Vox Sanguinis International Forum on the use of prehospital blood products and pharmaceuticals in the treatment of patients with traumatic haemorrhage.

While specific practices and transported blood products vary around the world, most of the respondents in this International Forum transported at least one blood product for the transfusion to bleeding patients en route to the hospital. The most commonly carried product was RBCs, while the use of whole blood will likely increase given the recent reports of its successful use in the civilian setting, and because of the change in the AABB's Standards regulating its use. It will be interesting to see if plasma use in the prehospital setting becomes more widely used given today's enhanced appreciated of the coagulopathy of trauma and plasma's beneficial effect in reversing it, and if blood products are transported to the scene of injury by more vehicles, that is, not just predominantly in helicopters. It was not surprising that TXA is being widely administered as close to the time of injury as possible given its potential benefit in these patients. This International Forum highlights the importance of focusing attention on prehospital transfusion management with a need to further high­quality research in this area to guide optimal resuscitation strategies.

Combined effect of therapeutic strategies for bleeding injury on early survival, transfusion needs and correction of coagulopathy.

BACKGROUND: The combined effects of balanced transfusion ratios and use of procoagulant and antifibrinolytic therapies on trauma-induced exsanguination are not known. The aim of this study was to investigate the combined effect of transfusion ratios, tranexamic acid and products containing fibrinogen on the outcome of injured patients with bleeding. METHODS: A prospective multicentre observational study was performed in six level 1 trauma centres. Injured patients who received at least 4 units of red blood cells (RBCs) were analysed and divided into groups receiving a low (less than 1 : 1) or high (1 or more : 1) ratio of plasma or platelets to RBCs, and in receipt or not of tranexamic acid or fibrinogen products (fibrinogen concentrates or cryoprecipitate). Logistic regression models were used to assess the effect of transfusion strategies on the outcomes 'alive and free from massive transfusion' (at least 10 units of RBCs in 24 h) and early 'normalization of coagulopathy' (defined as an international normalized ratio of 1·2 or less). RESULTS: A total of 385 injured patients with ongoing bleeding were included in the study. Strategies that were independently associated with an increased number of patients alive and without massive transfusion were a high platelet to RBC ratio (odds ratio (OR) 2·67, 95 per cent c.i. 1·24 to 5·77; P = 0·012), a high plasma to RBC ratio (OR 2·07, 1·03 to 4·13; P = 0·040) and treatment with tranexamic acid (OR 2·71, 1·29 to 5·71; P = 0·009). No strategies were associated with correction of coagulopathy. CONCLUSION: A high platelet or plasma to RBC ratio, and use of tranexamic acid were associated with a decreased need for massive transfusion and increased survival in injured patients with bleeding. Early normalization of coagulopathy was not seen for any transfusion ratio, or for use of tranexamic acid or fibrinogen products.

Three-year follow-up of implementation of evidence-based transfusion practice in a tertiary hospital.

BACKGROUND AND OBJECTIVES: Traditionally, Denmark has had a high rate of allogeneic red blood cell transfusion caused by a liberal transfusion practice despite the existence of restrictive guidelines. We established a Patient Blood Management programme in a tertiary hospital and report the results of the implementation of evidence-based transfusion practice. MATERIALS AND METHODS: Red blood cell transfusion quality indicators were compared with the evidence-based guideline at hospital and department level. Based on this evaluation, wards were selected for interventions targeting doctors and nurses. The implementation process was monitored by transfusion quality and utilization data over a 3-year period with totally 166 341 admissions in 98 960 mixed, adult medical and surgical patients. RESULTS: At the hospital level, transfusion above the upper guideline limit decreased from 23 to 10% (P < 0·001), and transfusion at or below the restrictive haemoglobin trigger of 7·3 g/dl increased from 7 to 19% (P < 0·001). The percentage of single-unit transfusions increased from 72 to 78% (P < 0·001), and the majority of transfusion rates and volumes decreased significantly. Red cell use decreased with 41% in surgical procedures and 28% in admissions (P < 0·001). CONCLUSION: The intervention was associated with a significant and sustained overall increase in compliance with national guidelines for red blood cell transfusion for non-bleeding patients, and led to significantly fewer patients being exposed to transfusion.

Comparing efficacy and safety of fibrinogen concentrate to cryoprecipitate in bleeding patients: a systematic review.

