Frozen for combat: Quality of deep-frozen thrombocytes, produced and used by The Netherlands Armed Forces 2001-2021.

BACKGROUND: The Netherlands Armed Forces (NLAF) are using -80°C deep-frozen thrombocyte concentrate (DTC) since 2001. The aim of this study is to investigate the effect of storage duration and alterations in production/measurement techniques on DTC quality. It is expected that DTC quality is unaffected by storage duration and in compliance with the European guidelines for fresh and cryopreserved platelets. STUDY DESIGN AND METHODS: Pre-freeze and post-thaw product platelet content and recovery were collected to analyze the effects of dimethyl sulfoxide (DMSO) type, duration of frozen storage (DMSO-1 max 12 years and DMSO-2 frozen DTC max 4 years at -80°C) and type of plasma used to suspend DTC. Coagulation characteristics of thawed DTC, plasma and supernatant of DTC (2× 2500 G) were measured with Kaolin thromboelastography (TEG) and phospholipid (PPL) activity assay. RESULTS: Platelet content and recovery of DTC is ±10%-15% lower in short-stored products and remained stable when stored beyond 0.5 years. Thawed DTC (n = 1724) were compliant to the European guidelines (98.1% post-thaw product recovery ≥50% from original product, 98.3% ≥200 × 109 platelets/unit). Compared to DMSO-1, products frozen with DMSO-2 showed ±8% reduced thaw-freeze recovery, a higher TEG clot strength (MA 58 [6] vs. 64 [8] mm) and same ±11 s PPL clotting time. The use of cold-stored thawed plasma instead of fresh thawed plasma did not influence product recovery or TEG-MA. DISCUSSION: Regardless of alterations, product quality was in compliance with European guidelines and unaffected by storage duration up to 12 years of -80°C frozen storage.

Prehospital Active and Passive Warming in Trauma Patients.

OBJECTIVE: Hypothermia is common among trauma patients and can lead to a serious rise in morbidity and mortality. This study was performed to investigate the effect of active and passive warming measures implemented in the prehospital phase on the body temperature of trauma patients. METHODS: In a multicenter, multinational prospective observational design, the effect of active and passive warming measures on the incidence of hypothermia was investigated. Adult trauma patients who were transported by helicopter emergency medical services (HEMS) or ground emergency medical services with an HEMS physician directly from the scene of injury were included. Four HEMS/ground emergency medical services programs from Canada, the United States, and the Netherlands participated. RESULTS: A total of 80 patients (n = 20 per site) were included. Eleven percent had hypothermia on presentation, and the initial evaluation occurred predominantly within 60 minutes after injury. In-line fluid warmers and blankets were the most frequently used active and passive warming measures, respectively. Independent risk factors for a negative change in body temperature were transportation by ground ambulance (odds ratio = 3.20; 95% confidence interval, 1.06-11.49; P = .03) and being wet on initial presentation (odds ratio = 3.64; 95% confidence interval, 0.99-13.36; P = .05). CONCLUSION: For adult patients transported from the scene of injury to a trauma center, active and passive warming measures, most notably the removal of wet clothing, were associated with a favorable outcome, whereas wet patients and ground ambulance transport were associated with an unfavorable outcome with respect to temperature.

Prolonged (post-thaw) shelf life of -80°C frozen AB apheresis plasma.

