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1.
BMC Anesthesiol ; 23(1): 97, 2023 03 29.
Article in English | MEDLINE | ID: mdl-36991313

ABSTRACT

INTRODUCTION: The current opioid epidemic poses patient safety and economic burdens to healthcare systems worldwide. Postoperative prescriptions of opioids contribute, with reported opioid prescription rates following arthroplasty as high as 89%. In this multi-centre prospective study, an opioid sparing protocol was implemented for patients undergoing knee or hip arthroplasty. The primary outcome is to report our patient outcomes in the context of this protocol, and to examine the rate of opioid prescription on discharge from our hospitals following joint arthroplasty surgery. This is possibly associated with the efficacy of the newly implemented Arthroplasty Patient Care Protocol. METHODS: Over three years, patients underwent perioperative education with the expectation to be opioid-free after surgery. Intraoperative regional analgesia, early postoperative mobilisation and multimodal analgesia were mandatory. Long-term opioid medication use was monitored and PROMs (Oxford Knee/Hip Score (OKS/OHS), EQ-5D-5 L) were evaluated pre-operatively, and at 6 weeks, 6 months and 1 year postoperatively. Primary and secondary outcomes were opiate use and PROMs at different time points. RESULTS: A total of 1,444 patients participated. Two (0.2%) knee patients used opioids to one year. Zero hip patients used opioids postoperatively at any time point after six weeks (p < 0.0001). The OKS and EQ-5D-5 L both improved for knee patients from 16 (12-22) pre-operatively to 35 (27-43) at 1 year postoperatively, and 70 (60-80) preoperatively to 80 (70-90) at 1 year postoperatively (p < 0.0001). The OHS and EQ-5D-5 L both improved for hip patients from 12 (8-19) preoperatively to 44 (36-47) at 1 year postoperatively, and 65 (50-75) preoperatively to 85 (75-90) at 1 year postoperatively (p < 0.0001). Satisfaction improved between all pre- and postoperative time points for both knee and hip patients (p < 0.0001). CONCLUSIONS: Knee and hip arthroplasty patients receiving a peri-operative education program can effectively and satisfactorily be managed without long-term opioids when coupled with multimodal perioperative management, making this a valuable approach to reduce chronic opioid use.


Subject(s)
Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Pain, Postoperative , Humans , Analgesics, Opioid/therapeutic use , Pain, Postoperative/drug therapy , Prospective Studies , Drug Prescriptions/statistics & numerical data
2.
J Orthop Surg Res ; 18(1): 119, 2023 Feb 17.
Article in English | MEDLINE | ID: mdl-36803363

ABSTRACT

BACKGROUND: The direct anterior approach (DAA) in total hip arthroplasty (THA) may demonstrate better functional recovery compared to the posterior approach (PA). METHODS: In this prospective multi-centre study, patient-related outcome measures (PROMs) and length of stay (LOS) were compared between DAA and PA THA patients. The Oxford Hip Score (OHS), EQ-5D-5L, pain and satisfaction scores were collected at four perioperative stages. RESULTS: 337 DAA and 187 PA THAs were included. The OHS PROM was significantly better in the DAA group at 6 weeks post-operatively (OHS: 33 vs. 30, p = 0.02, EQ-5D-5L: 80 vs. 75, p = 0.03), but there were no differences at 6 months and at 1 year. EQ-5D-5L scores were similar between both groups at all time points. LOS as inpatient was significantly different, in favour of DAA [median 2 days (IQR 2-3) vs. PA 3 (IQR 2-4), p ≤ 0.0001]. CONCLUSIONS: Patients undergoing DAA THA have shorter LOS and report better short-term Oxford Hip Score PROMs at 6 weeks, but DAA did not convey long-term benefits over PA THA.


Subject(s)
Arthroplasty, Replacement, Hip , Humans , Prospective Studies , Treatment Outcome , Patient Reported Outcome Measures
3.
Reg Anesth Pain Med ; 48(1): 14-21, 2023 01.
Article in English | MEDLINE | ID: mdl-36137734

