Improved outcomes for spinal versus general anesthesia for hip fracture surgery: a retrospective cohort study of the National Surgical Quality Improvement Program.

BACKGROUND: There is a lack of consensus in the literature as to whether anesthetic modality influences perioperative complications in hip fracture surgery. The aim of the present study was to assess the effect of spinal anesthesia compared with general anesthesia on postoperative morbidity and mortality in patients who underwent hip fracture surgery using data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). METHODS: We used the ACS NSQIP to identify patients aged 50 and older who received either spinal or general anesthesia for hip fracture surgery from 2016 to 2019. Propensity-score matching was performed to control for clinically relevant covariates. The primary outcome of interest was the combined incidence of stroke, myocardial infarction (MI) or death within 30 days. Secondary outcomes included 30-day mortality, hospital length of stay and operative time. RESULTS: Among the 40 527 patients aged 50 and over who received either spinal or general anesthesia for hip fracture surgery from 2016 to 2019, 7358 spinal anesthesia cases were matched to general anesthesia cases. General anesthesia was associated with a higher incidence of combined 30-day stroke, MI or death compared with spinal anesthesia (OR 1.219 (95% CI 1.076 to 1.381); p=0.002). General anesthesia was also associated with a higher frequency of 30-day mortality (OR 1.276 (95% CI 1.099 to 1.481); p=0.001) and longer operative time (64.73 vs 60.28 min; p<0.001). Spinal anesthesia had a longer average hospital length of stay (6.29 vs 5.73 days; p=0.001). CONCLUSION: Our propensity-matched analysis suggests that spinal anesthesia as compared with general anesthesia is associated with lower postoperative morbidity and mortality in patients undergoing hip fracture surgery.

Comparing Processed Nerve Allografts and Assessing Their Capacity to Retain and Release Nerve Growth Factor.

Peripheral nerve gap injuries continue to present a clinical challenge to today's surgeons. One method of surgical repair, implantation of acellular allografts, has been developed with the aim of bridging the gap with a cadaveric graft after removal of its cellular components, thereby accelerating axonal regeneration and eliminating the need for immunosuppression in recipient patients. Although decellularizing allografts reduces rates of graft rejection, the same chemical processing modifies the neural microenvironment, removing neutrotrophic factors and modifying the complex extracellular matrix. In this study, we explore 3 common methods for producing acellular allografts. Extracellular matrix content remaining after processing was investigated and was found to be highly dependent on the decellularization method. In addition, scanning electron micrographs were obtained to evaluate the structural effects of the decellularization methods. Though the content and structure of these processed allografts will contribute to their effectiveness as nerve gap repair candidates, we demonstrate that it also affects their capacity to be supplemented/preloaded with the prototypical neurotrophin, nerve growth factor (NGF), essential to neuronal regeneration. Although all allografts had some capacity for retaining NGF in the first 24 hours, only Sondell-processed grafts retained NGF over the entire experimental period of 21 days. Future studies will include validating these processed and supplemented allografts as viable alternatives to traditional autograft nerve gap repair.

Immediate Enhancement of Nerve Function Using a Novel Axonal Fusion Device After Neurotmesis.

BACKGROUND: The management of peripheral nerve injuries remains a large challenge for plastic surgeons. With the inability to fuse axonal endings, results after microsurgical nerve repair have been inconsistent. Our current nerve repair strategies rely upon the slow and lengthy process of axonal regeneration (~1 mm/d). Polyethylene glycol (PEG) has been investigated as a potential axonal fusion agent; however, the percentage of axonal fusion has been inconsistent. The purpose of this study was to identify a PEG delivery device to standardize outcomes after attempted axonal fusion with PEG. MATERIALS AND METHODS: We used a rat sciatic nerve injury model in which we completely transected and repaired the left sciatic nerve to evaluate the efficacy of PEG fusion over a span of 12 weeks. In addition, we evaluated the effectiveness of a delivery device's ability to optimize results after PEG fusion. RESULTS: We found that PEG rapidly (within minutes) restores axonal continuity as assessed by electrophysiology, fluorescent retrograde tracer, and diffusion tensor imaging. Immunohistochemical analysis shows that motor axon counts are significantly increased at 1 week, 4 weeks, and 12 weeks postoperatively in PEG-treated animals. Furthermore, PEG restored behavioral functions up to 50% compared with animals that received the criterion standard epineurial repair (control animals). CONCLUSIONS: The ability of PEG to rapidly restore nerve function after neurotmesis could have vast implications on the clinical management of traumatic injuries to peripheral nerves.