BACKGROUND: Bleeding is associated with the depletion of fibrinogen, thus increasing the risk of coagulopathy, further bleeding and transfusion requirements. Both fibrinogen concentrate and cryoprecipitate replenish low plasma fibrinogen levels. This systematic review aims to identify and evaluate evidence of efficacy and safety of fibrinogen concentrate and cryoprecipitate in bleeding patients. METHOD: Cochrane Central Register of Controlled Trials (CENTRAL), Medline, EMBASE up to 2nd of March 2015 were among the electronic search strategies of randomized controlled trials and non-randomized studies with meta-analysis employed. Studies for inclusion required bleeding patients being treated with either fibrinogen concentrate or cryoprecipitate. Mortality was the primary endpoint. Secondary outcomes included bleeding, coagulopathy, transfusion requirements and clinical complications related to the intervention. PRISMA methodology, a data-extraction form and the Cochrane risk of bias tool were all employed. RESULTS: Four studies were eligible for inclusion in this systematic review; one randomized controlled trial (RCT) consisting of 66 patients and three observational studies involving 218 patients in total. No mortality was reported in the published papers. There were no differences in fibrinogen-level increase, bleeding, RBC transfusions or thromboembolic complications. The RCT showed a possible increased functional improvement of haemostasis after cryoprecipitate therapy compared to fibrinogen concentrate. CONCLUSION: The available evidence directly comparing fibrinogen concentrate to cryoprecipitate is sparse and with high risk of bias. Recommendation of one product over the other for fibrinogen substitution in the bleeding patient with acquired hypofibrinogenaemia is currently not possible. Future research should guide us towards evidence-based decisions of product superiority.

Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial.

BACKGROUND: In early postpartum haemorrhage (PPH), a low concentration of fibrinogen is associated with excessive subsequent bleeding and blood transfusion. We hypothesized that pre-emptive treatment with fibrinogen concentrate reduces the need for red blood cell (RBC) transfusion in patients with PPH. METHODS: In this investigator-initiated, multicentre, double-blinded, parallel randomized controlled trial, we assigned subjects with severe PPH to a single dose of fibrinogen concentrate or placebo (saline). A dose of 2 g or equivalent was given to all subjects independent of body weight and the fibrinogen concentration at inclusion. The primary outcome was RBC transfusion up to 6 weeks postpartum. Secondary outcomes were total blood loss, total amount of blood transfused, occurrence of rebleeding, haemoglobin <58 g litre(-1), RBC transfusion within 4 h, 24 h, and 7 days, and as a composite outcome of 'severe PPH', defined as a decrease in haemoglobin of >40 g litre(-1), transfusion of at least 4 units of RBCs, haemostatic intervention (angiographic embolization, surgical arterial ligation, or hysterectomy), or maternal death. RESULTS: Of the 249 randomized subjects, 123 of 124 in the fibrinogen group and 121 of 125 in the placebo group were included in the intention-to-treat analysis. At inclusion the subjects had severe PPH, with a mean blood loss of 1459 (sd 476) ml and a mean fibrinogen concentration of 4.5 (sd 1.2) g litre(-1). The intervention group received a mean dose of 26 mg kg(-1) fibrinogen concentrate, thereby significantly increasing fibrinogen concentration compared with placebo by 0.40 g litre(-1) (95% confidence interval, 0.15-0.65; P=0.002). Postpartum blood transfusion occurred in 25 (20%) of the fibrinogen group and 26 (22%) of the placebo group (relative risk, 0.95; 95% confidence interval, 0.58-1.54; P=0.88). We found no difference in any predefined secondary outcomes, per-protocol analyses, or adjusted analyses. No thromboembolic events were detected. CONCLUSIONS: We found no evidence for the use of 2 g fibrinogen concentrate as pre-emptive treatment for severe PPH in patients with normofibrinogenaemia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: http://clinicaltrials.gov/show/NCT01359878. Published protocol: http://www.trialsjournal.com/content/pdf/1745-6215-13-110.pdf.

Fibrinogen concentrate for bleeding--a systematic review.

Fibrinogen concentrate as part of treatment protocols increasingly draws attention. Fibrinogen substitution in cases of hypofibrinogenaemia has the potential to reduce bleeding, transfusion requirement and subsequently reduce morbidity and mortality. A systematic search for randomised controlled trials (RCTs) and non-randomised studies investigating fibrinogen concentrate in bleeding patients was conducted up to November 2013. We included 30 studies of 3480 identified (7 RCTs and 23 non-randomised). Seven RCTs included a total of 268 patients (165 adults and 103 paediatric), and all were determined to be of high risk of bias and none reported a significant effect on mortality. Two RCTs found a significant reduction in bleeding and five RCTs found a significant reduction in transfusion requirements. The 23 non-randomised studies included a total of 2825 patients, but only 11 of 23 studies included a control group. Three out of 11 found a reduction in transfusion requirements while mortality was reduced in two and bleeding in one. In the available RCTs, which all have substantial shortcomings, we found a significant reduction in bleeding and transfusions requirements. However, data on mortality were lacking. Weak evidence from RCTs supports the use of fibrinogen concentrate in bleeding patients, primarily in elective cardiac surgery, but a general use of fibrinogen across all settings is only supported by non-randomised studies with serious methodological shortcomings. It seems pre-mature to conclude whether fibrinogen concentrate has a routine role in the management of bleeding and coagulopathic patients. More RCTs are urgently warranted.

