood pressure decreased significantly in all subjects (range, 13%-25% for systolic blood pressure and 13%-32% for diastolic blood pressure). Heart rate decreased significantly by 10%-16% between 75 and 105 min after injection. The slope of the ventilatory response to CO2 decreased significantly from 2.06 +/- 0.70 (baseline) to 1.37 +/- 0.68, 1.25 +/- 0.65, and 1.33 +/- 0.67 L.min-1.mm Hg-1 (mean +/- SD, P less than 0.05) at 15, 60, and 120 min. The authors conclude that epidural clonidine induces mild ventilatory and circulatory depression.     

Pharmacokinetics of clonidine after epidural administration in surgical patients. Lack of correlation between plasma concentration and analgesia and blood pressure changes

The pharmacokinetics of epidural clonidine 150 micrograms was studied in 13 patients who had undergone abdominal hysterectomy. Plasma clonidine concentrations were measured up to 19 h in eight patients. In another five patients frequent blood sampling was performed only during the first 20 min to define early vascular uptake better. Peak plasma clonidine concentrations of 1.08 +/- 0.35 ng ml-1 (mean +/- s.d.) were reached between 5 and 10 min after injection. Plasma elimination half-life was 829 +/- 157 min and plasma clearance was 177 +/- 28 ml min-1. There was a significant decrease in arterial blood pressure within 10 min of the injection of clonidine. The maximum decrease in systolic blood pressure, from a pre-injection value of 135 +/- 24.7 to 99 +/- 14.4 mmHg (18.0 +/- 3.3 to 13.2 +/- 1.9 kPa), occurred at 60 min. Blood pressure remained significantly lower than the pre-injection value for 4 h. There was no change in heart rate. Verbal analogue pain scores, on a scale 0-10, decreased from a median of 7.6 before clonidine to 5.0 after 30 min (P less than 0.05). The median score at 60 min was 4.3. Thereafter, pain scores were not significantly different from the control score. We conclude that epidural clonidine 150 micrograms produces only moderate and short-lived postoperative analgesia. Absorption of clonidine from the epidural space into the blood is very rapid and may contribute to the hypotension that occurs.     

The effect of flumazenil on alfentanyl-induced respiratory depression

Use of the benzodiazepine antagonist flumazenil may inhibit the effects of benzodiazepines in a competitive manner. The only known partially agonistic effect of flumazenil is a weak anticonvulsive action at high doses. However, reports have claimed that flumazenil reduces the MAC of isoflurane in animal studies. Other reports have found that antagonizing midazolam-induced sedation or anesthesia by flumazenil led to an increase in respiratory depression. The aim of this study was to examine whether flumazenil i.v. increases fentanyl-induced respiratory depression. METHODS. In two separate sessions, ten healthy young volunteers were given either 0.0027 mg/kg fentanyl alone or 0.0027 mg/kg and 1 mg flumazenil i.v. over 4 min each time. The CO2 rebreathing method was used to determine the ventilatory response. RESULTS. Fentanyl alone brought about a significant reduction in CO2 response, characterized by a shift to the right and a decrease in the slope of the rebreathing curve (from 1.95 +/- 0.76 l.min-1.mmHg-1 to 0.86 +/- 0.53 l.min-1.mmHg-1). The infusion of additional flumazenil caused similarly significant respiratory depression (from 2.21 +/- 1.0 l.min-1.mmHg-1 to 0.77 +/- 0.38 l.min-1.mmHg-1). In both groups changes persisted for at least 120 min. No statistically significant differences between the two groups could be detected. CONCLUSION. Flumazenil does not enhance fentanyl-induced respiratory depression. Flumazenil's weak, partially agonistic action is therefore of no clinical importance.     

The CSF and plasma pharmacokinetics of sufentanil after intrathecal administration.

Eight patients (7 men and 1 woman, 45-68 yr old) scheduled to undergo thoracotomy were given, preoperatively, 15 micrograms sufentanil in the lumbar intrathecal space for a study of cerebrospinal fluid (CSF) and plasma kinetics of sufentanil. Multiple samples of plasma and CSF from the lumbar region were obtained through indwelling catheters for 12 h and analyzed for sufentanil by radioimmunoassay. Pharmacokinetic parameters were derived by noncompartmental analysis. In plasma, the maximal concentration of sufentanil appeared after 0.65 +/- 0.17 h (mean +/- SEM). No equilibrium was reached between the sufentanil concentration in CSF and plasma, but the CSF/plasma concentration ratio declined from approximately 140 at 2 h to about 15 at 10 h. Extrapolation indicates that another 10 h would be required before the concentration in CSF would equal that in plasma. The mean residence time (MRT) of sufentanil in CSF was 0.92 +/- 0.08 h and in plasma was 6.8 +/- 0.6 h. The volume of distribution at steady state (Vss) in the subarachnoid compartment was 1.54 +/- 0.39 ml/kg, and the clearance from the CSF was 27 +/- 5 microliters.kg-1.min-1. The intrathecal administration of 15 micrograms sufentanil at the beginning of the operation did not produce analgesia that lasted into the postoperative period. Most patients had urinary retention, but none experienced any serious complications. This study demonstrates that the lipophilic opioid sufentanil undergoes rapid clearance from CSF and absorption to plasma after intrathecal administration. These pharmacokinetic characteristics are slower for the less lipophilic opioids meperidine and morphine. The rapid pharmacokinetics of sufentanil explain its rapid onset of action and short-lasting effects.     

Physostigmine antagonizes morphine-induced respiratory depression in human subjects

The effect of physostigmine on the respiratory depression induced by morphine was studied in human subjects who received morphine as part of their preanesthetic medication. After pretreatment with droperidol (2.5-5 mg, iv) to prevent nausea, the change in minute ventilation was measured in 16 patients in response to increasing concentrations of inspired CO2 (CO2-response curve) by the rebreathing method. This was repeated 30 min after morphine (0.166 mg/kg, iv) in nine subjects and in seven controls who did not receive morphine and again 5-10 min after physostigmine (13-33 micrograms/kg, iv) in all subjects. All subjects were given N-butylhyoscine hydrobromide (5 mg, iv) to antagonize any peripheral cholinergic effects of physostigmine. Morphine decreased the mean slope of the CO2-response curve from 1.78 +/- 0.18 to 1.12 +/- 0.14 1 X min-1 X mmHg-1 (P less than 0.01) and increased the alveolar PCO2 for a fixed minute ventilation (position of curve) from 45.0 +/- 1.3 to 51.9 +/- 1.5 mmHg (P less than 0.001). Physostigmine restored the mean slope after morphine to control value, i.e., 1.79 +/- 0.231 X min-1 X mmHg-1, and position to 46.2 +/- 1.2 mmHg (P less than 0.001). Physostigmine did not increase the slope or alter the position of the CO2-response curves of subjects given droperidol alone. The authors conclude that physostigmine can reverse the respiratory depressant effect of morphine and restore the sensitivity of the respiratory center of CO2, presumably by raising acetylcholine levels in the brain after these have been reduced by morphine.     

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.