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.

The application of a haemorrhage assessment tool in evaluating control of bleeding in a pilot trauma haemorrhage trial.

OBJECTIVES: To determine whether it was feasible to use a haemorrhage assessment tool (HAT) within a trauma trial and whether the data obtained could differentiate patients who had achieved haemostasis. BACKGROUND: Major haemorrhage is one of the leading causes of death worldwide, affecting 40% of trauma patients. Clinical trials evaluating haemostatic interventions often use transfusion outcomes as a primary endpoint. Transfusion is highly dependent on local practice, limiting its reliability as a robust, transferable endpoint. METHODS: A five-point HAT questionnaire was applied to participants enrolled into the EFIT-1 trial. This RCT evaluated the feasibility of administering a 6 g fibrinogen concentrate to patients with severe trauma haemorrhage. RESULTS: Of participants, 98% completed a HAT; 75% participants had 'achieved haemostasis' at the time of tool completion, as determined by clinical acumen alone. HAT scores were able to differentiate which participants required transfusion after 3 h. Of participants, 56% were transfused red blood cells when they scored 0-2, compared to 17% with HAT scores between 3 and 5. CONCLUSION: This study has confirmed the feasibility of using a HAT during the emergency care of patients suffering trauma haemorrhage, and future studies should be conducted to determine its value as an endpoint in haemostasis studies.

Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery.

Essentials Recombinant von Willebrand factor (rVWF) is effective in von Willebrand disease (VWD). A phase 3 study of rVWF, with/without recombinant factor VIII (rFVIII) before surgery in VWD. Overall rVWF's efficacy was rated excellent/good; rVWF was administered alone in most patients. rVWF was well-tolerated and hemostasis was achieved in patients with severe VWD undergoing surgery. SUMMARY: Background Recombinant von Willebrand factor (rVWF) has demonstrated efficacy for on-demand treatment of bleeding in severe von Willebrand disease (VWD), warranting evaluation in the surgical setting. Objectives This study (NCT02283268) evaluated the hemostatic efficacy/safety profile of rVWF, with/without recombinant factor VIII (rFVIII), in patients with severe VWD undergoing surgery. Patients/Methods Patients received rVWF 40-60 IU kg-1 , VWF ristocetin cofactor activity was measured 12-24 h before surgery. If endogenous FVIII activity (FVIII:C) target levels were achieved 3 h before surgery, rVWF was administered alone 1 h before surgery; rVWF was co-administered with rFVIII if target endogenous FVIII levels were not achieved. rVWF was infused postoperatively to maintain target trough levels. Overall and intraoperative hemostatic efficacy, the pharmacodynamics of rVWF administration and the incidence of adverse events (AEs) were assessed. Results All patients treated with rVWF for major (n = 10), minor (n = 4) and oral (n = 1) surgery had overall and intraoperative hemostatic efficacy ratings of excellent (73.3% and 86.7%) or good (26.7% and 13.3%). Most rVWF infusions (89.4%) were administered alone, resulting in hemostatically effective levels of endogenous FVIII within 6 h, which were sustained for 72-96 h; 70% (n = 7/10) of major surgeries were performed without rFVIII co-administration. Six patients reported 12 treatment-emergent AEs. Two patients each had one serious AE: diverticulitis (not treatment related) and deep vein thrombosis (sponsor-assessed as possibly treatment related). No severe allergic reactions or inhibitory antibodies were reported. Conclusions These data support the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery.

Mortality from trauma haemorrhage and opportunities for improvement in transfusion practice.