ABSTRACT

INTRODUCTION: Hip fractures are a common frailty injury affecting a vulnerable geriatric population. It is debated if anesthetic and analgesic techniques are associated with altered risk for outcomes in hip fracture patients. This study aimed to determine the association of anesthesia and regional analgesia with all cause 12-month mortality and even longer-term mortality after hip fracture surgery in Australia and New Zealand. METHODS: Data from the Australian and New Zealand Hip Fracture Registry collected from 2016 to 2018, with a minimum follow-up of 12 months, were reviewed. Anesthesia type and use of regional nerve blocks were investigated. The primary outcome was all cause 12-month mortality. RESULTS: 12-month mortality was 30.6% (n=5410) in a total of 17,635 patients. There was no difference in 12-month mortality between patients who received spinal or general anesthesia (p=0.238). The administration of a combination of general and spinal anesthesia for surgery to repair the fracture was an independent predictor of higher 12-month mortality (unadjusted complete case HR=1.17 (95% CI 1.04 to 1.31); p<0.001). Nerve blocks performed in both the emergency department (ED) and the operating theater (OT) were associated with reduced long-term mortality (median follow-up 21 months) with an unimputed unadjusted HR=0.86 (95% CI 0.77 to 0.96; p=0.043). CONCLUSION: There was no difference in the association of 12-month mortality between general and spinal anesthesia in patients undergoing hip fracture surgery. However, there was an association with a higher risk of 12-month mortality in patients who received both general and spinal anesthesia for the same surgery. Patients who received a regional nerve block in both the ED and the OT had a lower association of 12-month and longer-term mortality risk. The reasons for these findings remain unknown and should be the subject of further research investigation.


Subject(s)
Analgesia , Anesthesia, Conduction , Hip Fractures , Aged , Humans , Anesthesia, Conduction/adverse effects , Anesthesia, Conduction/methods , Australia/epidemiology , Hip Fractures/diagnosis , Hip Fractures/surgery , New Zealand/epidemiology , Registries , Nerve Block
4.
BMC Anesthesiol ; 22(1): 252, 2022 08 06.
Article in English | MEDLINE | ID: mdl-35933328

ABSTRACT

BACKGROUND: The PEricapsular Nerve Group (PENG) block is a novel regional analgesia technique that provides improved analgesia in patients undergoing hip surgery while preserving motor function. In this study the PENG block was investigated for analgesia in elective total hip arthroplasty (THA). METHODS: In this multi-centre double-blinded randomized-controlled trial, in addition to spinal anesthesia and local infiltration analgesia (LIA), THA patients received either a PENG block or a sham block. The primary outcome was pain score (numeric rating scale 0-10) 3 h postoperatively (Day 0). Secondary outcomes were postoperative quadriceps muscle strength, postoperative Day 1 pain scores, opiate use, complications, length of hospital stay, and patient-reported outcome measures. RESULTS: Sixty patients were randomized and equally allocated between groups. Baseline demographics were similar. Postoperative Day 0, the PENG group experienced less pain compared to the sham group (PENG: 14 (47%) patients no pain, 14 (47%) mild pain, 2 (6%) moderate/severe pain versus sham: 6 (20%) no pain, 14 (47%) mild pain, 10 (33%) moderate/severe pain; p = 0.03). There was no difference in quadriceps muscle strength between groups on Day 0 (PENG: 23 (77%) intact versus sham: 24 (80%) intact; p = 0.24) and there were no differences in other secondary outcomes. CONCLUSIONS: Patients receiving a PENG block for analgesia in elective THA experience less postoperative pain on Day 0 with preservation of quadriceps muscle strength. Despite these short-term benefits, no quality of recovery or longer lasting postoperative effects were detected.


Subject(s)
Analgesia , Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Nerve Block , Analgesia/methods , Anesthetics, Local , Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Knee/methods , Femoral Nerve , Humans , Nerve Block/methods , Pain, Postoperative/drug therapy , Pain, Postoperative/etiology , Pain, Postoperative/prevention & control
5.
J Patient Rep Outcomes ; 6(1): 71, 2022 Jun 20.
Article in English | MEDLINE | ID: mdl-35723750

