Preclinical Porcine Model Research Articles

An antimicrobial blue light prototype device controls infected wounds in a preclinical porcine model.

We developed a translational prototype antimicrobial blue light (ABL) device for treating skin wounds with ABL. Partial-thickness surgical wounds were created in live swine, an animal whose skin is considered the most like human skin, then heavily contaminated and left untreated for 24 hours with methicillin-resistant Staphylococcus aureus (MRSA). ABL treatment stabilized and reduced MRSA infection by greater than four orders of magnitude (>99.99%; p<0.0001) compared with untreated wounds in the same animal, after only two daily treatments. These data support further development of such devices for controlling infection in skin wounds. ABL, with or without concomitant administration of negative pressure, antimicrobials, or photosensitizers, could play an important role in modern wound care by reducing the amount, duration, and cost of antibiotics needed, helping reduce AMR. No such device for treating human cutaneous wounds currently exists. This deserves further development and study.

Therapeutic Use of Carbon Monoxide in Ex-Vivo Lung Perfusion in Donor With Prolonged Cold Ischemia

IntroductionCarbon monoxide (CO) has been shown to exert protective effects in multiple organs following ischemic injury, including the lung. The purpose of this study was to examine the effects of CO administration during ex vivo lung perfusion (EVLP) on lung grafts exposed to prolonged cold ischemia. MethodsTen porcine lungs were subjected to 18 h of cold ischemia followed by 6 h of EVLP. Lungs were randomized to EVLP alone (control, n = 5) or delivery of 500 ppm of CO during the 1st hour of EVLP (treatment, n = 5). Following EVLP, the left lungs were transplanted and reperfused for 4 h. ResultsAt the end of EVLP, pulmonary vascular resistance (P = 0.007) and wet to dry lung weight ratios (P = 0.027) were significantly reduced in CO treated lungs. Posttransplant, lung graft PaO2/FiO2 (P = 0.032) and compliance (P = 0.024) were significantly higher and peak airway pressure (P = 0.032) and wet to dry ratios (P = 0.003) were significantly lower in CO treated lungs. Interleukin-6 was significantly reduced in plasma during reperfusion in the CO treated group (P = 0.040). ConclusionsIn this preclinical porcine model, CO application during EVLP resulted in better graft performance and outcomes after reperfusion.

Ex vivo MFG-E8 treatment improves the function of lungs procured from cardiac death donors in preclinical porcine model

Ex vivo lung perfusion (EVLP) is a promising technology that allows the re-evaluation of donor lungs and has the potential to improve marginal lung reconditioning. The present study focused on the effects of milk fat globule epidermal growth factor 8 (MFG‐E8) on the function of donation after circulatory death (DCD) lungs during EVLP and transplant reperfusion. Domestic swine were assigned to 4 groups. In the control group, the donor lungs lacking warm ischemia were preserved in Perfadex for 4 h. The swine in the other three groups underwent hypoxic arrest, followed by 1 h of warm ischemia. The DCD lungs were procured and randomly divided into three groups: cold static preservation (DCD-CSP) group, DCD-EVLP group, and DCD-MFG-E8 group. The left lung of all groups was transplanted and reperfused. During EVLP and reperfusion, lung functions and pathological evaluations were performed. Treatment with MFG-E8 resulted in significantly improved blood oxygenation. The mean pulmonary artery pressure, peak airway pressure, and expression of IL-1β, IL-6, and IL-12 were significantly lower but IL-10 was higher in the DCD -MFG-E8 group. Furthermore, the lung injury severity score, pulmonary edema, and wet-to-dry weight ratio were also reduced in MFG-E8-treated lungs. However, the pulmonary vascular resistance and expression of TNF-α did not differ from the DCD -EVLP group but were significantly lower than in the DCD -CSP group. Adding MFG-E8 into the perfusate during EVLP obtains optimal graft function of lungs from DCD. This finding, if confirmed clinically, can be applied to recondition grafts and expanded use of DCD lungs.

Acute intracardiac electrogram changes and their relation to pulsed field ablation dose in porcine left ventricle