BACKGROUND: Early plasma transfusion is important in the treatment of patients with major hemorrhage. Prolonged shelf life of AB type frozen -80°C and cold-stored (4°C) deep frozen plasma (DFP) will improve strategic stock management, minimize need for resupply, and make pre-hospital implementation more feasible. METHODS AND MATERIALS: Plasma products type AB of different age and origin (-30°C Fresh Frozen [(FFP], -80°C DFP [short (±1 year) and long (±7 year)] stored) were thawed (Day 0), stored at 4°C, and sampled on Days 7 and 14. Additionally, samples of plasma containing blood products (Octaplas LG®, whole blood and platelets) were compared for coagulation factor activity, phospholipid clotting time (PPL), and kaolin TEG during 4°C or 22°C storage. RESULTS: Coagulation profiles of FFP, short- and long-stored -80°C DFP were not significantly different after thaw. Cold storage did not affect fibrinogen, Protein C, and Antithrombin III activities whereas factor V, VII, VIII, and Protein S decreased in all blood products. After 14 days DFP still meets the guidelines for clinical use, except for Protein S (0.4 IU/mL). With exception of Octaplas LG®, phospholipid activity and TEG coagulation were similar between plasma containing blood components during storage. CONCLUSION: AB DFP quality was unaffected by almost 7 years of frozen storage. Quality of thawed 14-day stored AB DFP met, with exception of Protein S, all minimal guidelines which implies that its quality is sufficient for use in the (pre)-hospital (military) environment for treatment of major hemorrhage.

The use of cryopreserved platelets in a trauma-induced hemorrhage model.

BACKGROUND: Cryopreserved platelet products can be stored for years and are mainly used in military settings. Following thawing, cryopreserved platelets are activated, resulting in faster clot formation but reduced aggregation in vitro, rendering their efficacy in bleeding unknown. Also, concerns remain on the safety of these products. The aim was to investigate the efficacy and safety of cryopreserved platelets in a rat model of traumatic hemorrhage. STUDY DESIGN AND METHODS: After 1 hour of shock, rats (n = 13/group) were randomized to receive a balanced transfusion pack (1:1:1 red blood cell:plasma:platelet) made from syngeneic rat blood, containing either liquid stored platelets or cryopreserved platelets. Primary outcome was the transfusion volume required to obtain a mean arterial pressure (MAP) of 60 mmHg. Secondary outcomes were coagulation as assessed by thromboelastometry (ROTEM®) and organ failure as assessed by biochemistry and histopathology. RESULTS: The transfusion volume to obtain a MAP of 60 mmHg was lower in animals receiving cryopreserved platelets (5.4 [4.1-7.1] mL/kg) compared to those receiving liquid stored platelets (7.5 [6.4-8.5] mL/kg, p < 0.05). ROTEM® clotting times were shorter (45 [41-48] vs. 49 [45-53]sec, p < 0.05), while maximum clot firmness was slightly lower (68 [67-68] vs. 69 [69-71]mm, p < 0.01). Organ failure was similar in both groups. CONCLUSIONS: Use of cryopreserved platelets required less transfusion volume to reach a targeted MAP compared to liquid stored platelets, while organ injury was similar. These results provide a rationale for clinical trials with cryopreserved platelets in (traumatic) bleeding.

-80 °C deep frozen erythrocytes during military operations. The Dutch frozen concept.

The Dutch military uses frozen blood products for the treatment of bleeding trauma patients during military deployments. With -80 °C frozen blood products it is possible to follow operational demand while reducing the number of resupply transports and loss of products due to expiration. In this paper lessons learned are described on efficient blood management with -80 °C deep-frozen erythrocytes (DEC).

Self-assessment of Skills by Surgeons and Anesthesiologists After a Trauma Surgery Masterclass.

BACKGROUND: In the Netherlands, each year a three-day international multidisciplinary trauma masterclass is organized to provide the knowledge and skills needed to care for critically injured trauma patients. This study was designed to longitudinally evaluate the effect of the course on participant's self-assessment of their own ability and confidence to perform general and specific skills. METHODS: Between 2013 and 2016, all participants were invited to complete a questionnaire before and during follow-up. Participants were asked to self-assess their level of confidence to perform general skills (communication, teamwork, leadership) and specific skills. Mean scores were calculated, and mixed models were used to evaluate correlation. RESULTS: We asked 265 participants to participate. Response rate was 64% for the pre-questionnaire, 63% for the post-questionnaire and for 3 months, 1 year and 2 years, respectively, 40%, 30%, 20%. The surgical group showed a statistically significant increase in self-assessed confidence for general skills (3.82-4.20) and specific technical skills (3.01-3.83; p < 0.001). In the anesthetic group, self-assessed confidence increased significantly in general skills (3.72-4.26) and specific technical skills (3.33-4.08; p < 0.001). For both groups statistical significance remained during follow-up. CONCLUSIONS: This study demonstrated a sustained positive effect of a dedicated multidisciplinary trauma training curriculum on participant's self-assessed confidence to perform both general and specific technical skills necessary for the care of injured patients. Given the known association between confidence and competence, these findings provide evidence that dedicated trauma training curricula can provide positive lasting results. LEVEL OF EVIDENCE: This is a basic science paper and therefore does not require a level of evidence.