ABSTRACT

PURPOSE: To evaluate the measurement properties of the Oxford Hip Score (OHS), EQ-5D-5L utility index and EQ-5D-5L visual analogue scale (EQ-VAS) in patients undergoing elective total hip arthroplasty in Australia. METHODS: In this prospective multi-centre study, the OHS and EQ-5D-5L were collected preoperatively, six weeks (6w) and six months (6m) postoperatively. The OHS, EQ-VAS and EQ-5D-5L index were evaluated for concurrent validity, predictive validity (Spearman's Rho of predicted and observed values from a generalised linear regression model (GLM)), and responsiveness (effect size (ES) and standard response mean (SRM)). RESULTS: 362 patients were included in this analysis for 6w and 269 for 6m. The EQ-5D-5L index showed good concurrent validity with the OHS (r = 0.71 preoperatively, 0.61 at 6w and 0.59 at 6m). Predictive validity for EQ-5D-5L index was similar to OHS when regressed (GLM). Responsiveness was good at 6w (EQ-5D-5L index ES 1.53, SRM 1.40; OHS ES 2.16, SRM 1.51) and 6m (EQ-5D-5L index ES 1.88, SRM 1.70; OHS ES 3.12, SRM 2.24). The EQ-VAS returned poorer results, at 6w an ES of 0.75 (moderate) and SRM 0.8. At 6m the EQ-VAS had an ES of 0.92 and SRM of 1.00. It, however, had greater predictive validity. CONCLUSIONS: The EQ-5D-5L index and the OHS demonstrate strong concurrent validity. The EQ-5D-5L index demonstrated similar predictive validity at 6w and 6m, and both PROMs had adequate responsiveness. The EQ-VAS should be used routinely together with the EQ-5D-5L index. The EQ-5D-5L is suitable to quantify health-related quality of life in Australian hip arthroplasty patients.

7.
J Int Med Res ; 50(3): 3000605221085073, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35291842

ABSTRACT

OBJECTIVE: The pericapsular nerve group (PENG) block is a regional block that possibly provides better analgesia than that of the femoral nerve block (FNB) for hip fracture surgery. A randomized comparative trial performed in our institution showed that the PENG block may provide improved pain reduction compared with the FNB while preserving quadriceps strength. METHODS: In this single-center, double-blinded, randomized comparative trial, patients who underwent hip fracture surgery were randomized to receive either a FNB or PENG block for analgesia. This analysis reviews the outcomes of the block effect duration and time to discharge readiness. RESULTS: Sixty patients with similar baseline demographics were randomized. The median FNB duration was 15 hours, 35 minutes (range (hours:minutes) 4:08-30:45), and the median PENG duration was 22 hours, 50 minutes (range 6:00-32:00). The time to discharge readiness was shorter in the PENG group (3 days, range 1-14 days) than that in the FNB group (4 days, range 2-15 days). CONCLUSIONS: The PENG block results in a faster recovery and shorter time to discharge readiness. The duration of the PENG block appears to be longer than that of the FNB.


Subject(s)
Femoral Nerve , Patient Discharge , Analgesics , Humans , Pain Measurement , Pain, Postoperative/etiology
11.
BMJ Open Qual ; 10(4)2021 11.
Article in English | MEDLINE | ID: mdl-34732540

ABSTRACT

Despite good quality evidence for benefits with its use, challenges have been encountered in the correct and consistent implementation of the surgical safety checklist (SSC). Previous studies of the SSC have reported a discrepancy between what is documented and what is observed in real time. A baseline observational audit at our institution demonstrated compliance of only 3.5% despite a documented compliance of 100%. This project used quality improvement principles of identifying the problem and designing strategies to improve staff compliance with the SSC. These included changing the SSC from paper-based to a reusable laminated form, a broad multidisciplinary education and marketing campaign, targeted coaching and modifying the implementation in response to ongoing staff feedback. Five direct observational audits were undertaken over four Plan-Do-Study-Act cycles to capture real-time information on staff compliance. Two staff surveys were also undertaken. Compliance with the SSC improved from 3.5% to 63% during this study. Staff reported they felt the new process improved patient safety and that the new SSC was easily incorporated into their workflow. Improving compliance with the SSC requires deep engagement with and cooperation of surgical, anaesthesia and nursing teams and understanding of their work practices and culture. The prospective observational audit highlighted an initial 3.5% compliance rate compared with 100% based on an audit of the patient notes. Relying solely on a retrospective paper-based model can lead to hospitals being unaware of significant safety and quality issues. While in-person prospective observations are more time-consuming and resource-consuming than retrospective audits, this study highlights their potential utility to gain a clear picture of actual events. The significant variation between documented and observed data may have considerable implications for other retrospective studies which rely on human-entered data for their results.


