Intrathecal Dose Research Articles

Intravenous Ondansetron for Attenuation of Post Spinal Anesthesia Hypotension

Abstract Background Spinal Anesthesia is a common type of anesthesia used during many surgical procedures. This regional technique can be accomplished by administering an intrathecal dose of hyperbaric local anesthetic solution. The local anesthetic within the subarachnoid space can block sensory, motor and sympathetic pathways. Objectives The Purpose of this study was to find out the effectiveness of prophylactic administration of intravenous ondansetron for attenuation of spinal anesthesia induced hypotension in non-obstetric spinal anesthesia surgeries. Patients and Methods Therefore, A prospective double-blind, placebo-controlled, randomized study was found to be the most suitable design in order to achieve the study objectives. A total of 90 patients males & females included in the study, aged 20-40 years, and were divided equally into two groups: Group A received 8 mg ondansetron diluted in volume of 10 cm normal saline 5 minutes prior to spinal anesthesia. Group B received a placebo of 10 cm normal saline 5 minutes prior to spinal anesthesia. Results There was no statistically significant difference found between the two studied groups regarding demographic data, anthropometric measures, ASA score and total time of surgery. There was statistically significant increase in the incidence of hypotension immediately after spinal and at 5 min in placebo group than ondansetron group with p-value = 0.026 and 0.014 respectively. Conclusion The present study demonstrated that, among patients who received spinal anesthesia with bupivacaine for elective for surgeries below umbilicus, prophylactic intravenous ondansetron 8mg iv 5 mins prior to spinal anesthesia reduced spinal anesthesia induced hypotension decreases in SBP, MAP, and heart rate. Ondansetron did not have a significant effect on DBP. Ondansetron did not have a significant effect on DBP. The incidence of nausea and vomiting was lower following the administration of ondansetron, and vasopressor use and dosages were reduced.

Initial Intrathecal Dose Titration and Predictors of Early Dose Escalation in Patients With Cancer Using a 100:1 Oral to Intrathecal Morphine Conversion Ratio

Pain is common in patients with advanced cancer, and intrathecal drug delivery (IDD) has been successfully used for recalcitrant pain. We report on our experience using a 100:1 oral-to-intrathecal morphine conversion ratio for initial dosing and factors predictive of early dose escalation. Retrospective review of an intrathecal drug delivery system (IDDS) data base at the Huntsman Cancer Institute-University of Utah in cancer patients initiated on IDD with morphine or hydromorphone. Demographic characteristics, preoperative opioid use, and initial and hospital discharge IDD settings were collected. A total of 275 patients were identified between June 2014 and May 2020. The median oral-to-intrathecal morphine conversion ratio for initial IDD dosing was 105.5:1 (interquartile range [IQR] 90-120, range 75-150). No serious adverse effects including respiratory depression or sedation were noted and the median length of stay was one night (IQR 1-2, range 1-22). Ninety-six percent of patients discontinued opioids immediately following IDDS implant. Initial IDD dosing was adequate in 42% of patients. Dose reduction was required in 4% prior to discharge due to nausea, patient request, weakness, pruritus, or urinary retention. Dose escalation was required in 54%, with a median dose increase of 66.7% (IQR 33-150%, range 5-1150%). Patients in the highest quartile of dose escalation, ≥70% between IDD initiation and discharge, had associations with younger age, higher preoperative opioid use, and inpatient status. No significant associations were found in patients who required dose reduction as compared to other patients. An oral-to-intrathecal morphine conversion ratio of approximately 100:1 for initiation of IDD in patients with cancer pain was safe and well tolerated and may facilitate rapid elimination of systemic opioids. Dose reduction was rare, while a majority of patients required further dose escalation prior to discharge.

A new approach for leptomeningeal metastases: chemotherapy administered through lumbar intrathecal port.

Intrathecal chemotherapy is a local therapeutic modality used for treatment of leptomeningeal metastases. However, the techniques currently used, i.e. repeated lumbar puncture and Ommaya reservoir, have certain disadvantages. Lumbar intrathecal port (LIP) placement is a relatively novel technique, which has been used for pain management in cancer patients. To investigate the use of LIP for intrathecal administration of chemotherapeutic agents in patients with leptomeningeal metastases. Retrospective study of 13 patients treated with intrathecal chemotherapy for secondary leptomeningeal involvement of a primary solid tumor were included in this retrospective study. The patients received intrathecal chemotherapy through a LIP. The patients received a total of 123 intrathecal chemotherapy doses. No grade 3-4 toxicity, technical problem or severe complication developed. During a median of 136 days of follow-up (range, 67-376 days), 12 patients died (92.3%). The treatment resulted in symptom improvement in all patients and self-rated overall health and quality of life improved, compared with baseline. The LIP system, which has been used for intrathecal pain management for decades, appears to offer a safe alternative for intrathecal chemotherapy in patients with leptomeningeal metastases. Further studies are warranted to clarify its potential use in this setting.

