The presence of an Emergency Airway Response Team and its effects on in-hospital Code Blue

The survival rate from in-hospital cardiac arrest due to pulseless electrical activity (PEA)/asystole in our institution was higher than expected (70%). It was the impression of the Emergency Department-led Code Blue Team (CBT) that many of these patients were actually suffering respiratory arrests before their cardiac events. To address this, the facility developed an early intervention team focused on early airway intervention-the Emergency Airway Response Team (EART). The objective of this study was to assess the effect of early intervention in patients during the "pre-Code Blue" period, specifically with regard to airway stabilization. Our hypothesis was that there would be fewer CBT calls (cardiac arrests) due to PEA and asystole and that the survival from these events would decrease. This was a retrospective review of all cardiac arrests responded to by the CBT and EART for a period of 2 years. Charts were reviewed for the initial presenting rhythm (as defined by the Utstein Format) and event survival for the 12-month period immediately before and immediately after the establishment of the EART (Time Periods 1 and 2, respectively). The total number of CBT calls decreased by 15%, return of spontaneous circulation from any rhythm decreased by 9%, and survival to discharge decreased by 8% (p = non-significant). The number of CBT calls specifically for asystole/PEA decreased by 8%. Deaths in hospital were significantly associated with Period 2 (odds ratio 1.84; 95% confidence interval 1.03-3.28) after adjusting for age, gender, and presenting rhythms. The total number of CBT calls decreased slightly with the creation of the Emergency Airway Response Team. Return of spontaneous circulation and survival to hospital discharge after cardiac arrest due to asystole/PEA were significantly decreased, suggesting early intervention may have benefit.     

The effects of lentiviral gene therapy with bone morphogenetic protein-2-producing bone marrow cells on spinal fusion in rats

STUDY DESIGN: Rat spinal fusion model. OBJECTIVE: This study aimed to assess the ability of rat bone marrow cells (RBMCs) transfected with bone morphogenetic protein (BMP)-2-containing lentivirus to induce a posterolateral spinal fusion in a rat model. SUMMARY OF BACKGROUND DATA: Spinal arthrodesis is a commonly performed spinal procedure and autograft remains the standard for achieving spinal fusion. However, its procurement is associated with significant morbidity, and the rate of pseudoarthrosis has been reported to be 5% to 43%. Nonunion frequently leads to an unsatisfactory resolution of clinical symptoms and usually results in high medical costs and morbidity as well as the need for additional surgeries. These problems have led surgeons to search for alternative solutions to stimulate bone formation. Recombinant BMPs have also been used successfully in clinical trials. However, large doses of BMPs were required to induce adequate bone repair. The development of a regional gene therapy may be a more efficient method to deliver proteins to a specific anatomic site. Furthermore, adeno-BMP-2-producing rat bone marrow-derived cells have been used successfully to induce posterior spinal fusion. Recently, lentiviral vectors on the basis of human immunodeficiency virus have been developed for gene therapy. Lentiviruses are capable of insertion into the host genome, ensuring a prolonged gene expression. However, safety issues are a major concern when adopting these vectors for clinical use. METHODS: In vitro study, we used RBMCs transfected with lentivirus vectors encoding BMP-2 (Lenti-BMP-2), RBMCs transfected with lentivirus vectors encoding the green fluorescent protein (GFP) (Lenti-GFP), and untransfected RBMCs; the latter 2 were used as controls. Alkaline phosphatase (ALP) staining and ALP activity were compared between the groups to assess the ability of the Lenti-BMP-2-transfected RBMCs to stimulate osteoblastic differentiation. In the rat posterolateral spine fusion model, the experimental study comprised 4 groups. Group 1 comprised 6 animals that were implanted with a collagen sponge containing 5 million RBMCs transfected with Lenti-BMP-2. Group 2 comprised 3 animals that were implanted with a collagen sponge containing 5 million RBMCs transfected with Lenti-GFP. Group 3 comprised 6 animals that were implanted with a collagen sponge containing 5 million untransfected RBMCs. Group 4 comprised 3 animals that were implanted with a collagen sponge alone. The rats were assessed by radiographs obtained at 4, 6, and 8 weeks. After death, their spines were explanted and assessed by manual palpation, high-resolution microcomputerized tomography, and histologic analysis. RESULTS: The ALP staining was significantly greater in the Lenti-BMP-2-transfected RBMCs than in the untransfected RBMCs and the Lenti-GFP-transfected RBMCs. The ALP activity was 3-fold greater in the Lenti-BMP-2-transfected RBMCs than in the untransfected RBMCs and the Lenti-GFP-transfected RBMCs. In the rat spine fusion model, radiographic evaluation, high-resolution microcomputerized tomography, and manual palpation revealed spinal fusion in all the rats in Group 1 at 8 weeks. Groups 2, 3, and 4 comprised the control group. None of the rats in the control group (0 of 12) developed fusion at L4-L5. CONCLUSIONS: The present study demonstrated that BMP-2-producing RBMCs, created through lentiviral gene transfer, induced sufficient spinal fusion. The use of lentiviral vectors that contain the cDNA for BMP-2 will be a novel and promising approach for a spinal fusion strategy.     