Abstract Background Pulsed field ablation (PFA) is an emerging cardiac ablation modality based on irreversible electroporation with promising preclinical and clinical results. Acute reduction of intracardiac electrograms (bipolar iEGMs) is consistently observed, similar to other ablation modalities, e.g. radiofrequency ablation. We and others have previously reported lesion size dependence on PFA dosing. However, the relevance of iEGM changes and their dependence on the PFA dose is not established. Furthermore, our study shows that unipolar iEGM signals may contain additional information about the effects of PFA in cardiac tissue. Purpose To quantify the effect of different PFA dosing on changes observed in bipolar and unipolar iEGMs within 5 minutes after the ablation. Methods In total, PFA was applied endocardially at 40 sites in the left ventricles of 8 pigs via a 5 mm tip catheter using a modified decapolar catheter in the inferior vena cava for current return (all electrodes). The following PFA doses (voltage and number of pulse trains) were used: 1000 V, 4 trains; 1300 V, 4 trains; 1500 V, 1 train; 1500 V, 4 trains; 1500 V, 8 trains; and 1500 V, 16 trains. For standard bipolar iEGMs (30 Hz – 500 Hz) the reduction in peak-to-peak amplitude after PFA was considered as a measure of the effect. In addition, unipolar iEGMs (0.5 Hz – 500 Hz) were decomposed into non-overlapping frequency sub-bands with Daubechies order 6 discrete wavelet transform (Figure 1A) allowing separate analysis in high-frequency (HF) and low-frequency (LF) ranges (63 Hz – 500 Hz and 0.5 Hz – 8 Hz, respectively). Results In total, 30 standard bipolar and 35 unipolar iEGMs (with at least 3.5 minutes of artefact-free post-ablation duration) were analysed. No dose dependency was observed for standard bipolar iEGMs within 5 minutes post-ablation (data not shown). However, the HF and LF content of unipolar iEGMs revealed opposing effects: a decrease in the HF and an increase in the LF content. Correlation with the dose was clearer in the LF content 3.5 minutes post-ablation, the difference being significant (p&amp;lt;0.05) between the lowest and the highest doses (Figure 1B and C). Discussion The decrease in HF content could reflect electrical silencing, ie. stunning of locally affected cardiomyocytes, most likely caused by irreversibly electroporated (ablated) cells located close to the catheter tip and by reversibly electroporated or otherwise temporarily silenced cells in adjacent tissue. The increase in LF content could reflect the current-of-injury effect, which is a broader area phenomenon derived from electrical potential differences between affected (reversibly and irreversibly electroporated) and non-affected regions. Conclusion Unipolar iEGMs acquired with a broadened frequency range and decomposed into HF and LF content provide new insight into the effects of PFA and correlate with PFA dosing in this pre-clinical porcine model.

Androgenic steroids induce pathologic scarring in a preclinical porcine model via dysfunctional extracellular matrix deposition.

Hypertrophic scarring is a major source of morbidity. Sex hormones are not classically considered modulators of scarring. However, based on increased frequency of hypertrophic scarring in patients on testosterone, we hypothesized that androgenic steroids induce abnormal scarring and developed a preclinical porcine model to explore these effects. Mini-swine underwent castration, received no testosterone (noT) or biweekly testosterone therapy (+T), and underwent excisional wounding. To create a delayed wound healing model, a subset of wounds were re-excised at 2 weeks. Scars from postoperative day 42 (POD42) and delayed wounds (POD28) were harvested 6 weeks after initial wounding for analysis via histology, bulk RNA-seq, and mechanical testing. Histologic analysis of scars from +T animals showed increased mean fibrosis area (16 mm2noT, 28 mm2+T; p = .007) and thickness (0.246 mm2noT, 0.406 mm2+T; p < .001) compared to noT. XX+T and XY+T scars had greater tensile burst strength (p = .024 and p = .013, respectively) compared to noT swine. Color deconvolution analysis revealed greater deposition of type I and type III collagen as well as increased collagen type I:III ratio in +T scars. Dermatopathologist histology scoring showed that +T exposure was associated with worse overall scarring (p < .05). Gene ontology analysis found that testosterone exposure was associated with upregulation of cellular metabolism and immune response gene sets, while testosterone upregulated pathways related to keratinization and laminin formation on pathway analysis. In conclusion, we developed a preclinical porcine model to study the effects of the sex hormone testosterone on scarring. Testosterone induces increased scar tissue deposition and appears to increase physical strength of scars via supraphysiologic deposition of collagen and other ECM factors. The increased burst strength seen in both XX and XY animals suggests that hormone administration has a strong influence on scar mechanical properties independent of chromosomal sex. Anti-androgen topical therapies may be a promising future area of research.

Proteoglycan 4 (PRG4) treatment improves skin wound healing in a porcine model.

