Reduction of Postburn Hyperalgesia after Local Injection of Ketorolac in Healthy Volunteers

Background: Nonsteroidal antiinflammatory drugs may be particularly effective against prostaglandin-mediated, postinjury hyperalgesia and related inflammatory pain. However, their usefulness may be limited by their systemic side effects. The current study determined if local effectiveness can be achieved by low-dose intradermal nonsteroidal antiinflammatory drug administration.

Methods: Ten healthy volunteers were asked to make magnitude estimations of the pain induced by a contact thermal stimulator at 1 degree C increments between 43 and 51 degrees C at three 1 x 1 cm study sites on each forearm during three study phases: (1) baseline; (2) after pretreatment with 10 micro liter 0.9% saline (n = 1 site on each forearm), 0.3 mg ketorolac (n = 1 on each forearm), or nothing (n = 1 on each forearm); and (3) after "injury" by a mild burn at the ketorolac- and saline-treated sites on one arm or by injection of 10 nmol bradykinin at all three sites on the other arm. The effects of pretreatment on the pain induced by thermal testing were assessed using repeated-measures analysis of variance.

Results: Pretreatment with ketorolac had a selective effect on the postburn injury hyperalgesia, reducing the increase in pain intensity (P < 0.05) but not the decline in pain threshold. It had no effect on the responses to thermal stimuli before injury or on the pain of burning, which were similar at ketorolac- and saline-treated sites. The effect of pretreatment with ketorolac on bradykinin-induced hyperalgesia could not be tested because hyperalgesia was not achieved after bradykinin injection at sites pretreated with saline as well as ketorolac.     

盐酸罗哌卡因腰麻加硬膜外阻滞在肛周手术中的应用

为探讨盐酸罗哌卡因腰麻加硬膜外阻滞在肛周手术中的麻醉效果,将80例肛周手术患者随机分为两组,分别采用0．5％布比卡因（B组）和0．5%罗哌卡因（L组）,施行腰麻加硬膜外阻滞用于肛周手术,观察两组患者感觉阻滞维持时间和麻醉效果。结果显示,两组患者麻醉效果满意率无明显差异,感觉阻滞时间L组明显长于B组。结果表明,0．5％罗哌卡因腰麻加硬膜外阻滞用于肛周手术具有良好的麻醉效果和安全性。     

Effect of Intestinal Pacing on Small Bowel Transit and Nutrient Absorption in Healthy Volunteers

Background  Intestinal pacing (IP) has been previously shown to delay gastric emptying and reduce food intake in animals. The aims of this study were to investigate the effect and mechanism of IP on nutrient absorption in healthy volunteers. Methods  Twelve healthy volunteers (six men, six women) were involved in a two-session (one session without IP and one with IP) study. At the beginning of each session, a nasal-duodenal feeding tube, with two ring electrodes (used for IP) on the tip of the tube, was incubated into the duodenum under endoscopy. After a complete recovery from the incubation, the duodenum was infused via the feeding tube with 150 ml 30% intralipid + 25 g D-xylose within 30 min, and the stool was collected for 24 h for the analysis of fecal lipid during which a controlled meal was taken. Then 100 ml 1mCi⁹⁹Tc-labeled non-absorbable solution was infused within 3 min. The subject was asked to lie under a γ camera for at least 1 h for the measurement of small bowel transit. The movement of isotopes was monitored by γ camera at an interval of 10 s. The first appearance of isotopes in the cecum was considered as small intestinal transit time. The order of the two sessions was randomized and 1 week apart. In the IP session, intestinal pacing was performed via the pair of the ring electrodes for 2 h initiated at the beginning of infusion with a pacing frequency of 13 pulses/min, pulse width of 300 ms and amplitude of 5 mA. Results  (1) IP significantly reduced lipid and D-xylose absorption. The fecal lipid was 6.6 ± 4.6 g without IP and almost doubled with IP (11.1 ± 6.5 g, P = 0.047). Similarly, the D-xylose in urine was 3.46 ± 2.22 g with IP, which was significantly lower than that without IP (6.63 ± 5.06 g, p = 0.049). (2) IP accelerated intestinal transit. The transit time was 39 ± 17 min in the control session and reduced to 28 ± 10 min in the IP session (p < 0.03). (3) Diarrhea was reported in one subject without IP but in six subjects with IP (p < 0.05). Conclusions  The increased fecal lipid and induction of diarrhea with intestinal pacing suggest that intestinal pacing is capable of inducing malabsorption. This effect maybe contributed to the acceleration of intestinal transit.     

