The effectiveness of ambulatory continuous popliteal sciatic nerve blockade on patient-reported overall benefit of analgesia in patients undergoing foot or ankle surgery (CAREFREE trial); a randomized, open label, non-inferiority trial.

STUDY OBJECTIVE: Management of pain after foot and ankle surgery remains a concern for patients and healthcare professionals. This study determined the effectiveness of ambulatory continuous popliteal sciatic nerve blockade, compared to standard of care, on overall benefit of analgesia score (OBAS) in patients undergoing foot or ankle surgery. We hypothesized that usage of ambulatory continuous popliteal sciatic nerve blockade is non-inferior to standard of care. DESIGN: Single center, randomized, non-inferiority trial. SETTING: Tertiary hospital in the Netherlands. PATIENTS: Patients were enrolled if ≥18 years and scheduled for elective inpatient foot or ankle surgery. INTERVENTION: Patients were randomized to ambulatory continuous popliteal sciatic nerve blockade or standard of care. MEASUREMENTS: The primary outcome was the difference in OBAS, which includes pain, side effects of analgesics, and patient satisfaction, measured daily from the first to the third day after surgery. A non-inferiority margin of 2 was set as the upper limit for the 90% confidence interval of the difference in OBAS score. Mixed-effects modeling was employed to analyze differences in OBAS scores over time. Secondary outcome was the difference in opioid consumption. MAIN RESULTS: Patients were randomized to standard of care (n = 22), or ambulatory continuous popliteal sciatic nerve blockade (n = 22). Analyzing the first three postoperative days, the OBAS was significantly lower over time in the ambulatory continuous popliteal sciatic nerve blockade group compared to standard of care, demonstrating non-inferiority (-1.9 points, 90% CI -3.1 to -0.7). During the first five postoperative days, patients with ambulatory continuous popliteal sciatic nerve blockade consumed significantly fewer opioids over time compared to standard of care (-8.7 oral morphine milligram equivalents; 95% CI -16.1 to -1.4). CONCLUSIONS: Ambulatory continuous popliteal sciatic nerve blockade is non-inferior to standard of care with single shot popliteal sciatic nerve blockade on patient-reported overall benefit of analgesia.

Chemotherapy-induced peripheral neuropathy models constructed from human induced pluripotent stem cells and directly converted cells: a systematic review.

ABSTRACT: Developments in human cellular reprogramming now allow for the generation of human neurons for in vitro disease modelling. This technique has since been used for chemotherapy-induced peripheral neuropathy (CIPN) research, resulting in the description of numerous CIPN models constructed from human neurons. This systematic review provides a critical analysis of available models and their methodological considerations (ie, used cell type and source, CIPN induction strategy, and validation method) for prospective researchers aiming to incorporate human in vitro models of CIPN in their research. The search strategy was developed with assistance from a clinical librarian and conducted in MEDLINE (PubMed) and Embase (Ovid) on September 26, 2023. Twenty-six peer-reviewed experimental studies presenting original data about human reprogrammed nonmotor neuron cell culture systems and relevant market available chemotherapeutics drugs were included. Virtually, all recent reports modeled CIPN using nociceptive dorsal root ganglion neurons. Drugs known to cause the highest incidence of CIPN were most used. Furthermore, treatment effects were almost exclusively validated by the acute effects of chemotherapeutics on neurite dynamics and cytotoxicity parameters, enabling the extrapolation of the half-maximal inhibitory concentration for the 4 most used chemotherapeutics. Overall, substantial heterogeneity was observed in the way studies applied chemotherapy and reported their findings. We therefore propose 6 suggestions to improve the clinical relevance and appropriateness of human cellular reprogramming-derived CIPN models.

Adductor canal block techniques do not lead to involvement of sciatic nerve branches: a radiological cadaveric study.

INTRODUCTION: Low and high volume mid-thigh (ie, distal femoral triangle) and distal adductor canal block approaches are frequently applied for knee surgical procedures. Although these techniques aim to contain the injectate within the adductor canal, spillage into the popliteal fossa has been reported. While in theory this could improve analgesia, it might also result in motor blockade due to coverage of motor branches of the sciatic nerve. This radiological cadaveric study, therefore, investigated the incidence of coverage of sciatic nerve divisions after various adductor canal block techniques. METHODS: Eighteen fresh, unfrozen and unembalmed human cadavers were randomized to receive ultrasound-guided distal femoral triangle or distal adductor canal injections, with 2 mL or 30 mL injectate volume, on both sides (36 blocks in total). The injectate was a 1:10 dilution of contrast medium in local anesthetic. Injectate spread was assessed using whole-body CT with reconstructions in axial, sagittal and coronal planes. RESULTS: No coverage of the sciatic nerve or its main divisions was found. The contrast mixture spread to the popliteal fossa in three of 36 nerve blocks. Contrast reached the saphenous nerve after all injections, whereas the femoral nerve was always spared. CONCLUSIONS: Adductor canal block techniques are unlikely, even when using larger volumes, to block the sciatic nerve, or its main branches. Furthermore, injectate reached the popliteal fossa in a small minority of cases, yet if a clinical analgesic effect is achieved by this mechanism is still unknown.