Proteoglycan 4 (PRG4) is a boundary lubricant originally identified in articular cartilage and has been since shown to have immunomodulation and antifibrotic properties. Previously, we have demonstrated that recombinant human (rh)PRG4 treatment accelerates auricular cartilage injury closure through an inhibition of the fibrotic response, and promotion of tissue regeneration in mice. The purpose of the current study was to examine the effects of rhPRG4 treatment (vs. a DMSO carried control) on full-thickness skin wound healing in a preclinical porcine model. Our findings suggest that while rhPRG4 did not significantly accelerate nor impede full-thickness skin wound closure, it did improve repair quality by decreasing molecular markers of fibrosis and increasing re-vascularization. We also demonstrated that rhPRG4 treatment increased dermal adipose tissue during the healing process specifically by retaining adipocytes in the wound area but did not inhibit lipolysis. Overall, the results of the current study have demonstrated that rhPRG4 acts as antifibrotic agent and regulates dermal adipose tissue during the healing processes resulting in a tissue with a trajectory that more resembles the native skin vs. a fibrotic patch. This study provides strong rationale to examine if rhPRG4 can improve regeneration in human wounds.

Design and Rationale of Cytokine Filtration in Lung Transplantation (GLUSorb): Protocol for a Multicenter Clinical Randomized Controlled Trial.

Lung transplantation (LTx) is the only treatment option for end-stage lung disease. Despite improvements, primary graft dysfunction (PGD) remains the leading cause of early mortality and precipitates chronic lung allograft dysfunction, the main factor in late mortality after LTx. PGD develops within the first 72 hours and impairs the oxygenation capacity of the lung, measured as partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2). Increasing the PaO2/FiO2 ratio is thus critical and has an impact on survival. There is a general lack of effective treatments for PGD. When a transplanted lung is not accepted by the immune system in the recipient, a systemic inflammatory response starts where cytokines play a critical role in initiating, amplifying, and maintaining the inflammation leading to PGD. Cytokine filtration can remove these cytokines from the circulation, thus reducing inflammation. In a proof-of-concept preclinical porcine model of LTx, cytokine filtration improved oxygenation and decreased PGD. In a feasibility study, we successfully treated patients undergoing LTx with cytokine filtration (ClinicalTrials.gov; NCT05242289). The purpose of this clinical trial is to demonstrate the superiority of cytokine filtration in improving LTx outcome, based on its effects on oxygenation ratio, plasma levels of inflammatory markers, PGD incidence and severity, lung function, kidney function, survival, and quality of life compared with standard treatment with no cytokine filtration. This study is a Swedish national interventional randomized controlled trial involving 116 patients. Its primary objective is to investigate the potential benefits of cytokine filtration when used in conjunction with LTx. Specifically, this study aims to determine whether the application of cytokine filtration, administered for a duration of 12 hours within the initial 24 hours following a LTx procedure, can lead to improved patient outcomes. This study seeks to assess various aspects of patient recovery and overall health to ascertain the potential positive impact of this intervention on the posttransplantation course. The process of patient recruitment for this study is scheduled to commence subsequent to a site initiation visit, which was slated to take place on August 28, 2023. The primary outcome measure that will be assessed in this research endeavor is the oxygenation ratio, a metric denoted as the highest PaO2/FiO2 ratio achieved by patients within a 72-hour timeframe following their LTx procedure. We propose that cytokine filtration could enhance the overall outcomes of LTx. Our hypothesis suggests potential improvements in LTx outcome and patient care. ClinicalTrials.gov NCT05526950; https://www.clinicaltrials.gov/study/NCT05526950. PRR1-10.2196/52553.

A novel self-gripping long-term resorbable mesh providing temporary support for open primary ventral and incisional hernia

A novel synthetic fully long-term resorbable self-gripping mesh has been recently developed to reinforce soft tissue where weakness exists during ventral hernia repair open procedures. This resorbable mesh is a macroporous, knitted, poly-L-lactide, poly-trimethylene carbonate copolymer monofilament mesh with the ProGrip™ technology, providing grips on one side of the mesh. A new poly-L-lactide, poly-trimethylene copolymer was developed to provide the required features for mechanical support during at least 20 weeks covering the critical healing period, including resistance to fatigue under cyclic loading conditions, as it occurs in patients. The yarns and mesh initial physical and biomechanical properties were characterized. Then, the mesh mechanical strength was evaluated over time. The mechanical properties of the proposed mesh were found to be above the generally recognized threshold value to mechanically support the repair site of a hernia over a 20-week period during in-vitro cyclic loading test. The mesh performance was evaluated in vivo using a published preclinical porcine model of hernia repair at 4-, 12- and 20-weeks post implantation. The burst strength of the hernia repair sites reinforced with the new mesh were higher at 4 & 12 weeks and comparable at 20 weeks to the one of the native abdominal walls. At all time points, the mesh was well tolerated with moderate inflammation and was fast integrated in the abdominal wall at 4 weeks. Particularly, the grips were nicely engulfed in the newly formed connective tissue. They must facilitate the anchoring of the mesh by their extension from the mesh and their mushroom shape. The preclinical data of the self-gripping resorbable mesh suggests that it has all the favorable characteristics for future clinical use during ventral hernia repair open procedures.Graphical

Development and validation of a radiofrequency ablation treatment planning system for vertebral metastases.

