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.     

Analgesia and ventilatory response to CO2 following epidural sufentanil in children

The authors studied the effects of epidural sufentanil (0.75 microgram.kg-1) after urologic surgery in 15 children ranging in age from 4 to 12 yr, and in weight from 14 to 47 kg. The onset and duration of analgesia were 3.0 +/- 0.3 and 198 +/- 19 min, respectively (mean +/- SEM). Side effects included pruritus (3/15), nausea and vomiting (5/15), drowsiness (10/15), and urinary retention (1/11). No apnea was observed. Periosteal analgesia and ventilation were studied in eight of the children (mean age 8.6 +/- 0.8 yr). There was significant periosteal analgesia of the tibia (30, 60, 90, and 120 min after injection) and of the radius (60, 90, and 120 min after injection). Resting respiratory rate and tidal volume did not change during the study. Resting minute-ventilation decreased from 6.3 +/- 0.5 l.min-1 preoperatively to 5.6 +/- 0.6 l.min-1 (P less than 0.05) postoperatively, before epidural sufentanil injection; it did not decrease further after epidural sufentanil. Similarly, end-tidal CO2 tension increased significantly from 37.2 +/- 0.7 mmHg preoperatively to 39.9 +/- 1.2 mmHg (P less than 0.05) postoperatively, before epidural sufentanil; epidural sufentanil did not cause a further significant increase in end-tidal CO2 tension. The slope of the CO2 ventilatory response curve decreased significantly from 1.68 +/- 0.12 l.min-1. mmHg-1 preoperatively to 1.10 +/- 0.13 l.min-1.mmHg-1 (P less than 0.01) postoperatively. There were further significant decreases to 0.68 +/- 0.10 and 0.89 +/- 0.16 l.min-1.mmHg-1 30 and 60 min after epidural sufentanil.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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 effects of continuous epidural infusion of fentanyl

The effects of a continuous epidural administration of fentanyl on pain and on ventilation were studied in eight patients scheduled for orthopedic surgery of the knee. In each subject, epidural fentanyl was given by a bolus dose of 1 microgram.kg-1, followed by a continuous infusion of 1 microgram.kg-1.h-1 over 18 hours. Ventilatory measurements were performed during quiet breathing and during CO2 stimulation tests before surgery. After surgery measurements were made before epidural administration of fentanyl; 1, 2, 5, 18 hours after the start of epidural fentanyl infusion; and 6 hours after its discontinuation. Adequate pain relief was achieved in all patients during fentanyl administration. No significant change in ventilation was noted during quiet breathing. The slope of the ventilatory response to CO2 (VE/PaCO2) decreased significantly from 1.46 +/- 0.2 to 0.75 +/- 0.1 L.min-1.mm Hg-1 (mean +/- SEM; P less than 0.05) one hour after the onset of fentanyl administration, and remained stable throughout the infusion. Eighteen hours after the onset of epidural fentanyl infusion, VE/PaCO2 was still 0.76 +/- 0.14 L.min-1.mm Hg-1. At the end of fentanyl administration, plasma fentanyl levels measured in six patients had progressively increased from 0.42 +/- 0.02 ng.ml one hour after the onset of the infusion to 1.54 +/- 0.19 ng.ml at the end of the infusion. These results suggest that a continuous epidural administration of fentanyl is a technique of analgesia that can provide adequate pain relief but which is associated with ventilatory depression. However, with the doses used in this study, the ventilatory depression remained moderate and of no demonstrable clinical consequence.     

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 and circulatory responses to carbon dioxide and high level sympathectomy induced by epidural blockade in awake humans

In order to examine the effects of cervico-thoracic epidural block with 1.5% lidocaine on ventilatory and circulatory responses to carbon dioxide, the authors studied the CO2-ventilatory response curves and the changes in heart rate (HR) and blood pressure (AP) to rebreathing of exhaled gas before and after the block in healthy volunteers. Neither resting ventilation nor ventilatory response to CO2 was affected by the epidural block (mean analgesic level extended from C4 to T7); the slope of the CO2-ventilatory response curve averaged 2.38 +/- 0.81 L X min-1 X mm Hg-1 (mean +/- SD) before and 2.32 +/- 0.82 L X min-1 X mm Hg-1 after the block. Resting HR and AP decreased significantly (P less than 0.01) after the block, but responses in HR and AP to CO2 rebreathing were not significantly changed by the block. Plasma concentrations of norepinephrine and epinephrine were similar before and after the block both with and without CO2 rebreathing. These results indicate that high levels of sympathetic denervation induced by epidural block do not impair circulatory and ventilatory responses to carbon dioxide in awake, healthy humans.     