Polyethylene glycol restores axonal conduction after corpus callosum transection.

Polyethylene glycol (PEG) has been shown to restore axonal continuity after peripheral nerve transection in animal models. We hypothesized that PEG can also restore axonal continuity in the central nervous system. In this current experiment, coronal sectioning of the brains of Sprague-Dawley rats was performed after animal sacrifice. 3Brain high-resolution microelectrode arrays (MEA) were used to measure mean firing rate (MFR) and peak amplitude across the corpus callosum of the ex-vivo brain slices. The corpus callosum was subsequently transected and repeated measurements were performed. The cut ends of the corpus callosum were still apposite at this time. A PEG solution was applied to the injury site and repeated measurements were performed. MEA measurements showed that PEG was capable of restoring electrophysiology signaling after transection of central nerves. Before injury, the average MFRs at the ipsilateral, midline, and contralateral corpus callosum were 0.76, 0.66, and 0.65 spikes/second, respectively, and the average peak amplitudes were 69.79, 58.68, and 49.60 µV, respectively. After injury, the average MFRs were 0.71, 0.14, and 0.25 spikes/second, respectively and peak amplitudes were 52.11, 8.98, and 16.09 µV, respectively. After application of PEG, there were spikes in MFR and peak amplitude at the injury site and contralaterally. The average MFRs were 0.75, 0.55, and 0.47 spikes/second at the ipsilateral, midline, and contralateral corpus callosum, respectively and peak amplitudes were 59.44, 45.33, 40.02 µV, respectively. There were statistically differences in the average MFRs and peak amplitudes between the midline and non-midline corpus callosum groups (P < 0.01, P < 0.05). These findings suggest that PEG restores axonal conduction between severed central nerves, potentially representing axonal fusion.

Mass spectrometry comparison of nerve allograft decellularization processes.

Peripheral nerve repair using nerve grafts has been investigated for several decades using traditional techniques such as histology, immunohistochemistry, and electron microscopy. Recent advances in mass spectrometry techniques have made it possible to study the proteomes of complex tissues, including extracellular matrix rich tissues similar to peripheral nerves. The present study comparatively assessed three previously described processing methods for generating acellular nerve grafts by mass spectrometry. Acellular nerve grafts were additionally examined by F-actin staining and nuclear staining for debris clearance. Application of newer techniques allowed us to detect and highlight differences among the 3 treatments. Isolated proteins were separated by mass on polyacrylamide gels serving 2 purposes. This further illustrated that these treatments differ from one another and it allowed for selective protein extractions within specific bands/molecular weights. This approach resulted in small pools of proteins that could then be analyzed by mass spectrometry for content. In total, 543 proteins were identified, many of which corroborate previous findings for these processing methods. The remaining proteins are novel discoveries that expand the field. With this pilot study, we have proven that mass spectrometry techniques complement and add value to peripheral nerve repair studies.

A novel therapy to promote axonal fusion in human digital nerves.

