The minimum effective concentration (MEC90) of ropivacaine for ultrasound-guided caudal block in anorectal surgery. A dose finding study

Background Caudal epidural block (CEB) provides reliable anesthesia for adults undergoing anorectal surgery. Despite the widely utilization, the minimum effective concentration for 90% patients (MEC90) of ropivacaine for CEB remains unknown. Objective To estimate MEC of ropivacaine for CEB in anorectal surgery. Design A prospective dose-finding study using biased coin design up-and-down sequential method. Setting Operating room and postoperative recovery area of Chengdu Shangjin Nanfu Hospital, from October 2019 to January 2020. Patients 50 males and 51 females scheduled for anorectal surgery. Interventions We conducted two independent biased coin design up-and down trials by genders. The concentration of ropivacaine administered to the first patient of male and female were 0.25% with fixed volume of 14ml for male and 12ml for female patients based on our previous study. In case of failure, the concentration was increased by 0.05% in the next subject. Otherwise, the next subject was randomized to a concentration 0.05% less with a probability of 0.11, or the same concentration with a probability of 0.89. Success was defined as complete sensory blockade of perineal area 15 min after the block evidenced by the presence of a lax anal sphincter and pain-free surgery. Main outcome measures The MEC of ropivacaine to achieve a successful CEB in 90%(MEC90) of the patients. Results The MEC90 of ropivacaine for CEB were estimated to be 0.35% (95% CI 0.29 to 0.4%) for male and 0.353% (95%CI 0.22 to 0.4%) for female. By extrapolation to MEC in 99% of subjects (MEC99) and pooled adjacent violators algorithm (PAVA) adjusted responses, it would be optimal to choose 0.4% ropivacaine with a volume of 14ml for male and 12ml for female. Conclusions A concentration of 0.35% ropivacaine with a volume of 14ml provided a successful CEB in 90% of the male patients, while 0.353% ropivacaine with a volume of 12ml provided a successful CEB in 90% of the female patients. A concentration of 0.4% and a volume of 14ml for male and 12 ml for female would be successful in 99% of the patients. Trial registration Chictr.org.cn identifier: No. ChiCTR 1900024315.

Cadaveric study investigating the phrenic-sparing volume for anterior suprascapular nerve block

BackgroundThis cadaveric study investigated the maximum effective volume of dye in 90% of cases (MEV90), required to stain the suprascapular nerve while sparing the phrenic nerve during the performance of an anterior suprascapular nerve block.MethodsIn cadaveric neck specimens, using ultrasound guidance, the block needle was advanced until its tip was positioned underneath the omohyoid muscle next to the suprascapular nerve. The dye was injected in order to achieve circumferential spread around the latter. Successful phrenic-sparing suprascapular nerve block was defined as the non-staining of the phrenic nerve on dissection. Volume assignment was carried out using a Biased Coin Design, whereby the volume of dye administered to each cadaveric specimen depended on the response of the previous one. In case of failure (ie, stained phrenic nerve), the next one received a lower volume (defined as the previous volume with a decrement of 2 mL). If the previous cadaveric specimen had a successful block (ie, non-stained phrenic nerve), the next one was randomized to a higher volume (defined as the previous volume with an increment of 2 mL), with a probability of b=0.11, or the same volume, with a probability of 1 – b=0.89.ResultsThirty-one cadavers (56 cadaveric neck specimens) were included in the study. Using isotonic regression and bootstrap CI, the MEV90 for phrenic-sparing anterior suprascapular nerve block was estimated to be 4.2 mL (95% CI 3.0 to 5.0 mL). The probability of a successful response was estimated to be 0.90 (95% CI 0.84 to 0.96).ConclusionFor ultrasound-guided anterior suprascapular nerve block, the MEV90 of dye required to spare the phrenic nerve is 4.2 mL. Further studies are required to correlate this finding with the MEV90 of local anesthetic in live subjects.

Cadaveric investigation of the minimum effective volume for ultrasound-guided suprainguinal fascia iliaca block

BackgroundThis cadaveric dose-finding study investigated the minimum effective volume of dye in 90% of cases (MEV90), required to stain the femoral, lateral femoral cutaneous and obturator nerves for ultrasound-guided suprainguinal fascia iliaca block (SIFIB).MethodsIn cadaveric specimens of the lower limb, the block needle was advanced, medial to the anterosuperior iliac spine, until its tip was positioned between the internal oblique and iliacus muscles underneath the fascia iliaca. The dye was injected inside the fascia iliaca compartment. Volume assignment was carried out using a biased coin design, whereby the volume of dye administered to each cadaveric specimen depended on the response of the previous one. In case of failure, the next one received a higher volume (defined as the previous volume with an increment of 2.5 mL). If the previous cadaveric specimen had a successful block, the next one was randomized to a lower volume (defined as the previous volume with a decrement of 2.5 mL), with a probability of b=0.11, or the same volume, with a probability of 1–b=0.89. Success was defined as the staining of the femoral, lateral femoral cutaneous, and obturator nerves on dissection.ResultsThirty-six cadavers (60 cadaveric specimens) were included in the study. Using isotonic regression and bootstrap CI, the MEV90 for ultrasound-guided SIFIB was estimated to be 62.5 mL (95% CI 60 to 65).ConclusionFor ultrasound-guided SIFIB, the MEV90 of dye required to stain the femoral, lateral femoral cutaneous and obturator nerves is 62.5 mL. Further studies are required to correlate this finding with the MEV90 of local anesthetic in human subjects.