Ventilatory response to carbon dioxide after intramuscular and epidural fentanyl

The authors compared the effects of administration of fentanyl 200 micrograms on the ventilatory response to carbon dioxide in two groups of nine healthy unpremedicated subjects: one group received fentanyl as an intramuscular injection; in the other group, fentanyl was injected into the epidural space. In the intramuscular group, the slope of the ventilatory response to CO2 did not decrease significantly. In the epidural group, the slope of the ventilatory response to CO2 decreased significantly from 2.48 +/- 1.05 to 1.77 +/- 0.7, 1.74 +/- 0.7, and 2.07 +/- 0.74 L X min-1 X mm Hg-1 at 30, 60, and 120 min after injection (chi +/- SD, P less than or equal to 0.05), respectively. At each time of the study, plasma fentanyl levels were significantly lower in the epidural group than in the intramuscular group (P less than or equal to 0.05). These results suggest that epidural fentanyl induces a nonsystemic ventilatory depression that may be due to the rostral spread of the drug.     

Time course of ventilatory response to carbon dioxide after intravenous diazepam

Dual isohypercapnic studies on the time course of depression following intravenous diazepam permit detailed analysis of changes in the ventilatory response to carbon dioxide. The mean slope of the CO2 response curves of eight healthy volunteers dropped from 2.38 to 1.21 1 . min-1 . mmHg-1 ( P less than 0.05) within three minutes after injection of diazepam 0.4 mg/kg. Twenty-five minutes after injection, the slope was only 1.49 1 . min-1 . mmHg-1, still significantly lower than control (P less than 0.05). At 30 min, the slope has increased to 1.73 1 . min-1 . mmHg-1 and was no longer different from control at the 0.05 level of significance. There was also a significant correlation between the slope of the CO2 response curve and level of consciousness (r = 0. 81). There was little or no displacement of the response curve at any selected ventilation except as accounted for by the slope change. The authors conclude that ventilatory depression resulting from intravenous diazepam begins within one minute and lasts at least 25 min after injection.     

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.     

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.     

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.     

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.     

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).     

Butorphanol improves CO2 response and ventilation after fentanyl anesthesia

We have determined that the mixed agonist-antagonist narcotic, butorphanol, improves CO2 response and ventilation after fentanyl anesthesia. A tentative dosage range has been established. Twenty-two patients were anesthetized with isoflurane, nitrous oxide, and fentanyl, which was continuously infused throughout the study. Postoperatively three 1-mg doses of butorphanol were administered IV. Blood pressure, heart rate, plasma epinephrine and norepinephrine concentrations, and pain intensity were essentially unchanged after butorphanol. Most of the improvement in breathing occurred after the first 1-mg dose. Mean respiratory rate increased from 7.8 +/- 5.0 to 11.0 +/- 4.8 min-1 (P less than or equal to 0.005), tidal volume increased from 469 +/- 302 to 844 +/- 390 ml (P less than or equal to 0.005), minute ventilation increased from 4.32 +/- 2.97 to 8.51 +/- 3.14 L/min (P less than or equal to 0.005), and the slope of the ventilatory response to CO2 increased from 0.36 +/- 0.37 to 0.90 +/- 0.80 L X min-1 X mm Hg-1 (P less than or equal to 0.05). Resting PaCO2 decreased from a baseline of 57.8 +/- 11.1 to 51.7 +/- 5.12 mm Hg (P less than or equal to 0.05) after the third dose.     