Transfusion in critically ill children: an ongoing dilemma.

Transfusion of blood products is a cornerstone in managing many critically ill children. Major improvements in blood product safety have not diminished the need for caution in transfusion practice. In this review, we aim to discuss the interplay between benefits and potential adverse effects of transfusion in critically ill children by including 65 papers, which were evaluated based on previously agreed selection criteria. Current practice on transfusing critically ill children is mainly founded on the basis of adult studies, common practices with cut-off values, and expert opinions, rather than evidence-based medicine. Paediatric patients have explicit physiological challenges and requirements to be addressed. Critically ill children often suffer from anaemia, have substantial iatrogenic blood loss with subsequent transfusions, and are at a higher risk of complications, often due to human errors. Transfusion in children is associated with increased morbidity. A restrictive transfusion strategy is not associated with increased morbidity. Thus, transfusion in paediatrics should be considered a high-risk treatment and requires individual clinical assessment. Current level of evidence support the notion that in most stable cases, despite high severity of illness (cyanotic children and neonates excluded), a restrictive haemoglobin threshold of 70 g/l (4.3 mmol/l) is no more harmful than to transfuse at a liberal trigger, e.g. haemoglobin 95 g/l (5.9 mmol/l). Thus, balanced against potential benefits and often its necessity, a restrictive approach may be appropriate due to the associated risks of transfusion.

Older females have increased mortality after trauma as compared to younger females and males, associated with increased fibrinolysis.

INTRODUCTION: Female sex may provide a survival benefit after trauma, possibly attributable to protective effects of estrogen. This study aims to compare markers of coagulation between male and female trauma patients across different ages. METHODS: Secondary analysis of a prospective cohort study at six trauma centers. Trauma patients presenting with full trauma team activation were eligible for inclusion. Patients with a penetrating trauma or traumatic brain injury were excluded. Upon hospital arrival, blood was drawn for measurement of endothelial and coagulation markers and for rotational thromboelastometry (ROTEM) measurement.Trauma patients were divided into four categories: males <45 years, males ≥45 years, females <45 years and females ≥45 years. In a sensitivity analysis, patients between 45 - 55 years were excluded to control for menopausal transitioning. Groups were compared with a Kruskall-Wallis test with Bonferroni correction. A logistic regression was performed to assess whether the independent effect of sex and age on mortality. RESULTS: 1345 patients were available for analysis. Compared to the other groups, mortality was highest in females ≥45, albeit not independent from injury severity and shock. In the group of females ≥45 there was increased fibrinolysis, demonstrated by increased levels of plasmin-antiplasmin complexes with a concomitant decrease in α2-antiplasmin. Also, a modest decrease in coagulation factors II and X was observed. Fibrinogen levels were comparable between groups. The sensitivity analysis in 1104 patients demonstrated an independent relationship between female sex and age ≥ 55 years and mortality. ROTEM profiles did not reflect the changes in coagulation tests. CONCLUSION: Female trauma patients past their reproductive age have an increased risk of mortality compared to younger females and males, associated with augmented fibrinolysis and clotting factor consumption. ROTEM parameters did not reflect coagulation differences between groups. LEVEL OF EVIDENCE: Level III prognostic and epidemiological data.

Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial.

