Pain relief after major ankle and hindfoot surgery with repetitive peripheral nerve blocks: A feasibility study.

BACKGROUND: Major ankle and hindfoot surgery (e.g., ankle, triple and subtalar arthrodesis) typically causes severe postoperative pain, especially the first two postoperative days. Current modalities of postoperative analgesic treatment often include continuous peripheral nerve blocks of the saphenous and sciatic nerves via catheters in order to extend the duration of pain- and opioid-free nerve blockade to 48 h. Unfortunately, the 48 h-efficacy of continuous infusion via a catheter is reduced by a high displacement rate. We hypothesised that one-time repetition of the single injection peripheral nerve blocks would provide effective analgesia with a low opioid consumption the first 48 postoperative hours. METHODS: Eleven subjects preoperatively received a popliteal sciatic and a saphenous single injection nerve block with a protracted local anaesthetic mixture. Surgery was performed under general anaesthesia. The one-time repetition of the single injection nerve block was carried out approximately 24 h after the primary nerve block. The main outcomes were pain and cumulative opioid consumption during the first 48 postoperative hours. RESULTS: Nine of the 11 (82%) patients had effective analgesia without opioids during the first 48 postoperative hours. Two patients each required a single dose of 7.5 mg of oral morphine equivalents after 43 h. CONCLUSION: One-time repetition of single injection saphenous and sciatic nerve blocks consistently provided effective analgesia practically without opioids for 48 h after major elective ankle and hindfoot surgery.

Effects of tourniquet inflation on peri- and postoperative cefuroxime concentrations in bone and tissue.

Background and purpose - Tourniquet is widely used in orthopedic surgery to reduce intraoperative bleeding and improve visualization. We evaluated the effect of tourniquet application on peri- and postoperative cefuroxime concentrations in subcutaneous tissue, skeletal muscle, calcaneal cancellous bone, and plasma. The primary endpoint was the time for which the free cefuroxime concentration was maintained above the clinical breakpoint minimal inhibitory concentration (T > MIC) for Staphylococcus aureus (4 µg/mL).Patients and methods - 10 patients scheduled for hallux valgus or hallux rigidus surgery were included. Microdialysis catheters were placed for sampling of cefuroxime concentrations bilaterally in subcutaneous tissue, skeletal muscle, and calcaneal cancellous bone. A tourniquet was applied on the thigh of the leg scheduled for surgery (tourniquet duration time [range]: 65 minutes [58-77]). Cefuroxime (1.5 g) was administered intravenously 15 minutes prior to tourniquet inflation, followed by a second dose 6 hours later. Dialysates and venous blood samples were collected for 12 hours.Results - A cefuroxime concentration of 4 µg/mL was reached within 23 minutes in all compartments and patients. For cefuroxime the T > MIC (4 µg/mL) ranged between 4.8 and 5.4 hours across compartments, with similar results for the tourniquet and non-tourniquet leg. Comparable T > MIC and penetration ratios were found for the first and second dosing intervals.Interpretation - Administration of cefuroxime (1.5 g) 15 minutes prior to tourniquet inflation is safe in order to achieve tissue concentrations above 4 µg/mL throughout surgery. A tourniquet application time of approximately 1 hour did not affect the cefuroxime tissue penetration in the following dosing interval.

How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin.

Glycosaminoglycans (GAGs) bind all known amyloid plaques and help store protein hormones in (acidic) granular vesicles, but the molecular mechanisms underlying these important effects are unclear. Here we investigate GAG interactions with the peptide hormone salmon calcitonin (sCT). GAGs induce fast sCT fibrillation at acidic pH and only bind monomeric sCT at acidic pH, inducing sCT helicity. Increasing GAG sulfation expands the pH range for binding. Heparin, the most highly sulfated GAG, binds sCT in the pH interval 3-7. Small angle x-ray scattering indicates that sCT monomers densely decorate and pack single heparin chains, possibly via hydrophobic patches on helical sCT. sCT fibrillates without GAGs, but heparin binding accelerates the process by decreasing the otherwise long fibrillation lag times at low pH and accelerates fibril growth rates at neutral pH. sCT·heparin complexes form ß-sheet-rich heparin-covered fibrils. Solid-state NMR reveals that heparin does not alter the sCT fibrillary core around Lys(11) but makes changes to Val(8) on the exterior side of the ß-strand, possibly through contacts to Lys(18) Thus GAGs significantly modulate sCT fibrillation in a pH-dependent manner by interacting with both monomeric and aggregated sCT.

