ED50 and ED95 of Intrathecal Hyperbaric Bupivacaine Coadministered with Opioids for Cesarean Delivery

Background: Successful cesarean delivery anesthesia has been reported with use of small doses (5-9 mg) of intrathecal bupivacaine coadministered with opioids. This double-blind, randomized, dose-ranging study determined the ED50 and ED95 of intrathecal bupivacaine (with adjuvant opioids) for cesarean delivery anesthesia.

Methods: Forty-two parturients undergoing elective cesarean delivery with use of combined spinal-epidural anesthesia received intrathecal hyperbaric bupivacaine in doses of 6, 7, 8, 9, 10, 11, or 12 mg in equal volumes with an added 10 [mu]g intrathecal fentanyl and 200 [mu]g intrathecal morphine. Sensory levels (pinprick) were evaluated every 2 min until a T6 level was achieved. The dose was a success(induction) if a bilateral T6 block occurred in 10 min; otherwise, it was a failure(induction). In addition to being a success(induction), the dose was a success(operation) if no intraoperative epidural supplement was required; otherwise, it was a failure(operation). ED50 and ED95 for both success(induction) and success(operation) were determined with use of a logistic regression model.

Results: ED50 for success(induction) and success(operation) were 6.7 and 7.6 mg, respectively, whereas the ED95 for success(induction) and success(operation) were 11.0 and 11.2 mg. Speed of onset correlated inversely with dose. Although no clear advantage for low doses could be demonstrated (hypotension, nausea, vomiting, pruritus, or maternal satisfaction), this study was underpowered to detect significance in these variables.     

The ED50 and ED95 of intrathecal isobaric bupivacaine with opioids for cesarean delivery

BACKGROUND: The ideal intrathecal isobaric bupivacaine dose for cesarean delivery anesthesia is uncertain. While small doses (5-9 mg) of bupivacaine may reduce side effects such as hypotension, they potentially increase spinal anesthetic failures. This study determined the ED50 and ED95 of intrathecal isobaric bupivacaine (with adjuvant opioids) for cesarean delivery. METHODS: After institutional review board approval and written informed consent were obtained, 48 parturients undergoing elective cesarean delivery under combined spinal-epidural anesthesia were enrolled in this double-blind, randomized, dose-ranging study. Patients received a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-mg intrathecal isobaric bupivacaine dose with 10 microg fentanyl and 200 microg morphine. Overall anesthetic success was recorded when no intraoperative epidural supplement was required during the cesarean delivery. ED50 and ED95 values for overall anesthetic success were determined using a logistic regression model. RESULTS: ED50 and ED95 values for overall anesthetic success were 7.25 and 13.0 mg, respectively. No advantages for low doses could be demonstrated with regard to hypotension, nausea, vomiting, pruritus, or maternal satisfaction, although this study was underpowered to detect significant differences in secondary outcome variables. CONCLUSIONS: The ED50 and ED95 values (7.25 and 13.0 mg, respectively) for intrathecal isobaric bupivacaine in this circumstance are similar to values the authors determined recently for hyperbaric bupivacaine using similar methodology. These ED50 and ED95 values are significantly higher than those advocated in previous reports in which success was claimed using lower intrathecal bupivacaine doses. The current study used stricter criteria to define "successful" anesthesia and support the use of larger bupivacaine doses to ensure adequate patient comfort.     

ED50 and ED95 of intrathecal hyperbaric bupivacaine coadministered with opioids for cesarean delivery