Massive transfusion in The Netherlands.

OBJECTIVES: Massive transfusion protocols (MTPs) may improve survival in patients with uncontrolled haemorrhage. An MTP was introduced into the Dutch transfusion guidelines in 2011, the ninth edition of the advanced trauma life support course in 2012 and the third version of the European guideline in 2013. This is the first survey of MTPs in Dutch trauma centres. METHODS: The aim of the study was to compare MTP strategies in level 1 trauma centres in The Netherlands, and with (inter)national guidelines. A contact in each government assigned level 1 trauma centre in The Netherlands and the Dutch Ministry of Defence was approached to share their MTPs and elucidate their protocol in a survey and oral follow-up interview. RESULTS: All 11 level 1 trauma centres responded. The content of the packages and transfusion ratios (red blood cells/plasma/platelets) were 3:3:1, 5:5:1, 5:3:1, 2:3:1, 4:4:1, 5:2:1, 2:2:1 and 4:3:1. Tranexamic acid was used in all centres and an additional dose was administered in eight centres. Fibrinogen was given directly (n=4), with persistent bleeding (n=3), based on Clauss fibrinogen (n=3) or rotational thromboelastometry (n=1). All centres used additional medication in patients in the form of anticoagulants, but their use was ambiguous. CONCLUSION: MTPs differed between institutes and guidelines. The discrepancies in transfusion ratios can be explained by (inter)national differences in preparation and volume of blood components and/or interpretation of the '1:1:1' guideline. We recommend updating MTPs every year using the latest guidelines and evaluating the level of evidence for treatment during massive transfusion.

Impact of accidental hypothermia in trauma patients: A retrospective cohort study.

BACKGROUND: Trauma patients with hypothermia have substantial increases in mortality and morbidity. In severely injured patients, hypothermia is common with a rate up to 50% in various geographic areas. This study aims to elucidate the incidence, predictors, and impact of hypothermia on outcomes in severely injured patients. METHODS: This was a retrospective cohort study which included trauma patients with an Injury Severity Score (ISS) ≥ 16 admitted to a level 1 trauma center in the Netherlands between January 1, 2015 and December 31, 2021. Primary outcome was incidence of hypothermia on arrival at the emergency department. Factors associated with hypothermia were identified. Secondary outcomes were transfusion requirement, mortality, and intensive care unit (ICU) admission. Logistic regression analysis was used to identify associations. RESULTS: A total of 2032 severely injured patients were included of which 257 (12.6%) were hypothermic on hospital arrival. Predictors for hypothermia on hospital arrival included higher ISS, prehospital intubation, cervical spine immobilization, winter months, systolic blood pressure (SBP) < 90 mmHg and Glasgow Coma Scale (GCS) ≤ 8. Hypothermia was independently associated with transfusion requirement (OR, 2.68; 95% CI, 1.94 - 3.73; p < 0.001), mortality (OR, 2.12; 95% CI, 1.40 - 3.19; p < 0.001) and more often ICU admission (OR, 1.81; 95% CI, 1.10 - 2.97, p = 0.019). CONCLUSIONS: In this study, hypothermia was present in 12.6% of severely injured patients. Hypothermia was associated with increased transfusion requirement, mortality, and ICU admission. Identified predictors for hypothermia included the severity of injury, intubation, and immobilization, as well as winter season, SBP < 90 mmHg, and GCS ≤ 8.