Ultrasound assisted lumbar intrathecal administration of nusinersen in adult patients with spinal muscular atrophy: A case series.

Intrathecal nusinersen administration can be challenging in certain adult spinal muscular atrophy (SMA) patients with difficult spinal anatomy who require imaging techniques (fluoroscopy or computed tomography scans) or invasive approaches (catheter placement, laminotomy) to identify the intrathecal space. We used ultrasound (US) assistance to access the lumbar intrathecal space in patients with SMA who experienced previous difficulties or failures with intrathecal dosing. Eighteen adult patients with difficult spines were enrolled. We used US assistance, and we recorded the successful administrations, number of attempts, procedure times, and "patient satisfaction." There were 57 consecutive successful nusinersen spinal administrations in all patients enrolled. In 50% of patients, two or fewer attempts were needed to obtain a successful administration, with four or fewer attempts in 83.3%; only three patients reported more than four attempts because of both severe scoliosis and severe spine rotation (two patients) and obesity (one patient). The mean procedure time was 11.8min (range, 1.7-28.9). Patient satisfaction was 4.97/5 (range, 4-5; median, 5) on Likert scale at 5min and at 72 h. No major adverse events were reported, and two post dural puncture headaches were managed with medical therapy and with complete resolution within 72 h. US assistance seems to be a valid option among treatment choices for intrathecal nusinersen administration in patients with difficult spine. The absence of radiation exposure and the lack of need for intravenous sedation or general anesthesia are additional potential advantages to US assisted administration.

Effects of fadolmidine, an α2 -adrenoceptor agonist, as an adjuvant to spinal bupivacaine on antinociception and motor function in rats and dogs.

α2‐Adrenoceptor agonists such as clonidine and dexmedetomidine are used as adjuvants to local anesthetics in regional anesthesia. Fadolmidine is an α2‐adrenoceptor agonist developed especially as a spinal analgesic. The current studies investigate the effects of intrathecally administered fadolmidine with a local anesthetic, bupivacaine, on antinociception and motor block in conscious rats and dogs. The antinociceptive effects of intrathecal fadolmidine and bupivacaine alone or in combination were tested in the rat tail‐flick and the dog's skin twitch models. The durations of motor block in rats and in dogs were also assessed. In addition, the effects on sedation, mean arterial blood pressure, heart rate, respiratory rate and body temperature were evaluated in telemetrized dogs. Concentrations of fadolmidine in plasma and spinal cord were determined after intrathecal and intravenous administration in rats. Co‐administration of intrathecal fadolmidine with bupivacaine increased the magnitude and duration of the antinociceptive effects and prolonged motor block without hypotension. The interaction of the antinociceptive effect was synergistic in its nature in rats. Concentration of fadolmidine in plasma was very low after intrathecal dosing. Taken together, these studies show that fadolmidine as an adjuvant to intrathecal bupivacaine provides enhanced sensory‐motor block and enables a reduction of the doses of both drugs. The results indicate that co‐administration of fadolmidine with intrathecal bupivacaine was able to achieve an enhanced antinociceptive effect without hypotension and could thus represent a suitable combination for spinal anesthesia.

Application of in vitro data in physiologically-based kinetic models for quantitative in vitro-in vivo extrapolation: A case-study for baclofen

Physiologically-based kinetic (PBK) models can simulate concentrations of chemicals in tissues over time without animal experiments. Nevertheless, in vivo data are often used to parameterise PBK models. This study aims to illustrate that a combination of kinetic and dynamic readouts from in vitro assays can be used to parameterise PBK models simulating neurologically-active concentrations of xenobiotics. Baclofen, an intrathecally administered drug to treat spasticity, was used as a proof-of-principle xenobiotic.An in vitro blood-brain barrier (BBB) model was used to determine the BBB permeability of baclofen needed to simulate plasma and cerebrospinal concentrations. Simulated baclofen concentrations in individuals and populations of adults and children generally fall within 2-fold of measured clinical study concentrations. Further, in vitro micro-electrode array recordings were used to determine the effect of baclofen on neuronal activity (cell signalling). Using quantitative in vitro-in vivo extrapolations (QIVIVE) corresponding doses of baclofen were estimated. QIVIVE showed that up to 4600 times lower intrathecal doses than oral and intravenous doses induce comparable neurological effects. Most simulated doses were in the range of administered doses. This show that PBK models predict concentrations in the central nervous system for various routes of administration accurately without the need for additional in vivo data.