The Effectiveness of Adductor Canal Block Compared to Femoral Nerve Block on Readiness for Discharge in Patients Undergoing Outpatient Anterior Cruciate Ligament Reconstruction: A Multi-Center Randomized Clinical Trial.

This study evaluated the effect of adductor canal block (ACB) versus femoral nerve block (FNB) on readiness for discharge in patients undergoing outpatient anterior cruciate ligament (ACL) reconstruction. We hypothesized that ACB would provide sufficient pain relief while maintaining motor strength and safety, thus allowing for earlier discharge. This was a randomized, multi-center, superiority trial. From March 2014 to July 2017, patients undergoing ACL reconstruction were enrolled. The primary outcome was the difference in readiness for discharge, defined as Post-Anesthetic Discharge Scoring System score ≥ 9. Twenty-six patients were allocated to FNB and twenty-seven to ACB. No difference in readiness for discharge was found (FNB median 1.8 (95% CI 1.0 to 3.5) vs. ACB 2.9 (1.5 to 4.7) hours, p = 0.3). Motor blocks and (near) falls were more frequently reported in patients with FNB vs. ACB (20 (76.9%) vs. 1 (3.7%), p < 0.001, and 7 (29.2%) vs. 1 (4.0%), p = 0.023. However, less opioids were consumed in the post-anesthesia care unit for FNB (median 3 [0, 21] vs. 15 [12, 42.5] oral morphine milligram equivalents, p = 0.004) for ACB. Between patients with FNB or ACB, no difference concerning readiness for discharge was found. Despite a slight reduction in opioid consumption immediately after surgery, FNB demonstrates a less favorable safety profile compared to ACB, with more motor blocks and (near) falls.

A radiological cadaveric study of obturator nerve involvement and cranial injectate spread after different approaches to the fascia iliaca compartment block.

Whether the fascia iliaca compartment block (FICB) involves the obturator nerve (ON) remains controversial. Involvement may require that the injectate spreads deep in the cranial direction, and might thus depend on the site of injection. Therefore, the effect of suprainguinal needle insertion with five centimeters of hydrodissection-mediated needle advancement (S-FICB-H) on ON involvement and cranial injectate spread was studied in this radiological cadaveric study. Results were compared with suprainguinal FICB without additional hydrodissection-mediated needle advancement (S-FICB), infrainguinal FICB (I-FICB), and femoral nerve block (FNB). Seventeen human cadavers were randomized to receive ultrasound-guided nerve block with a 40 mL solution of local anesthetic and contrast medium, on both sides. Injectate spread was objectified using computed tomography. The femoral and lateral femoral cutaneous nerves were consistently covered when S-FICB-H, S-FICB or FNB was applied, while the ON was involved in only one of the 34 nerve blocks. I-FICB failed to provide the same consistency of nerve involvement as S-FICB-H, S-FICB or FNB. Injectate reached most cranial in specimens treated with S-FICB-H. Our results demonstrate that even the technique with the most extensive cranial spread (S-FICB-H) does not lead to ON involvement and as such, the ON seems unrelated to FICB. Separate ON block should be considered when clinically indicated.

Comparison of Postoperative Neurocognitive Function in Older Adult Patients with and without Diabetes Mellitus.