Bone-targeted radiofrequency ablation (RFA) is widely used in the treatment of vertebral metastases. While radiation therapy utilizes established treatment planning systems (TPS) based on multimodal imaging to optimize treatment volumes, current RFA of vertebral metastases has been limited to qualitative image-based assessment of tumour location to direct probe selection and access. This study aimed to design, develop and evaluate a computational patient-specific RFA TPS for vertebral metastases. A TPS was developed on the open-source 3D slicer platform, including procedural setup, dose calculation (based on finite element modelling), and analysis/visualization modules. Usability testing was carried out by 7 clinicians involved in the treatment of vertebral metastases on retrospective clinical imaging data using a simplified dose calculation engine. In vivo evaluation was performed in a preclinical porcine model (n = 6 vertebrae). Dose analysis was successfully performed, with generation and display of thermal dose volumes, thermal damage, dose volume histograms and isodose contours. Usability testing showed an overall positive response to the TPS as beneficial to safe and effective RFA. The in vivo porcine study showed good agreement between the manually segmented thermally damaged volumes vs. the damage volumes identified from the TPS (Dice Similarity Coefficient = 0.71 ± 0.03, Hausdorff distance = 1.2 ± 0.1mm). A TPS specifically dedicated to RFA in the bony spine could help account for tissue heterogeneities in both thermal and electrical properties. A TPS would enable visualization of damage volumes in 2D and 3D, assisting clinicians in decisions about potential safety and effectiveness prior to performing RFA in the metastatic spine.

Abstract 128: Safety And Efficacy Of Pro-efferocytic Nanoparticles To Treat Atherosclerosis In A Porcine Model

Background and Aims: Within the atherosclerotic plaque, the formation of a necrotic core is, in part, a consequence of impaired macrophage efferocytosis in which apoptotic vascular cells upregulate “don’t-eat-me,” anti-phagocytic ligand CD47. In vivo , translational murine model studies demonstrating off-target effects of anti-CD47 antibody-mediated blockade prompted the development and successful validation of a macrophage-specific nanotherapy loaded with a chemical inhibitor of Src homology 2 domain-containing phosphatase-1 (SHP-1), a small molecule downstream of the CD47-SIRPα signaling axis. We aimed to test the safety and efficacy of this SHP-1 inhibitor nanotherapy in preventing atherosclerosis in a pre-clinical porcine model. Methods and Results: Sixteen LDLR -/- pigs were fed an atherogenic diet and treated with single-walled carbon nanotubes (SWNT) loaded with SHP1 inhibitor (SWNT-SHP1i) (n=8) or with SWNT alone (n=8), dosed weekly for three months. Blood samples were collected at baseline and at monthly intervals. The lipid panel, CMP, and CBC demonstrated no significant difference between the SWNT-SHP1i and control treatment groups at each timepoint. Survey of major arterial beds by histology revealed early-stage fatty streak disease within the left and right coronary artery (RCA) ostium in addition to the abdominal aorta distal to the renal arteries. Pigs underwent PET/CT in the final week of treatment. The SWNT-SHP1i treated cohort displayed a reduced carotid artery uptake of 18F-FDG compared to the controls (p = 0.017). Bulk RNA sequencing analysis of the carotid artery demonstrated multiple differentially expressed pathways related to hemostasis and the immune response. Conclusion: In a porcine model, macrophage-specific SWNT-SHP1i treatment is not significantly associated with anemia, thus circumventing off-target effects of global anti-CD47 blockade. PET/CT reveals evidence of significantly decreased vascular inflammation in the carotid arteries in the SWNT-SHP1i treated cohort. Bulk RNA-seq confirms numerous significant differentially expressed genes. Ongoing blinded, quantitative histological analysis will further compare both plaque burden and plaque M1/M2 macrophage content between the two cohorts.