Enhanced effects of BMP‐binding peptide combined with recombinant human BMP‐2 on the healing of a rodent segmental femoral defect

BMP‐binding peptide (BBP) enhances the osteogenic activity of recombinant human bone morphogenetic protein‐2 (rhBMP‐2), but the mechanism underlying the enhancement remains unclear. We aimed to elucidate the potential enhanced efficacy of BBP using critical‐sized segmental femoral bone defects in rats. Seventy defects in seven groups of rats were filled with various amounts (0, 2, 5, and 10 µg) of rhBMP‐2 with or without 1000 µg BBP. Radiographs were obtained after 4 and 8 weeks. The animals were euthanized at 8 weeks, and femoral specimens were assessed manually, evaluated for bone volume using microcomputed tomography, and subjected to histological or biomechanical analysis. Although 10 µg rhBMP‐2 yielded consistent results in terms of bone healing and quality of bone repair across the segmental defect, lower doses of rhBMP‐2 failed to induce satisfactory bone healing. However, the combined administration of lower doses of rhBMP‐2 and BBP induced the formation of significantly large amounts of bone. Our results suggest that the combined administration of rhBMP‐2 and BBP facilitates bone healing and has potential clinical applications. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:258–264, 2010     

Carboxy terminus of secreted phosphoprotein‐24 kDa (spp24) is essential for full inhibition of BMP‐2 activity

Secreted phosphoprotein‐24 kDa (spp24) is a bone morphogenetic protein (BMP)‐binding protein isolated from bone. It exists in a number of size forms and is hypothesized to function as a BMP latency protein and/or a “slow release” mechanism for BMPs involved in bone turnover and repair. We have examined the hypothesis that proteolytic modification of the C‐terminus of spp24 affects its BMP‐2–binding properties and bioactivity in the BMP‐2–stimulated ectopic bone forming bioassay. Three different size forms of recombinant spp24 that correspond to predicted 18.1 kDa, 16.0 kDa, and 14.5 kDa proteolytic products were compared to full‐length (fl) spp24. One of these forms (spp18.1) we hypothesize to be the protein which Urist initially, but apparently inaccurately, called “BMP.” Only full‐length spp24 completely inhibited BMP‐2–induced bone formation. The 18.1 kDa truncated isoform of spp24 which we hypothesize to be Urist's protein did not. The inhibitory capacity of the proteins was correlated with their kinetic constants, assessed by surface plasmon resonance. At the highest, inhibitory, dose of spp24 and its derivatives, k_d (“stability”) best predicted the extent of ectopic bone formation whereas at the lowest dose, which was not inhibitory, k_a (“recognition”) best predicted the extent of ectopic bone formation. We conclude that proteolytic processing of spp24 affects the interaction of this protein with BMP‐2 and this affects the function of the protein. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1200–1207, 2010     

A porcine collagen-derived matrix as a carrier for recombinant human bone morphogenetic protein-2 enhances spinal fusion in rats

Background contextRecombinant bone morphogenetic proteins (rhBMPs) have been used successfully in clinical trials. However, large doses of rhBMPs were required to induce adequate bone repair. Collagen sponges (CSs) have failed to allow a more sustained release of rhBMPs. Ongoing research aims to design carriers that allow a more controlled and sustained release of the protein. E-Matrix is a injectable scaffold matrix that may enhance rhBMP activity and stimulate bone regeneration.PurposeThe purpose of this study was to test E-Matrix as a carrier for rhBMPs in a CS and examine its feasibility in clinical applications by using a rat spinal fusion model.Patient sampleA total of 80 Lewis rats aged 8–16 weeks were divided into nine groups.Study design/settingRat spinal fusion model.Outcome measuresRadiographs were obtained at 4, 6, and 8 weeks. The rats were sacrificed and their spines were explanted and assessed by manual palpation, high-resolution microcomputed tomography (micro-CT), and histologic analysis.MethodsGroup I animals were implanted with CS alone (negative control); Group II animals with CS containing 10 μg rhBMP-2 (positive control); Group III animals with CS containing 3 μg rhBMP-2; Group IV animals with CS containing 3 μg rhBMP-2 and E-Matrix; Group V animals with CS containing 1 μg rhBMP-2; Group VI animals with CS containing 1 μg rhBMP-2 and E-Matrix; Group VII animals with CS containing 0.5 μg rhBMP-2; Group VIII animals with CS containing 0.5 μg rhBMP-2 and E-Matrix; and Group IX animals with CS and E-Matrix without rhBMP-2.ResultsRadiographic evaluation, micro-CT, and manual palpation revealed spinal fusion in all rats in the BMP-2 and E-Matrix groups (IV, VI, and VIII) and high-dose BMP-2 groups (II and III). Four spines in the 3 μg rhBMP-2 group (V) fused, and one spine in the 0.5 μg rhBMP-2 group (VII) exhibited fusion. No spines were fused in Groups I (CS alone) and IX (E-Matrix alone). The volume of new bone in the area between the tip of the L4 transverse process and the base of the L5 transverse process in Group IV was equivalent to the volumes observed in Group II.ConclusionE-matrix enhances spinal fusion as a carrier for rhBMP-2 in a rat spinal fusion model. The results of this study suggest that E-Matrix as a growth factor carrier may be applicable to spinal fusion and may improve rhBMP-2's activity at the fusion site.