Subject(s)
Checklist , Quality Improvement , Humans , Patient Safety , Prospective Studies , Retrospective Studies
12.
Reg Anesth Pain Med ; 46(5): 398-403, 2021 05.
Article in English | MEDLINE | ID: mdl-33637625

ABSTRACT

BACKGROUND: The femoral nerve block (FNB) may be used for analgesia in hip fracture surgery. The pericapsular nerve group (PENG) block is a novel regional technique and may provide better pain reduction while preserving motor function, but these blocks have not been directly compared. METHODS: In a single-center double-blinded randomized comparative trial, patients presenting for hip fracture surgery received analgesia with either FNB or PENG block. The primary outcome measure was pain scores (Numeric Rating Scale (NRS) 0 to 10). Secondary outcomes were postoperative quadriceps strength, opiate use, complications, length of hospital stay, and patient-reported outcomes. RESULTS: Sixty patients were randomized and equally allocated between groups. Baseline demographics were similar. Postoperatively in recovery (day 0), the PENG group experienced less pain compared with the FNB group. (In the PENG group, 63% experienced no pain, 27% mild pain, and 10% moderate to severe pain. In comparison, 30% of the FNB group reported no pain, 27% mild pain, and 36% moderate to severe pain; p=0.04). This was assessed using an 11-point Likert NRS. Quadriceps strength was better preserved in the PENG group in the recovery unit (assessed using Oxford muscle strength grading, 60% intact in the PENG group vs none intact in the FNB group; p<0.001) and on day 1 (90% intact vs 50%, respectively; p=0.004). There was no difference in other outcomes. CONCLUSIONS: Patients receiving a PENG block for intraoperative and postoperative analgesia during hip fracture surgery experience less postoperative pain in the recovery room with no difference detected by postoperative day 1. Quadriceps strength was better preserved with the PENG block. Despite the short-term analgesic benefit and improved quadriceps strength, there were no differences detected in the quality of recovery.


Subject(s)
Analgesia , Nerve Block , Femoral Nerve , Humans , Pain Management , Pain, Postoperative/diagnosis , Pain, Postoperative/etiology , Pain, Postoperative/prevention & control
13.
Reg Anesth Pain Med ; 46(2): 169-175, 2021 02.
Article in English | MEDLINE | ID: mdl-33109730

ABSTRACT

INTRODUCTION: Pericapsular nerve group (PENG) block is a novel regional analgesia technique to reduce pain after hip surgery and hip fractures. This review was conducted to summarize current literature. METHODS: A scoping review was carried out using the Joanna Briggs Institute framework. All articles describing the use of PENG block as a regional analgesia and/or anesthesia technique for hip pain were considered eligible for inclusion. Ovid Medline, Embase, CINAHL, PubMed and Google Scholar were searched. Adult and pediatric studies were included. Excluded were articles not available in English language, not available in full-text, related to non-orthopedic indications such as soft tissue surgery, and pelvic or femoral shaft fractures. RESULTS: Database searches identified 345 articles, 20 of which could be included in the current review, with a combined patient number of 74. Included articles comprised case reports and case series only, describing 1 to 10 patients. In all studies, PENG block was described to provide sufficient analgesia or anesthesia. Transient motor side effects occurred only when the local anesthetic was deposited in an unintended location (n=2). CONCLUSIONS: Current evidence of using PENG block for hip surgery or hip pain is limited to case reports and case series only. PENG block is a promising regional analgesia technique as an alternative to other regional nerve blocks such as femoral nerve block or iliac fascia nerve block. Observational and experimental studies are required to determine the effectiveness, efficacy and safety of the PENG block.


Subject(s)
Analgesia , Hip Fractures , Nerve Block , Adult , Child , Femoral Nerve , Hip Fractures/surgery , Humans , Nerve Block/adverse effects , Pain , Pain Management , Pain, Postoperative/diagnosis , Pain, Postoperative/etiology , Pain, Postoperative/prevention & control
14.
BMJ Open Qual ; 8(2): e000346, 2019.
Article in English | MEDLINE | ID: mdl-31206045

ABSTRACT

University Hospital is a tertiary academic centre in London, Ontario, Canada. A designated space known as the block room (BR) supports a model of care to perform regional anaesthesia prior to entering the resource intense operating room (OR). Stress due to time pressure was reported by BR staff. It was presumed that upstream delays in patient admission, preparation, transportation and in the BR resulted in late OR starts. There was limited data for a patient's preoperative transit at our institution. A prospective quality improvement project was conceived to understand and address concerns surrounding patient flow. Using Plan-Do-Study-Act (PDSA) methodology, we collected baseline data of patients perioperative transit and performed three PDSA cycles for improvement. We established targets for OR entry time and patient arrival to the BR. We examined communication between the surgical preparation unit, BRandORs, involved stakeholders in decision making and continuously sourced feedback for improvement. Over three incremental rapid PDSA cycles and reaudit of our baseline, we found a statistically significant improvement in patients arriving to the BR 60 min prior to the scheduled OR time from a baseline of 31%-53% (p=0.04) and patient operations commencing on time improved from 52% to 65% (p=0.03). The availability of patients in the BR within 15 min of a decision to have them available reached 98% from a baseline of 69% (p<0.001). As a result of the quality improvement process, we were able to significantly improve the flow of the preoperative patient journey at our institution. With a better understanding of complex preoperative processes, we can strategically intervene and potentially improve efficiency, morale and safety.