An endoscopically compatible fast-gelation powder forms Janus-adhesive hydrogel barrier to prevent postoperative adhesions

Postoperative adhesions occur widely in various tissues, bringing the risk of secondary surgery and increased medical burden. Hydrogel barriers with Janus-adhesive ability can achieve physical isolation of adjacent tissues and are therefore considered an ideal solution. However, integrating endoscopic delivery convenience and viscoelastic Janus hydrogel formation remains a great challenge. Here, we present a report of the insitu formation of Janus-adhesive hydrogel barrier using a sprayable fast-Janus-gelation (FJG) powder. We first methacrylate the polysaccharide macromolecules to break the intermolecular hydrogen bonds and impart the ability of rapid hydration. FJG powder can rapidly absorb interfacial water and crosslink through borate ester bonds, forming a toughly adhesive viscoelastic hydrogel. The Janus barrier can be simply formed by further hydrating the upper powder with cationic solution. We construct rat models to demonstrate the antiadhesions efficiency of viscoelastic FJG hydrogels in organs with different motion modalities (e.g., intestine, heart, liver). We also developed a low-cost delivery device with a standardized surgical procedure and further validated the feasibility and effectiveness of FJG powder in minimally invasive surgery using a preclinical translational porcine model. Considering the advantages in terms of therapeutic efficacy, clinical convenience, and commercialization, our results reveal the great potential of Janus-gelation powder materials as a next-generation antiadhesions barrier.

Feasibility study using longitudinal bioelectrical impedance analysis to evaluate body water status during fluid resuscitation in a swine sepsis model

Fluid resuscitation is crucial in the initial management of sepsis; however, little is known about the serial changes and overall distribution of fluids administered into the body. To identify the feasibility of longitudinal bioelectrical impedance analysis during fluid treatment, a preclinical porcine model of Escherichia coli-induced sepsis was used. After sepsis induction, pigs were treated with fluid and vasopressors and monitored for up to 12 h after bacterial infusion or until death. Bipolar electrodes for bioelectrical impedance analysis were attached to the left extremities and measurements were performed every 10 min. Among the 12 subjects, 7 pigs expired during the experiment, and the median survival was 9.5 h. As sepsis progressed with an increase in cumulative fluid balance, R0 [∝ 1/extracellular water (ECW)] decreased, while Ri [∝ 1/intracellular water (ICW)] and ratio of extracellular water to total body water (ECW/TBW) increased. The phase angle constantly decreased throughout the monitoring period, and all non-survivors died when the phase angle decreased by more than 10%. Among the variables, ΔR0 and Δphase angle showed moderate negative correlations, and ΔECW/TBW showed a moderate positive correlation with the hourly fluid balance. Compared to survivors, a greater increase in ΔECW/TBW and a decrease in phase angle were observed in non-survivors over time, with an increase in cumulative fluid balance. Differences in ΔECW/TBW and phase angle emerged at 240 min when the difference in cumulative fluid balance between the two groups (survivors vs non-survivors) exceeded 1000 mL. In conclusion, continuous measurements of bioelectrical impedance analysis in a porcine sepsis model are feasible and may reflect changes in the body water profile during fluid resuscitation.

OC-070 A NOVEL SELF-GRIPPING LONG-TERM RESORBABLE MESH PROVIDING TEMPORARY SUPPORT FOR PRIMARY VENTRAL AND INCISIONAL HERNIA

Abstract Medtronic recently developed a novel synthetic fully long-term resorbable self-gripping mesh to reinforce soft tissue where weakness exists during ventral hernia repair procedures. This resorbable mesh is a macroporous, knitted, poly-L-lactide, poly-trimethylene carbonate copolymer monofilament mesh with the ProGrip™ technology. The biocompatibility profile of the mesh has been extensively established and documented. No systemic nor local adverse reactions have been observed from implantation to complete resorption and metabolization of the mesh in a subcutaneous implantation preclinical rabbit model. Its performance was evaluated at 20 weeks using a modified published preclinical porcine model of hernia repair (Martin, 2013; Deeken, 2013). Histologic examination of the implantation sites confirmed that this novel mesh was well tolerated and led to new extracellular collagen matrix formation. The burst strength of the hernia repair sites reinforced with the new mesh was statistically equivalent to the one of the native abdominal walls. Currently marketed ProGrip™ meshes have been clinically and successfully used with less mechanical fixation devices than non-self-gripping meshes (Chastan, 2009; Rangwani, 2021). The new self-gripping long-term resorbable mesh fixation performance was demonstrated to be statistically equivalent to the one of ProGrip™ Self-Gripping Polyester Mesh both in ex-vivo testing and in an in vivo porcine model. This should support the ease-of-use feature of the mesh with a limited need for additional mechanical fixation, which will likely be associated with a shorter surgical time. The preclinical tests of the self-gripping resorbable mesh are compelling enough to make it a new mesh candidate for future clinical use.

