Yehuda Ginosar

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

BackgroundSuccessful 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. MethodsForty-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 &mgr;g intrathecal fentanyl and 200 &mgr;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. ResultsED50 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. ConclusionsThe 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.

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 &mgr;g fentanyl and 200 &mgr;g 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.

Halothane Prevents Postischemic Production of Hydroxyl Radicals in the Canine Heart

Background Recent studies indicate that during regional myocardial ischemia and subsequent reperfusion, volatile anesthetics may provide protection against free radical‐related injury. The effect of halothane on free radical production during ischemia and reperfusion, in the canine heart, was investigated. The level of hydroxyl radical ([center dot] OH)‐mediated conversion of salicylate to its dehydroxybenzoate derivatives (2,3‐DHBA and 2,5‐DHBA) was monitored. Methods Under general anesthesia, the heart was exposed through median sternotomy. Salicylate (100 mg/kg given intravenously) was administered 30 min before left anterior descending artery occlusion. Six dogs were studied using inhaled halothane (1.6%) 10 min before and during the 10‐min ischemic period, followed by 50 min of reperfusion, and then they were compared with seven other dogs used as controls. Blood concentrations of salicylate, 2,3‐DHBA and 2,5‐DHBA, K+, lactate, oxygen content, and pH were monitored. Results An acute increase in the normalized concentrations of 2,3‐DHBA and 2,5‐DHBA was observed in the control animals during reperfusion. In contrast, halothane inhalation completely inhibited the production of both metabolites (P < 0.02), but 2,5‐DHBA concentrations in the halothane‐treated group were even less than the basal level (P <0.05). The increase in lactate concentrations in the experimental animals was significantly less than that of controls (P < 0.05) and followed the same time‐dependent pattern as the changes in K+ and pH. Halothane significantly decreased (P < 0.0001) the difference in oxygen content between coronary sinus and aortic root blood, suggesting decreased oxygen utilization during reperfusion. Conclusions Halothane completely inhibited the production of [center dot] OH, and its administration may protect the heart from the deleterious effect of oxygen‐derived reactive species, with attenuation of the metabolic response to ischemia.

External cephalic version for breech presentation with or without spinal analgesia in nulliparous women at term: a randomized controlled trial.

OBJECTIVE: To compare the success of external cephalic version using spinal analgesia with no analgesia among nulliparas. METHODS: A prospective randomized controlled trial was performed in a tertiary referral center delivery suite. Nulliparous women at term requesting external cephalic version for breech presentation were randomized to receive spinal analgesia (7.5 mg bupivacaine) or no analgesia before the external cephalic version. An experienced obstetrician performed the external cephalic version. Primary outcome was successful conversion to vertex presentation. RESULTS: Seventy-four women were enrolled, and 70 analyzed (36 spinal, 34 no analgesia). Successful external cephalic version occurred among 24 of 36 (66.7%) women randomized to receive spinal analgesia compared with 11 of 34 (32.4%) without, P=.004 (95% confidence interval [CI] of the difference: 0.0954–0.5513). External cephalic version with spinal analgesia resulted in a lower visual analog pain score, 1.76±2.74 compared with 6.84±3.08 without, P<.001. A secondary analysis logistic regression model demonstrated that the odds of external cephalic version success was 4.0-fold higher when performed with spinal analgesia P=.02 (95% CI, odds ratio [OR] 1.2–12.9). Complete breech presentation before attempting external cephalic version increased the odds of success 8.2-fold, P=.001 (95% CI, OR 2.2–30.3). Placental position, estimated fetal weight, and maternal weight did not contribute to the success rate when spinal analgesia was used. There were no cases of placental abruption or fetal distress. CONCLUSION: Administration of spinal analgesia significantly increases the success rate of external cephalic version among nulliparous women at term, which allows possible normal vaginal delivery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00119184 LEVEL OF EVIDENCE: I

Pulse oximeter perfusion index as an early indicator of sympathectomy after epidural anesthesia.

Background: The pulse oximeter perfusion index (PI) has been used to indicate sympathectomy‐induced vasodilatation. We hypothesized that pulse oximeter PI provides an earlier and clearer indication of sympathectomy following epidural anesthesia than skin temperature and arterial pressure.