Lumbar Plexus Block Using High-pressure Injection Leads to Contralateral and Epidural Spread

Background: The main advantage of lumbar plexus block over neuraxial anesthesia is unilateral blockade; however, the relatively common occurrence of bilateral spread (up to 27%) makes this advantage unpredictable. The authors hypothesized that high injection pressures during lumbar plexus block carry a higher risk of bilateral or neuraxial anesthesia.

Methods: Eighty patients undergoing knee arthroscopy (age 18-65 yr; American Society of Anesthesiologists physical status I or II) during a standard, nerve stimulator-guided lumbar plexus block using 35 ml mepivacaine, 1.5%, were scheduled to be studied. Patients were randomly assigned to receive either a low-pressure (< 15 psi) or a high-pressure (> 20 psi) injection, as assessed by an inline injection pressure monitor (BSmart(R); Concert Medical LLC, Norwell, MA). The block success rate and the presence of bilateral sensory and/or motor blockade were assessed.

Results: An interim analysis was performed at n = 20 after an unexpectedly high number of patients had neuraxial spread, necessitating early termination of the study. Five of 10 patients (50%) in the high-pressure group had a neuraxial block with a dermatomal sensory level T10 or higher. In contrast, no patient in the low-pressure group (n = 10) had evidence of neuraxial spread. Moreover, 6 patients (60%) in the high-pressure group demonstrated bilateral sensory blockade in the femoral distribution, whereas no patient in the low-pressure group had evidence of a bilateral femoral block.     

Dose-Response Study of Epidural Ropivacaine for Labor Analgesia

Background: Ropivacaine has been introduced for use in epidural analgesia in labor. However, there have been few formal dose-response studies of ropivacaine in this setting.

Methods: The authors performed a prospective, randomized, double-blind study examining the effectiveness of five different doses of ropivacaine (10, 20, 30, 40, and 50 mg) administered epidurally in a volume of 10 ml to establish analgesia in 66 parturients who were in active labor with cervical dilatation less than 4 cm. A dose was considered effective when the visual analog scale pain score decreased by 50% or more from baseline.

Results: A sigmoid dose-response curve and a probit log dose-response plot (linear regression coefficient, r = 0.84; coefficient of determination, r2 = 0.71) were obtained. The ED50 (median effective dose) obtained based on the maximum likelihood estimation was 18.4 mg (95% confidence interval, 13.4-25.4 mg). Time to onset of analgesia, duration of analgesia, time to two-segment regression of sensory block level, and incidence of motor block were not affected by the dosage of ropivacaine administered (P = 0.93, 0.12, 0.55, and 0.39, respectively). However, the upper level of sensory block was dose-related (P < 0.01).     

Epidural Infusion of Ropivacaine for Postoperative Analgesia after Major Orthopedic Surgery: Pharmacokinetic Evaluation

Background: Changing plasma protein concentrations may affect the protein binding and pharmacokinetics of drugs in the postoperative phase. Therefore, the authors evaluated the pharmacokinetics of ropivacaine, administered by 72-h epidural infusion to provide postoperative analgesia.

Methods: Twenty-eight patients, scheduled for major orthopedic surgery during combined epidural and general anesthesia received a bolus dose of ropivacaine (50 or 75 mg), followed by constant-rate (10 ml/h) epidural infusion of ropivacaine 2 mg/ml (group 1) or 3 mg/ml (group 2). Total and unbound plasma concentrations of ropivacaine and pipecoloxylidide and plasma concentrations of [alpha]1-acid glycoprotein were determined. In addition, the urinary excretion of ropivacaine and major metabolites was measured.

Results: Total plasma concentrations of ropivacaine increased steadily during the infusion, reaching 2.7 +/- 0.7 and 2.9 +/- 0.5 mg/l in groups 1 and 2 after 72 h constant-rate infusion. Unbound ropivacaine concentrations reached average steady state levels of approximately 0.06 and 0.07 mg/l. Total and unbound concentrations of pipecoloxylidide increased to 1.0 +/- 0.4 and 0.4 +/- 0.2 mg/l (group 1) and 1.2 +/- 0.4 and 0.5 +/- 0.1 mg/l (group 2) after 72 h infusion. [alpha]1-Acid glycoprotein concentrations initially decreased, but thereafter increased steadily to approximately twice the baseline values.     

Pharmacokinetics of Mivacurium Isomers and Their Metabolites in Healthy Volunteers after Intravenous Bolus Administration

Background: Previous studies report the pharmacokinetics of mivacurium isomers after an infusion using venous blood sampling. Although the extent of the mivacurium arterial-venous gradient is not known, the sampling site is likely to influence mivacurium pharmacokinetic parameters because the drug is rapidly metabolized as it traverses the circulation. The objectives of this study were (1) to determine the pharmacokinetics of mivacurium isomers in healthy persons after intravenous bolus administration using intensive arterial blood sampling, and (2) to characterize the formation and elimination of mivacurium metabolites in human plasma.