The Outcome of Childhood B-Cell Precursor ALL with ETV6-RUNX1 Treated with Japan Association of Childhood Leukemia Study (JACLS) ALL-02 Trial

Background: It is well known that ETV6-RUNX1 positive pediatric B cell precursor acute lymphoblastic leukemia (B-ALL) shows excellent outcome when they are treated with contemporary chemotherapeutic regimens. However, the prognosis of ETV6-RUNX1 positive B-ALL wasn't determined in Japanese pediatric cohort which was uniformly treated. Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol achieved 83.7±1.1% of 4-year event free survival of pediatric B-ALL (Hasegawa et al. 58th ASH annual meeting) which was comparable to that in major recent pediatric ALL clinical trials, although risk stratification based on minimal residual disease (MRD) was not employed. Herein, we report the outcome and analyze the prognostic factors of ETV6-RUNX1 positive B-ALL treated with JACLS ALL-02 protocol.Patients and treatment: Between April 2002 and March 2008, newly diagnosed de novo ETV6-RUNX1 positive ALL with 1-18 years of age were enrolled to JACLS ALL-02 trial. Patients were stratified into 3 groups: standard-risk (SR), high-risk (HR), extremely high-risk (ER), based on initial prednisolone (PSL) response and the modified National Cancer Institute(NCI) workshop criteria. Prednisolone poor response (PPR) was determined after 7 days of monotherapy with prednisone and one intrathecal dose of methotrexate. PSL good responders (PGR; < 1,000 blasts/μL) were divided into SR and HR according to the modified NCI workshop criteria by WBC 10K and age 10, and received conventional therapy. BCP-ALL with PPR (≥ 1,000 blasts/μL) were assigned to ER and received intensified post-induction therapy. Estimation of event free survival (EFS) and overall survival (OS) was performed using the Kaplan-Meier method and the differences were compared using the log-rank test. Multivariate analysis was performed using a Cox regression model.Results: 205 newly diagnosed ETV6-RUNX1 positive ALL patients were enrolled in JACLS ALL-02 clinical trial, which included 108 patients in SR group (52.7%), 89 in HR group (43.3%) and 8 in ER group (3.9%). The median age at diagnosis was 4.3 years (range, 1.0 to 15.0 years) and the median WBC count was 6,800/μL (range, 370 to 384,700 /μL). The median follow-up time was 6 year and 6 months. 4y/8y EFS and OS (±SE) are 92.5±2.6/ 89.8±2.5% and 96.5±1.5/ 95.5±1.6%, respectively. 4y / 8y EFS of the patients of NCI-SR (n=167) and NCI-HR (n=38) are 95.6±1.6% / 91.3±2.7% and 89.5±5.0% / 83.0±6.4%, respectively (log rank p=0.04). 4y / 8y OS of the patients with PSL good response (n=197) was 97.9±1.1% / 97.0±1.3%, while those of the patients with PPR (n=8) was 87.5±11.7% / 58.3±18.6% (log rank p<0.001). Eighteen of 205 (8.8%) patients experienced relapse. According to BFM risk stratification of relapsed ALL (S1 to S4), 13 of 18 patients were in S2 and ten of them were rescued by salvage therapy. However, 5 patients in S3 or S4 group died of disease progression. Although two patients showing PPR belonged to S2, all of them died of disease progression. Multivariate analysis identifies NCI-HR (HR=2.92, p=0.05) as a predictor of poor prognosis in EFS, and PPR (HR=12.0, p<0.01) as predictor of poor prognosis in OS.Discussion: Although JACLS ALL-02 protocol didn't employ MRD based risk stratification, good outcome of the 4y EFS and OS (92.5±2.6 % and 96.5±1.5 %) was achieved for ETV6-RUNX1 positive B-ALL patients. Because NCI-SR and PGR were predictors of excellent outcome for ETV6-RUNX1 positive B-ALL, less intensive treatment should be explored for this group. On the other hand, NCI-HR and PPR indicated poor outcome. We hope that MRD based monitoring might improve outcome of this subgroup in our next clinical trial. DisclosuresNo relevant conflicts of interest to declare.

Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study

Nusinersen showed a favourable benefit-risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of nusinersen over 3 years. This phase 2, open-label, multicentre, dose-escalation study was done in three university hospital sites in the USA and one in Canada. Infants aged between 3 weeks and 6 months with two or three SMN2 gene copies and infantile-onset spinal muscular atrophy were eligible for inclusion. Eligible participants received multiple intrathecal loading doses of 6 mg equivalent nusinersen (cohort 1) or 12 mg dose equivalent (cohort 2), followed by maintenance doses of 12 mg equivalent nusinersen. The protocol amendment on Jan 25, 2016, changed the primary efficacy endpoint from safety and tolerability to reaching motor milestones, assessed using the Hammersmith Infant Neurological Examination section 2 (HINE-2) at the last study visit, in all participants who successfully completed the loading dose period and day 92 assessment. The statistical analysis plan was amended on Feb 10, 2016, to include additional analyses of the subgroup of participants with two SMN2 copies. Adverse events were assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov (NCT01839656). Between May 3, 2013, and July 9, 2014, 20 symptomatic participants with infantile-onset spinal muscular atrophy (12 boys and 8 girls; median age at diagnosis 78 days [range 0-154]) were enrolled. Median time on study was 36·2 months (IQR 20·6-41·3). The primary endpoint of an incremental improvement in HINE-2 developmental motor milestones was reached by 12 (63%) of 19 evaluable participants. In the 13 participants with two SMN2 copies treated with 12 mg nusinersen, the HINE-2 motor milestone total score increased steadily from a baseline mean of 1·46 (SD 0·52) to 11·86 (6·18) at day 1135, representing a clinically significant change of 10·43 (6·05). At study closure (Aug 21, 2017), 15 (75%) of 20 participants were alive. 101 serious adverse events were reported in 16 (80%) of 20 participants; all five deaths (one in cohort 1 and four in cohort 2) were likely to be related to spinal muscular atrophy disease progression. Our findings are consistent with other trials of nusinersen and show improved survival and attainment of motor milestones over 3 years in patients with infantile-onset spinal muscular atrophy, with a favourable safety profile. Biogen and Ionis Pharmaceuticals.

P.32 Intrathecal anaesthetic drug dosing strategies for repair of perineal tears: An evaluation of current practice

Introduction: Spinal anaesthesia is the method of choice for obstetric procedures due to avoidance of the additional risks posed by general anaesthesia to the obstetric population. [1] Bloom SL, Spong CY, Weiner SJ, et al. Complications of anesthesia for cesarean delivery. Obstet Gynecol 2005;106:281–7. Google Scholar Excessive intrathecal dosage during neuraxial blockade is associated with greater incidence of side effects, [2] Van de Velde M, Van Schoubroeck D, Jani J, et al. Combined spinal- epidural anesthesia for cesarean delivery: dose-dependent effects of hyperbaric bupivacaine on maternal hemodynamics. Anesth Analg 2006;103:187–90. Google Scholar including hypotension, nausea and vomiting and an increased length of time to recovery from anaesthesia [3] Nair GS, Abrishami A, Lermitte J, Chung F. Systematic review of spinal anaesthesia using bupivacaine for ambulatory knee arthroscopy. Br J Anaesth 2009:307–15. Google Scholar that may adversely affect breastfeeding, bonding with the child and overall maternal satisfaction. To date there is no literature supporting a standardised intrathecal dose for perineal tear repair and we sought to investigate the range of current practice.

A physiologically-based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration

Antisense oligonucleotides (ASOs) are promising therapeutic agents for a variety of neurodegenerative and neuromuscular disorders, e.g., Alzheimer's, Parkinson's and Huntington's diseases, spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), caused by genetic abnormalities or increased protein accumulation. The blood-brain barrier (BBB) represents a challenge to the delivery of systemically administered ASOs to the relevant sites of action within the central nervous system (CNS). Intrathecal (IT) delivery, in which drugs are administered directly into the cerebrospinal fluid (CSF) space, enables to bypass the BBB. Several IT-administered ASO therapeutics have already demonstrated clinical effect, e.g., nusinersen (SMA) and tofersen (ALS). Due to novelty of IT dosing for ASOs, very limited pharmacokinetic (PK) data is available and only a few modeling reports have been generated. The objective of this work is to advance fundamental understanding of whole-body distribution of IT-administered ASOs. We propose a physiologically-based pharmacokinetic modeling approach to describe the distribution along the neuroaxis based on PK data from non-human primate (NHP) studies. We aim to understand the key processes that drive and limit ASO access to the CNS target tissues. To elucidate the trade-off between parameter identifiability and physiological plausibility of the model, several alternative model structures were chosen and fitted to the NHP data. The model analysis of the NHP data led to important qualitative conclusions that can inform projection to human. In particular, the model predicts that the maximum total exposure in the CNS tissues, including the spinal cord and brain, is achieved within two days after the IT injection, and the maximum amount absorbed by the CNS tissues is about 4% of the administered IT dose. This amount greatly exceeds the CNS exposures delivered by systemic administration of ASOs. Clearance from the CNS is controlled by the rate of transfer from the CNS tissues back to CSF, whereas ASO degradation in tissues is very slow and can be neglected. The model also describes local differences in ASO concentration emerging along the spinal CSF canal. These local concentrations need to be taken into account when scaling the NHP model to human: due to the lengthier human spinal column, inhomogeneity along the spinal CSF may cause even higher gradients and delays potentially limiting ASO access to target CNS tissues.

Age- and Intravenous Methotrexate-Associated Leukoencephalopathy and Its Neurological Impact in Pediatric Patients with Lymphoblastic Leukemia.

