Whole blood in prehospital damage control resuscitation : -Safety, feasibility, and logistics

Bakgrunn De siste tiårene har det vært et paradigmeskifte i behandlingen av blødningsjokk. Skadebegrensende resuscitering har som hensikt å understøtte hemostatisk evne hos pasienten og reversere og dempe konsekvensene av sjokk slik at pasienten har tilstrekkelige fysiologiske reserver til å overleve påfølgende behandling i sykehus. Strategien baserer seg i all hovedsak på å starte tidlig behandling med blod og blodprodukter. I økende grad har sivile og militære prehospitale tjenester vurdert fullblod som et alternativ for den intiale resusciteringen av blødningsjokk. Selv om fullblod har tiltalende egenskaper er det flere utfordringer ved implementering av fullblod i et prehospitalt system. Forhold knyttet til sikkerhet, logistikk, lagring og praktisk bruk bør evalueres. Mål Å undersøke og evaluere implementeringen av et program for implementering av prehospitalt lavtiter gruppe O fullblod (LTOWB). Metode Paper I undersøkte gjennomførbarhet, sikkerheten og effektivitet av intraossøs sternal autolog re-infusjon av varmt friskt fullblod (WFWB) i en prospektiv human komparativ studie. Paper II undersøkte ex vivo kvaliteten til lav titer type O fullblod (LTOWB) under fremskutt lagring i opptil 21 dager i en lufttett temperaturregulert beholder ved en luftambulansebase sammenlignet med LTOWB lagret i blodbanken. Paper III identifiserte nåværende prehospitale blodtransfusjonsprogrammer, fremtidige behov og potensielle barriærer for implementering av LTOWB i en spørreundersøkelse blant medisinsk ansvarligeleger ved luft og redningshelikoptertjenestene i Norge. Paper IV beskrev implementeringen av et LTOWB-transfusjonsprogram i Luftambulansetjenesten i Bergen i perioden 2015-2020 i en prospektiv observasjonsstudie. Resultater Det var ingen hemolyse etter sternal intraossøs re-infusjon av fullblod. Median infusjonshastighet var 46,2 ml/min for FAST-1-IO nålen, og feilraten ved innleggelse av IO tilgangen for uerfarent personell var 9 %. Fremskutt lagring av LTOWB opptil 21 dager førte ikke til konsekvenser som kan true pasientsikkerheten. Blodet tilfredstilte EU krav i hele lagringsperioden. Det var ingen signifikante forskjeller i de hematologiske variablene, blodplateaggregering eller viskoelastiske egenskaper mellom blod lagret fremskutt og blod lagret i blodbanken. Alle luft og redningshelikopter i Norge har blodprodukter tilgjengelig. Fire av 20 (20 %) har implementert LTOWB. Et flertall av tjenestene har en preferanse for LTOWB siden dette muliggjør tidlig balansert transfusjon og kan ha logistiske fordeler i tidskritiske situasjoner. Blodbanker som leverer LTOWB rapporterer gunstige erfaringer. I løpet av 2015-2020 responderte Luftambulansen i Bergen til 5124 pasienter. Syttito (1,4%) mottok blodtransfusjon. 52 pasientene samtykket til deltagelse i studien. Av disse fikk 48 LTOWB. Førtiseks (88 %) ble innlagt på sykehuset i live, og 76 % av disse fikk ytterligere transfusjoner i løpet av de første 24 timene. De fleste pasienter presenterte med stump skademekanikk (69 %), etterfulgt av blødninger som ikke var relatert til traumer (29 %). Totalt overlevde 36 (69%) 24 timer, og 28 (54%) overlevde 30 dager. Ingen transfusjonsreaksjoner eller logistiske problemer ble rapportert. Konklusjon Intraossøs infusjon av WFWB er trygt, pålitelig og gir tilstrekkelig flow for den initielle resuscitering ved blødningsjokk. Fremskutt lagring av LTOWB i Luftambulansetjenesten er gjennomførbart og trygt. Kvalitet tilfredstiller EU krav opptil 21 dagers lagring, og hemostatiske egenskaper e LTOWB sammenlingbar med LTOWB lagret i blodbanken. Luftambulansetjenestene og blodbankene som leverer LTOWB har gode erfaringer med implementering av LTOWB. Våre undersøkelser viser at implementering av et prehospitalt transfusjonsprogram med fullblod er mulig og sikkert. Det er videre behov for studier som ser på effektiviteten av fullblod sammenlignet med blodkomponenter.Background In the last two decades, resuscitation of hemorrhagic shock has undergone a paradigm shift. Modern damage control resuscitation strategies aim to improve outcomes by facilitating early hemostatic resuscitation with blood and blood products. The ultimate goal is to prevent, reverse or mitigate the severity and duration of shock and its consequences until definitive hemorrhage control can be achieved. As a result, both civilian and military EMS systems are considering whole blood for prehospital resuscitation of hemorrhagic shock. Although appealing, establishing a robust system for forward resuscitation with whole blood is challenging as several vital factors regarding safety, logistics, and implementation barriers need to be considered. Aim To investigate and evaluate the implementation of a pre-hospital low titer group O whole blood (LTOWB) transfusion program. Methods Paper I investigated the feasibility, safety, and efficacy of autologous re-infusion of warm fresh whole blood (WFWB) through an intraosseous sternal device in a prospective human comparative study. Paper II investigated the ex vivo quality of LTOWB during storage for up to 21 days in an airtight thermal container at a helicopter emergency medical system (HEMS) base compared to LTOWB stored in the blood bank. Paper III identified current pre-hospital blood transfusion programs, future needs, and potential obstacles in implementing LTOWB in a national survey among the medical directors of the Norwegian HEMS and Search and Rescue (SAR) helicopter bases. Finally, in a prospective observational study, paper IV described and evaluated the implementation of a LTOWB program in one of the Norwegian HEMS services in 2015-2020. Results There was no evidence of hemolysis following sternal intraosseous re-infusion of whole blood. The median infusion rate was 46.2mL/min for the FAST-1 device, and the failure rate for inexperienced personnel was 9%. Storage of LTOWB complied with the EU regulations throughout remote and in- hospital storage for 21 days. In addition, there were no significant differences in hematology variables, platelet aggregation, or viscoelastic properties between blood stored remotely and in the blood bank. All HEMS and SAR helicopter services in Norway carry LTOWB or blood components. A majority of services have a preference for LTOWB because LTOWB enables early balanced transfusion and may have logistical benefits in time-critical emergencies. This far, four of 20 (20%) have implemented LTOWB. Blood banks and services that provide LTOWB report favorable experiences. During the five years, the Bergen HEMS in study IV responded to 5124 patients. Seventy-two (1.4%) were transfused. Twenty patients were excluded mainly due to a lack of informed consent. Of the 52 patients, 48 received LTOWB. Forty-six (88%) were admitted to the hospital alive, and 76% of these received additional transfusions during the first 24 hours. Most patients presented with blunt trauma mechanisms (69%), followed by hemorrhage unrelated to trauma (29%). Overall 36 (69%) survived 24 hours, and 28 (54%) survived 30 days. No suspected transfusion reactions or logistical issues were reported. Conclusion WFWB transfusion through the IO route is safe, reliable, and provides sufficient flow for the initial resuscitation of hemorrhagic shock. Storage of LTOWB in thermal containers in a pre-hospital HEMS service is feasible and safe. Hemostatic properties are present for up to 21 days of storage and are similar to LTOWB stored in the blood bank. HEMS services and blood banks report favorable experiences implementing and utilizing LTOWB in Norway. The logistics of LTOWB emergency transfusions are manageable and safe in a Norwegian HEMS service.Doktorgradsavhandlin