234.11: Impact of Hypothermic Oxygenated PErfusion (HOPE) During Hypothermic Preservation and Normothermic Reperfusion in a Preclinical Porcine Model of Pancreatic Transplantation

234.11: Impact of Hypothermic Oxygenated PErfusion (HOPE) During Hypothermic Preservation and Normothermic Reperfusion in a Preclinical Porcine Model of Pancreatic Transplantation

214.7: Impact of Hypothermic Oxygenated Perfusion (HOPE) on Endothelial Cell Biology in a Preclinical Porcine Model of Pancreatic Transplantation

214.7: Impact of Hypothermic Oxygenated Perfusion (HOPE) on Endothelial Cell Biology in a Preclinical Porcine Model of Pancreatic Transplantation

197. Subtherapeutic perioperative levels of cefuroxime inside cannulated pedicle screw commonly used in spine surgery: results from an experimental microdialysis study

BACKGROUND CONTEXT Despite minimal invasive spine techniques, postoperative implant associated vertebral osteomyelitis remains a risk of great morbidity for the patient. Perioperative antibiotic prophylaxis is important for prevention of postoperative infection and local tissue concentrations can be measured with microdialysis. We hypothesized that cefuroxime concentrations in relation to a cannulated pedicle screws may be insufficient for prevention of postoperative infection. PURPOSE The aim was to compare perioperative cefuroxime concentrations inside a cannulated pedicle screw to the adjacent noninstrumented lumbar vertebral pedicle. STUDY DESIGN/SETTING In vivo experimental pharmacokinetics study of cefuroxime concentrations in an acute preclinical porcine model. PATIENT SAMPLE Not applicable. OUTCOME MEASURES The primary end-point was the time above cefuroxime clinical breakpoint minimal inhibitory concentration for Staphylococcus aureus of 4 µg/mL (T>MIC4) METHODS Microdialysis probes were placed in a cannulated pedicle screw and the adjacent non-instrumented lumbar vertebral pedicle (L1) in 8 female pigs through a surgical posterior open lumbar approach. Following a single-dose intravenous cefuroxime administration (1.5 g), microdialysates and plasma were dynamically sampled over 8 hours. RESULTS Mean T>MIC4 (range) was 123 min (112-175) in plasma, 101 min (68-144) in the non-instrumented vertebral pedicle and 0 min (0-0) inside the cannulated pedicle screw. CONCLUSIONS A single-dose intravenous cefuroxime administration (1.5 g) seems insufficient for antibiotic prophylaxis inside a cannulated pedicle screw placed in the lumbar spine. Sufficient concentrations were achieved in the adjacent non-instrumented vertebral pedicle for up to 1.5-2 hours. Therefore, alternative dosing regimens should be considered in minimal invasive spine surgery longer than 1.5 hours and additional prophylactic strategies against infection may be applied in high-risk patients. FDA DEVICE/DRUG STATUS Cefuroxime (Approved for this indication) Despite minimal invasive spine techniques, postoperative implant associated vertebral osteomyelitis remains a risk of great morbidity for the patient. Perioperative antibiotic prophylaxis is important for prevention of postoperative infection and local tissue concentrations can be measured with microdialysis. We hypothesized that cefuroxime concentrations in relation to a cannulated pedicle screws may be insufficient for prevention of postoperative infection. The aim was to compare perioperative cefuroxime concentrations inside a cannulated pedicle screw to the adjacent noninstrumented lumbar vertebral pedicle. In vivo experimental pharmacokinetics study of cefuroxime concentrations in an acute preclinical porcine model. Not applicable. The primary end-point was the time above cefuroxime clinical breakpoint minimal inhibitory concentration for Staphylococcus aureus of 4 µg/mL (T>MIC4) Microdialysis probes were placed in a cannulated pedicle screw and the adjacent non-instrumented lumbar vertebral pedicle (L1) in 8 female pigs through a surgical posterior open lumbar approach. Following a single-dose intravenous cefuroxime administration (1.5 g), microdialysates and plasma were dynamically sampled over 8 hours. Mean T>MIC4 (range) was 123 min (112-175) in plasma, 101 min (68-144) in the non-instrumented vertebral pedicle and 0 min (0-0) inside the cannulated pedicle screw. A single-dose intravenous cefuroxime administration (1.5 g) seems insufficient for antibiotic prophylaxis inside a cannulated pedicle screw placed in the lumbar spine. Sufficient concentrations were achieved in the adjacent non-instrumented vertebral pedicle for up to 1.5-2 hours. Therefore, alternative dosing regimens should be considered in minimal invasive spine surgery longer than 1.5 hours and additional prophylactic strategies against infection may be applied in high-risk patients.