Simple SummaryIn this study, we investigated standardized post-chemotherapy magnetic resonance (MR) scans for leukoencephalopathy and patient- and treatment-related risk factors in childhood leukemia patients. As prevalence numbers are limited, our study provides the required estimations for this population. Furthermore, we demonstrate that younger patients might be more at-risk for development of leukoencephalopathy (LE), and that a higher intravenous methotrexate (IV-MTX) dose has a cumulative toxic effect, while the number of intrathecal administrations was not significantly associated with the extent of LE. This can suggest we should modify chemotherapeutic treatment regimens by decreasing the number of IV-MTX applications, with special attention for younger patients.Methotrexate (MTX) is associated with leukoencephalopathy (LE) in children treated for lymphoblastic leukemia/lymphoma (ALL/LBL). However, large-scale studies with systematic MR acquisition and quantitative volumetric lesion information remain limited. Hence, the prevalence of lesion burdens and the potential risk factors of LE in this population are still inconclusive. FLAIR-MRI scans were acquired at the end of treatment in children who were treated for ALL/LBL, which were quantitatively analyzed for LE. Voxels were assigned to the lesion segmentation if indicated by two raters. Logistic and linear regression models were used to test whether lesion presence and size were predicted by risk factors such as age at diagnosis, gender, intrathecal (IT-) or intravenous (IV-)MTX dose, CNS invasion, and acute neurological events. Patients with a pre-existing neurological condition or low-quality MR scan were excluded from the analyses. Of the 129 patients, ten (8%) suffered from CNS invasion. Chemotherapy-associated neurological events were observed in 13 patients (10%) during therapy, and 68 patients (53%) showed LE post-treatment. LE was more frequent in cases of lower age and higher cumulative IV-MTX doses, while the extent of LE and neurological symptoms were associated only with IV-MTX doses. Neurological events were not significantly associated with LE, even though symptomatic patients demonstrated a higher ratio of LE (n = 9/13) than asymptomatic patients (n = 59/116). This study suggests leukoencephalopathy frequently occurs in both symptomatic and asymptomatic leukemia patients. Younger children and patients treated with higher cumulative IV-MTX doses might need more regular screening for early detection and follow-up of associated sequelae.

A prediction model using machine-learning algorithm for assessing intrathecal hyperbaric bupivacaine dose during cesarean section

BackgroundThe intrathecal hyperbaric bupivacaine dosage for cesarean section is difficult to predetermine. This study aimed to develop a decision-support model using a machine-learning algorithm for assessing intrathecal hyperbaric bupivacaine dose based on physical variables during cesarean section.MethodsTerm parturients presenting for elective cesarean section under spinal anaesthesia were enrolled. Spinal anesthesia was performed at the L3/4 interspace with 0.5% hyperbaric bupivacaine at dosages determined by the anesthesiologist. A spinal spread level between T4-T6 was considered the appropriate block level. We used a machine-learning algorithm to identify relevant parameters. The dataset was split into derivation (80%) and validation (20%) cohorts. A decision-support model was developed for obtaining the regression equation between optimized intrathecal 0.5% hyperbaric bupivacaine volume and physical variables.ResultsA total of 684 parturients were included, of whom 516 (75.44%) and 168 (24.56%) had block levels between T4 and T6, and less than T6 or higher than T4, respectively. The appropriate block level rate was 75.44%, with the mean bupivacaine volume [1.965, 95%CI (1.945,1.984)]ml. In lasso regression, based on the principle of predicting a reasonable dose of intrathecal bupivacaine with fewer physical variables, the model is “Y=0.5922+ 0.055117* X1-0.017599*X2” (Y: bupivacaine volume; X1: vertebral column length; X2: abdominal girth), with λ 0.055, MSE 0.0087, and R2 0.807.ConclusionsAfter applying a machine-learning algorithm, we developed a decision model with R2 0.8070 and MSE due to error 0.0087 using abdominal girth and vertebral column length for predicting the optimized intrathecal 0.5% hyperbaric bupivacaine dosage during term cesarean sections.

Dosing Patterns In Treatment of Disabling Spasticity With Intrathecal Baclofen.

The aim of this study was to describe and analyze dosing patterns for patients with ITB treatment over time and to identify possible subgroups demonstrating diversity in patterns. A retrospective design. For 81 patients from six different hospitals, baclofen doses from the first 2 years of treatment were identified using medical records. Line graphs of each patient's doses were analyzed and grouped based on similarities in dosing pattern. The analyses of the dosing patterns resulted in four different subgroups classified as stable, slow increase, rapid increase, and fluctuating. The results highlight the clinical challenge of predicting dose development over time. This study provides rehabilitation healthcare professionals with a better understanding of intrathecal baclofen dose development. Illustrations of the four subgroups can be used as an educational tool for patients, family, and caregivers.