Liprotides made of α-lactalbumin and cis fatty acids form core-shell and multi-layer structures with a common membrane-targeting mechanism.

α-Lactalbumin (aLA) has been shown to form complexes with oleic acid (OA), which may target cancer cells. We recently showed that aLA and several other proteins all form protein-OA complexes called liprotides with a generic structure consisting of a micellar OA core surrounded by a shell of partially denatured protein. Here we report that a heat treatment and an alkaline treatment method both allow us to prepare liprotide complexes composed of aLA and a range of unsaturated fatty acids (FA), provided the FAs contain cis (but not trans) double bonds. All liprotides containing cis-FA form both small and large species, which all consist of partially denatured aLA, though the overall shape of the species differs. Small liprotides have a simple core-shell structure while the larger liprotides are multi-layered, i.e. they have an additional layer of both FA and aLA surrounding the outside of the core-shell structure. All liprotides can transfer their entire FA content to vesicles, releasing aLA as monomers and softening the lipid membrane. The more similar to OA, the more efficiently the different FAs induce hemolysis. We conclude that aLA can take up and transfer a wide variety of FA to membranes, provided they contain a cis-bond. This highlights liprotides as a general class of complexes where both protein and cis-FA component can be varied without departing from a generic (though sometimes multi-layered) core-shell structure.

Low-resolution structures of OmpA⋠DDM protein-detergent complexes.

We have used SAXS to determine the low-resolution structure of the outer-membrane protein OmpA from E. coli solubilized by the surfactant dodecyl maltoside (DDM). We have studied three variants of the transmembrane domain of OmpA-namely monomers, self-associated dimers, and covalently linked dimers-as well as the monomeric species of the full-length protein with the periplasmic domain. We can successfully model the structures of the monomeric and covalently linked dimer as one and two natively folded proteins in a DDM micelle, respectively, whereas the noncovalently linked dimer presents a more complicated structure, possibly due to higher-order species. We have determined the structure of the full-length protein to be that of a globular periplasmic domain attached through a flexible linker to the transmembrane domain. This approach provides valuable information about how membrane proteins are embedded in amphiphilic environments.

Perioperative anaphylactic shock caused by propofol.

Perioperative anaphylaxis is rare and the diagnosis is difficult to distinguish from normal side effects from anaesthesia. Anaesthetists should be able to diagnose anaphylaxis and treat promptly with adrenaline and fluids. Allergy investigation should be performed subsequently. This is a case report of perioperative anaphylaxis to propofol. Propofol contains refined soya oil and egg lecithin, but no connection between allergy to soy, egg or peanut and allergy to propofol has been proven, and international guidelines recommend that propofol can be used in patients with these food allergies.

Subpectineal obturator nerve block reduces opioid consumption after hip arthroscopy: a triple-blind, randomized, placebo-controlled trial.

BACKGROUND: Hip arthroscopy causes severe pain during the first few hours in the postoperative care unit. This is probably due to the intraoperative stretching of the hip joint capsule. Pain relief requires high doses of opioids which may prolong recovery and may cause opioid-related adverse events.The majority of hip joint capsule nociceptors are located anteriorly. The obturator nerve innervates the anteromedial part of the hip joint capsule. We hypothesized that a subpectineal obturator nerve block using 15 ml bupivacaine 5 mg/mL with added epinephrine 5 µg/mL would reduce the opioid consumption after hip arthroscopy. METHODS: 40 ambulatory hip arthroscopy patients were enrolled in this randomized, triple-blind controlled trial. All patients were allocated to a preoperative active or placebo subpectineal obturator nerve block. The primary outcome was opioid consumption for the first 3 hours in the postanesthesia care unit. Secondary outcomes were pain, nausea, and hip adductor strength. RESULTS: 34 patients were analyzed for the primary outcome. The mean intravenous morphine equivalent consumption in the subpectineal obturator nerve block group was 11.9 mg vs 19.7 mg in the placebo group (p<0.001). The hip adductor strength was significantly reduced in the active group. No other intergroup differences were observed regarding the secondary outcomes. CONCLUSION: We found a significant reduction in the opioid consumption for patients receiving an active subpectineal obturator nerve block. The postoperative intravenous morphine equivalent reduction the first painful 3 hours was reduced by 40% for patients receiving a subpectineal obturator nerve block in this randomized, triple-blind trial. TRIAL REGISTRATION NUMBER: EudraCT database 2021-006575-42.

The Anterior Branch of the Medial Femoral Cutaneous Nerve Innervates Cutaneous and Deep Surgical Incisions in Total Knee Arthroplasty.