BACKGROUND: Successful cesarean delivery anesthesia has been reported with use of small doses (5-9 mg) of intrathecal bupivacaine coadministered with opioids. This double-blind, randomized, dose-ranging study determined the ED50 and ED95 of intrathecal bupivacaine (with adjuvant opioids) for cesarean delivery anesthesia. METHODS: Forty-two parturients undergoing elective cesarean delivery with use of combined spinal-epidural anesthesia received intrathecal hyperbaric bupivacaine in doses of 6, 7, 8, 9, 10, 11, or 12 mg in equal volumes with an added 10 microg intrathecal fentanyl and 200 microg intrathecal morphine. Sensory levels (pinprick) were evaluated every 2 min until a T6 level was achieved. The dose was a success(induction) if a bilateral T6 block occurred in 10 min; otherwise, it was a failure(induction). In addition to being a success(induction), the dose was a success(operation) if no intraoperative epidural supplement was required; otherwise, it was a failure(operation). ED50 and ED95 for both success(induction) and success(operation) were determined with use of a logistic regression model. RESULTS: ED50 for success(induction) and success(operation) were 6.7 and 7.6 mg, respectively, whereas the ED95 for success(induction) and success(operation) were 11.0 and 11.2 mg. Speed of onset correlated inversely with dose. Although no clear advantage for low doses could be demonstrated (hypotension, nausea, vomiting, pruritus, or maternal satisfaction), this study was underpowered to detect significance in these variables. CONCLUSIONS: The ED95 of intrathecal bupivacaine under the conditions of this study is considerably in excess of the low doses proposed for cesarean delivery in some recent publications. When doses of intrathecal bupivacaine less than the ED95, particularly near the ED50, are used, the doses should be administered as part of a catheter-based technique.     

β2-Adrenoceptor Genotype Affects Vasopressor Requirements during Spinal Anesthesia for Cesarean Delivery

Background: Maternal hypotension is common after spinal anesthesia for cesarean delivery. There is wide variability in the incidence and severity of hypotension and in the response to treatment. The [beta]2 adrenoceptor ([beta]2AR) possesses several polymorphic sites. Codons 16 (Arg16Gly) and 27 (Glu27Gln) have been shown to affect desensitization of the receptor. The goal of this study was to determine whether genetic variants of the [beta]2AR alter incidence of hypotension or the amount of vasopressor treatment required during spinal anesthesia for cesarean delivery.

Methods: One hundred seventy healthy women undergoing elective cesarean delivery were studied. Spinal anesthesia was performed with 12 mg hyperbaric bupivacaine, 25 [mu]g fentanyl, and 200 [mu]g morphine. Hypotension was treated with ephedrine and/or phenylephrine intravenously, and [beta]2AR genotype at codons 16 and 27 was determined. Analysis of variance was used to compare variables between genotypes, with data expressed as mean +/- SD.

Results: Ephedrine or phenylephrine was used in more than 90% of patients, with no difference in the incidence of hypotension between [beta]2AR genotypes. However, there was a significant effect of genotype on the amount of vasopressor required. Gly16 homozygotes received significantly less ephedrine (18 +/- 14 mg) than Arg16 homozygotes (28 +/- 13 mg) and Arg16Gly heterozygotes (30 +/- 20 mg; P = 0.0005). Glu27 homozygotes required significantly less ephedrine than Gln 27 homozygotes (14 +/- 13 vs. 30 +/- 19 mg; P = 0.002). Gln27Glu heterozygotes received less ephedrine than Gln27 homozygotes (23 +/- 16 vs. 30 +/- 19 mg; P = 0.03).     

Antinociceptive and Hemodynamic Effects of a Novel α2-Adrenergic Agonist, MPV-2426, in Sheep

Background: [alpha]2-Adrenergic agonists produce analgesia primarily by a spinal action and hypotension and bradycardia by actions at several sites. Clonidine is approved for epidural use in the treatment of neuropathic pain, but its wider application is limited by hemodynamic side effects. This study determined the antinociceptive and hemodynamic effects of a novel [alpha]2-adrenergic agonist, MPV-2426, in sheep.

Methods: Forty sheep of mixed Western breeds with indwelling catheters were studied. In separate studies, antinociception to a mechanical stimulus, hemodynamic effects, arterial blood gas tensions, cerebrospinal fluid pharmacokinetics, and spinal cord blood flow was determined after epidural, intrathecal, and intravenous injection of MPV-2426.

Results: MPV-2426 produced antinociception with greater potency intrathecally (ED50 = 49 [mu]g) than epidurally (ED50 = 202 [mu]g), whereas intravenous administration had no effect. Intrathecal injection, in doses up to three times the ED95, failed to decrease systemic or central arterial blood pressures or heart rate, whereas larger doses, regardless of route, increased systemic arterial pressure. Bioavailability in cerebrospinal fluid was 7% after epidural administration and 0.17% after intravenous administration. Intrathecal MPV-2426, in an ED95 dose and three times this dose, produced a dose-independent reduction in thoracic and lumbar spinal cord blood flow.     