INTRODUCTION: Delayed neurocognitive recovery (DNR; neurocognitive disorder up to 30 days postoperative) and postoperative neurocognitive disorders (POCD; neurocognitive disorder 1-12 months postoperative) occur frequently after surgery, with diabetes mellitus (DM) suggested to contribute to this. This was a single-center prospective cohort study. The main aim of this study was to investigate the role of DM and preoperative hemoglobin A1c (HbA1c) in the development of POCDs after noncardiac surgery. METHODS: Older adult patients ≥65 years of age scheduled for elective surgery were recruited. The Modified Telephone Interview for Cognitive Status questionnaire (TICS-M), a test of global cognitive functioning, was administered to determine cognition. Preoperative, 30-day postoperative, and 6-month postoperative cognition were compared for patients with and without DM. Cognitive decline was subdivided into mild (1 to 2 standard deviations below controls) and major (≥2 standard deviations below controls) DNR or POCD. Preoperative HbA1c levels were correlated with TICS-M scores. RESULTS: We analyzed 102 patients [median (IQR [range]) age 72.0 (5 [68-74])]), who were divided into patients with DM (80 patients [78%]) and patients without DM (22 patients [22%]). Baseline cognitive function was similar for both groups. Repeated measures ANOVA showed that mean DM patient TICS-M scores decreased 30 days postoperative (F(2, 200) = 4.0, p = 0.02), with subsequent recovery 6-month postoperative, compared to stable TICS-M scores in non-DM patients. There were significantly more DM patients with DNR than non-DM patients (n = 11 [50%] vs. n = 14 [17.5%]; p = 0.031). There were no between-group differences in mild or major POCD. Higher preoperative HbA1c levels were significantly correlated with decreased 30-day Δcognition scores (F(1, 54) = 9.4, p = 0.003) with an R2 of 0.149 (ß -0.45, 95% confidence interval: -0.735 to -0.154). CONCLUSIONS: Older adult patients with DM undergoing surgery have an increased risk of DNR compared to older adult non-DM patients, but no increased risk of POCD. In DM patients, higher preoperative HbA1c levels were associated with an increased risk of DNR.

The role of intraoperative hypotension on the development of postoperative cognitive dysfunction: a systematic review.

STUDY OBJECTIVE: To clarify whether intraoperative hypotension contributes to the development of postoperative cognitive dysfunction. DESIGN: A systematic review of prospective studies reporting on intraoperative hypotension and postoperative cognitive dysfunction in elective, non-cognitive impaired, adult surgical patients. PubMed, EMBASE and the Cochrane Library were searched up to the 1st of January 2021. SETTING: Studies had to use a clear definition of hypotension, although differing definitions were accepted. Neurocognitive tests to determine postoperative cognitive dysfunction had to be done pre- and postoperatively, with a minimum follow-up of seven days postoperatively. MEASUREMENTS: Risk of bias was assessed using the Cochrane Risk of Bias Tool 2.0 for randomized controlled trials and the Newcastle-Ottawa Scale for cohort studies. MAIN RESULTS: Out of 941 studies screened, five randomized controlled trials and four cohort studies were included for qualitative analysis. Extensive methodological differences between studies were present hindering proper quantitive analysis. No studies reported statistically significant differences in incidence of postoperative cognitive dysfunction in hypo- compared to normotensive patients. Five studies reported exact incidences of postoperative cognitive dysfunction. CONCLUSIONS: This systematic review showed no conclusive association between intraoperative hypotension and the development of postoperative cognitive dysfunction. Given the vast methodological differences of the included studies, the role of intraoperative hypotension in the development of postoperative cognitive dysfunction remains uncertain. Future research into the association between intraoperative hypotension and postoperative cognitive dysfunction should be conducted in a standardized manner.

Optimal Perioperative Pain Management in Esophageal Surgery: An Evaluation of Paravertebral Analgesia.

BACKGROUND: For esophagectomy, thoracic epidural analgesia (TEA) is the standard of care for perioperative pain management. Although effective, TEA is associated with moderate to serious adverse events such as hypotension and neurologic complications. Paravertebral analgesia (PVA) may be a safe alternative. The authors hypothesized that TEA and PVA are similar in efficacy for pain treatment in thoracolaparoscopic Ivor Lewis esophagectomy. METHODS: This retrospective cohort study compared TEA with PVA in two consecutive series of 25 thoracolaparoscopic Ivor Lewis esophagectomies. In this study, TEA consisted of continuous epidural bupivacaine and sufentanil infusion with a patient-controlled bolus function. In PVA, the catheter was inserted by the surgeon under thoracoscopic vision during surgery. Administration of PVA consisted of continuous paravertebral bupivacaine infusion after a bolus combined with patient-controlled analgesia using intravenous morphine. The primary outcome was the median highest recorded Numeric Pain Rating Scale (NRS) during the 3 days after surgery. The secondary outcomes were vasopressor consumption, fluid administration, and length of hospital stay. RESULTS: In both groups, the median highest recorded NRS was 4 or lower during the first three postoperative days. The patients with PVA had a higher overall NRS (mean difference, 0.75; 95% confidence interval 0.49-1.44). No differences were observed in any of the other secondary outcomes. CONCLUSION: For the patients undergoing thoracolaparoscopic Ivor Lewis esophagectomy, TEA was superior to PVA, as measured by NRS during the first three postoperative days. However, both modes provided adequate analgesia, with a median highest recorded NRS of 4 or lower. These results could form the basis for a randomized controlled trial.