Whole blood transfusion in the treatment of acute hemorrhage, a systematic review and meta-analysis.

BACKGROUND: Whole blood (WB) transfusion received renewed interest after recent armed conflicts. The effectiveness as compared with blood component transfusion (BCT) is, however, still topic of debate. Therefore, this study investigated the effect of WB ± BCT as compared with BCT transfusion on survival in trauma patients with acute hemorrhage. METHODS: Studies published up to January 16, 2023, including patients with traumatic hemorrhage comparing WB ± BCT and BCT were included in meta-analysis. Subanalyses were performed on the effectiveness of WB in the treatment of civilian or military trauma patients, patients with massive hemorrhage and on platelet (PLT)/red blood cell (RBC), plasma/RBC and WB/RBC ratios. Methodological quality of studies was interpreted using the Cochrane risk of bias tool. The study protocol was registered in PROSPERO under number CRD42022296900. RESULTS: Random effect pooled odds ratio (OR) for 24 hours mortality in civilian and military patients treated with WB as compared with BCT was 0.72 (95% confidence interval [CI], 0.53-0.97). In subanalysis of studies conducted in civilian setting (n = 20), early (4 hours, 6 hours, and emergency department) and 24 hours mortality was lower in WB groups compared with BCT groups (OR, 0.65; 95% CI, 0.44-0.96 and OR, 0.71; 95% CI, 0.52-0.98). No difference in late mortality (28 days, 30 days, in-hospital) was found. In military settings (n = 7), there was no difference in early, 24 hours, or late mortality between groups. The WB groups received significant higher PLT/RBC ( p = 0.030) during early treatment and significant higher PLT/RBC and plasma/RBC ratios during 24 hours of treatment ( p = 0.031 and p = 0.007). The overall risk of bias in the majority of studies was judged as serious due to serious risk on confounding and selection bias, and unclear information regarding cointerventions. CONCLUSION: Civilian trauma patients with acute traumatic hemorrhage treated with WB ± BCT as compared to BCT had lower odds on early and 24-hour mortality. In addition, WB transfusion resulted in higher PLT/RBC and plasma/RBC ratios. LEVEL OF EVIDENCE: Systematic Review and Meta-Analysis; Level III.

Prehospital body temperature measurement in trauma patients: A literature review.

OBJECTIVES: Accidental hypothermia in trauma patients can contribute to cardiorespiratory dysfunction, acidosis, and coagulopathy, causing increased morbidity and mortality. The early recognition of the clinical signs of hypothermia and the accurate measurement of body temperature by prehospital care providers are essential to avoid deterioration. This review provides an overview of studies that examine the reliability of different core temperature measurement options, with a focus on the prehospital setting. METHODS: A search was performed in PubMed, Embase, Cochrane Library, and CINAHL using combinations of the Medical Subject Headings terms "ambulances," "emergency medical services," "thermometers," "body temperature," "hypothermia," and "body temperature regulation." Studies up to October 2021 were included, and different measurement options were listed and discussed. Eligible studies included those that identified the specific type of thermometer and focused on the out-of-hospital environment. RESULTS: The search strategy yielded 521 studies, five of which met the eligibility criteria. Four studies focused on tympanic temperature measurement, and one focused on temporal artery temperature measurement. Among the noninvasive options, tympanic temperature measurement was most frequently identified as a reliable option for out-of-hospital use. CONCLUSION: A thermistor-based tympanic thermometer that features insulation of the ear and a temperature probe with a cap is likely the most suitable option for prehospital body temperature measurement in trauma patients. These results are based on outdated literature with currently more novel temperature measurement devices available. Future studies are necessary to provide strong recommendations regarding temperature measurement due to emerging technology, the lack of studies, and the heterogeneity of existing studies.

Massive transfusion protocols in the Netherlands. Consensus or confusion?