Effect of dopamine on hypoxic-hypercapnic interaction in humans

To investigate the effect of intravenous dopamine on the chemical regulation of ventilation, we studied the ventilatory responses to hypercapnic hypoxia during dopamine infusion. Intravenous dopamine (3 micrograms X kg-1 X min-1) was administered to six healthy human subjects. Two hypoxic challenges (PETO2 = 52.5 +/- 2.5 mm Hg, SaO2 = 88.8 +/- 2.2%; mean +/- SD) were administered at three CO2 levels (PETCO2 = 40.8 +/- 0.5, 45.6 +/- 0.2, 49.8 +/- 0.3 mm Hg) to each subject. The ventilatory responses were quantified by calculation of slopes and intercepts of the relationship between minute exhaled ventilation (VE) and arterial hemoglobin saturation (SaO2), and by the relationship between this slope (delta VE/delta SaO2) and carbon dioxide tension. Dopamine caused a 77% reduction in delta VE/delta SaO2 (hypoxic sensitivity) during eucapnia, a 39.5% reduction in hypoxic sensitivity at PETCO2 = 46 mm Hg, and 38% reduction at PETCO2 = 50 mm Hg (P less than 0.05). Dopamine also reduced normoxic ventilation at all carbon dioxide levels. There was a greater depression in VE during hypercapnia (25.7% reduction) than during eucapnia (12% reduction). This indicates that dopamine depresses the normoxic ventilatory response to carbon dioxide. Intravenous dopamine reduces the ventilatory response to both hypoxia and hypercapnia but preserves the augmentation of hypoxic ventilatory drive by hypercapnia.     

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.     

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.     

Plasma concentrations of lidocaine and its principal metabolites during intermittent epidural anesthesia

Plasma concentration-time courses of lidocaine and its principal metabolites (monoethylglycinexylidide, MEGX, and glycinexylidide, GX) were studied during intermittent epidural injections of lidocaine HCl in eight female patients (ASA status 1). The initial dose (320-400 mg without epinephrine) followed by top-up injections of about 60% of the mean initial dose every 35-55 min resulted in a plasma accumulation of lidocaine: the peak concentration increased from 2.30 +/- 0.46 (mean +/- SD) microgram/ml following the first injection and 3.34 +/- 0.76 microgram/ml after the second, to 4.11 +/- 0.72 microgram/ml following the third. The maximum concentrations of MEGX and GX were 0.66 +/- 0.22 and 0.28 +/- 0.08 microgram/ml, respectively. A pharmacokinetic model could successfully fit the entire plasma concentration-time profile of lidocaine during repeated epidural injections (r2 = 0.886 to 0.983). Such pharmacokinetic variables as elimination half-life (t1/2, 2.33 +/- 0.43 h), apparent volume of distribution divided by bioavailability (Vd/F, 2.51 +/- 0.61 l/kg), and clearance divided by bioavailability (Cl/F, 11.65 +/- 1.21 ml X kg-1 X min-1) obtained from the female patients were in reasonable agreement with those reported from healthy females receiving the intravenous lidocaine HCl. A computer-aided simulation generated from using the mean kinetic data in a 50-kg woman predicted that plasma lidocaine concentration would reach the postulated toxic range (approximately equal to 6 microgram/ml) after the fourth supplementary dose under a similar dosing scheme as performed in this study. In conclusion, an accumulation of lidocaine in plasma occurs during a usual intermittent epidural dosing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of succinylcholine on respiratory and nonrespiratory muscle strength in humans

Succinylcholine was administered to 10 healthy unanesthetized volunteers to assess its effect on respiratory and nonrespiratory muscle strength and the ventilatory response to CO2. Iso hypercapnia with PETCO2 8-10 mmHg above control was maintained throughout the study, succinylcholine infusion rates were increased from 20 micrograms X kg-1 X min-1 until grip strength (GS) was 20% of control. CO2-stimulated ventilation was 16.1 +/- 1.8 l/min (mean +/- SD), approximately three times control, and remained at that level throughout the study because of nonsignificant decreases in tidal volume and increases in respiratory frequency. Respiratory strength, as measured by maximum inspiratory pressure (IP), maximum expiratory pressure (EP), and forced vital capacity (FVC), was spared relative to GS. When GS = 50% of control, IP = 86 +/- 8% of control, EP = 78 +/- 15%, and FVC = 86 +/- 9%. Wide variation occurred from subject to subject in the succinylcholine versus GS dose-response curve position. However, in all subjects the slope of the dose-response curve was very steep.