BACKGROUND: Peripheral nerve injury can have a devastating impact on our military and veteran population. Current strategies for peripheral nerve repair include techniques such as nerve tubes, nerve grafts, tissue matrices, and nerve growth guides to enhance the number of regenerating axons. Even with such advanced techniques, it takes months to regain function. In animal models, polyethylene glycol (PEG) therapy has shown to improve both physiologic and behavioral outcomes after nerve transection by fusion of a portion of the proximal axons to the distal axon stumps. The objective of this study was to show the efficacy of PEG fusion in humans and to retrospectively compare PEG fusion to standard nerve repair. METHODS: Patients with traumatic lacerations involving digital nerves were treated with PEG after standard microsurgical neurorrhaphy. Sensory assessment after injury was performed at 1 week, 2 weeks, 1 month, and 2 months using static two-point discrimination and Semmes-Weinstein monofilament testing. The Medical Research Council Classification (MRCC) for Sensory Recovery Scale was used to evaluate the level of injury. The PEG fusion group was compared to patient-matched controls whose data were retrospectively collected. RESULTS: Four PEG fusions were performed on four nerve transections in two patients. Polyethylene glycol therapy improves functional outcomes and speed of nerve recovery in clinical setting assessed by average MRCC score in week 1 (2.8 vs 1.0, p = 0.03). At 4 weeks, MRCC remained superior in the PEG fusion group (3.8 vs 1.3, p = 0.01). At 8 weeks, there was improvement in both groups with the PEG fusion cohort remaining statistically better (4.0 vs 1.7, p = 0.01). CONCLUSION: Polyethylene glycol fusion is a novel therapy for peripheral nerve repair with proven effectiveness in animal models. Clinical studies are still in early stages but have had encouraging results. Polyethylene glycol fusion is a potential revolutionary therapy in peripheral nerve repair but needs further investigation. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Peripheral Venous Waveform Analysis for Detecting Hemorrhage and Iatrogenic Volume Overload in a Porcine Model.

BACKGROUND: Unrecognized hemorrhage and unguided resuscitation is associated with increased perioperative morbidity and mortality. The authors investigated peripheral venous waveform analysis (PIVA) as a method for quantitating hemorrhage as well as iatrogenic fluid overload during resuscitation. METHODS: The authors conducted a prospective study on Yorkshire Pigs (n = 8) undergoing hemorrhage, autologous blood return, and administration of balanced crystalloid solution beyond euvolemia. Intra-arterial blood pressure, electrocardiogram, and pulse oximetry were applied to each subject. Peripheral venous pressure was measured continuously through an upper extremity standard peripheral IV catheter and analyzed with LabChart. The primary outcome was comparison of change in the first fundamental frequency (f1) of PIVA with standard and invasive monitoring and shock index (SI). RESULTS: Hemorrhage, return to euvolemia, and iatrogenic fluid overload resulted in significantly non-zero slopes of f1 amplitude. There were no significant differences in heart rate or mean arterial pressure, and a late change in SI. For the detection of hypovolemia the PIVA f1 amplitude change generated an receiver operator curves (ROC) curve with an area under the curve (AUC) of 0.93; heart rate AUC = 0.61; mean arterial pressure AUC = 0.48, and SI AUC = 0.72. For hypervolemia the f1 amplitude generated an ROC curve with an AUC of 0.85, heart rate AUC = 0.62, mean arterial pressure AUC = 0.63, and SI AUC = 0.65. CONCLUSIONS: In this study, PIVA demonstrated a greater sensitivity for detecting acute hemorrhage, return to euvolemia, and iatrogenic fluid overload compared with standard monitoring and SI. PIVA may provide a low-cost, minimally invasive monitoring solution for monitoring and resuscitating patients with perioperative hemorrhage.

An Evaluation of Induced Failure Modes in the Belmont® Rapid Infuser.

BACKGROUND: Rapid infusers are vital tools during massive hemorrhage and resuscitation. Sporadic reports of overheating and shutdown of the Belmont® Rapid Infuser, a commonly used system, have been attributed to 1-sided clot blockage of the fluid path. We investigated multiple causes of failure of this device. METHODS: Packed red blood cells and thawed fresh frozen plasma with normal saline solution were used as base fluids for serial 10-minute trials using standard disposable sets in 2 Belmont devices. Possible contributors to device failure, including calcium-containing solutions and external leakage currents, were evaluated. Thermographic images of the heater and disposable cartridges were recorded. The effects of complete unilateral clotting were modeled by sealing half of the disposable cartridge with epoxy. RESULTS: Clotting on the surface of the heat exchanger coil increased with calcium concentration and was only observed at calcium concentrations >12.0 mmol/L (P < 0.0001) in a 1:1 plasma:red blood cell mixture, resulting in high-pressure downstream occlusion alarms and interruption of flow. CONCLUSIONS: Clot-based occlusion can be induced in the Belmont Rapid Infuser under unrealistic conditions. In the absence of complete unilateral flow blockage, we did not observe any significant overheating of the infuser under extreme operating conditions.