Registration of attentional function as a predictor of incident delirium (the RAPID study).

INTRODUCTION: Older adults undergoing elective surgery have a high risk of developing postoperative delirium (POD). Validated models predicting POD are scarce. This study investigated whether preoperative impairment of attentional function predicts POD in older adults without previously diagnosed cognitive impairment. METHODS: In this prospective cohort study we recruited patients aged ≥70 years preceding major elective surgery. Preoperatively a visual vigilance test was administered to determine intra-individual reaction-time variability. Postoperatively, presence of delirium was screened daily. RESULTS: We recruited 152 patients, 25 (16.4%) developed POD. Intra-individual reaction-time variability was not significantly different between patients with or without POD (0.18 ± 0.08 ms vs 0.22 ± 0.11 ms; P = 0.087). Receiver operating characteristic analyses indicated a poor accuracy for POD (area under the curve 0.609 ± 0.63). Except for surgery duration, no clinically significant between-group differences were found for secondary outcome parameters. DISCUSSION: Preoperative intra-individual reaction time variability does not predict the incidence of POD in older patients undergoing major elective surgery.

Pharmacodynamics and Pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy.

BACKGROUND: Clinical and experimental data show that peripheral nerve blocks last longer in the presence of diabetic neuropathy. This may occur because diabetic nerve fibers are more sensitive to local anesthetics or because the local anesthetic concentration decreases more slowly in the diabetic nerve. The aim of this study was to investigate both hypotheses in a rodent model of neuropathy secondary to type 2 diabetes. METHODS: We performed a series of sciatic nerve block experiments in 25 Zucker Diabetic Fatty rats aged 20 weeks with a neuropathy component confirmed by neurophysiology and control rats. We determined in vivo the minimum local anesthetic dose of lidocaine for sciatic nerve block. To investigate the pharmacokinetic hypothesis, we determined concentrations of radiolabeled (C) lidocaine up to 90 min after administration. Last, dorsal root ganglia were excised for patch clamp measurements of sodium channel activity. RESULTS: First, in vivo minimum local anesthetic dose of lidocaine for sciatic nerve motor block was significantly lower in diabetic (0.9%) as compared to control rats (1.4%). Second, at 60 min after nerve block, intraneural lidocaine was higher in the diabetic animals. Third, single cell measurements showed a lower inhibitory concentration of lidocaine for blocking sodium currents in neuropathic as compared to control neurons. CONCLUSIONS: We demonstrate increased sensitivity of the diabetic neuropathic nerve toward local anesthetics, and prolonged residence time of local anesthetics in the diabetic neuropathic nerve. In this rodent model of neuropathy, both pharmacodynamic and pharmacokinetic mechanisms contribute to prolonged nerve block duration.

Regional anesthesia in diabetic peripheral neuropathy.

PURPOSE OF REVIEW: The aim of this review is to summarize recent relevant literature regarding regional anesthesia in the diabetic neuropathic patient and formulate recommendations for clinical practice. RECENT FINDINGS: Diabetic neuropathic nerves, but not nerves of diabetic patients per se, exhibit complex functional changes. As a result, they seem more sensitive to local anesthetics, and are more difficult to stimulate. When catheters are used postoperatively, diabetes is an independent risk factor for infection. SUMMARY: The pathophysiologic mechanisms underlying diabetic polyneuropathy are complex. Several pathways are thought to contribute to the development of diabetic neuropathy, triggered most importantly by chronic hyperglycemia. The latter induces inflammation and oxidative stress, causing microvascular changes, local ischemia and decreased axonal conduction velocity. Regional anesthesia is different in patients with diabetic neuropathy in several regards. First, the electric stimulation threshold of the nerve is markedly increased whereby the risk for needle trauma in stimulator-guided nerve blocks is theoretically elevated. Second, the diabetic nerve is more sensitive to local anesthetics, which results in longer block duration. Third, local anesthetics have been conjectured to be more toxic in diabetic neuropathy but the evidence is equivocal and should not be a cause to deny regional anesthesia to patients with a valid indication. Lastly, when peripheral nerve catheters are used, diabetes is an independent predisposing factor for infection.

Minimum local anesthetic volumes for a selective saphenous nerve block: a dose-finding study.