Subject(s)
Efficiency, Organizational/standards , Nerve Block/methods , Efficiency, Organizational/statistics & numerical data , Hospitals, University/organization & administration , Hospitals, University/statistics & numerical data , Humans , Nerve Block/statistics & numerical data , Ontario , Preoperative Care/standards , Preoperative Care/statistics & numerical data , Prospective Studies , Quality Improvement
15.
J Clin Anesth ; 48: 67-72, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29778971

ABSTRACT

STUDY OBJECTIVE: To compare the effectiveness of supraclavicular and infraclavicular approaches to brachial plexus block for elbow surgery. DESIGN: Prospective, parallel arm, observer-blinded, randomized controlled trial. SETTING: This study occurred in a designated block room at St. Joseph's hospital, a large academic tertiary hospital in London, Canada. PATIENTS: 150 adult ASA class I-III patients undergoing elective ambulatory elbow surgery. INTERVENTIONS: Patients were randomized to receive either an ultrasound-guided infraclavicular or a supraclavicular block with ropivacaine. MEASUREMENTS: Both groups were assessed for performance and sensory block onset times. Motor block, effective surgical anesthesia, procedure-related pain, axillary nerve block and ulnar nerve sparing were additional outcomes. We analyzed continuous and non-continuous variables with the independent t-test and chi-square test respectively and considered statistical significance when type 1 error was under 0.05. MAIN RESULTS: We observed similar mean block procedure times at 285 (±128) seconds in infra and 307 (±138) seconds in supra group (p = 0.3). The mean time of sensory block onset in both groups was similar: Infra 20.4 (±7.9) and supra 18.9 (±7.1) min (p = 0.4). Conversion to general anesthesia (4.2 vs 5.5%; p = 0.73) and the need for local anesthetic supplement (4.2 vs 4.1%; p = 0.98) was similar in both groups. We observed an increased incidence of paresthesia in the supra group (8.3 vs 23.2%; p = 0.014). CONCLUSION: We found that both blocks were equally effective for elbow surgery with similar procedure and block onset times and failure rates. Lower incidence of paresthesia was associated with the infraclavicular block with no change in other complications compared to the supraclavicular technique.


Subject(s)
Ambulatory Surgical Procedures/adverse effects , Brachial Plexus Block/methods , Orthopedic Procedures/adverse effects , Pain, Postoperative/prevention & control , Paresthesia/epidemiology , Adult , Aged , Ambulatory Surgical Procedures/methods , Anesthetics, Local/administration & dosage , Brachial Plexus/diagnostic imaging , Brachial Plexus/drug effects , Brachial Plexus Block/adverse effects , Elbow/diagnostic imaging , Elbow/innervation , Elbow/surgery , Elbow Joint/diagnostic imaging , Elbow Joint/innervation , Elbow Joint/surgery , Female , Humans , Incidence , Injections/adverse effects , Injections/methods , Male , Middle Aged , Orthopedic Procedures/methods , Pain Measurement , Pain, Postoperative/diagnosis , Pain, Postoperative/etiology , Paresthesia/etiology , Ropivacaine/administration & dosage , Treatment Outcome , Ultrasonography, Interventional
16.
BMJ Case Rep ; 20142014 Dec 22.
Article in English | MEDLINE | ID: mdl-25535233

ABSTRACT

Extravasation occurs frequently with intravenous infusions. In this case report we describe the occurrence of epidermal detachment and multiple cutaneous bullous eruptions in a patient's forearm following the extravasation of hydroxyethyl starch (Voluven, Fresenius Kabi)-a colloid solution derived from corn starch, which is used to replace lost blood volume. The patient's affected body surface area was managed under the direction of our plastic surgical team. Despite a prolonged admission in hospital from other perioperative complications, he made a full recovery and was successfully discharged home. The probable pathogenesis relevant to extravasation of Voluven is discussed; as well as its management principles.