INTRODUCTION: Transfusion strategy for trauma patients with massive haemorrhage is often incorporated in massive transfusion protocols (MTP). Albeit correct MTP use results in better patient outcome, research regarding the state of MTP knowledge is scarce. The objective of this study is therefore to assess knowledge of local MTP and massive transfusion strategy in the level 1 trauma centres in the Netherlands. Our hypothesis is that actual MTP knowledge is low and transfusion strategy differs. MATERIALS AND METHODS: Surveys were sent out in January 2020 to all trauma and vascular surgeons, anaesthesiologists, emergency department physicians of the largest level 1 trauma centre (locally, n = 113) and to one trauma surgeon, emergency physician and anaesthesiologist in each of the nine other governmentally assigned level 1 trauma centres in the Netherlands (nationally, n = 27). The respondents were subdivided into a frequent user group (MTP usage ≥ 4 times in 2019) and a non-frequent user group (MTP usage < 4 in 2019). Data are expressed as numbers and percentages. RESULTS: Response rate was (n = 48; 42%) for the local survey and (n = 14; 52%) for the national survey. Locally, (n = 23; 48%) and (n = 25; 52%) respondents were defined frequent and non-frequent users respectively and national respondents all as frequent users. In total, (n = 13; 27%) of local respondents were aware of the current local composition of the MTP. Respondents indicated to transfuse erythrocytes first, followed by plasma and platelets (local non-frequent users n = 23; 92%, local frequent users n = 21; 91% and national frequent users n = 13; 93%). The indication for platelet transfusion was units erythrocytes transfused (local non-frequent users n = 10; 40% frequent users locally n = 11; 48% and nationally n = 5; 36%) and clinical view (local non-frequent users n = 9; 36%, frequent users locally n = 8; 35% and n<5 nationally. Whereas few respondents claimed (n = 5; 21% non-frequent users locally and n <5 nationally) to transfuse platelets based on platelet counts. Viscoelastic haemostatic assays were performed during MTP, but only by frequent users. CONCLUSION: The majority of physicians dealing with massive transfusion in trauma patients were not aware of the exact composition of the MTP and consensus regarding transfusion strategy and indication for platelet transfusion was low.

The haemostatic effect of deep-frozen platelets versus room temperature-stored platelets in the treatment of surgical bleeding: MAFOD-study protocol for a randomized controlled non-inferiority trial.

BACKGROUND: The Netherlands Armed Forces have been successfully using deep-frozen (- 80 °C) thrombocyte concentrate (DTC) for the treatment of (massive) bleeding trauma patients in austere environments since 2001. However, high-quality evidence for the effectiveness and safety of DTCs is currently lacking. Therefore, the MAssive transfusion of Frozen bloOD (MAFOD) trial is designed to compare the haemostatic effect of DTCs versus room temperature-stored platelets (RSP) in the treatment of surgical bleeding. METHODS: The MAFOD trial is a single-blinded, randomized controlled non-inferiority trial and will be conducted in three level 1 trauma centres in The Netherlands. Patients 12 years or older, alive at hospital presentation, requiring a massive transfusion including platelets and with signed (deferred) consent will be included. The primary outcome is the percentage of patients that have achieved haemostasis within 6 h and show signs of life. Haemostasis is defined as the time in minutes from arrival to the time of the last blood component transfusion (plasma/platelets or red blood cells), followed by a 2-h transfusion-free period. This is the first randomized controlled study investigating DTCs in trauma and vascular surgical bleeding. DISCUSSION: The hypothesis is that the percentage of patients that will achieve haemostasis in the DTC group is at least equal to the RSP group (85%). With a power of 80%, a significance level of 5% and a non-inferiority limit of 15%, a total of 71 patients in each arm are required, thus resulting in a total of 158 patients, including a 10% refusal rate. The data collected during the study could help improve the use of platelets during resuscitation management. If proven non-inferior in civilian settings, frozen platelets may be used in the future to optimize logistics and improve platelet availability in rural or remote areas for the treatment of (massive) bleeding trauma patients in civilian settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05502809. Registered on 16 August 2022.