Prehospital Whole Blood Transfusion Programs in Norway

Background: Prehospital management of severe hemorrhage has evolved significantly in Norwegian medical emergency services in the last 10 years. Treatment algorithms for severe bleeding were previously focused on restoration of the blood volume by administration of crystalloids and colloids, but now the national trauma system guidelines recommend early balanced transfusion therapy according to remote damage control resuscitation principles. Materials and Methods: This survey describes the implementation, utilization, and experience of the use of low titer group O whole blood (LTOWB) and blood components in air ambulance services in Norway. Medical directors from all air ambulance bases in Norway as well as the blood banks that support LTOWB were invited to participate. Results: Medical directors from all 13 helicopter emergency medical services (HEMS) bases, the 7 search and rescue (SAR) helicopter bases, and the 4 blood banks that support HEMS with LTOWB responded to the survey. All HEMS and SAR helicopter services carry LTOWB or blood components. Four of 20 (20%) HEMS bases have implemented LTOWB. A majority of services (18/20, 90%) have a preference for LTOWB, primarily because LTOWB enables early balanced transfusion and has logistical benefits in time-critical emergencies and during prolonged evacuations. Conclusion: HEMS services and blood banks report favorable experiences in the implementation and utilization of LTOWB. Prehospital balanced blood transfusion using whole blood is feasible in Norway.publishedVersio