PURPOSE: Contemporary trauma resuscitation prioritizes control of bleeding and uses major haemorrhage protocols (MHPs) to prevent and treat coagulopathy. We aimed to determine whether augmenting MHPs with Viscoelastic Haemostatic Assays (VHA) would improve outcomes compared to Conventional Coagulation Tests (CCTs). METHODS: This was a multi-centre, randomized controlled trial comparing outcomes in trauma patients who received empiric MHPs, augmented by either VHA or CCT-guided interventions. Primary outcome was the proportion of subjects who, at 24 h after injury, were alive and free of massive transfusion (10 or more red cell transfusions). Secondary outcomes included 28-day mortality. Pre-specified subgroups included patients with severe traumatic brain injury (TBI). RESULTS: Of 396 patients in the intention to treat analysis, 201 were allocated to VHA and 195 to CCT-guided therapy. At 24 h, there was no difference in the proportion of patients who were alive and free of massive transfusion (VHA: 67%, CCT: 64%, OR 1.15, 95% CI 0.76-1.73). 28-day mortality was not different overall (VHA: 25%, CCT: 28%, OR 0.84, 95% CI 0.54-1.31), nor were there differences in other secondary outcomes or serious adverse events. In pre-specified subgroups, there were no differences in primary outcomes. In the pre-specified subgroup of 74 patients with TBI, 64% were alive and free of massive transfusion at 24 h compared to 46% in the CCT arm (OR 2.12, 95% CI 0.84-5.34). CONCLUSION: There was no difference in overall outcomes between VHA- and CCT-augmented-major haemorrhage protocols.

Effect of Haemostatic Control Resuscitation on mortality in massively bleeding patients: a before and after study.

BACKGROUND AND OBJECTIVES: Evidence supporting the use of platelets and plasma in resuscitation of massive bleedings is questionable. Current consensus guidelines recommend restrictive use. Our aim was to determine the effect of changing the transfusion practice on 30-day survival in massively bleeding patients. MATERIALS AND METHODS: Consecutive adult patients receiving more than 10 units of red blood cells (RBC) within 24 h 2 years prior to (2002-2003) and 2 years after (2005-2006) a change in transfusion practice were included. In 2004, we implemented Haemostatic Control Resuscitation (HCR) with preemptive use of platelets and plasma, administered in transfusion packages, comprising 5 units of RBCs, 5 units of fresh-frozen plasma and 2 units of platelet concentrates (PC), when massive bleeding occurred or upon arrival at the emergency room and thereafter directed by thrombelastography throughout the peri- and postoperative period. RESULTS: In 2005-2006, the 442 patients received more PCs within 24 h from admission [mean 5.0 (SD 4.2) vs. 1.7 (2.0); P < 0.0001] and had a smaller decrease in platelet count during the bleeding episode [91.5 (81.2) vs. 119.7 (100.8) x 10(9)/l; P = 0.0025] than the 390 patients treated in 2002-2003. Thirty-day mortality was reduced in 2005-2006 (20.4% vs. 31.5%; P = 0.0002) and at 90-day (22.4% vs. 34.6%; P < 0.0001) as compared to 2002-2003. CONCLUSIONS: In patients who experience massive bleeding, HCR with platelets and plasma, as guided by thrombelastography, is associated with improved survival. While confirmation from a randomized controlled trial is urgently needed, HCR may be considered in these patients.

The early IL-6 and IL-10 response in trauma is correlated with injury severity and mortality.

BACKGROUND: Trauma has previously been shown to influence interleukin (IL)-6 and IL-10 levels, but the association of injury severity and mortality with IL-6 and IL-10 responses in the early phase of accidental trauma remains to be investigated. We wished to describe serum levels of IL-6 and IL-10 in the first 24 h after trauma and to assess the relationship with severity of injury and mortality. METHODS: Prospective, descriptive cohort study in a Level 1 trauma centre, Copenhagen, Denmark. We included 265 consecutive adult trauma patients admitted directly from the accident scene during an 18-month period. Serum levels of IL-6 and IL-10 were measured upon arrival and at 6, 12, and 24 h after admittance using an enzyme-linked immunosorbent assay. Correlation analysis was used to assess the relationship between Injury Severity Score (ISS) and levels of IL-6 and IL-10. Analysis of variance was used to describe the IL-6 and IL-10 concentrations in relation to 30-day mortality in a mixed-effect model repeated measures analysis. RESULTS: Mortality was 10.9% (29/265) at 30 days. A significant increase of both IL-6 and IL-10 concentrations was found over time, and a significant correlation was found between ISS and the levels of both IL-6 and IL-10 at all sampling points. Serum concentrations of IL-6 and IL-10 were significantly higher in patients not surviving 30 days (P<0.0001). CONCLUSION: The early systemic inflammatory response measured as IL-6 and IL-10 in serum is correlated with injury severity and 30-day mortality following trauma.

Life-threatening systemic toxicity and airway compromise from a common European adder bite to the tongue.