Combined Spinal-Epidural versus Epidural Labor Analgesia

Background: Despite the growing popularity of combined spinal-epidural analgesia in laboring women, the exact role of intrathecal opioids and the needle-through-needle technique remains to be determined. The authors hypothesized that anesthetic technique would have little effect on obstetric outcome or anesthetic complications.

Methods: Data were prospectively collected from 2,183 laboring women randomly assigned to have labor analgesia induced with either 10 [mu]g intrathecal sufentanil with or without 2.0 mg bupivacaine (n = 1,071) or 10 [mu]g epidural sufentanil and 12.5-25.0 mg bupivacaine (n = 1,112). Immediately after induction, a continuous epidural infusion of 0.083% bupivacaine plus 0.3 [mu]g/ml sufentanil was begun in all patients and continued until delivery. Labor was managed by nurses, obstetricians, and obstetric residents who were unaware of the anesthetic technique used.

Results: Anesthetic technique lacked impact on our primary outcome: mode of delivery or labor duration. Infants whose mothers were allocated to the combined spinal-epidural group had a slightly higher umbilical artery carbon dioxide partial pressure (54.2 +/- 10.4 vs. 53.2 +/- 10.2 mmHg). However, only achieving at least 5 cm cervical dilation before induction of analgesia and having a cesarean delivery were independent risk factors for elevated umbilical artery carbon dioxide partial pressure. The frequencies of accidental dural puncture, failed epidural analgesia, headache, and epidural blood patch were low and similar in the two groups.     

Fentanyl shows different effects by administration routes on bispectral index during spinal anesthesia in patients undergoing cesarean section

BACKGROUND: Spinal anesthesia using a local anesthetic with fentanyl has been reported to induce sedation. We previously reported that the bispectral index (BIS) value was significantly decreased by spinal anesthesia using only bupivacaine and fetanyl after cesarean delivery. In the present study, we studied the effect of different fentanyl administration routes on BIS values during spinal anesthesia for cesarean section. METHODS: Forty-six women scheduled for cesarean section were allocated into five-groups according to the route of fentanyl administration and amount of local anesthetic: intrathecal 0.5% isobaric bupivacaine 2.5 ml plus fentanyl 20 microg (n = 11), intrathecal 0.5% isobaric bupivacaine 2.5 ml plus intravenous fentanyl 100 microg (n = 12), intrathecal 0.5% isobaric bupivacaine 2.5 ml plus epidural fentanyl 100 microg (n = 8), intrathecal 0.5% isobaric bupivacaine 2.5 ml (n = 8), and intrathecal 0.5% isobaric bupivacaine 3.0 ml (n = 7). BIS values were recorded during anesthesia. RESULTS: BIS values in intrathecal fentanyl group were lower than those of other groups (P = 0.03). The cumulative duration of BIS values 80 and below 80 was longer in the intrathecal fentanyl group than those of other groups (P = 0.004). CONCLUSION: The BIS value was significantly decreased only by intrathecal fentanyl for cesarean section.     