Spinal anaesthesia with Chloroprocaine HCl 1% for elective lower limb procedures of short duration: a prospective, randomised, observer-blind study in adult patients

BackgroundThis prospective, randomised, observer-blinded study has been conducted in patients undergoing procedures of the lower extremities to evaluate the time to complete block resolution of 2-chloroprocaine 1% at three intrathecal doses (30, 40 and 50 mg).MethodsAfter informed consent, we enrolled 45 male and female patients, aged 18–65 years, ASA score I-II, BMI 18–32 kg/m2, undergoing elective lower limb procedures lasting ≤40 min and with a requested dermatomeric level of sensory block ≥ T12.The patients were randomised in a 1:1:1 ratio to receive Chloroprocaine HCl 1% at one of the three different intrathecal doses (Group 30 = 30 mg, Group 40 = 40 mg or Group 50 = 50 mg). The progression and regression of both sensory and motor blocks were evaluated blindly. Urine and venous blood samples were collected for pharmacokinetic analysis.ResultsTimes to regression of spinal blocks were 1.76 ± 0.35 h, 2.13 ± 0.46 h and 2.23 ± 0.38 h, in Group 30, 40 and 50 respectively: the 30 mg dose showed a significantly faster resolution of spinal block than the 40 mg (p = 0.034) and the 50 mg (p = 0.006). Time to readiness for surgery was significantly reduced with the dose of 50 mg when compared to dose of 30 mg (p = 0.0259).ConclusionsThe doses of 50 mg and 40 mg yielded a longer resolution of spinal block than the dose of 30 mg. Nevertheless, the dose of 30 mg resulted in a higher secondary failure rate.Trial registrationRegistration of clinical trial: clinicaltrials.gov (NCT02481505).

A Comparative Study of Intrathecal Low dose Isobaric and Hyperbaric Levobupivacaine in Ambulatory Perianal Surgeries: A Prospective, Double Blind Study

Background: Perianal surgeries can be conveniently performed under saddle block . We intended to compare intrathecal low dose isobaric and hyperbaric levobupivacaine and study their efficacy in perianal surgeries under saddle block on ambulatory basis. Methods: In this prospective, randomised controlled, double blind trial involving 20 patients in each group were randomised into two groups, Group I and Group H. Group I received 1ml of 0.5% levobupivacaine(5 mg) + 0.16 ml of Normal Saline ( total volume-1.16 ml) and Group H : 1 ml of 0.5% levobupivacaine (5 mg) + 0.16 ml of 50% dextrose (total volume-1.16 ml). Duration for ambulation being the primary criteria, we also noted maximum cephalic spread, time to reach maximum height of sensory blockade, 2 segment regression, duration of motor and sensory blockade, time for voiding and time for rescue analgesia . Appropriate statistical tests were used for final analysis. P value less than 0.05 was considered statistically significant. Results: There were no significant differences between the two groups in terms of the maximum height of sensory blockade and 2 segment regression that was achieved and request for first rescue analgesic. Duration of motor blockade, time to full recovery of sensory block and first voiding were all statistically significantly shorter in group H than group I. Conclusions: We conclude that hyperbaric levobupivacaine is superior to isobaric form while being closer to ideal choice of anaesthetic agent on ambulatory basis required for perianal anaesthesia while both the concentrations are similar in their safety profile.

Determination of the initial minimum effective dose of 0.5% bupivacaine with 20 μg of fentanyl for an operative fixation of fractured neck of femur: a prospective, observational trial.

Fractured neck of femur (FNF) is a common cause of morbidity and mortality in elderly. Spinal catheter allows fractionation of local anesthetic dose which combined with intrathecal opioid leads to a dose reduction and better hemodynamic stability. The primary objective of this paper was to investigate the initial minimum local anesthetic dose (iMLAD) of 0.5% isobaric bupivacaine with 20 μg of fentanyl administered via spinal catheter in order to commence the operative fixation of FNF. A prospective, single-blinded, adaptive clinical trial with patients undergoing dynamic hip screw implantation (DHS) or hemiarthroplasty (HEMI) due to FNF. The Dixon and Massey's up and down method was used to determine the ED50 of intrathecal bupivacaine. This figure was confirmed with Probit analysis, in addition to the ED95. Using the Dixon and Massey's approach, the iMLADED50 for DHS was 0.29 mL (1.45 mg) and the iMLADED50 for HEMI was 0.33 mL (1.65 mg) of 0.5% isobaric bupivacaine. The Probit analyses demonstrated that the iMLADED95 for DHS and HEMI were 0.32 mL (1.6 mg) and 0.34 mL (1.7 mg) respectively. The mean cumulative dose of 0.5% bupivacaine for the whole surgery was 0.67 mL (3.35 mg) and 0.87 mL (4.35 mg) in the DHS and HEMI groups, respectively. This study demonstrates that the placement of a spinal catheter allows for careful titration of local anesthetic, enabling a reduction of the initial intrathecal dose of 0.5% isobaric bupivacaine below 0.4 mL (2 mg) and leading to a significant reduction of a dose required for the whole surgery when combined with an intrathecal opioid.

