A Monte Carlo simulation study comparing the up and down, biased-coin up and down and continual reassessment methods used to estimate an effective dose (ED95 or ED90) in anaesthesiology research.

Background: Dose-finding studies in anaesthesiology aim to target the effective dose (ED) of an anaesthetic agent in a specific population. The common dose-finding designs used are the up and down method (UDM), the biased-coin up and down (BCD), and the continual reassessment method (CRM). Although the advantages of CRM over the UDM and BCD methods have been described in the statistical literature in terms of precision and direct estimation of ED, CRM may also offer attractive properties from an ethical point of view. Methods: Based on Monte Carlo simulations, this article aims to compare the three methods with regard to 1) their ability to find as close an estimate as possible for the ED95 or ED90 and 2) the total number of patients needed to treat and the number of failures. Results: In contrast to BCD and UDM, CRM does find an estimate for ED95 and ED90. UDM underestimates both ED95 and ED90. BCD is close to the targeted EDs when the starting dose does not exceed the ED of interest, otherwise it overestimates it. CRM with cohorts of two patients is closest to the ED of interest independently of the starting doses. CRM requires between 20 and 50 observations, UDM should include 90 patients, and BCD 100 or 60 observations. Lastly, CRM is associated with fewer failures, compared with BCD and UDM. Conclusions: Based on Monte Carlo simulations, our work suggests that the UDM is not an adequate dose-finding method because it underestimates the ED of interest. Compared with BCD, CRM offers the advantages of being more efficient, requires fewer patients to be included, and is associated with fewer failures.

Comparison of the effectiveness of ultrasound-guided versus fluoroscopy-guided medial lumbar bundle branch block on pain related to lumbar facet joints: a multicenter randomized controlled non-inferiority study.

BACKGROUND: The aim of this multicenter randomized interventional prospective study was to compare the ultrasound (US)-guided lumbar medial branch block (LMBB) with the fluoroscopy (FS)-guided LMBB in terms of analgesic efficacy and disability in the setting of the treatment of pain arising from the lumbar facet joints (LFJ). METHODS: Fifty adults with a "LFJ" syndrome were randomized into two groups: in group FS, fluoroscopic-guidance was used to block the medial branch at three lumbar levels (L3-L4, L4-L5 and L5-S1); in group US, same blocks were performed under ultrasound. Needle transverse approach was used with both techniques. Effects of these procedures were assessed with a Visual Analogue Pain Scale (VAPS), the Oswestry Disability Index (ODI) and the Duke's Activity Status Index (DASI) scale, before the treatment, 1 week and 1 month after. Hospital Anxiety and Depression Scale (HADS) score was also collected before the procedure. Analysis of variance, one (for non-inferiority) and two-sided Mann-Whitney tests and Chi-square tests were performed. RESULTS: LMBB under US-guidance was not inferior to FS-guidance (P = 0.047) in terms of VAPS, ODI and DASI at 1 week and 1 month. Duration of techniques and HADS were similar between groups (=0.34; p = 0.59). CONCLUSIONS: The medial lumbar bundle branch block under ultrasound-guidance is not inferior to the fluoroscopy-guidance procedure in effectively alleviating pain arising from the facet joints. Considering that this ultrasound technique has the benefit of an irradiation-free, real-time procedure, it can be considered as an effective alternative to the fluoroscopy-guided technique.

Influence of height on ED95 of intrathecal 2-chloroprocaine for knee arthroscopy: A prospective dose-response clinical trial.