Practical considerations for omics experiments in biomedical sciences

Modern analytical techniques provide an unprecedented insight to biomedical samples, allowing an in depth characterization of cells or body fluids, to the level of genes, transcripts, peptides, proteins, metabolites, or metallic ions. The fine grained picture provided by such approaches holds the promise for a better understanding of complex pathologies, and consequently the personalization of diagnosis, prognosis and treatment procedures. In practice however, technical limitations restrict the resolution of the acquired data, and thus of downstream biomedical inference. As a result, the study of complex diseases like leukemia and other types of cancer is impaired by the high heterogeneity of pathologies as well as patient profiles. In this review, we propose an introduction to the general approach of characterizing samples and inferring biomedical results. We highlight the main limitations of the technique with regards to complex and heterogeneous pathologies, and provide ways to overcome these by improving the ability of experiments in discriminating samples.acceptedVersio

Current landscape and future perspectives in preclinical MR and PET imaging of brain metastasis

Brain metastasis (BM) is a major cause of cancer patient morbidity. Clinical magnetic resonance imaging (MRI) and positron emission tomography (PET) represent important resources to assess tumor progression and treatment responses. In preclinical research, anatomical MRI and to some extent functional MRI have frequently been used to assess tumor progression. In contrast, PET has only to a limited extent been used in animal BM research. A considerable culprit is that results from most preclinical studies have shown little impact on the implementation of new treatment strategies in the clinic. This emphasizes the need for the development of robust, high-quality preclinical imaging strategies with potential for clinical translation. This review focuses on advanced preclinical MRI and PET imaging methods for BM, describing their applications in the context of what has been done in the clinic. The strengths and shortcomings of each technology are presented, and recommendations for future directions in the development of the individual imaging modalities are suggested. Finally, we highlight recent developments in quantitative MRI and PET, the use of radiomics and multimodal imaging, and the need for a standardization of imaging technologies and protocols between preclinical centers.publishedVersio

Remission of Invasive, Cancer Stem-Like Glioblastoma Xenografts Using Lentiviral Vector-Mediated Suicide Gene Therapy

Background: Glioblastoma is the most frequent and most malignant primary brain tumor with a poor prognosis. The translation of therapeutic strategies for glioblastoma from the experimental phase into the clinic has been limited by insufficient animal models, which lack important features of human tumors. Lentiviral gene therapy is an attractive therapeutic option for human glioblastoma, which we validated in a clinically relevant animal model. Methodology/Principal Findings: We used a rodent xenograft model that recapitulates the invasive and angiogenic features of human glioblastoma to analyze the transduction pattern and therapeutic efficacy of lentiviral pseudotyped vectors. Both, lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) and vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped lentiviral vectors very efficiently transduced human glioblastoma cells in vitro and in vivo. In contrast, pseudotyped gammaretroviral vectors, similar to those evaluated for clinical therapy of glioblastoma, showed inefficient gene transfer in vitro and in vivo. Both pseudotyped lentiviral vectors transduced cancer stem-like cells characterized by their CD133-, nestin- and SOX2-expression, the ability to form spheroids in neural stem cell medium and to express astrocytic and neuronal differentiation markers under serum conditions. In a therapeutic approach using the suicide gene herpes simplex virus thymidine kinase (HSV-1-tk) fused to eGFP, both lentiviral vectors mediated a complete remission of solid tumors as seen on MRI resulting in a highly significant survival benefit (p<0.001) compared to control groups. In all recurrent tumors, surviving eGFP-positive tumor cells were found, advocating prodrug application for several cycles to even enhance and prolong the therapeutic effect. Conclusions/Significance: In conclusion, lentiviral pseudotyped vectors are promising candidates for gene therapy of glioma in patients. The inefficient gene delivery by gammaretroviral vectors is in line with the results obtained in clinical therapy for GBM and thus confirms the high reproducibility of the invasive glioma animal model for translational research