Methods: Eight persons classified as American Society of Anesthesiologists physical status 1 or 2 who were scheduled to undergo elective surgery under balanced anesthesia received 0.15 mg/kg mivacurium chloride as an intravenous bolus. Arterial blood samples were collected every 10 s during the first 2 min and at frequent intervals for 4 h thereafter. Plasma concentrations of mivacurium isomers and their metabolites were determined by two stereoselective high-performance liquid chromatographic methods coupled with fluorometric detection and noncompartmental pharmacokinetic parameters.

Results: Mean elimination half-lives of the trans-trans, cis-trans, and cis-cis isomers were 2.4, 2, and 28.5 min, respectively, with corresponding mean plasma clearances of 29.2, 45.7, and 6.7 ml [center dot] min-1 [center dot] kg-1. The volumes of distribution at steady state of the trans-trans, cis-trans, and cis-cis isomers were 0.047, 0.054, and 0.189 l/kg, respectively. Plasma concentrations of monoester and alcohol metabolites peaked 25 s (median) after mivacurium injection, with half-lives in the range of 90 min, except for the cis alcohol metabolite, which was only negligibly and transiently formed.     

Lung Uptake of Lidocaine in Healthy Volunteers

Eleven patients with no known history of heart or lung disease received an i.v. bolus injection of a mixture of lidocaine and indocyanine green dye (Cardiogreen). The dose of lidocaine, given once (or twice 10 min apart), was 0.5 mg/kg b.w. Time concentration curves from the appearance of indocyanine green were constructed for both substances from blood samples taken from the common femoral artery for approx. 50 s at the rate of one sample every 1.2 s. The extraction of lidocaine in each sample and the uptake of lidocaine, when 95% of the injected dose of indocyanine green had been recovered, were calculated. Nine patients showed an initial plateau of high extraction, which was 0.92 +/- 0.02 (mean +/- s.e mean) and 0.91 +/- 0.02 for the first and second injections, respectively, for the entire material. In two cases, however, a short plateau and a rapid decline in the extraction curve were observed. The 95% first pass uptake was 60 +/- 5% in the first injection and 55 +/- 12% for the second injection. Extraction of lidocaine dominated over back diffusion for the approximately 25 s. It is concluded that: (1) The described technique for studying lung uptake gave consistent and reproducible results in human volunteers; (2) Lung uptake of lidocaine in healthy man exceeds that previously observed in anaesthetized pigs; (3) The initial uptake during the first 5 s after appearance of indocyanine green in the arterial samples was more than 90%. (4) The lungs thus have a dampening effect on the arterial concentration, which might be of importance if lidocaine is accidentally injected intravenously.     

Arterial and Venous Pharmacokinetics of Ropivacaine with and without Epinephrine after Thoracic Paravertebral Block

Background: Animal and volunteer studies indicate that ropivacaine is associated with less neurologic and cardiac toxicity than bupivacaine. Ropivacaine may offer advantages when used for thoracic paravertebral block. This study was designed to describe the pharmacokinetics of ropivacaine after thoracic paravertebral block.

Methods: Twenty female patients undergoing elective unilateral breast surgery were randomly assigned to receive a single bolus thoracic paravertebral injection of 2 mg/kg ropivacaine, with or without 5 [mu]g/ml epinephrine. Simultaneous arterial and venous blood samples were obtained for plasma ropivacaine assay. Data were analyzed with NONMEM, using two possible absorption models: conventional first-order absorption and absorption following the inverse gaussian density function.

Results: Epinephrine reduced the peak plasma concentrations and delayed the time of peak concentration of ropivacaine in both the arterial and venous blood. The time course of drug input into the systemic circulation was best described by two inverse gaussian density functions. The median bioavailability of the rapid component was approximately 20% higher when epinephrine was not used. The mean absorption times were 7.8 min for the rapid absorption phase and 697 min for the slow absorption phase, with wide dispersion of the absorption function for the acute phase. The half-time of arterial-venous equilibration was 1.5 min.     

Hyperbaric Spinal Ropivacaine: A Comparison to Bupivacaine in Volunteers

Background: Ropivacaine is a newly introduced local anesthetic that may be a useful alternative to low-dose bupivacaine for outpatient spinal anesthesia. However, its relative potency to bupivacaine and its dose-response characteristics are unknown. This double-blind, randomized, crossover study was designed to determine relative potencies of low-dose hyperbaric spinal ropivacaine and bupivacaine and to assess the suitability of spinal ropivacaine for outpatient anesthesia.