BACKGROUND: Plain 2-chloroprocaine , a rapid acting amino-ester-type local anaesthetic, is used in short ambulatory procedures under spinal anaesthesia. The ED 95 of 2-chloroprocaine for lower limb surgery has not yet been defined. Moreover, patients' body height could influence the effects of the administered dose. OBJECTIVES: The aim of this study was to determine the ED 95 of plain 2-chloroprocaine based on the height of patients undergoing ambulatory knee arthroscopy under spinal anaesthesia using the continual reassessment statistical method (CRM). DESIGN: Prospective, dose-response, double blind, controlled, bi-center, clinical trial. SETTING: One university teaching hospital in Brussels and one general teaching hospital, Braine l'Alleud, Belgium. Université libre de Bruxelles. PATIENTS: ASA I-III (120 patients) scheduled for day-case knee arthroscopy under spinal anaesthesia. INTERVENTIONS: Patients were divided into three groups of 40, each comprising 10 cohorts of 4 patients, according to their respective heights (Group 1: 150-165 cm, Group 2: 166-180 cm, Group 3: 181-195 cm). Each patient enrolled into one of the 3 groups received an intrathecal dose of plain 2-chloroprocaine determined by the CRM. The starting doses for the first cohorts of four were 40 mg in group 1, 45 mg in group 2 and 50 mg in group 3. The doses for subsequent cohorts were determined by CRM of outcomes in all patients in the previous competed cohorts. Anaesthesia was considered successful when there was a lack of pinprick or cold sensation up to T12, the visual analogue scale score for tourniquet pain was < 2 and no pain during surgery. MAIN OUTCOMES: The primary outcome was the success or failure of the block. Side effects were also recorded. RESULTS: ED 95 of 2-chloroprocaine is 40 mg in group 1, 35 mg in group 2, 45 mg in group 3. Groups were different in terms of height and gender ( P  < 0.05) and similar in terms of body mass index and age ( P  > 0.05). CONCLUSION: The ED95 of intrathecal 2-chloroprocaine for patients undergoing ambulatory knee arthroscopy is between 35 and 45 mg. Height could be a factor involved in the calculation, and patient sex could partly explain the nonlinear relation between height and dose. TRIAL REGISTRY NUMBER: Clinicaltrials.gov NCT03882489.

Quantification of systemic o-toluidine after intrathecal administration of hyperbaric prilocaine in humans: a prospective cohort study.

Hyperbaric 2% prilocaine is increasingly used for spinal anesthesia. It is the only local anesthetic metabolized to o-toluidine, a human bladder carcinogen. Increase of o-toluidine hemoglobin adducts, a marker of o-toluidine ability to modify the DNA structure, was described following subcutaneous injection. In this prospective cohort study we aimed to assess and quantify o-toluidine hemoglobin adducts and urinary o-toluidine after a single intrathecal dose of hyperbaric prilocaine.10 patients undergoing surgery received 50 mg of hyperbaric prilocaine intrathecally. Blood and urine samples were collected before injection and up to 24 h later (Hospital Braine l'Alleud-Waterloo, Braine l'Alleud, Belgium). Urinary o-toluidine and o-toluidine hemoglobin adducts were measured by tandem mass-spectrometry after gas-chromatographic separation (Institute of the Ruhr-Universität, Bochum Germany). The trial was registered to ClinicalTrials.gov (NCT03642301; 22-08-2018)Intrathecal administration of 50 mg of hyperbaric prilocaine leads to a significant increase of o-toluidine hemoglobin adducts (0.1 ± 0.02-11.9 ± 1.9 ng/g Hb after 24 h, p = 0.001). Peak of urinary o-toluidine was observed after 8 h (0.1 ± 0.1-460.5 ± 352.8 µg/L, p = 0.001) and declined to 98 ± 66.8 µg/L after 24 h (mean ± SD)Single intrathecal administration of hyperbaric prilocaine leads to a systemic burden with o-toluidine and o-toluidine hemoglobin adducts. O-toluidine-induced modifications of DNA should be examined and intrathecal hyperbaric prilocaine should not be proposed to patients chronically exposed to o-toluidine.Clinical trial number and registry URL NCT03642301.

ED50 and ED90 of intrathecal hyperbaric 2% prilocaine in ambulatory knee arthroscopy.

PURPOSE: Hyperbaric 2% prilocaine (HP) is increasingly used for spinal anesthesia in day-case surgery. The aim of this prospective double-blind study was to determine the effective dose (ED)50 and the ED90 of HP for patients undergoing knee arthroscopy. METHODS: Doses of HP were determined using an up-and-down sequential allocation technique. Sequences were analyzed by isotonic regression analysis. A subsequent observational study was performed with the calculated ED90 in 50 patients to confirm the initial result and to describe the induced blockade effects and side effects. Times corresponding to onset and duration of sensory and motor block, surgical data, and side effects were recorded. RESULTS: The ED50 was estimated at 28.9 mg (95% confidence interval [CI]: 26.5 to 35.3) and the ED90 was estimated to be 38.5 mg (95% CI: 35.7 to 39.5). A 40 mg dose of HP provided efficient anesthesia in 46 patients (92%, 95% CI: 82 to 98). The average (SD) time to effective anesthesia was 14.5 (3.9) min. Complete sensory block at level T12 was obtained after ten minutes in 44 of 50 patients. The average (SD) duration of the sensory block was 205 (36.1) min. Maximal level of sensory block was obtained at the T8-T11 levels in 41 of 50 patients without hemodynamic instability. A Bromage 3 score was obtained in 40 of the 46 patients who achieved successful anesthesia after 30 min. Patients did not experience urinary retention, nor were any signs of transient neurologic symptoms observed. CONCLUSION: This study determined the ED50 of HP is 28.9 mg and suggests that a 40-mg dose of HP is adequate to provide successful spinal anesthesia for outpatient knee arthroscopy.