Photoplethysmographic measurement of changes in total and pulsatile tissue blood volume, following sympathetic blockade

Epidural anaesthesia, used for pain relief, is based on blocking the sensory and the sympathetic nerves in the lower part of the body. Since the sympathetic nervous system regulates blood vessel diameter, the sympathetic block is also associated with several haemodynamic changes. In the current study photoplethysmography (PPG) was measured on toes and fingers of patients undergoing epidural anaesthesia. Three parameters, which are related to the change in total and pulsatile tissue blood volume, were derived from the PPG baseline and amplitude. All parameters showed statistically significant increase in the toes after the sympathetic block, indicating higher arterial and venous blood volume and higher pulsatile increase in the arterial blood volume (higher arterial compliance) in the toe. These haemodynamic changes originate from the lower tonus of the arterial and venous wall muscles after the sympathetic block. In the fingers the PPG parameters based on the change in PPG amplitude decreased after the sympathetic block, indicating lower compliance. The measurement of the haemodynamic changes by PPG enables the assessment of the depth of anaesthesia, and can help control the adverse effects of the blockade on the vascular system.

A Randomized Controlled Trial of the Efficacy and Respiratory Effects of Patient-controlled Intravenous Remifentanil Analgesia and Patient-controlled Epidural Analgesia in Laboring Women

BACKGROUND:Safe and effective alternatives are required in labor when epidural analgesia is not appropriate. We hypothesized that patient-controlled IV remifentanil labor analgesia would not be inferior to patient-controlled epidural labor analgesia. METHODS:This randomized nonblinded controlled noninferiority study in healthy women with a singleton fetus and vertex presentation was performed at 1 site. Women were randomized to receive patient-controlled IV analgesia titrated from 20 mcg up to a maximum bolus dose of 60 mcg with a lockout interval of 1 to 2 minutes, or patient-controlled epidural analgesia 0.1% bupivacaine with 2 mcg/mL fentanyl (initiation bolus 15 mL; maintenance bolus 10 mL, lockout interval 20 minutes, basal infusion 5 mL/h). Crossover was permitted after 30 minutes. The primary study outcome was efficacy (assessed as hourly numerical rating scale [NRS] pain score [11-point NRS] and maternal satisfaction [11-point NRS]); the secondary outcome was safety (maternal apnea). Supplementary oxygen was administered continuously during the respiratory monitoring period. During the first hour of analgesia, the heart rate, respiratory rate, pulse oximetry (SpO2), and end-tidal CO2, as an indication of apnea, were compared. Apnea lasting >40 seconds was managed by light stimulation by the attending anesthesiologist. RESULTS:Forty women were recruited to the following groups: remifentanil n = 19 (1 exclusion), epidural n = 20. Four crossed over: 3 from the remifentanil to epidural group and 1 from the epidural to remifentanil group. Mean (± SD) baseline NRS pain scores were similar, 8.4 ± 1.5 for remifentanil and 8.7 ± 1.2 for epidural analgesia, P = 0.52. Baseline adjusted mean NRS reduction at 30 minutes for remifentanil was −4.5 (± 0.6) vs −7.1(± 0.6) for epidural analgesia, P < 0.0001 for both. Pain score at 30 minutes was 3.7 ± 2.8 for remifentanil and 1.5 ± 2.2 for epidural analgesia, P = 0.009. Remifentanil was inferior to epidural analgesia with respect to the NRS at all time points, because the observed difference in NRS was greater than the expected −1.5 units. Maternal satisfaction was 8.6 ± 1.4 for the remifentanil group and 9.1 ± 1.5 for epidural group, P = 0.26. Mean respiratory rate was lower in the remifentanil group, 18 ± 4 vs 21 ± 4 breaths/min in the epidural group, P = 0.03. Mean SpO2 was lower in the remifentanil group 96.8% ± 1.4 vs 98.4 ± 1.2 for epidural group, P < 0.0001. There were 9 apnea events; all occurred in 5 women receiving remifentanil (5/19 [26.3%], P = 0.046). Apgar scores and neonatal respiratory outcomes were similar. CONCLUSION:IV remifentanil is inferior to epidural analgesia for provision of labor analgesia; however, remifentanil does provide a satisfactory level of labor analgesia. Laboring women receiving remifentanil require suitable monitoring to detect and alert for apnea.

High-dose bupivacaine remotely loaded into multivesicular liposomes demonstrates slow drug release without systemic toxic plasma concentrations after subcutaneous administration in humans.

