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

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

Dendriticâ cellâ based immunotherapy evokes potent antiâ tumor immune responses in CD105+ human renal cancer stem cells

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138877/1/mc22697.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138877/2/mc22697_am.pd

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

Risk of Harm Associated With Using Rapid Sequence Induction Intubation and Positive Pressure Ventilation in Patients With Hemorrhagic Shock

Based on limited published evidence, physiological principles, clinical experience, and expertise, the author group has developed a consensus statement on the potential for iatrogenic harm with rapid sequence induction (RSI) intubation and positive-pressure ventilation (PPV) on patients in hemorrhagic shock. In hemorrhagic shock, or any low flow (central hypovolemic) state, it should be noted that RSI and PPV are likely to cause iatrogenic harm by decreasing cardiac output. The use of RSI and PPV leads to an increased burden of shock due to a decreased cardiac output (CO)2 which is one of the primary determinants of oxygen delivery (DO2). The diminishing DO2 creates a state of systemic hypoxia, the severity of which will determine the magnitude of the shock (shock dose) and a growing deficit of oxygen, referred to as oxygen debt. Rapid accumulation of critical levels of oxygen debt results in coagulopathy and organ dysfunction and failure. Spontaneous respiration induced negative intrathoracic pressure (ITP) provides the pressure differential driving venous return. PPV subsequently increases ITP and thus right atrial pressure. The loss in pressure differential directly decreases CO and DO2 with a resultant increase in systemic hypoxia. If RSI and PPV are deemed necessary, prior or parallel resuscitation with blood products is required to mitigate post intervention reduction of DO2 and the potential for inducing cardiac arrest in the critically shocked patient

“Blood failure” time to view blood as an organ: how oxygen debt contributes to blood failure and its implications for remote damage control resuscitation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/119110/1/trf13500_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/119110/2/trf13500.pd

Surgical resection of glioblastomas induces pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors

Background Glioblastomas are highly resistant to therapy, and virtually all patients experience tumor recurrence after standard-of-care treatment. Surgical tumor resection is a cornerstone in glioblastoma therapy, but its impact on cellular phenotypes in the local postsurgical microenvironment has yet to be fully elucidated. Methods We developed a preclinical orthotopic xenograft tumor resection model in rats with integrated 18F-FET PET/CT imaging. Primary and recurrent tumors were subject to bulk and single-cell RNA sequencing. Differentially expressed genes and pathways were investigated and validated using tissue specimens from the xenograft model, 23 patients with matched primary/recurrent tumors, and a cohort including 190 glioblastoma patients. Functional investigations were performed in vitro with multiple patient-derived cell cultures. Results Tumor resection induced microglia/macrophage infiltration, angiogenesis as well as proliferation and upregulation of several stem cell-related genes in recurrent tumor cells. Expression changes of selected genes SOX2, POU3F2, OLIG2, and NOTCH1 were validated at the protein level in xenografts and early recurrent patient tumors. Single-cell transcriptomics revealed the presence of distinct phenotypic cell clusters in recurrent tumors which deviated from clusters found in primary tumors. Recurrent tumors expressed elevated levels of pleiotrophin (PTN), secreted by both tumor cells and tumor-associated microglia/macrophages. Mechanistically, PTN could induce tumor cell proliferation, self-renewal, and the stem cell program. In glioblastoma patients, high PTN expression was associated with poor overall survival and identified as an independent prognostic factor. Conclusion Surgical tumor resection is an iatrogenic driver of PTN-mediated self-renewal in glioblastoma tumor cells that promotes therapeutic resistance and tumor recurrence.publishedVersio