A study of intrathecal low dose bupivacaine and fentanyl versus conventional dose of bupivacaine alone for elective caesarean section

Background: Spinal anesthesia is the most common method of the regional block in cesarean section, because it is easy to perform, economical produces rapid onset of anesthesia, and good muscle relaxation, and most importantly, it gives immense pleasure to the conscious mother. To improve the quality of subarachnoid block, intrathecal opioids are used as adjuvants to Bupivacaine. Fentanyl has a rapid onset of action as a lipophilic opioid following intrathecal administration. Because of high lipid solubility, it undergoes rapid uptake by the spinal cord, and hence the chances of delayed respiratory depression are less. Methods: We randomly selected 60 patients belonging to the American Society of Anesthesiologists (ASA) class I and II, who are scheduled for elective LSCS. These patients were divided randomly into two groups of 30 each. Group B received 10mg of 0.5% hyperbaric bupivacaine (2ml). Group BF received 7.5mg of 0.5% hyperbaric bupivacaine (1.5ml) with 25mcg of Fentanyl (0.5ml). Lumbar puncture was performed at the level of L3-L4 with 23 Guage Quincke Babcock's needle with the patient in the right lateral position. The sensory block was assessed with the loss of pin prick sensation, and the motor block was set using the Bromage scale technique. We also recorded the hemodynamic parameters like pulse rate, blood pressure, oxygen saturation. Results: No significant statistical difference was found in demographic data between the two groups. Group BF showed early onset of the sensory block with a P value of 0.001. Time taken to attain peak sensory level was early in the BF group with a P value of 0.001. The total duration of sensory block and duration of effective analgesia was longer in the BF group with a P value of 0.001. The onset of motor blockade was early in the bupivacaine only group with a P value of 0.02. Conclusion: The intrathecal fentanyl 25mcg reduces the dose of 7.5 mg of 0.5% hyperbaric Bupivacaine for spinal anesthesia in cesarean section, thus reducing the incidence of side effects associated with it. By its synergistic effect with 0.5% hyperbaric bupivacaine, it provides better excellent sensory blockade and postoperative analgesia, good hemodynamic stability, less incidence of complications like Nausea, vomiting, and shivering without compromising the safety of mother and fetus in comparison to intrathecal 10mg of 0.5% hyperbaric Bupivacaine alone.

Dexmedetomidine versus fentanyl as adjunct to ropivacaine-dexamethasone for labor analgesia: a randomized control study

Background and aims Although intrathecal analgesia is an effective option during labor, there is a need to establish sustainable and assured analgesia during the entire labor process. We aimed to compare the effect of dexmedetomidine versus fentanyl as an adjuvant to low-dose ropivacaine-dexamethasone for intrathecal labor analgesia in primigravida women.Patients and methods The study was conducted after approval of ethical committee of Al Azhar University Hospital. A total of 60 primiparous women classified in American Society of Anesthesiologists classes II with a singleton pregnancy in active labor were given combined spinal epidural analgesia. This was a double-blind randomized controlled trial that allocated them in two groups of 30 patients each. Group I received intrathecal 2.5 mg of 0.1% ropivacaine (diluted to 2.5 ml with normal saline)+5 μg dexmedetomidine+4 mg dexamethasone. Occurrence of any adverse reaction was observed for ten min. Group II received 25 μg of fentanyl instead of 5 μg dexmedetomidine. For both groups, epidural top-ups of 10 ml of 1% ropivacaine were given when parturients complained of two painful contractions (visual analog scale ≥4), after epidural test dose of 3 ml of 0.5% ropivacaine was slowly injected via epidural catheter and no occurrence of adverse reaction was observed 10 min later. Data collected were demographic profile of the patients, intrathecal block characteristics, needs for epidural activation before delivery, and maternal and fetal adverse effects. The primary study goal was to prove the analgesic efficacy and safety of intrathecal selective sensory block on both mother and fetus, whereas the study secondary goal was to prove that intrathecal single dose injection could be used as an effective alternative option in labor analgesia as well as epidural analgesia. Catecholamine level (epinephrine and norepinephrine) was measured using enzyme-linked immunosorbent assay technique.Results The mean age (years), weight (kg), height (cm), and BMI (kg/m2) in group I were 24.3±3.30, 65.4±16.2, 161.3±4.6, and 22.3±3.4, respectively, whereas in group II were 25.23±4.44, 66.3±15.6, 160.4±4.3, and 22.2±3.1, respectively, with insignificant difference (P>0.05). Mean visual analog scale score before onset of analgesia in group I and group II was 8.59±1.22 and 8.7±1.14, respectively. The time to full cervical dilatation was 120.14±10.2 in group I and 120.0±10.6 in group II, and the mean duration of second stage of labor was 12.02±1.37 min in group I and 11.83±0.93 min in group II. The mean duration of analgesia was statistically significant (lower) in group II (221.83±22.26) as compared with group I (296.33±44.83) (P<0.001). The mean analgesia in group I (12.3±1.8) and group II (12.1±1.7) was statistically insignificant (P>0.05). The mean highest sensory levels in group I and group II were statistically insignificant, that is, T5 (T4–T8) versus T6 (T4–T7) (P>0.05). The sensory region time in group II was greater (241.83±22.26 min) as compared with group I (329.83±44.10), with P value less than 0.001. Neither maternal nor fetal adverse events were statistically significant different between both groups (P>0.05). The mean basal norepinephrine level in pg/ml in group I was 130.30±27.6 and in group II was 103.50±20.6, with P value more than 0.05. At 2 h, norepinephrine level in pg/ml was 119.90±24.1 in group I and 90.50±13.6 in group II, with P value more than 0.05. At baseline, the epinephrine level in pg/ml in group I and group II was 59.20±11.3 and 53.20±10.3, respectively, whereas at 2 h, the epinephrine level in pg/ml was 57.90±9.1 in group I and 49.20±8.6 in group II, with P value more than 0.05.Conclusion Ropivacaine-dexamethasone combined with dexmedetomidine for intrathecal block achieved a potent selective sensory block with prolonged duration of analgesia, delayed S1 regression time, and limited maternal and fetal adverse effects than intrathecal ropivacaine-dexamethasone combined with fentanyl. However, dexmedetomidine or fentanyl provides a safe and efficacious adjuvant to intrathecal ropivacaine-dexamethasone in primigravida women with rapid onset, profound analgesia, and hemodynamic stability throughout the labor.