Low-dose bupivacaine-fentanyl spinal anesthesia for cesarean delivery

BACKGROUND AND OBJECTIVES: The hypotension following spinal anesthesia remains commonplace in cesarean delivery. Intrathecal opioids are synergistic with local anesthetics and intensify sensory block without increasing sympathetic block. The combination makes it possible to achieve spinal anesthesia with otherwise inadequate doses of local anesthetic. We hypothesized that this phenomenon could be used to provide spinal anesthesia for cesarean delivery while incurring less frequent hypotension. METHODS: Thirty-two women scheduled for cesarean delivery were divided into 2 groups of patients who received a spinal injection of either 10 mg of isobaric (plain) bupivacaine 0.5% or 5 mg of isobaric bupivacaine with 25 microg fentanyl added. Each measurement of a systolic blood pressure less than 95 mm Hg or a decrease in systolic pressure of greater than 25% from baseline was considered as hypotension and treated with a bolus of 5 to 10 mg of intravenous ephedrine. RESULTS: Spinal block provided surgical anesthesia in all patients. Peak sensory level was higher (T3 v T4. 5) and motor block more intense in the plain bupivacaine group. The plain bupivacaine patients were more likely to require treatment for hypotension (94% v 31%) and had more persistent hypotension (4.8 v 0.6 hypotensive measurements per patient) than patients in the minidose bupivacaine-fentanyl group. Mean ephedrine requirements were 23.8 mg and 2.8 mg, respectively, for the 2 groups. Patients in the plain bupivacaine group also complained of nausea more frequently than patients in the minidose bupivacaine-fentanyl group (69% v 31%). CONCLUSIONS: Bupivacaine 5 mg + fentanyl 25 microg provided spinal anesthesia for cesarean delivery with less hypotension, vasopressor requirements, and nausea than spinal anesthesia with 10 mg bupivacaine.     

Determination of the EC50 Amnesic Concentration of Etomidate and Its Diffusion Profile in Brain Tissue: Implications for In Vitro Studies

Background: Etomidate is a widely used general anesthetic that has become a useful tool to investigate mechanisms of anesthetic action in vivo and in brain slices. However, the free aqueous concentration of etomidate that corresponds to amnesia in vivo and the diffusion profile of etomidate in brain slices are not known.

Methods: The authors assessed the effect of intraperitoneally injected etomidate on contextual fear conditioning in mice. Etomidate concentrations in brain tissue were obtained by high-performance liquid chromatography. Uptake studies in 400-[mu]m-thick brain slices were used to calculate the diffusion and partition coefficients of etomidate. A diffusion model was used to calculate the expected concentration profile within a brain slice as a function of time and depth. The predicted rate of drug equilibration was compared with the onset of electrophysiologic effects on inhibitory circuit function in recordings from hippocampal brain slices.

Results: Etomidate impaired contextual fear conditioning with an ED50 dose of 11.0 +/- 0.1 mg after intraperitoneal injection, which corresponded to an EC50 brain concentration of 208 +/- 9 ng/g. The brain:artificial cerebrospinal fluid partition coefficient was 3.35, yielding an EC50,amnesia aqueous concentration of 0.25 [mu]m. The diffusion coefficient was approximately 0.2 x 10-6 cm2/s. The development of etomidate action in hippocampal brain slices was compatible with the concentration profile predicted by this diffusion coefficient.     

Isobaric bupivacaine via spinal catheter for hip replacement surgery: ED50 and ED95 dose determination

BACKGROUND: Continuous spinal anaesthesia with spinal catheters allows incremental dosing of the local anaesthetic and, consequently, less haemodynamic change. However, little is known about the required doses. Therefore, we designed a study to assess the local anaesthetic doses of isobaric bupivacaine which were effective in 50% (ED50) and 95% (ED95) of patients undergoing hip replacement surgery. METHODS: Forty-eight patients undergoing hip replacement surgery were randomly allocated to one of six possible groups of eight patients to receive 6, 7, 8, 9, 10 or 12 mg of isobaric bupivacaine in a double-blind manner. The ED50 and ED95 values were calculated by a logistic regression model. The position of the spinal catheter tip was confirmed by X-rays. RESULTS: The ED50 and ED95 values were 7.1 mg (95% confidence interval, 6.0-8.4) and 12.3 mg (95% confidence interval, 8.9-15.7), respectively. The location of the tip of the intrathecal catheter had no effect on local anaesthetic requirements. Eight patients required ephedrine after anaesthesia induction and a further 11 patients required ephedrine for correction of hypotension during surgery. CONCLUSION: The observed ED50 and ED95 values may guide us to use small doses of isobaric bupivacaine for hip replacement surgery. Hypotension is still possible even if low doses of isobaric bupivacaine are used.     

Cerebral Blood Flow and CO2 Reactivity Is Similar during Remifentanil/N2 O and Fentanyl/N2 O Anesthesia

Background: Remifentanil, a rapidly metabolized [micro sign]-opioid agonist, may offer advantages for neurosurgical procedures in which prolonged anesthetic effects can delay assessment of the patient. This study compared the effects of remifentanil-nitrous oxide on cerebral blood flow (CBF) and carbon dioxide reactivity with those of fentanyl-nitrous oxide anesthesia during craniotomy.