BACKGROUND:Depot formulations prolong the analgesic effect of local anesthetics and reduce peak plasma drug concentration. This allows for safer administration of larger doses of local anesthetics, which further prolongs the duration of analgesic effect. We previously reported the development of large multivesicular vesicles (LMVVs) remotely loaded with bupivacaine (LMVV liposomal bupivacaine) and demonstrated a >5-fold prolongation of analgesic effect in animals and humans. In this study, we present pharmacokinetic data of LMVV liposomal bupivacaine in humans. METHODS:Healthy volunteers received subcutaneous injections of 20 mL plain 0.5% bupivacaine and, 1 week later, 20 mL of 2% LMVV liposomal bupivacaine in a prospective, open-label, crossover, controlled study. RESULTS:Eight subjects were studied. No subjective side effects of local anesthetics were observed. The maximal plasma concentration and the time to achieve maximal plasma concentration were assessed by modeling plasma concentration–time profiles. Maximal plasma concentration was not significantly different between groups (0.87 ± 0.45 &mgr;g/mL and 0.83 ± 0.34 &mgr;g/mL for plain and liposomal bupivacaine, respectively; P = not significant, 0.83). These values are well below the putative toxic plasma concentration of 2 to 4 &mgr;g/mL. Time to achieve maximal plasma concentration was 7-fold greater for the liposomal preparation (262 ± 149 minutes vs 37.5 ± 16 minutes, P < 0.01). CONCLUSIONS:Peak plasma bupivacaine concentrations were not different in the 2 groups, despite a 4-fold increase in total bupivacaine dose administered in the novel liposomal preparation. The delayed elimination and prolonged redistribution of liposomal bupivacaine to plasma is compatible with the depot-related slow-release effect leading to the prolonged pharmacodynamic effect previously reported.

The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain: A Prospective Open-label Study.

Objectives:The objective of this prospective, open-label study was to determine the long-term effect of medicinal cannabis treatment on pain and functional outcomes in participants with treatment-resistant chronic pain. Patients and Methods:The primary outcome was the change in the pain symptom score on the S-TOPS (Treatment Outcomes in Pain Survey—Short Form) questionnaire at the 6-month follow-up in an intent-to-treat population. Secondary outcomes included the change in S-TOPS physical, social, and emotional disability scales, the pain severity, and pain interference on the Brief Pain Inventory, sleep problems, and the change in opioid consumption. Results:A total of 274 participants were approved for treatment; complete baseline data were available for 206 (intent-to-treat), and complete follow-up data for 176 participants. At follow-up, the pain symptom score improved from median 83.3 (95% confidence interval [CI], 79.2-87.5) to 75.0 (95% CI, 70.8-79.2) (P<0.001). The pain severity score (7.50 [95% CI, 6.75-7.75] to 6.25 [95% CI, 5.75-6.75]) and the pain interference score (8.14 [95% CI, 7.28-8.43] to 6.71 [95% CI, 6.14-7.14]) improved (both P<0.001), together with most social and emotional disability scores. Opioid consumption at follow-up decreased by 44% (P<0.001). Serious adverse effects led to treatment discontinuation in 2 participants. Discussion:The treatment of chronic pain with medicinal cannabis in this open-label, prospective cohort resulted in improved pain and functional outcomes, and a significant reduction in opioid use. Results suggest long-term benefit of cannabis treatment in this group of patients, but the study’s noncontrolled nature should be considered when extrapolating the results.

Randomized controlled trial of external cephalic version in term multiparae with or without spinal analgesia

BACKGROUND Neuraxial analgesia significantly increases the success rate of external cephalic version (ECV) among nulliparae. The study objective was to compare ECV success among multiparae with and without spinal analgesia. METHODS Prospective randomized controlled trial performed over a pre-defined 6 yr period in a tertiary referral delivery suite. Healthy multiparae at term requesting ECV for breech presentation, without fetal or uterine anomaly, were enrolled after written informed consent. Women were randomized to receive either spinal analgesia (bupivacaine 7.5 mg) or no analgesia before the ECV. The primary outcome was successful conversion from breech to vertex presentation, confirmed by ultrasound. Visual analogue pain score and adverse outcomes (complications of anaesthesia or ECV) were recorded. Statistical analysis was performed according to intention to treat using two-sided tests. RESULTS Among 265 multiparae who underwent ECV, 65 consented to enrol, one subsequently refused ECV; therefore, data from 64 women were analysed. ECV was successful in 27 of 31 patients (87.1%) receiving spinal analgesia vs 19 of 33 (57.5%) with no analgesia (P=0.009; 95% CI of difference: 0.075-0.48). ECV with spinal analgesia reduced visual analogue pain score, mean (sd) 1.7 (2.4) vs 5.5 (2.9) without (P<0.0001). Maternal hypotension was seen after spinal analgesia in 10 of 31 (32%) (P=0.0003) and easily treated without adverse outcome. No complications were noted after the ECV. CONCLUSIONS Administration of spinal analgesia significantly increased the rate of successful ECV among multiparae at term with increased patient comfort. The trial was registered at the National Institute of Health Trials Registry, NCT00119184, www.clinicaltrials.gov.