Axonal fusion via conduit-based delivery of hydrophilic polymers.

BACKGROUND: Hydrophilic polymers have been shown to improve physiologic recovery following repair of transected nerves with microsutures. Our study was designed to combine hydrophilic polymer therapy with nerve tubes (NT) to enhance polymer delivery to the site of nerve injury. METHODS: Using a rat sciatic nerve injury model, a single transection injury was repaired in an end-to-end fashion with NT + polyethylene glycol (PEG) to NT alone. Compound action potentials (CAPs) were recorded before nerve transection and after repair. Behavioral testing was performed for 5 weeks. RESULTS: PEG therapy restored CAPS in all, but one, animals, while no CAPS were recorded in animals not receiving PEG. Behavioral nerve function was measured using the standardized functional assessment technique and foot fault asymmetry scores (FF). FF scores were improved for the PEG therapy groups on postoperative days 7, 14, and 21. However, after expected eventual axonal outgrowth, the benefit was less noticeable at days 28 and 35. Immunohistochemistry of the distal axon segments showed an increase number of sensory and motor axons in the NT + PEG group as compared to NT alone. CONCLUSION: These data suggest that PEG delivery via a conduit may provide a simple, effective way to fuse severed axons and regain early nerve function. For proximal nerve injuries in large animals, recovery of axonal continuity could dramatically improve outcomes, even if fusion only occurs in a small percentage of axons.

4.7-T diffusion tensor imaging of acute traumatic peripheral nerve injury.

Diagnosis and management of peripheral nerve injury is complicated by the inability to assess microstructural features of injured nerve fibers via clinical examination and electrophysiology. Diffusion tensor imaging (DTI) has been shown to accurately detect nerve injury and regeneration in crush models of peripheral nerve injury, but no prior studies have been conducted on nerve transection, a surgical emergency that can lead to permanent weakness or paralysis. Acute sciatic nerve injuries were performed microsurgically to produce multiple grades of nerve transection in rats that were harvested 1 hour after surgery. High-resolution diffusion tensor images from ex vivo sciatic nerves were obtained using diffusion-weighted spin-echo acquisitions at 4.7 T. Fractional anisotropy was significantly reduced at the injury sites of transected rats compared with sham rats. Additionally, minor eigenvalues and radial diffusivity were profoundly elevated at all injury sites and were negatively correlated to the degree of injury. Diffusion tensor tractography showed discontinuities at all injury sites and significantly reduced continuous tract counts. These findings demonstrate that high-resolution DTI is a promising tool for acute diagnosis and grading of traumatic peripheral nerve injuries.

Methods to identify saline-contaminated electrolyte profiles.

BACKGROUND: With providers becoming more selective in ordering daily chemistry profiles, it is critical that profiles ordered are accurate. Contaminated electrolyte profiles are an overlooked and potentially dangerous source of inaccurate clinical data. This study aimed to develop a method to accurately identify electrolyte profiles contaminated with normal saline to prevent reporting of erroneous measurements. METHODS: We conducted a retrospective cohort study of 76,497 electrolyte profiles from 5032 patients in a deidentified clinical database of all patients in the electronic medical record at Vanderbilt University Medical Center. Five methods to identify errors in quantification based on either deviations from observed concentration distributions or expected numerical changes from saline contamination were developed and tested. Potentially contaminated measurements were validated based on changes in electrolyte concentrations observed in the subsequent sample. RESULTS: Identification of erroneous electrolyte profiles based on absolute and percent deviations from normal variation rarely resulted in >50% of identified samples validated as contaminated. A targeted methodology based on expected changes in calcium and chloride concentrations due to saline contamination validated approximately 80% of identified samples when higher thresholds for changes in electrolyte concentration were used and 50% of identified samples when lower thresholds were used. CONCLUSIONS: Targeted methodology based on changes in chloride and calcium successfully identified electrolyte profiles suspicious for contamination. Implementation of this methodology could prevent misinterpretation of a patient's clinical course, inappropriate interventions, and unwarranted changes in treatment strategy.