Methods: After institutional approval and informed patient consent were obtained, 23 patients scheduled to undergo supratentorial tumor surgery were randomly assigned to remifentanil or fentanyl infusion groups in a double-blinded manner. Midazolam, thiopental, and pancuronium induction was followed by equipotent narcotic loading infusions of remifentanil (1 [micro sign]g [middle dot] kg-1 [middle dot] min-1) or fentanyl (2 [micro sign]g [middle dot] kg-1 [middle dot] min-1) for 5-10 min. Patients were ventilated with 2:1 nitrous oxide-oxygen, and opioid rates were reduced and then titrated to a stable hemodynamic effect. After dural exposure, CBF was measured by the intravenous133 xenon technique at normocapnia and hypocapnia. Reactivity of CBF to carbon dioxide was calculated as the absolute increase in CBF per millimeters of mercury increase in the partial pressure of carbon dioxide (PaCO2). Data were analyzed by repeated-measures analysis of variance, unpaired Student's t tests, or contingency analysis.

Results: In the remifentanil group (n = 10), CBF decreased from 36 +/- 11 to 27 +/- 8 ml [middle dot] 100 g-1 [middle dot] min-1 as PaCO2 decreased from 33 +/- 5 to 25 +/- 2 mmHg. In the fentanyl group (n = 8), CBF decreased from 37 +/- 11 to 25 +/- 6 ml [middle dot] 100 g-1 [middle dot] min-1 as PaCO2 decreased from 34 +/- 3 to 25 +/- 3 mmHg. Absolute carbon dioxide reactivity was preserved with both agents: 1 +/- 1.2 ml [middle dot] 100 g-1 [middle dot] min-1 [middle dot] mmHg-1 for remifentanil and 1.5 +/- 0.5 ml [middle dot] 100 g-1 [middle dot] min-1 [middle dot] mmHg-1 for fentanyl (P = 0.318).     

Effects of Radolmidine, A Novel α2-Adrenergic Agonist Compared with Dexmedetomidine in Different Pain Models in the Rat

Background: Intrathecally administered [alpha]2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Radolmidine is a novel [alpha]2-adrenoceptor agonist with a different pharmacokinetic profile compared with the well-researched dexmedetomidine. This study determined the antinociceptive and sedative effects of radolmidine in different models of acute and chronic pain. Dexmedetomidine and saline served as controls.

Methods: Male Sprague-Dawley rats were studied in acute pain (tail flick), carrageenan inflammation, and the spinal nerve ligation model of neuropathic pain. Mechanical allodynia was assessed with von Frey filaments, cold allodynia with the acetone test, and thermal hyperalgesia with the paw flick test. Locomotor activity-vigilance was assessed in a dark field. Dexmedetomidine and radolmidine were administered intrathecally in doses of 0.25 [mu]g, 2.5 [mu]g, 5 [mu]g, and 10 [mu]g.

Results: In the tail flick test, radolmidine showed a dose-dependent antinociceptive effect, being equipotent compared with dexmedetomidine. In carrageenan inflammation, intrathecal doses of 2.5 [mu]g or 5 [mu]g of dexmedetomidine/radolmidine produced significant antinociception compared with saline (P < 0.01). The two drugs were equianalgesic. In the neuropathic pain model, an intrathecal dose of 5 [mu]g dexmedetomidine-radolmidine had a significant antiallodynic effect compared with saline (P < 0.01). The two drugs were equipotent. Intrathecal administration of both dexmedetomidine and radolmidine dose dependently decreased spontaneous locomotor acitivity-vigilance, but this effect was significantly smaller after intrathecal administration of radolmidine than after intrathecal dexmedetomidine.     

Optimal dose of intrathecal isobaric bupivacaine in total knee arthroplasty

Purpose

Early mobilization is an important aspect of fast-track protocols and intrathecal bupivacaine is often used in primary total knee arthroplasty (TKA). Although the optimal dose is not known, conventional doses leave patients unable to mobilize for two to four hours. The dose of an intrathecally administered local anesthetic should therefore be optimized to achieve immediate postoperative mobilization. This study determined the median effective dose (ED) of intrathecal bupivacaine for primary unilateral TKA.