Background/Objectives: The intermediate femoral cutaneous nerve (IFCN), the saphenous nerve, and the medial femoral cutaneous nerve (MFCN) innervate the skin of the anteromedial knee region. However, it is unknown whether the MFCN has a deeper innervation. This would be relevant for total knee arthroplasty (TKA) that intersects deeper anteromedial genicular tissue layers. Primary aim: to investigate deeper innervation of the anterior and posterior MFCN branches (MFCN-A and MFCN-P). Secondary aim: to investigate MFCN innervation of the skin covering the anteromedial knee area and medial parapatellar arthrotomy used for TKA. Methods: This study consists of (1) a dissection study and (2) unpublished data and post hoc analysis from a randomized controlled double-blinded volunteer trial (EudraCT number: 2020-004942-12). All volunteers received bilateral active IFCN blocks (nerve block round 1) and saphenous nerve blocks (nerve block round 2). In nerve block round 3, all volunteers were allocated to a selective MFCN-A block. Results: (1) The MFCN-A consistently innervated deeper structures in the anteromedial knee region in all dissected specimens. No deep innervation from the MFCN-P was observed. (2) Sixteen out of nineteen volunteers had an unanesthetized skin gap in the anteromedial knee area and eleven out of the nineteen volunteers had an unanesthetized gap on the skin covering the medial parapatellar arthrotomy before the active MFCN-A block. The anteromedial knee area and medial parapatellar arthrotomy was completely anesthetized after the MFCN-A block in 75% and 82% of cases, respectively. Conclusions: The MFCN-A shows consistent deep innervation in the anteromedial knee region and the area of MFCN-A innervation overlaps the skin area covering the medial parapatellar arthrotomy. Further trials are mandated to investigate whether an MFCN-A block translates into a clinical effect on postoperative pain after total knee arthroplasty or can be used for diagnosis and interventional pain management for chronic neuropathic pain due to damage to the MFCN-A during surgery.

Mapping of unfolding states of integral helical membrane proteins by GPS-NMR and scattering techniques: TFE-induced unfolding of KcsA in DDM surfactant.

Membrane proteins are vital for biological function, and their action is governed by structural properties critically depending on their interactions with the membranes. This has motivated considerable interest in studies of membrane protein folding and unfolding. Here the structural changes induced by unfolding of an integral membrane protein, namely TFE-induced unfolding of KcsA solubilized by the n-dodecyl ß-d-maltoside (DDM) surfactant is investigated by the recently introduced GPS-NMR (Global Protein folding State mapping by multivariate NMR) (Malmendal et al., PlosONE 5, e10262 (2010)) along with dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS). GPS-NMR is used as a tool for fast analysis of the protein unfolding processes upon external perturbation, and DLS and SAXS are used for further structural characterization of the unfolding states. The combination allows addressing detergent properties and protein conformations at the same time. The mapping of the states reveals that KcsA undergoes a series of rearrangements which include expansion of the tetramer in several steps followed by dissociation into monomers at 29% TFE. Supplementary studies of DDM and TFE in the absence of KcsA suggest that the disintegration of the tetramer at 29% TFE is caused by TFE dissolving the surrounding DDM rim. Above 34% TFE, KcsA collapses to a new structure that is fully formed at 44% TFE.

Efficacy of iliopsoas plane block for patients undergoing hip arthroscopy: a prospective, triple-blind, randomized, placebo-controlled trial.

BACKGROUND: Intraoperative stretching of the hip joint capsule often generates severe pain during the first 3 hours after hip arthroscopy. The short-lived severe pain mandates high opioid consumption, which may result in adverse events and delay recovery. The femoral nerve nociceptors are located anteriorly in the hip joint capsule. A femoral nerve block reduces pain and opioid demand after hip arthroscopy. It impedes, however, ambulation and home discharge after outpatient surgery. The iliopsoas plane block selectively anesthetizes the femoral sensory nerve branches innervating the hip joint capsule without compromising ambulation. We aimed to assess reduction of opioid consumption after iliopsoas plane block during the short-lived painful postsurgical period of time after hip arthroscopy. METHODS: In a randomized, triple-blind trial, 50 patients scheduled for hip arthroscopy in general anesthesia were allocated to active or placebo iliopsoas plane block. The primary outcome was opioid consumption during the first three postoperative hours in the postanesthesia care unit. Secondary outcomes included pain, nausea, and ability to ambulate. RESULTS: Forty-nine patients were analyzed for the primary outcome. The mean 3-hour intravenous morphine equivalent consumption in the iliopsoas plane block group was 10.4 mg vs 23.8 mg in the placebo group (p<0.001). No intergroup differences were observed for the secondary outcomes during the postoperative follow-up. CONCLUSION: An iliopsoas plane block reduces opioid consumption after hip arthroscopy. The reduction of opioid consumption during the clinically relevant 3-hour postsurgical period of time was larger than 50% for active versus placebo iliopsoas plane block in this randomized, triple-blind trial.