Response-adaptive treatment allocation for clinical studies with ordinal responses

Ordinal responses are common in clinical studies. Although the proportional odds model is a popular option for analyzing ordered-categorical data, it cannot control the type I error rate when the proportional odds assumption fails to hold. The latent Weibull model was recently shown to be a superior candidate for modeling ordinal data, with remarkably better performance than the latent normal model when the data are highly skewed. In clinical trials with ordinal responses, a balanced design is common, with equal sample allocation for each treatment. However, a more ethical approach is to adopt a response-adaptive allocation scheme in which more patients receive the better treatment. In this paper, we propose the use of the doubly adaptive biased coin design to generate treatment allocations that benefit the trial participants. The proposed treatment allocation scheme not only allows more patients to receive the better treatment, it also maintains compatible test power for the comparison of treatment efficiencies. A clinical example is used to illustrate the proposed procedure.

Merged block randomisation: A novel randomisation procedure for small clinical trials

Background/Aims: Randomisation in small clinical trials is a delicate matter, due to the tension between the conflicting aims of balanced groups and unpredictable allocations. The commonly used method of permuted block randomisation has been heavily criticised for its high predictability. This article introduces merged block randomisation, a novel and conceptually simple restricted randomisation design for small clinical trials (less than 100 patients per stratum). Merged block randomisation is a simple procedure that can be carried out without need for a computer. Merged block randomisation is not restricted to 1:1 randomisation, but is readily applied to unequal target allocations and to more than two treatment groups. Methods: The position of merged block randomisation on the spectrum of balance and predictability is investigated in a simulation study, in two common situations: a single-centre study and a multicentre study (with sampling stratified per centre). Methods included for comparison were permuted block randomisation, Efron’s biased coin design, the maximal procedure, the block urn design and the big stick design. Results: Compared to permuted block randomisation with blocks of size 4, merged block randomisation has the same maximum tolerated imbalance and is thus as impervious to chronological bias, with the added benefit of being less predictable. Each method in the study takes a different position on the balance/determinism spectrum, and none was uniformly best. Merged block randomisation was either less predictable or more balanced than the other methods, in all simulation settings. Conclusion: Merged block randomisation is a versatile restricted randomisation method that outperforms permuted block randomisation and is a good choice for small clinical trials where imbalance is a main concern, especially in multicentre trials where the number of patients per centre may be small.

Intraneural Ultrasound-guided Sciatic Nerve Block

What We Already Know about This Topic What This Article Tells Us That Is New Background Both extra- and intraneural sciatic injection resulted in significant axonal nerve damage. This study aimed to establish the minimum effective volume of intraneural ropivacaine 1% for complete sensory-motor sciatic nerve block in 90% of patients, and related electrophysiologic variations. Methods Forty-seven consecutive American Society of Anesthesiologists physical status I-II patients received an ultrasound-guided popliteal intraneural nerve block following the up-and-down biased coin design. The starting volume was 15 ml. Baseline, 5-week, and 6-month electrophysiologic tests were performed. Amplitude, latency, and velocity were evaluated. A follow-up telephone call at 6 months was also performed. Results The minimum effective volume of ropivacaine 1% in 90% of patients for complete sensory-motor sciatic nerve block resulted in 6.6 ml (95% CI, 6.4 to 6.7) with an onset time of 19 ± 12 min. Success rate was 98%. Baseline amplitude of action potential (mV) at ankle, fibula, malleolus, and popliteus were 8.4 ± 2.3, 7.1 ± 2.0, 15.4 ± 6.5, and 11.7 ± 5.1 respectively. They were significantly reduced at the fifth week (4.3 ± 2.1, 3.5 ± 1.8, 6.9 ± 3.7, and 5.2 ± 3.0) and at the sixth month (5.9 ± 2.3, 5.1 ± 2.1, 10.3 ± 4.0, and 7.5 ± 2.7) (P < 0.001 in all cases). Latency and velocity did not change from the baseline. No patient reported neurologic symptoms at 6-month follow-up. Conclusions The intraneural ultrasound-guided popliteal local anesthetic injection significantly reduces the local anesthetic dose to achieve an effective sensory-motor block, decreasing the risk of systemic toxicity. Persistent electrophysiologic changes suggest possible axonal damage that will require further investigation.

Adaptive Designs for Non-inferiority Trials with Multiple Experimental Treatments

The increase in the popularity of non-inferiority clinical trials represents the increasing need to search for substitutes for some reference (standard) treatments. A new treatment would be preferred to the standard treatment if the benefits of adopting it outweigh a possible clinically insignificant reduction in treatment efficacy (non-inferiority margin). Statistical procedures have recently been developed for treatment comparisons in non-inferiority clinical trials that have multiple experimental (new) treatments. An ethical concern for non-inferiority trials is that some patients undergo the less effective treatments; this problem is more serious when multiple experimental treatments are included in a balanced trial in which the sample sizes are the same for all experimental treatments. With the aim of giving fewer patients the inferior treatments, we propose a response-adaptive treatment allocation scheme that is based on the doubly adaptive biased coin design. The proposed adaptive design is also shown to be superior to the balanced design in terms of testing power.