BACKGROUND: Saphenous nerve block contributes to analgesia after knee and lower leg surgery. However, literature reports a wide range of volumes of local anesthetic being used for this block. METHODS: A non-randomized controlled trial in a single university hospital in March 2015. Eighteen healthy volunteers (ASA 1 status, aged 27-43 years; male-to-female ratio 11/7) were needed to determine the minimum local anesthetic volume (MLAV) of mepivacaine 2% using the Dixon up-and-down method to achieve a selective ultrasound-guided saphenous nerve block. The primary endpoint MLAV (ED50 and ED95) for an ultrasound-guided saphenous nerve block were determined. The secondary endpoints were the position of the saphenous nerve, block onset and duration of action, cutaneous spread of the block, and the occurrence of femoral nerve motor block. RESULTS: The measured MLAV dose that was effective in 50% of cases (ED50) for a complete saphenous nerve block was 1.5 mL; the calculated MLAV dose for 95% of cases (ED95) was 1.9 mL. The saphenous nerve was encountered in almost all cases on the anterior/anteromedial aspect of the femoral artery. We found no correlation between local anesthetic volume and the onset or duration of the block. Cutaneous spread of the nerve block was observed on the anteromedial aspect of the lower leg, with considerable individual variation between individuals in the study. No femoral motor block was observed. CONCLUSIONS: For a selective ultrasound-guided saphenous nerve block, the ED95 MLAV of mepivacaine 2% is 1.9 mL.

Localization of the potential zonal marker clusterin in native cartilage and in tissue-engineered constructs.

An increasing number of studies aim to engineer cartilage tissue that more closely mimic the zonal organization of native articular tissue. Further understanding of zonal differences is crucial for successful development and evaluation of such grafts. We therefore aimed to characterize the secretion of the potential zonal marker clusterin by zonal articular chondrocytes in osteoarthritic and healthy articular cartilage and in tissue-engineered constructs. Clusterin secreted by superficial, middle, and deep zones equine chondrocytes was immunolocalized in cytospins of alginate cultured superficial, middle, and deep zones equine chondrocytes. Clusterin was present within the superficial zone of native cartilage; after isolation of the cells from healthy articular cartilage, staining for clusterin was limited to cells derived from the superficial zone. Staining disappeared after expansion, but reappeared during (re)differentiation and was more pronounced within the cultures derived from the superficial zones of the cartilage. The presence of clusterin was associated with clusters of differentiating chondrocytes, rather than highly proliferative cells and did not specifically colocalize with proteoglycan-4. Because staining for clusterin was more abundant in cultures of superficial chondrocytes compared to those of cells of the deeper layers, it may be used to further characterize zonal cartilage constructs.

Zonal chondrocyte subpopulations reacquire zone-specific characteristics during in vitro redifferentiation.

BACKGROUND: If chondrocytes from the superficial, middle, and deep zones of articular cartilage could maintain or regain their characteristic properties during in vitro culture, it would be feasible to create constructs comprising these distinctive zones. HYPOTHESIS: Zone-specific characteristics of zonal cell populations will disappear during 2-dimensional expansion but will reappear after 3-dimensional redifferentiation, independent of the culture technique used (alginate beads versus pellet culture). STUDY DESIGN: Controlled laboratory study. METHODS: Equine articular chondrocytes from the 3 zones were expanded in monolayer culture (8 donors) and subsequently redifferentiated in pellet and alginate bead cultures for up to 4 weeks. Glycosaminoglycans and DNA were quantified, along with immunohistochemical assessment of the expression of various zonal markers, including cartilage oligomeric protein (marking cells from the deeper zones) and clusterin (specifically expressed by superficial chondrocytes). RESULTS: Cell yield varied between zones, but proliferation rates did not show significant differences. Expression of all evaluated zonal markers was lost during expansion. Compared to the alginate bead cultures, pellet cultures showed a higher amount of glycosaminoglycans produced per DNA after redifferentiation. In contrast to cells in pellet cultures, cells in alginate beads regained zonal differences, as evidenced by zone-specific reappearance of cartilage oligomeric protein and clusterin, as well as significantly higher glycosaminoglycans production by cells from the deep zone compared to the superficial zone. CONCLUSION: Chondrocytes isolated from the 3 zones of equine cartilage can restore their zone-specific matrix expression when cultured in alginate after in vitro expansion. CLINICAL RELEVANCE: Appreciation of the zonal differences can lead to important advances in cartilage tissue engineering. Findings support the use of hydrogels such as alginate for engineering zonal cartilage constructs.