Ultrasound-guided block of the brachial plexus at the humeral canal.

PURPOSE: Conduction block of the brachial plexus block at the humeral canal, as described by Dupre, has certain clinical indications. The aim of this preliminary study was to assess the feasibility of this technique under ultrasound guidance. METHODS: After ultrasound evaluation of the brachial plexus at the humeral canal in 61 adult volunteers, we performed ultrasound-guided blocks in another 20 adult patients. A linear 38 mm probe, 13-6 MHz, and a 50-mm insulated block needle were used to guide injection of lidocaine 1.5% with epinephrine. RESULTS: Ulnar and median nerves are superficial and located at similar depths. Ultrasound imaging showed the musculocutaneous nerve to be located dorsally. The radial nerve is dorsal to the plane of the musculocutaneous nerve. Relative to the brachial artery, the median nerve is situated between 12 and 1 o'clock in 66% of the cases. Relative to the basilic vein, the ulnar nerve is situated at 3 o'clock in 46% of the cases. The evaluated block sequence was radial, ulnar, musculocutaneous and median nerve; two points of puncture were mandatory, and 6.85 +/- 0.37 min were required to perform the blocks. Sensory onset times were similar for the four nerves. Injectate volume was lower for the musculocutaneous nerve compared to other nerves (P < 0.05). All 20 patients experienced complete sensory and motor blocks. CONCLUSION: We describe an approach to, and the feasibility of ultrasound-guided block of the brachial plexus at the humeral canal. Further study will be required to establish the effectiveness and the safety of this technique.

Expression of adenosine A 2A receptors in the rat lumbar spinal cord and implications in the modulation of N-methyl-d-aspartate receptor currents.

BACKGROUND: The presence of A(2A) receptors in the dorsal horn of the spinal cord remains controversial. At this level, activation of N-methyl-d-aspartate (NMDA) receptors induces wind-up, which is clinically expressed as hyperalgesia. Inhibition of NMDA receptor currents after activation of A(2A) receptors has been shown in rat neostriatal neurons. In this study, we sought to establish the presence of adenosine A(2A) receptors in the lamina II of the rat lumbar dorsal horn neurons and investigated whether the activation of A(2A) receptors is able to modulate NMDA receptor currents. METHODS: Experiments were conducted in the rat lumbar spinal cord. The presence of adenosine A(2A) receptor transcripts inside the lumbar spinal cord is assessed with the reverse transcriptase polymerase chain reaction (RT-PCR) technique. Western blot experiments are performed at the same level. The RT-PCR technique is also performed specifically in the lamina II, and the presence of adenosine A(2A) receptor transcripts is assessed in neurons from the lamina II with the single-cell RT-PCR technique. The effect of adenosine A(2A) receptor activation on NMDA receptor currents is studied by the whole-cell configuration of the patch clamp technique. RESULTS: RT-PCR performed on the lumbar spinal cord revealed the presence of adenosine A(2A) receptor transcripts. Western blot experiments revealed the presence of A(2A) receptors in the lumbar spinal cord. RT-PCR performed on the substantia gelatinosa also revealed the presence of adenosine A(2A) receptor transcripts. Finally, single cell RT-PCR revealed the presence of adenosine A(2A) receptor transcripts in a sample of lamina II neurons. Patch clamp recordings showed an inhibition of NMDA currents during the application of a selective A(2A) agonist. CONCLUSIONS: These results demonstrate the presence of A(2A) receptor on neurons from the substantia gelatinosa of the rat lumbar dorsal horn and the inhibition of NMDA-induced currents by the application of a selective A(2A) receptor agonist. Therefore, A(2A) receptor ligands could modulate pain processing at the spinal cord level.