Platelet to erythrocyte transfusion ratio and mortality in massively transfused trauma patients. A systematic review and meta-analysis.

BACKGROUND: Platelet transfusion during major hemorrhage is important and often embedded in massive transfusion protocols. However, the optimal ratio of platelets to erythrocytes (platelet-rich plasma [PLT]/red blood cell [RBC] ratio) remains unclear. We hypothesized that high PLT/RBC ratios, as compared with low PLT/RBC ratios, are associated with improved survival in patients requiring massive transfusion. METHODS: Four databases (Pubmed, CINAHL, EMBASE, and Cochrane) were systematically screened for literatures published until January 21, 2021, to determine the effect of PLT/RBC ratio on the primary outcome measure mortality at 1 hour to 6 hours and 24 hours and at 28 days to 30 days. Studies comparing various PLT/RBC ratios were included in the meta-analysis. Secondary outcomes included intensive care unit length of stay and in-hospital length of stay and total blood component use. The study protocol was registered in PROSPERO under number CRD42020165648. RESULTS: The search identified a total of 8903 records. After removing the duplicates and second screening of title, abstract, and full text, a total of 59 articles were included in the analysis. Of these articles, 12 were included in the meta-analysis. Mortality at 1 hour to 6 hours, 24 hours, and 28 days to 30 days was significantly lower for high PLT/RBC ratios as compared with low PLT/RBC ratios. CONCLUSION: Higher PLT/RBC ratios are associated with significantly lower 1-hour to 6-hour, 24-hour, 28-day to 30-day mortalities as compared with lower PLT/RBC ratios. The optimal PLT/RBC ratio for massive transfusion in trauma patients is approximately 1:1. LEVEL OF EVIDENCE: Systematic review and meta-analysis, therapeutic Level III.

Is prehospital blood transfusion effective and safe in haemorrhagic trauma patients? A systematic review and meta-analysis.

BACKGROUND: Life-threatening haemorrhage accounts for 40% mortality in trauma patients worldwide. After bleeding control is achieved, circulating volume must be restored. Early in-hospital transfusion of blood components is already proven effective, but the scientific proof for the effectiveness of prehospital blood-component transfusion (PHBT) in trauma patients is still unclear. OBJECTIVE: To systematically review the evidence for effectiveness and safety of PHBT to haemorrhagic trauma patients. METHODS: CINAHL, Cochrane, EMBASE, and Pubmed were searched in the period from 1988 until August 1, 2018. Meta-analysis was performed for matched trauma patients receiving PHBT with the primary outcomes 24-hour mortality and long-term mortality. Secondary outcome measure was adverse events as a result of PHBT. RESULTS: Trauma patients who received PHBT with simultaneous use of packed red blood cells (pRBCs) and plasma showed a statistically significant reduction in long-term mortality (OR = 0.51; 95% CI, 0.36-0.71; P < 0.0001) but no difference in 24-hour mortality (OR = 0.47, 95% CI, 0.17-1.34; P = 0.16). PHBT with individual use of pRBCs showed no difference in long-term mortality (OR = 1.18; 95% CI, 0.93-1.49; P = 0.17) or 24-hour mortality (OR = 0.92; 95% CI, 0.46-1.85; P = 0.82). In a total of 1341 patients who received PHBT, 14 adverse events were reported 1.04%, 95% CI 0.57-1.75%. CONCLUSIONS: PHBT with simultaneous use of both pRBCs and plasma resulted in a significant reduction in the odds for long-term mortality. However, based on mainly poor quality evidence no hard conclusion can be drawn about a possible survival benefit for haemorrhagic trauma patients receiving PHBT. Overall, PHBT is safe but results of currently ongoing randomised controlled trials have to be awaited to demonstrate a survival benefit. STUDY TYPE: Systematic review and meta-analysis.