Subject(s)
Epidermis/pathology , Hydroxyethyl Starch Derivatives/adverse effects , Skin Diseases/etiology , Aged , Blood Volume , Forearm , Humans , Hydroxyethyl Starch Derivatives/administration & dosage , Infusions, Intravenous/adverse effects , Male , Skin Diseases, Vesiculobullous/etiology
17.
BMJ Case Rep ; 20142014 May 30.
Article in English | MEDLINE | ID: mdl-24879737

ABSTRACT

Amniotic fluid embolism (AFE) is a rare and potentially fatal complication of pregnancy. In this case report, we highlight the successful use of sodium bicarbonate in a patient with an AFE. We present a case of a 38-year-old mother admitted for an elective caesarean section. Following the delivery of her baby, the mother suffered a cardiac arrest. Following a protracted resuscitation, transoesophageal echocardiography demonstrated evidence of acute pulmonary hypertension, with an empty left ventricle and an over-distended right ventricle. In view of these findings and no improvement noted from on-going resuscitation, sodium bicarbonate was infused as a pulmonary vasodilator. Almost instantaneous return of spontaneous circulation was noted, with normalisation of cardiac parameters. We propose that in patients suspected with AFE and who have been unresponsive to advance cardiac life support measures, and where right ventricular failure is present with acidosis and/or hypercarbia, the use of sodium bicarbonate should be considered.


Subject(s)
Embolism, Amniotic Fluid/drug therapy , Sodium Bicarbonate/therapeutic use , Vasodilator Agents/therapeutic use , Adult , Female , Heart Arrest/drug therapy , Heart Arrest/etiology , Humans , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/etiology , Pregnancy
18.
Stud Health Technol Inform ; 163: 611-5, 2011.
Article in English | MEDLINE | ID: mdl-21335866

ABSTRACT

Endotracheal intubation is a skill employed by a diverse range of healthcare professionals in a wide variety of circumstances. Failure to put this tube in the right place (in the trachea) can result in serious injury and death. There are a wide variety of methods for verification of proper placement. Some are more widely accepted than others. A universal guideline should be adopted to allow consistent and safe practice in all situations by all who do this procedure. Training for endotracheal intubation must also include training in the verification methods. We have developed a new airway part-task trainer that allows the use of all of the methods of tube placement verification.


Subject(s)
Computer-Assisted Instruction/methods , Intubation, Intratracheal/methods , Models, Biological , Outcome Assessment, Health Care/methods , Surgery, Computer-Assisted/methods , Task Performance and Analysis , User-Computer Interface , Computer Simulation , Humans , Teaching/methods , Treatment Outcome
19.
Neuropharmacology ; 55(2): 204-14, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18602124

ABSTRACT

The effects of a synthetic apoE peptide, viz., residues 133-149 (apoE[133-149]), a mimetic that comprises the apoE receptor binding domain, on N-methyl-D-aspartate (NMDA)/glycine-induced ion flow through NMDA receptor (NMDAR) channels, have been investigated. The activity of apoE[133-149] was found to depend on the low-density lipoprotein receptor-related protein (LRP). Competition experiments with receptor-associated protein (RAP) and activated alpha(2)-macroglobulin (alpha(2)M*), two proteins that compete for apoE binding to LRP, demonstrate that apoE[133-149] inhibition of NMDAR function is mediated at a locus in LRP that overlaps with the binding sites of RAP and alpha(2)M*. A coreceptor of LRP, cell surface heparin sulfate proteoglycan, did not function in this system. Additional electrophysiology experiments demonstrated that the inhibitory potency of apoE[133-149] was threefold greater for NMDAR-transfected wild-type Chinese hamster ovary (CHO) cells compared with NMDAR-transfected CHO cells deficient in LRP. Studies with truncation and replacement variants of the apoE peptide demonstrated that the NMDAR inhibitory properties of these peptides correlate with their binding affinities for LRP. These novel results indicate that apoE functions as an inhibitor of NMDAR ion channels indirectly via LRP, and are suggestive of a participatory role for LRP in NMDAR-based neuropathies.


Subject(s)
Apolipoproteins E/chemistry , LDL-Receptor Related Proteins/metabolism , Peptide Fragments/pharmacology , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Binding Sites/drug effects , Cell Line, Transformed , Cell Membrane/drug effects , Cell Membrane/metabolism , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Drug Interactions , Glycine/pharmacology , Humans , LDL-Receptor Related Proteins/pharmacology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , N-Methylaspartate/pharmacology , Patch-Clamp Techniques/methods , Protein Binding/drug effects , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/genetics , Spermine/pharmacology , Transfection/methods
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