Methods

Between April 2016 and February 2017 all patients who qualified for unilateral primary TKA were eligible for inclusion. In this dose-finding study, the up-and-down method by Dixon and Massey was used, which is a sequential allocation model. Patients received a dose of isobaric bupivacaine according to the outcome of the preceding patient with an initial starting dose of 5 mg. The dose was increased or decreased by steps of 0.5 mg, depending on the outcome of the preceding patient. During surgery, patients were closely monitored for indications of pain. Time points of regaining motor and sensory functions were determined.

Results

Twenty-five patients were included. Mean (SD) age was 70.1 (8.8) yr old, median [IQR] body mass index was 29.5 [27.3-30.9 kg·m^?2], and 48% were female. In 11 patients the dose was inadequate; of these, nine patients needed additional anesthesia during surgery, and in four of these nine patients a conversion to general anesthesia was required. The median ED was 3.5 (95% confidence interval [CI], 3.1 to 4.0) mg of intrathecal bupivacaine. The calculated ED50 was 3.4 (95% CI, 2.7 to 4.0) mg; the calculated ED95 was 5 (95% CI, 3.7 to 8.0) mg.

Conclusion

In this small study with tight control over operative duration, the median effective dosage of intrathecal isobaric bupivacaine for primary unilateral TKA was 3.5 mg and the ED95 was 5 mg. Reduction of conventional dosages of intrathecal bupivacaine is feasible at centres using fast-track arthroplasty protocols.

     

Epidural Lidocaine Decreases Sevoflurane Requirement for Adequate Depth of Anesthesia as Measured by the Bispectral Index ® Monitor

Background: Epidural anesthesia potentiates sedative drug effects and decreases minimum alveolar concentration (MAC). The authors hypothesized that epidural anesthesia also decreases the general anesthetic requirements for adequate depth of anesthesia as measured by Bispectral Index (BIS).

Methods: After premedication with 0.02 mg/kg midazolam and 1 [mu]g/kg fentanyl, 30 patients aged 20-65 yr were randomized in a double-blinded fashion to receive general anesthesia with either intravenous saline placebo or intravenous lidocaine control (1-mg/kg bolus dose; 25 [mu]g [middle dot] kg-1 [middle dot] min-1). A matched group was prospectively assigned to receive epidural lidocaine (15 ml; 2%) with intravenous saline placebo. All patients received 4 mg/kg thiopental and 1 mg/kg rocuronium for tracheal intubation. After 10 min of a predetermined end-tidal sevoflurane concentration, BIS was measured. The ED50 of sevoflurane for each group was determined by up-down methodology based on BIS less than 50 (MACBIS50). Plasma lidocaine concentrations were measured.

Results: The MACBIS50 of sevoflurane (0.59% end tidal) was significantly decreased with lidocaine epidural anesthesia compared with general anesthesia alone (0.92%) or with intravenous lidocaine (1 %;P < 0.0001). Plasma lidocaine concentrations in the intravenous lidocaine group (1.9 [mu]g/ml) were similar to those in the epidural lidocaine group (2.0 [mu]g/ml).     

Long QT 1 Mutation KCNQ1A344V Increases Local Anesthetic Sensitivity of the Slowly Activating Delayed Rectifier Potassium Current

Background: Anesthesia in patients with long QT syndrome (LQTS) is a matter of concern. Congenital LQTS is most frequently caused by mutations in KCNQ1 (Kv7.1), whereas drug-induced LQTS is a consequence of HERG (human ether-a-go-go-related gene) channel inhibition. The aim of this study was to investigate whether the LQT1 mutation A344V in the S6 region of KCNQ1, at a position corresponding to the local anesthetic binding site in HERG, may render drug insensitive KCNQ1 channels into a toxicologically relevant target of these pharmacologic agents. This may suggest that LQTS constitutes not only a nonspecific but also a specific pharmacogenetic risk factor for anesthesia.