The anterior branch of the medial femoral cutaneous nerve innervates the anterior knee: a randomized volunteer trial.

BACKGROUND: The midline skin incision for total knee arthroplasty may be an important generator of chronic neuropathic pain. The incision is innervated by the medial femoral cutaneous nerve (MFCN), the intermediate femoral cutaneous nerves (IFCN) and the infrapatellar branch from the saphenous nerve. The MFCN divides into an anterior (MFCN-A) and a posterior branch (MFCN-P). The primary aim was to compare the areas anesthesized by MFCN-A versus MFCN-P block for coverage of the incision. METHODS: Nineteen healthy volunteers had IFCN and saphenous nerve blocks. The subgroup of volunteers with a non-anesthetized gap between the areas anesthetized by the saphenous and the IFCN blocks was defined as the study group for the primary outcome. Subsequently selective MFCN-A block and MFCN block (MFCN-A + MFCN-P) were performed to investigate the contributions from MFCN-A and MFCN-P to the innervation of the midline incision. All assessments were performed blinded. RESULTS: Ten out of 19 volunteers had a non-anesthetized gap. Nine out of these 10 volunteers had coverage of the non-anesthetized gap after selective anesthesia of the MFCN-A, whereas anesthesia of the MFCN-P did not contribute to coverage of the gap in any of the 10 volunteers. CONCLUSIONS: In half of the cases, a gap of non-anesthetized skin was present on the surgical midline incision after anesthesia of the saphenous nerve and the IFCN. This gap was covered by selective anesthesia of the MFCN-A without contribution from MFCN-P. The selective MFCN-A block may be relevant for diagnosis and interventional management of neuropathic pain due to injury of MFCN-A.

Use of the flexible bronchoscope and Infrared Red Intubation System in a known difficult airway in the intensive care unit.

This case report describes a patient in the ICU in need of urgent intubation, for whom video laryngoscope-guided intubation had previously failed. The Infrared Red Intubation System (IRRIS) may enhance the chance of successful flexible bronchoscope intubation, especially when performed by non-expert anesthesiologists.

Managing Known Difficult Airways in Obstetric Patients Using a Flexible Bronchoscope and IRRIS: A Case-Illustrated Guide for Nonexpert Anesthesiologists, without Surgical Backup.

Pregnancy is associated with anatomical and physiological changes leading to potential difficult airway management. Some pregnant women have known difficult airways and cannot be intubated even with a hyperangulated videolaryngoscope. If neuraxial techniques are also impossible, awake tracheal intubation with a flexible bronchoscope may be one of the few available options to avoid more invasive techniques. The Infrared Red Intubation System (IRRIS) may help nonexpert anesthesiologists in such situations and may enhance the chance of successful intubation increasing safety for the mother and the fetus, especially in hospitals without the ear, nose, and throat surgical backup.

Predictive factors for response and prognostic factors for long-term survival in consecutive, single institution patients with locally advanced and/or metastatic transitional cell carcinoma following cisplatin-based chemotherapy.

PURPOSE: The study was undertaken to identify pre-treatment clinical and histopathological factors of importance for response and survival after cisplatin-based combination chemotherapy, in patients with locally advanced or metastatic transitional cell carcinoma of the urothelium. PATIENTS AND METHODS: Clinical, laboratory and histopathological data from 178 consecutive patients, representing all patients treated between 1991 and 2001 in a single institution, were collected. Correlations between these data and response and survival after chemotherapy were analysed using univariate and multivariate analyses. RESULTS: Absence of visceral metastasis was the only parameter with independent correlation to the response to chemotherapy. Two of the analysed parameters were independently associated with increased survival: good performance status (PS< or =1) and absence of visceral metastases. Stratification of the patient material according to number of these risk-factors present showed strong association with survival. CONCLUSION: It was possible to predict survival from pre-treatment clinical parameters and consequently it is possible to select groups with a high and low probability of obtaining long term survival following cisplatin-containing chemotherapy.

Acute Awake Fiberoptic Intubation in the ICU in a Patient with Limited Mouth Opening and Hypoxemic Acute Respiratory Failure.