Tumor-penetrating peptide for systemic targeting of Tenascin-C

Extracellular matrix in solid tumors has emerged as a specific, stable, and abundant target for affinity-guided delivery of anticancer drugs. Here we describe the homing peptide that interacts with the C-isoform of Tenascin-C (TNC-C) upregulated in malignant tissues. TNC-C binding PL3 peptide (amino acid sequence: AGRGRLVR) was identified by in vitro biopanning on recombinant TNC-C. Besides TNC-C, PL3 interacts via its C-end Rule (CendR) motif with cell-and tissue penetration receptor neuropilin-1 (NRP-1). Functionalization of iron oxide nanoworms (NWs) and metallic silver nanoparticles (AgNPs) with PL3 peptide increased tropism of systemic nanoparticles towards glioblastoma (GBM) and prostate carcinoma xenograft lesions in nude mice (eight and five-fold respectively). Treatment of glioma-bearing mice with proapoptotic PL3-guided NWs improved the survival of the mice, whereas treatment with untargeted particles had no effect. PL3-coated nanoparticles were found to accumulate in TNC-C and NRP-1-positive areas in clinical tumor samples, suggesting a translational relevance. The systemic tumor-targeting properties and binding of PL3-NPs to the clinical tumor sections, suggest that the PL3 peptide may have applications as a targeting moiety for the selective delivery of imaging and therapeutic agents to solid tumors.publishedVersio

Validation of a point-of-care capillary lactate measuring device (Lactate Pro 2)

Background The measurement of lactate in emergency medical services has the potential for earlier detection of shock and can be performed with a point-of-care handheld device. Validation of a point-of-care handheld device is required for prehospital implementation. Aim The primary aim was to validate the accuracy of Lactate Pro 2 in healthy volunteers and in haemodynamically compromised intensive care patients. The secondary aim was to evaluate which sample site, fingertip or earlobe, is most accurate compared to arterial lactate. Methods Arterial, venous and capillary blood samples from fingertips and earlobes were collected from intensive care patients and healthy volunteers. Arterial and venous blood lactate samples were analysed on a stationary hospital blood gas analyser (ABL800 Flex) as the reference device and compared to the Lactate Pro 2. We used the Bland-Altman method to calculate the limits of agreement and used mixed effect models to compare instruments and sample sites. A total of 49 intensive care patients with elevated lactate and 11 healthy volunteers with elevated lactate were included. Results There was no significant difference in measured lactate between Lactate Pro 2 and the reference method using arterial blood in either the healthy volunteers or the intensive care patients. Capillary lactate measurement in the fingertip and earlobe of intensive care patients was 47% (95% CI (29 to 68%), p < 0.001) and 27% (95% CI (11 to 45%), p < 0.001) higher, respectively, than the corresponding arterial blood lactate. In the healthy volunteers, we found that capillary blood lactate in the fingertip was 14% higher than arterial blood lactate (95% CI (4 to 24%), p = 0.003) and no significant difference between capillary blood lactate in the earlobe and arterial blood lactate. Conclusion Our results showed that the handheld Lactate Pro 2 had good agreement with the reference method using arterial blood in both intensive care patients and healthy volunteers. However, we found that the agreement was poorer using venous blood in both groups. Furthermore, the earlobe may be a better sample site than the fingertip in intensive care patients.publishedVersio

Quality in the feed grain Market

Diffuse gliomas comprise a group of primary brain tumors that originate from glial (precursor) cells and present as a variety of malignancy grades which have in common that they grow by diffuse infiltration. This phenotype complicates treatment enormously as it precludes curative surgery and radiotherapy. Furthermore, diffusely infiltrating glioma cells often hide behind a functional blood-brain barrier, hampering delivery of systemically administered therapeutic and diagnostic compounds to the tumor cells. The present review addresses the biological mechanisms that underlie the diffuse infiltrative phenotype, knowledge of which may improve treatment strategies for this disastrous tumor type. The invasive phenotype is specific for glioma: most other brain tumor types, both primary and metastatic, grow as delineated lesions. Differences between the genetic make-up of glioma and that of other tumor types may therefore help to unravel molecular pathways, involved in diffuse infiltrative growth. One such difference concerns mutations in the NADP+-dependent isocitrate dehydrogenase (IDH1 and IDH2) genes, which occur in >80% of cases of low grade glioma and secondary glioblastoma. In this review we present a novel hypothesis which links IDH1 and IDH2 mutations to glutamate metabolism, possibly explaining the specific biological behavior of diffuse glioma