10. Incomplete cefuroxime penetration to the anterior and posterior column of the lumbar spine: an experimental porcine study

BACKGROUND CONTEXT Surgical site infection following spine surgery is associated with increased morbidity and mortality. Perioperative antibiotic prophylaxis is a key factor in lowering the risk of acquiring an infection. Previous studies have assessed perioperative cefuroxime concentrations in the anterior column of the cervical spine with an anterior surgical approach. However, the majority of surgeries are performed in the posterior column and many surgeries involve the lumbar spine. PURPOSE The objective of this study was to compare the perioperative tissue concentrations of cefuroxime in the anterior and posterior column during lumbar spine surgery with a posterior surgical approach. STUDY DESIGN/SETTING In vivo experimental pharmacokinetics study of cefuroxime concentrations in an acute preclinical porcine model. OUTCOME MEASURES The primary end-point was the time above cefuroxime clinical breakpoint minimal inhibitory concentration (T>MIC) for Staphylococcus aureus of 4 µg/mL. The secondary end-point was tissue penetration (AUCtissue/AUCplasma). METHODS The lumbar vertebral column was exposed from L1 to L5 in eight female pigs. Microdialysis catheters were placed for sampling in the anterior column (vertebral body) and posterior column (posterior arch) within the same vertebra (L5). Cefuroxime (1.5 g) was administered intravenously. Microdialysates and plasma samples were continously obtained over eight hours. Cefuroxime concentration were quantified by ultra high-performance liquid chromatography tandem mass spectrometry. RESULTS Mean T>MIC 4 µg/mL (95% confidence interval) was 123 min (105-141) in plasma, 97 min (79-115) in the anterior column and 93 min (75-111) in the posterior column. Tissue penetration (95% confidence interval) was incomplete for both the anterior column 0.48 (0.40-0.56) and posterior column 0.40 (0.33-0.48). CONCLUSIONS T>MIC was comparable between the anterior and posterior column. Mean cefuroxime concentrations decreased below the clinical breakpoint MIC for S. aureus of 4 µg/mL after 123 min (plasma), 97 min (anterior column) and 93 min (posterior column). Open lumbar spine surgery often involves extensive soft tissue dissection, stripping and retraction of the paraspinal muscles which may impair the local blood flow exposing the lumbar vertebra to postoperative infections. A single intravenous administration of 1.5 g cefuroxime only provided sufficient prophylactic target tissue concentrations in the vertebrae of the lumber spine for up to 1.5 hours. This is shorter than the duration of most lumbar spine surgeries, and therefore alternative dosing regimens should be considered in posterior open lumbar spine surgeries lasting more than 1.5 hours. FDA DEVICE/DRUG STATUS cefuroxime (Approved for this indication). Surgical site infection following spine surgery is associated with increased morbidity and mortality. Perioperative antibiotic prophylaxis is a key factor in lowering the risk of acquiring an infection. Previous studies have assessed perioperative cefuroxime concentrations in the anterior column of the cervical spine with an anterior surgical approach. However, the majority of surgeries are performed in the posterior column and many surgeries involve the lumbar spine. The objective of this study was to compare the perioperative tissue concentrations of cefuroxime in the anterior and posterior column during lumbar spine surgery with a posterior surgical approach. In vivo experimental pharmacokinetics study of cefuroxime concentrations in an acute preclinical porcine model. The primary end-point was the time above cefuroxime clinical breakpoint minimal inhibitory concentration (T>MIC) for Staphylococcus aureus of 4 µg/mL. The secondary end-point was tissue penetration (AUCtissue/AUCplasma). The lumbar vertebral column was exposed from L1 to L5 in eight female pigs. Microdialysis catheters were placed for sampling in the anterior column (vertebral body) and posterior column (posterior arch) within the same vertebra (L5). Cefuroxime (1.5 g) was administered intravenously. Microdialysates and plasma samples were continously obtained over eight hours. Cefuroxime concentration were quantified by ultra high-performance liquid chromatography tandem mass spectrometry. Mean T>MIC 4 µg/mL (95% confidence interval) was 123 min (105-141) in plasma, 97 min (79-115) in the anterior column and 93 min (75-111) in the posterior column. Tissue penetration (95% confidence interval) was incomplete for both the anterior column 0.48 (0.40-0.56) and posterior column 0.40 (0.33-0.48). T>MIC was comparable between the anterior and posterior column. Mean cefuroxime concentrations decreased below the clinical breakpoint MIC for S. aureus of 4 µg/mL after 123 min (plasma), 97 min (anterior column) and 93 min (posterior column). Open lumbar spine surgery often involves extensive soft tissue dissection, stripping and retraction of the paraspinal muscles which may impair the local blood flow exposing the lumbar vertebra to postoperative infections. A single intravenous administration of 1.5 g cefuroxime only provided sufficient prophylactic target tissue concentrations in the vertebrae of the lumber spine for up to 1.5 hours. This is shorter than the duration of most lumbar spine surgeries, and therefore alternative dosing regimens should be considered in posterior open lumbar spine surgeries lasting more than 1.5 hours.