Adjuvant neurotrophic factors in peripheral nerve repair with chondroitin sulfate proteoglycan-reduced acellular nerve allografts.

BACKGROUND: Acellular nerve allografts are now standard tools in peripheral nerve repair because of decreased donor site morbidity and operative time savings. Preparation of nerve allografts involves several steps of decellularization and modification of extracellular matrix to remove chondroitin sulfate proteoglycans (CSPGs), which have been shown to inhibit neurite outgrowth through a poorly understood mechanism involving RhoA and extracellular matrix-integrin interactions. Chondroitinase ABC (ChABC) is an enzyme that degrades CSPG molecules and has been shown to promote neurite outgrowth after injury of the central and peripheral nervous systems. Variable results after ChABC treatment make it difficult to predict the effects of this drug in human nerve allografts, especially in the presence of native extracellular signaling molecules. Several studies have shown cross-talk between neurotrophic factor and CSPG signaling pathways, but their interaction remains poorly understood. In this study, we examined the adjuvant effects of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) on neurite outgrowth postinjury in CSPG-reduced substrates and acellular nerve allografts. MATERIALS AND METHODS: E12 chicken DRG explants were cultured in medium containing ChABC, ChABC + NGF, ChABC + GDNF, or control media. Explants were imaged at 3 d and neurite outgrowths measured. The rat sciatic nerve injury model involved a 1-cm sciatic nerve gap that was microsurgically repaired with ChABC-pretreated acellular nerve allografts. Before implantation, nerve allografts were incubated in NGF, GDNF, or sterile water. Nerve histology was evaluated at 5 d and 8 wk postinjury. RESULTS: The addition of GDNF in vitro produced significant increase in sensory neurite length at 3 d compared with ChABC alone (P < 0.01), whereas NGF was not significantly different from control. In vivo adjuvant NGF produced increases in total myelinated axon count (P < 0.005) and motor axon count (P < 0.01), whereas significantly reducing IB4+ nociceptor axon count (P < 0.01). There were no significant differences produced by in vivo adjuvant GDNF. CONCLUSIONS: This study provides initial evidence that CSPG-reduced nerve grafts may disinhibit the prosurvival effects of NGF in vivo, promoting motor axon outgrowth and reducing regeneration of specific nociceptive neurons. Our results support further investigation of adjuvant NGF therapy in CSPG-reduced acellular nerve grafts.

Blocking the P2X7 receptor improves outcomes after axonal fusion.

BACKGROUND: Activation of the P2X7 receptor on peripheral neurons causes the formation of pannexin pores, which allows the influx of calcium across the cell membrane. Polyethylene glycol (PEG) and methylene blue have previously been shown to delay Wallerian degeneration if applied during microsuture repair of the severed nerve. Our hypothesis is that by modulating calcium influx via the P2X7 receptor pathway, we could improve PEG-based axonal repair. The P2X7 receptor can be stimulated or inhibited using bz adenosine triphosphate (bzATP) or brilliant blue (FCF), respectively. METHODS: A single incision rat sciatic nerve injury model was used. The defect was repaired using a previously described PEG methylene blue fusion protocol. Experimental animals were treated with 100 µL of 100 µM FCF solution (n = 8) or 100 µL of a 30 µM bzATP solution (n = 6). Control animals received no FCF, bzATP, or PEG. Compound action potentials were recorded prior to transection (baseline), immediately after repair, and 21 d postoperatively. Animals underwent behavioral testing 3, 7, 14, and 21 d postoperatively. After sacrifice, nerves were fixed, sectioned, and immunostained to allow for counting of total axons. RESULTS: Rats treated with FCF showed an improvement compared with control at all time points (n = 8) (P = 0.047, 0.044, 0.014, and 0.0059, respectively). A statistical difference was also shown between FCF and bzATP at d 7 (P < 0.05), but not shown with d 3, 14, and 21 (P > 0.05). CONCLUSIONS: Blocking the P2X7 receptor improves functional outcomes after PEG-mediated axonal fusion.