A 24-year-old man was bit on the tongue by a European common adder. Within 15 min following envenomation, he experienced tongue swelling, hypotension and impaired consciousness. Antihistamine, corticosteroid and crystalloids were administered. Within 105 min of envenomation, increasing oral, pharyngeal and facial oedema compromised the airway, leading to respiratory failure, concomitant with circulatory failure related to hypoxaemia and systemic toxic effects. Acute tracheotomy secured the airway, and two doses of antivenom successfully treated the systemic, toxic effects. The reaction was severe due to rapid and suspected high-dose uptake of venom, underlining the need for early advanced symptomatic treatment with airway control and early and eventually repeated dosing of antivenom.

Maternal mortality in Guinea-Bissau: the use of verbal autopsy in a multi-ethnic population.

BACKGROUND: In developing countries with scanty resources it is very important to have reliable data to establish priorities for the health sector; e.g. to reduce maternal mortality it is necessary to determine the most important causes. The majority of deaths, however, occur without previous contact with the health system and consequently conventional analyses of death certificates are not feasible. Instead, studies have been carried out in some developing countries with various forms of post-mortem interviews, the so-called verbal autopsies (VA). METHODS: We developed a structured interview with filter questions, which was applied to all deaths of women of fertile age in a cohort of 10,000 women living in 100 clusters in Guinea-Bissau and followed over a period of 6 years. The cause of death was ascertained by means of a series of diagnostic algorithms for the most common causes of maternal mortality, including postpartum haemorrhage, antepartum haemorrhage, puerperal infection, obstructed labour, eclampsia, abortion, and ectopic pregnancy. RESULTS: Of the 350 deaths of women of fertile age, 32% were maternal and it seems unlikely that a significant proportion of maternal deaths have not been classified correctly. Using the diagnostic algorithm 70% could be given a specific diagnosis, the most important causes being postpartum haemorrhage (42% [29/69]), obstructed labour (19% [13/69]), and puerperal infection (16% [11/69]). We attempted to identify the factors that are critical for obtaining sufficient information to reach a diagnosis. In the univariate analyses, it was important whether the respondent had been present during the last illness (P = 0.04) and whether the death occurred more than one week after delivery (P = 0.04). The husband was a better respondent than a co-wife (P = 0.08), and men in general provided more specific information than women (P = 0.08). Furthermore, information appeared to be better if the woman had died in the rainy season (P = 0.08). The length of the recall period, parity, age of woman, place of death, rural/urban residence, and ethnic group were not decisive. In the multivariate analysis sex and presence of respondent and time after delivery were significantly associated with the risk of not reaching a specific diagnosis. Women are less likely to provide adequate information for a diagnosis than men (odds ratio [OR] 3.1; 95% confidence interval [CI]: 1.2-8.1). Respondents that did not reside in the village during the departed woman's illness/delivery carried equal risk of not reaching a conclusion (OR 3.1; CI: 1.1-9.1). Deaths occurring more than one week after delivery were also less likely to be classified (OR 6.1; CI: 1.7-22.0). CONCLUSION: The VA described in the present paper left 30% of the maternal deaths unclassified without a specific diagnosis. Had all interviews been with husbands, only 14% would have remained unclassified. If we had only asked people who were present during the terminal phase of the victim's illness the proportion of classified deaths would have risen from 70% to 75%. It is likely that delayed maternal deaths have not been adequately covered by the present algorithms, but they may also simply be more difficult to describe due to the duration of the disease episode. In contrast to methods by which cause of death is established by a panel of medical experts, the present VA should be economically and technically viable in areas where health workers have only minimal training.

Hydrophilic-coated catheters for intermittent catheterisation reduce urethral micro trauma: a prospective, randomised, participant-blinded, crossover study of three different types of catheters.

OBJECTIVE: To compare two hydrophilic-coated (SpeediCath and LoFric and one uncoated gel-lubricated catheter (InCare Advance Plus) concerning withdrawal friction force and urethral micro trauma. METHODS: 49 healthy male volunteers participated in this prospective, randomised, blinded, crossover study of three different bladder catheters. The withdrawal friction force was measured, and urine analysis of blood, nitrite and leucocytes, microbiological analysis of urine cultures and subjective evaluation of the catheters were performed. RESULTS: 40 participants completed the study and were included in the analysis. SpeediCath exerted a significantly lower mean withdrawal friction force and work than the gel-lubricated uncoated catheter, whereas LoFric exerted a significantly higher mean friction force than both of the other catheters. The hydrophilic catheters caused less microscopic haematuria and less pain than the gel-lubricated uncoated catheter. Furthermore, 93% of the participants preferred the hydrophilic catheters. CONCLUSION: Hydrophilic-coated catheters perform better than uncoated catheters with regard to haematuria and preference. SpeediCath, but not LoFric, exerts less withdrawal friction force than InCare Advance Plus.