The incidence and survival of patients with head-and-neck cancer have been on the increase for decades. Following surgery or radiation therapy, complications such as difficult airways may evolve. These difficult airways may be unique and not manageable with conventional intubation methods as well as video laryngoscopes. Acute awake fiberoptic intubation may be a feasible option also for urgent emergency airway management of known difficult airways. The "cannot intubate-cannot oxygenate" (CI-CO) situation has to be avoided at all costs, since emergency cricothyrotomy has a fail ratio of more than 50% when performed by an anesthesiologist.

Awake Fiberoptic Intubation in Fast Track Ambulatory Surgery: A Case Report.

An increasing number of surgical procedures are performed in the ambulatory setting, leading to improved patient comfort and cost-effectiveness. Patients with suspected or known difficult airways represent a challenge when anesthetized. This may explain why this patient group may be rejected for day-case surgery. We present 3 cases scheduled for day-case procedures with predicted difficult airways, where the feasibility of awake fiberoptic intubation is demonstrated in a Scandinavian fast track setting. Our hypothesis is that, with accurate preparations, intubation times are comparable with conventional intubation and that the procedure is associated with only minor patient discomfort.

Erector Spinae Plane Block for Elective Laparoscopic Cholecystectomy in the Ambulatory Surgical Setting.

Postoperative pain after laparoscopic cholecystectomy can be severe. Despite multimodal analgesia regimes, administration of high doses of opioids is often necessary. This can further lead to several adverse effects such as drowsiness and respiratory impairment as well as postoperative nausea and vomiting. This will hinder early mobilization and discharge of the patient from the day surgery setting and is suboptimal in an Early Recovery after Surgery setting. The ultrasound-guided Erector Spinae Plane (ESP) block is a novel truncal interfascial block technique providing analgesia of the thoracic or abdominal segmental innervation depending on the level of administration. Local anesthetic penetrates anteriorly presumably through the costotransverse foramina to the paravertebral space. We demonstrate the analgesic efficacy of the ESP block in a case series of three patients scheduled for ambulatory laparoscopic cholecystectomy.

Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State.

α-Synuclein (αSN) aggregation is central to the etiology of Parkinson's disease (PD). Large-scale screening of compounds to identify aggregation inhibitors is challenged by stochastic αSN aggregation and difficulties in detecting early-stage oligomers (αSOs). We developed a high-throughput screening assay combining SDS-stimulated αSN aggregation with FRET to reproducibly detect initial stages in αSN aggregation. We screened 746,000 compounds, leading to 58 hits that markedly inhibit αSN aggregation and reduce αSOs' membrane permeabilization activity. The most effective aggregation inhibitors were derivatives of (4-hydroxynaphthalen-1-yl)sulfonamide. They interacted strongly with the N-terminal part of monomeric αSN and reduced αSO-membrane interactions, possibly by affecting electrostatic interactions. Several compounds reduced αSO toxicity toward neuronal cell lines. The inhibitors introduced chemical modifications of αSN that were, however, not a prerequisite for inhibitory activity. We also identified several phenyl-benzoxazol compounds that promoted αSN aggregation (proaggregators). These compounds may be useful tools to modulate αSN aggregation in cellula.

Structure, Aggregation, and Activity of a Covalent Insulin Dimer Formed During Storage of Neutral Formulation of Human Insulin.

A specific covalently linked dimeric species of insulin high molecular weight products (HMWPs), formed during prolonged incubation of a neutral pharmaceutical formulation of human insulin, were characterized in terms of tertiary structure, self-association, biological activity, and fibrillation properties. The dimer was formed by a covalent link between A21Asn and B29Lys. It was analyzed using static and dynamic light scattering and small-angle X-ray scattering to evaluate its self-association behavior. The tertiary structure was obtained using nuclear magnetic resonance and X-ray crystallography. The biological activity of HMWP was determined using 2 in vitro assays, and its influence on fibrillation was investigated using Thioflavin T assays. The dimer's tertiary structure was nearly identical to that of the noncovalent insulin dimer, and it was able to form hexamers in the presence of zinc. The dimer exhibited reduced propensity for self-association in the absence of zinc but significantly postponed the onset of fibrillation in insulin formulations. Consistent with its dimeric state, the tested species of HMWP showed little to no biological activity in the used assays. This study is the first detailed characterization of a specific type of human insulin HMWP formed during storage of a marketed pharmaceutical formulation. These results indicate that this specific type of HMWP is unlikely to antagonize the physical stability of the formulation, as HMWP retained a tertiary structure similar to the noncovalent dimer and participated in hexamer assembly in the presence of zinc. In addition, increasing amounts of HMWP reduce the rate of insulin fibrillation.