BACKGROUND: The aim of this study was to describe the prevalence, patterns of blood use and outcomes of major haemorrhage in trauma. METHODS: This was a prospective observational study from 22 hospitals in the UK, including both major trauma centres and smaller trauma units. Eligible patients received at least 4 units of packed red blood cells (PRBCs) in the first 24 h of admission with activation of the massive haemorrhage protocol. Case notes, transfusion charts, blood bank records and copies of prescription/theatre charts were accessed and reviewed centrally. Study outcomes were: use of blood components, critical care during hospital stay, and mortality at 24 h, 30 days and 1 year. Data were used to estimate the national trauma haemorrhage incidence. RESULTS: A total of 442 patients were identified during a median enrolment interval of 20 (range 7-24) months. Based on this, the national incidence of trauma haemorrhage was estimated to be 83 per million. The median age of patients in the study cohort was 38 years and 73·8 per cent were men. The incidence of major haemorrhage increased markedly in patients aged over 65 years. Thirty-six deaths within 24 h of admission occurred within the first 3 h. At 24 h, 79 patients (17·9 per cent) had died, but mortality continued to rise even after discharge. Patients who received a cumulative ratio of fresh frozen plasma to PRBCs of at least 1 : 2 had lower rates of death than those who received a lower ratio. There were delays in administration of blood. Platelets and cryoprecipitate were either not given, or transfused well after initial resuscitation. CONCLUSION: There is a high burden of trauma haemorrhage that affects all age groups. Research is required to understand the reasons for death after the first 24 h and barriers to timely transfusion support.

Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial.

BACKGROUND: Low fibrinogen (Fg) concentrations in trauma haemorrhage are associated with poorer outcomes. Cryoprecipitate is the standard source for Fg administration in the UK and USA and is often given in the later stages of transfusion therapy. It is not known whether early cryoprecipitate therapy improves clinical outcomes. The primary aim of this feasibility study was to determine whether it was possible to administer cryoprecipitate, within 90 min of admission to hospital. Secondary aims were to evaluate laboratory measures of Fg and clinical outcomes including thrombotic events, organ failure, length of hospital stay and mortality. METHODS: This was an unblinded RCT, conducted at two civilian UK major trauma centres of adult trauma patients (age ≥16 yrs), with active bleeding and requiring activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy (STANDARD) (n=22), or to standard haemorrhage therapy plus two early pools of cryoprecipitate (CRYO) (n=21). RESULTS: 85% (95% CI: 69-100%) CRYO participants received cryoprecipitate within 90 min, median time 60 min (IQR: 57-76) compared with 108 min (67-147), CRYO and STANDARD arms respectively (P=0.002). Fg concentrations were higher in the CRYO arm and were maintained above 1.8 g litre(-1) at all time-points during active haemorrhage. All-cause mortality at 28 days was not significantly different (P=0.14). CONCLUSIONS: Early Fg supplementation using cryoprecipitate is feasible in trauma patients. This study supports the need for a definitive RCT to determine the effect of early Fg supplementation on mortality and other clinical outcomes. TRIAL REGISTRY NUMBER: ISRCTN55509212.

Usefulness of standard plasma coagulation tests in the management of perioperative coagulopathic bleeding: is there any evidence?

Standard laboratory coagulation tests (SLTs) such as prothrombin time/international normalized ratio or partial thromboplastin time are frequently used to assess coagulopathy and to guide haemostatic interventions. However, this has been challenged by numerous reports, including the current European guidelines for perioperative bleeding management, which question the utility and reliability of SLTs in this setting. Furthermore, the arbitrary definition of coagulopathy (i.e. SLTs are prolonged by more than 1.5-fold) has been questioned. The present study aims to review the evidence for the usefulness of SLTs to assess coagulopathy and to guide bleeding management in the perioperative and massive bleeding setting. Medline was searched for investigations using results of SLTs as a means to determine coagulopathy or to guide bleeding management, and the outcomes (i.e. blood loss, transfusion requirements, mortality) were reported. A total of 11 guidelines for management of massive bleeding or perioperative bleeding and 64 studies investigating the usefulness of SLTs in this setting were identified and were included for final data synthesis. Referenced evidence for the usefulness of SLTs was found in only three prospective trials, investigating a total of 108 patients (whereby microvascular bleeding was a rare finding). Furthermore, no data from randomized controlled trials support the use of SLTs. In contrast, numerous investigations have challenged the reliability of SLTs to assess coagulopathy or guide bleeding management. There is actually no sound evidence from well-designed studies that confirm the usefulness of SLTs for diagnosis of coagulopathy or to guide haemostatic therapy.

Simulation training improves clinical knowledge of major haemorrhage management in foundation year doctors.