Resuscitation with whole blood or blood components improves survival and lessens the pathophysiological burden of trauma and haemorrhagic shock in a pre-clinical porcine model

PurposeIn military trauma, disaster medicine, and casualties injured in remote locations, times to advanced medical and surgical treatment are often prolonged, potentially reducing survival and increasing morbidity. Since resuscitation with blood/blood components improves survival over short pre-surgical times, this study aimed to evaluate the quality of resuscitation afforded by blood/blood products or crystalloid resuscitation over extended ‘pre-hospital’ timelines in a porcine model of militarily relevant traumatic haemorrhagic shock.MethodsThis study underwent local ethical review and was done under the authority of Animals (Scientific Procedures) Act 1986. Forty-five terminally anaesthetised pigs received a soft tissue injury to the right thigh, haemorrhage (30% blood volume and a Grade IV liver injury) and fluid resuscitation initiated 30 min later [Group 1 (no fluid); 2 (0.9% saline); 3 (1:1 packed red blood cells:plasma); 4 (fresh whole blood); or 5 (plasma)]. Fluid (3 ml/kg bolus) was administered during the resuscitation period (maximum duration 450 min) when the systolic blood pressure fell below 80 mmHg. Surviving animals were culled with an overdose of anaesthetic.ResultsSurvival time was significantly shorter for Group 1 compared to the other groups (P < 0.05). Despite the same triggers for resuscitation when compared to blood/blood components, saline was associated with a shorter survival time (P = 0.145), greater pathophysiological burden and significantly greater resuscitation fluid volume (P < 0.0001).ConclusionWhen times to advanced medical care are prolonged, resuscitation with blood/blood components is recommended over saline due to the superior quality and stability of resuscitation achieved, which are likely to lead to improved patient outcomes.

Cefuroxime concentrations in the anterior and posterior column of the lumbar spine – an experimental porcine study

BACKGROUND CONTEXTSurgical site infection following spine surgery is associated with increased morbidity and mortality. Perioperative antibiotic prophylaxis is a key factor in lowering the risk of acquiring an infection. Previous studies have assessed perioperative cefuroxime concentrations in the anterior column of the cervical spine with an anterior surgical approach. However, the majority of surgeries are performed in the posterior column and many surgeries involve the lumbar spine. PURPOSEThe objective of this study was to compare the perioperative tissue concentrations of cefuroxime in the anterior and posterior column during lumbar spine surgery with a posterior surgical approach. STUDY DESIGNIn vivo experimental pharmacokinetic study of cefuroxime concentrations in an acute preclinical porcine model. METHODSThe lumbar vertebral column was exposed from L1 to L5 in 8 female pigs. Microdialysis catheters were placed for sampling in the anterior column (vertebral body) and posterior column (posterior arch) within the same vertebra (L5). Cefuroxime (1.5 g) was administered intravenously. Microdialysates and plasma samples were continuously obtained over 8 hours. Cefuroxime concentrations were quantified by Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry. The primary endpoint was the time above the cefuroxime clinical breakpoint minimal inhibitory concentration (T>MIC) for Staphylococcus aureus of 4 µg/mL. The secondary endpoint was tissue penetration (AUCtissue/AUCplasma). RESULTSMean T>MIC 4 µg/mL (95% confidence interval) was 123 min (105–141) in plasma, 97 min (79–115) in the anterior column and 93 min (75–111) in the posterior column. Tissue penetration (95% confidence interval) was incomplete for both the anterior column 0.48 (0.40–0.56) and posterior column 0.40 (0.33–0.48). CONCLUSIONST>MIC was comparable between the anterior and posterior column. Mean cefuroxime concentrations decreased below the clinical breakpoint minimal inhibitory concentration for S. aureus of 4 µg/mL after 123 minutes (plasma), 97 minutes (anterior column) and 93 minutes (posterior column). This is shorter than the duration of most lumbar spine surgeries, and therefore alternative dosing regimens should be considered in posterior open lumbar spine surgeries lasting more than 1.5 hours. CLINICAL SIGNIFICANCEOpen lumbar spine surgery often involves extensive soft tissue dissection, stripping and retraction of the paraspinal muscles which may impair the local blood flow exposing the lumbar vertebra to postoperative infections. A single intravenous administration of 1.5 g cefuroxime only provided sufficient prophylactic target tissue concentrations in the vertebra of the lumbar spine for up to 1.5 hours.

A step forward toward establishing a novel preclinical porcine model to study ischemia/reperfusion-induced acute and chronic kidney injures

A step forward toward establishing a novel preclinical porcine model to study ischemia/reperfusion-induced acute and chronic kidney injures