Methods: The authors examined electrophysiologic and pharmacologic properties of wild-type and mutant KCNQ1 channels. The effects of bupivacaine, ropivacaine, and mepivacaine were investigated using two-electrode voltage clamp and whole cell patch clamp recordings.

Results: The mutation A344V induced voltage-dependent inactivation in homomeric KCNQ1 channels and shifted the voltage dependence of KCNQ1/KCNE1 channel activation by +30 mV. The mutation furthermore increased the sensitivity of KCNQ1/KCNE1 channels for bupivacaine 22-fold (KCNQ1wt/KCNE1: IC50 = 2,431 +/- 582 [mu]m, n = 20; KCNQ1A344V/KCNE1: IC50 = 110 +/- 9 [mu]m, n = 24). Pharmacologic effects of the mutant channels were dominant when mutant and wild-type channels were coexpressed. Simulation of cardiac action potentials with the Luo-Rudy model yielded a prolongation of the cardiac action potential duration and induction of early afterdepolarizations by the mutation A344V that were aggravated by local anesthetic intoxication.     

Minidose Bupivacaine-Fentanyl Spinal Anesthesia for Surgical Repair of Hip Fracture in the Aged

Background: Spinal anesthesia for surgical repair of hip fracture in the elderly is associated with a high incidence of hypotension. The synergism between intrathecal opioids and local anesthetics may make it possible to achieve reliable spinal anesthesia with minimal hypotension using a minidose of local anesthetic.

Methods: Twenty patients aged >= 70 yr undergoing surgical repair of hip fracture were randomized into two groups of 10 patients each. Group A received a spinal anesthetic of bupivacaine 4 mg plus fentanyl 20 [mu]g, and group B received 10 mg bupivacaine. Hypotension was defined as a systolic pressure of < 90 mmHg or a 25% decrease in mean arterial pressure from baseline. Hypotension was treated with intravenous ephedrine boluses 5-10 mg up to a maximum 50 mg, and thereafter by phenylephrine boluses of 100-200 [mu]g.

Results: All patients had satisfactory anesthesia. One of 10 patients in group A required ephedrine, a single dose of 5 mg. Nine of 10 patients in group B required vasopressor support of blood pressure. Group B patients required an average of 35 mg ephedrine, and two patients required phenylephrine. The lowest recorded systolic, diastolic, and mean blood pressures as fractions of the baseline pressures were, respectively, 81%, 84%, and 85%versus 64%, 69%, and 64% for group A versus group B.     

ED95 of phenylephrine to prevent spinal-induced hypotension and/or nausea at elective cesarean delivery

BackgroundThe purpose of this trial was to determine the 95% effective dose (ED95) of phenylephrine by intermittent i.v. bolus, to prevent spinal-induced hypotension and/or nausea at elective cesarean delivery.MethodsThe study was conducted in a double-blinded fashion in 50 patients undergoing elective cesarean delivery under spinal anesthesia. The dose of phenylephrine was determined using up-down sequential allocation, modified by a variation of the Narayana rule. Systolic pressure and heart rate were assessed every minute until uterine incision. The first patient was assigned a 40-μg dose, and the dose to subsequent patients varied by 10-μg increments or decrements. An adequate response was defined as absence of hypotension (systolic pressure <80% of baseline) and nausea. The study solution was given immediately after spinal administration, without prior pressure measurement, and thereafter when the systolic pressure was ? control values. fell below baseline. The ED95 was determined by a logistic model with non-log-transformed doses, using Firth’s penalized maximum likelihood method with 95% confidence intervals based on penalized profile likelihood.ResultsThe ED95 of phenylephrine was estimated as 159 μg (95% confidence interval: 122–371 μg), although the largest dose given in the study was only 120 μg. Hypertension (systolic blood pressure >120% of baseline) was observed in 14 cases, immediately after intrathecal injection and prophylactic phenylephrine administration in all cases.ConclusionThe ED95 of phenylephrine, administered as intermittent boluses to prevent pre-delivery spinal-induced hypotension and/or nausea at elective cesarean delivery, is at least 122 μg (lower limit of the confidence interval). The safety of this dose warrants further studies.     