Clinical utility of epidural volume extension following reduced intrathecal doses: a randomized controlled trial

Background and objectivesEpidural Volume Extension (EVE) involves instillation of normal saline into the epidural space soon after an intrathecal injection, with the aim to augment the sensory block height. Its clinical relevance lies in the possibility of using reduced intrathecal dose and yet achieving the desired sensory block level. Intrathecal dose is a known determinant of the level of sensory block. Whether EVE is dependent on intrathecal dose is not known. MethodsWe conducted a randomized, controlled, double-blind study to compare the maximum sensory level (Smax) achieved with or without application of EVE to two different reduced intrathecal doses. Eighty four adult male patients of ASA status I or II with body weight between 50–70kg and height in the range of 150–180cm, scheduled for orthopedic lower limb surgery using combined spinal epidural anesthesia were randomized to receive, either intrathecal dose (5 or 8mg) with or without EVE, in accordance to group allocation. ResultsSmax was lowered by application of EVE to 5mg intrathecal bupivacaine (T8.9±4.3 vs. T6.4±1.9 with and without EVE respectively; p = 0.030). Smax was similar when EVE was applied to 8mg intrathecal bupivacaine than without it (T5.8±1.8 vs. T6.4±2.2 respectively; p= 0.324). ConclusionEVE should not be applied to 5mg plain bupivacaine during a combined spinal epidural block in patients undergoing lower limb orthopedic surgery as it may result in a decrease in the maximum sensory level.

Lower, Variable Intrathecal Opioid Doses, and the Incidence of Prolonged Fetal Heart Rate Decelerations After Combined Spinal Epidural Analgesia for Labor: A Quality Improvement Analysis.

BackgroundCombined spinal-epidurals with low-dose intrathecal opioids and local anesthetics are commonly used to initiate labor analgesia due to the fast onset of analgesia and good patient satisfaction. Intrathecal fentanyl has been associated with fetal bradycardia, and the rate may be higher at doses of 25 mcg and above. As such, our institution limits intrathecal fentanyl doses to less than 15 mcg for labor. Prompted by a few incidents of prolonged fetal bradycardia at even these low doses, we sought to audit the side effects associated with varying low doses of intrathecal fentanyl.MethodsAfter IRB approval, a retrospective review was performed on 555 labor records from May–December, 2016. All the patients received combined spinal epidurals for labor analgesia. Intrathecal medication consisted of 1 mL of 0.25% bupivacaine, and varying fentanyl doses: 2.5, 5, 10, and 15 mcg. The incidences of prolonged fetal heart rate decelerations, emergent cesarean delivery, magnitude of pain reduction, pruritus requiring treatment, and hypotension were compared.ResultsDemographic variables were equivalent between the groups. There were no differences in the rates of prolonged fetal decelerations (in order of increasing fentanyl dose: 4.4%, 2.3%, 7.6%, 3.0%, p-value = 0.11), emergent cesarean delivery, magnitude of pain reduction, pruritus, or maternal hypotension.ConclusionsIn conclusion, the rates of prolonged fetal heart rate decelerations after combined spinal epidural with intrathecal bupivacaine and fentanyl does not differ for fentanyl doses of 15 mcg and below.