Effects of remifentanil on N-methyl-D-aspartate receptor: an electrophysiologic study in rat spinal cord.

BACKGROUND: Remifentanil hydrochloride contained in Ultiva (GlaxoSmithKline, Genval, Belgium) has been incriminated in difficult postoperative pain management, promotion of hyperalgesia, and direct N-methyl-D-aspartate (NMDA) receptor activation, but the involved mechanisms have remained unclear. In the current study, the authors investigated the effects of remifentanil hydrochloride, with and without its vehicle, glycine, on the activation of NMDA receptors and the modulation of NMDA-induced current on neurons inside the lamina II from the dorsal horn of rat spinal cord. METHODS: To test these effects, whole cell patch clamp recordings were conducted on acute rat lumbar spinal cord slices. Considering that both components of Ultiva (remifentanil hydrochloride and glycine) could be involved in NMDA receptor activation, experiments were performed first with remifentanil hydrochloride, second with glycine, and third with the two components within Ultiva. RESULTS: Remifentanil hydrochloride does not induce any current, whereas 3 mm glycine induced a current that was abolished by the specific NMDA glutamate site antagonist D-2-amino-5-phosphonovalerate. Ultiva (remifentanil hydrochloride with its vehicle, glycine) also evoked an inward current that was abolished by D-2-amino-5-phosphonovalerate and not significantly different from the glycine-induced current. Application of remifentanil hydrochloride potentiated the NMDA-induced inward current, and this potentiation was abolished by the mu-opioid receptor antagonist naloxone. CONCLUSION: These results show that remifentanil hydrochloride does not directly activate NMDA receptors. The NMDA current recorded after application of Ultiva is related to the presence of glycine. Induced NMDA current is potentiated by application of remifentanil hydrochloride through a pathway involving the mu-opioid receptor.

Sciatic nerve block in the popliteal fossa: description of a new medial approach.

PURPOSE: Sciatic nerve blocks through lateral approaches in the popliteal fossa have been proposed. We describe a new medial approach to the sciatic nerve at this level. METHODS: After an anatomical study on six cadavers, we performed sciatic nerve blocks on 20 patients. A 100-mm insulated needle and a nerve stimulator were used; 20 mL of lidocaine 1.5% with epinephrine were injected. RESULTS: Patients lied in the supine position, the thigh flexed, abducted and rotated externally (30 degrees in all directions). The leg was flexed at 130 degrees . In this position, above the adductor tubercle, a depression known as Jobert's fossa is palpated. Through this groove, a medial approach to the sciatic nerve at the level of the popliteal fossa is possible. The mean distance between the adductor tubercle and the puncture site is 6.18 cm (range 4-8 cm) and the mean distance between the skin and the sciatic nerve is 6.62 cm (range 4-9 cm). Mean time to perform the block was 100 sec (range 55-165 sec). Complete motor blockade was obtained after a mean time of 30 min (range 5-60 min) inside the common peroneal nerve area and 43 min (range 15-75 min) inside the tibial nerve area. Motor block was complete in 17 patients and sensory block in 18 patients. No vessel puncture was observed. CONCLUSION: We describe a new medial approach to the sciatic nerve in the popliteal fossa. More studies will be required to demonstrate the technique is effective and safe.

The radial nerve should be blocked before the ulnar nerve during a brachial plexus block at the humeral canal.

PURPOSE: The brachial plexus block through the humeral canal as described by Dupré is indicated in hand and forearm surgery. This block requires a multi-stimulation technique that emphasizes the necessity of a rigorous and safe technique. Nerve injury associated with regional anesthesia can entail significant morbidity for patients. Thus, we investigated the brachial block sequence in terms of unintended nerve stimulation as a surrogate of potential nerve injury. METHODS: Sixty patients were randomly allocated in two groups of 30. In Group I the radial nerve was blocked before the ulnar nerve. In Group II the ulnar nerve was blocked before the radial nerve. During the radial nerve approach we recorded, if present, an ulnar nerve response. During the ulnar nerve approach we recorded, if present, a radial nerve response. RESULTS: In Group I while looking for the radial nerve, in 50% of the cases, an ulnar motor response was recorded. In Group II while looking for the ulnar nerve, a radial motor response was recorded in 10% of the cases. CONCLUSION: Our results indicate that the radial nerve should be blocked before the ulnar nerve when performing a brachial plexus block at the humeral canal.