Droperidol Inhibits GABAA and Neuronal Nicotinic Receptor Activation

Background: Droperidol is used in neuroleptanesthesia and as an antiemetic. Although its antiemetic effect is thought to be caused by dopaminergic inhibition, the mechanism of droperidol's anesthetic action is unknown. Because [gamma]-aminobutyric acid type A (GABAA) and neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as putative targets of other general anesthetic drugs, the authors tested the ability of droperidol to modulate these receptors.

Methods: [gamma]-Aminobutyric acid type A [alpha]1[beta]1[gamma]2 receptor, [alpha]7 and [alpha]4[beta]2 nAChRs were expressed in Xenopus oocytes and studied with two-electrode voltage clamp recording. The authors tested the ability of droperidol at concentrations from 1 nm to 100 [mu]m to modulate activation of these receptors by their native agonists.

Results: Droperidol inhibited the GABA response by a maximum of 24.7 +/- 3.0%. The IC50 for inhibition was 12.6 +/- 0.47 nm droperidol. At high concentrations, droperidol (100 [mu]m) activates the GABAA receptor in the absence of GABA. Inhibition of the GABA response is significantly greater at hyperpolarized membrane potentials. The activation of the [alpha]7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 [mu]m. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant.     

Ephedrine Blocks Rat Sciatic Nerve In Vivo and Sodium Channels In Vitro

Background: The sympathomimetic drug ephedrine has been used intrathecally as the sole local anesthetic for labor and delivery. Because ephedrine may be a useful adjuvant to local anesthetics, the authors investigated the local anesthetic properties of ephedrine in a rat sciatic nerve block model and the underlying mechanism in cultured cells stably expressing Na+ channels.

Methods: After approval of the animal protocol, the sciatic nerves of anesthetized rats were exposed by lateral incision of the thighs, 0.2 ml ephedrine at 0.25, 1, 2.5, or 5% and/or bupivacaine at 0.125% was injected, and the wound was closed. Motor and sensory/nociceptive functions were evaluated by the force achieved by pushing against a balance and the reaction to pinch, respectively. The whole cell configuration of the patch clamp technique was used to record Na+ currents from human embryonal kidney cells stably transfected with Nav1.4 channels.

Results: The nociception blockade was significantly longer than the motor blockade at test doses of 2.5 and 5% of ephedrine, or when 1% ephedrine was combined with 0.125% bupivacaine (analysis of variance with repeated measures, P < 0.001, n = 8/group). In vitro, the 50% inhibitory concentrations of ephedrine at -150 and -60 mV were 1,043 +/- 70 and 473 +/- 13 [mu]m, respectively. High-frequency stimulation revealed a use-dependent block of 18%, similar to most local anesthetics.     

Median Effective Dose (ED50) of Nefopam and Ketoprofen in Postoperative Patients: A Study of Interaction Using Sequential Analysis and Isobolographic Analysis

Background: The analgesic efficacy of ketoprofen has been shown after moderate- and severe-pain surgery, and the analgesic efficacy of nefopam has been shown after moderate-pain surgery. The aim of this study was to define the median effective analgesic doses of each drug and to determine whether the interaction of nefopam and of ketoprofen is synergistic.

Methods: Seventy-two patients scheduled to undergo moderately painful surgery were enrolled in one of three groups. The dose of nefopam and ketoprofen received by a particular patient was determined by the response of the previous patient of the same group, using an up-and-down technique. Initial doses were 18 and 40 mg, with dose adjustment intervals of 2 and 5 mg, in the nefopam and ketoprofen groups, respectively. The initial doses of nefopam and ketoprofen were 8 and 20 mg, respectively, in the nefopam-ketoprofen group, with the same dose adjustment intervals. Analgesic efficacy was defined as a decrease to less than 3 on a 0-10 numeric pain scale, 45 min after the beginning of drug infusion.

Results: The median effective analgesic dose (median value and 95% confidence interval) of nefopam and ketoprofen were, respectively, 28 mg (17-39 mg) and 30 mg (14-46 mg). The median effective analgesic dose of the combination was 1.75 mg (0.9-2.3 mg) for nefopam and 4.3 mg (2.2-6.5 mg) for ketoprofen.