Methods: Eighteen healthy volunteers were randomized into three equal groups to receive one spinal administration with bupivacaine and a second with ropivacaine, of equal-milligram doses (4, 8, or 12 mg) of 0.25% drug with 5% dextrose. The duration of blockade was assessed with (1) pinprick, (2) transcutaneous electrical stimulation, (3) tolerance to high tourniquet, (4) electromyography and isometric force dynamometry, and (5) achievement of discharge criteria. Differences between ropivacaine and bupivacaine were assessed with linear and multiple regression. P < 0.05 was considered significant.

Results: Ropivacaine and bupivacaine provided dose-dependent prolongation of sensory and motor block and time until achievement of discharge criteria (R2 ranges from 0.33-0.99; P values from < 0.001 through 0.01). Spinal anesthesia with ropivacaine was significantly different from bupivacaine and was approximately half as potent for all criteria studied. A high incidence of back pain (28%; P = 0.098) was noted after intrathecal ropivacaine was given.     

Epidural Block in Twin Labour and Delivery

In a clinical study, 28 twin mothers were provided with epidural block during labour and delivery. This group was compared to 24 twin mothers who received conventional analgesics throughout labour. General anaesthesia was administered when operative delivery was indicated in the control group. In the epidural group, duration of labour was significantly prolonged. A delayed second stage of labour caused an increased number of operative vaginal deliveries. Intra-uterine asphyxia was not more frequent in the epidural group. Judged by the Apgar score and the neonatal course, there was no difference between the newborn in the two groups. Neither clinical evaluation, nor acid-base investigations showed any difference between the condition of Twin I and Twin II in the epidural group.     

Interaction between Intrathecal Neostigmine and Epidural Clonidine in Human Volunteers

Background: alpha2 -Adrenergic agonists are thought to produce analgesia, in part, by activating spinal acetylcholine release. The purpose of the current study was to examine the interaction between intrathecal neostigmine and epidural clonidine for analgesia and side effects in humans.

Methods: A total of 58 volunteers received an intrathecal injection of 5% dextrose in normal saline (D5NS) or neostigmine (50, 100, or 200 micro gram in D5NS), followed in 1 h by epidural saline or clonidine (computer-controlled infusion targeted to 50, 100, 200, or 400 ng/ml in cerebrospinal fluid) using an isobolographic design. Visual analog scale pain to a noxious cold stimulus, nausea, weakness, sedation, and other safety variables was measured before and at specified intervals after drug administration.

Results: The first 21 volunteers randomized to receive intrathecal hyperbaric neostigmine rather than D5NS received the drug while in the sitting position, and had none-to-minimal analgesia 1 h later. The remaining volunteers received the drug while in the lateral position, and demonstrated dose-dependent analgesia in the foot 1 h later. Epidural clonidine also caused dose-dependent analgesia. The combination of neostigmine and clonidine resulted in an additive enhancement for analgesia, but no enhancement of each drug's side effects, and a reduction in clonidine-induced hypotension. Neostigmine injected into subjects in the lateral position diminished clonidine-induced reductions in blood pressure and plasma norepinephrine.     

Relative Analgesic Potencies of Levobupivacaine and Ropivacaine for Epidural Analgesia in Labor

Background: The minimum local analgesic concentration has been defined as the median effective local analgesic concentration (EC50) in a 20-ml volume for epidural analgesia in the first stage of labor. The aim of this study was to assess the relative analgesic potencies of epidural levobupivacaine and ropivacaine by determination of their respective minimum local analgesic concentrations.

Methods: Parturients at 7 cm of cervical dilation or less who requested epidural analgesia were allocated to one of two groups in this double-blind, randomized, prospective study. After lumbar epidural catheter placement, 20 ml of the test solution was given: levobupivacaine (n = 35) or ropivacaine (n = 35). The concentration of local anesthetic was determined by the response of the previous patient in that group to a higher or lower concentration using up-down sequential allocation. Analgesic efficacy was assessed using 100-mm visual analog pain scale scores, with 10 mm or less within 30 min defined as effective. An effective result directed a 0.01% wt/vol decrement for the next patient. An ineffective result directed a 0.01% wt/vol increment.

Results: Of 105 women enrolled, 35 were excluded, leaving 70 for analysis. The minimum local analgesic concentration of levobupivacaine was 0.087% wt/vol (95% CI, 0.081-0.094%), and the minimum local analgesic concentration of ropivacaine was 0.089% wt/vol (95% CI, 0.075-0.103%). Levobupivacaine and ropivacaine were of similar potency with a ropivacaine:levobupivacaine potency ratio of 0.98 (95% CI, 0.80-1.20). No difference in motor effects was observed.