OBJECTIVES: (i) To develop a major haemorrhage simulation training programme. (ii) To design an assessment tool to measure the effectiveness of this programme. (iii) To use simulation training to create more effective protocols. BACKGROUND: Major haemorrhage is a time-critical medical emergency that can be faced by every Foundation Year (FY) doctor. Standard methods of teaching provide limited opportunity for junior doctors to improve their knowledge and practical skills for major haemorrhage situations. Simulation is increasingly used in medical training but has not been used as a means both to facilitate learning and refine hospital major haemorrhage policy. METHODS: The effect of major haemorrhage simulation on attendees' learning was compared to a comparator group not exposed to simulation. Questionnaire pre-simulation and 3 months post-simulation training assessed knowledge of the Trust Major Haemorrhage Protocol (MHP). RESULTS: Sixteen FY1 doctors attended simulation training. The comparator group included 47 FY1 doctors. No significant difference was found between simulation and comparator groups on baseline questionnaire scores. The simulation group showed significant improvement (total score, mean standard deviation (SD) pre-test 27.15 (4.02), post-test 39.13 (3.91), p < 0.001). The comparator group showed no significant change (total score, pre-test 25.06 (5.70), post-test 23.54 (6.85), p = 0.33) (19 lost to follow up). The study resulted in the production of a new MHP. CONCLUSION: This study has demonstrated that simulation training improved doctors' knowledge in major haemorrhage management and that the experience of observing the simulation training allowed senior staff to undertake analysis and improvement of an existing MHP.

SOX3 deletion in mouse and human is associated with persistence of the craniopharyngeal canal.

CONTEXT: SOX3 is an early developmental transcription factor involved in pituitary development. In humans, over- and underdosage of SOX3 is associated with X-linked hypopituitarism with variable phenotypes ranging from isolated GH deficiency (GHD) to panhypopituitarism, with or without mental retardation and, in most cases, with reported pituitary imaging, an ectopic/undescended posterior pituitary. PATIENT: We present a young patient with hemophilia B and developmental delay who had a 2.31-Mb deletion on Xq27 including SOX3, F9, and eight other contiguous genes. He developed GH and gonadotropin deficiency, whilst his thyroid function was in the low normal range. Magnetic resonance imaging revealed a eutopic posterior pituitary and the unusual finding of a persistent craniopharyngeal canal that has not previously been described in patients with congenital hypopituitarism. OBJECTIVE AND METHODS: To establish whether loss of SOX3 can account for the human phenotype, we examined in detail the hypothalamo-pituitary region of neonatal Sox3 null mice. RESULTS: Consistent with the patient's phenotype, Sox3 null mice exhibit a ventral extension of the anterior pituitary that penetrates, and generates a mass beneath, the sphenoid bone. This suggests that the defect results from abnormal induction of Rathke's pouch, leading to a persistent connection between Rathke's pouch and the oral ectoderm. CONCLUSIONS: Our observations expand the spectrum of phenotypes observed in association with altered SOX3 dosage and may affect the approach to genetic screening. Screening for SOX3 should be advised not only for hypopituitary patients with an ectopic posterior pituitary, but also for those with a structurally normal pituitary and additional findings, including clefts and a persistent craniopharyngeal canal, with or without mental retardation.

Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes.

BACKGROUND: Low fibrinogen levels are known to occur in trauma. However, the extent of fibrinogen depletion during trauma hemorrhage, the response to replacement therapy and association with patient outcomes remain unclear. OBJECTIVES: The study aims were to: characterize admission fibrinogen level and correlate it with factors associated with injury; describe the time course of fibrinogen depletion and response to replacement therapy; determine the correlation of fibrinogen level with rotational thromboelastography (ROTEM) parameters; evaluate the effect of fibrinogen supplementation ex vivo; and establish the association between fibrinogen level and clinical outcomes. METHODS: This was a prospective cohort study of 517 patients. Blood samples were drawn on admission and after admistration of every 4 units of packed red blood cells. Fibrinogen levels were determined with the Clauss method, and global hemostatic competence was assessed with thromboelastometry. The effect of fibrinogen supplementation was assessed in a subgroup of coagulopathic patients. RESULTS: Low admission fibrinogen level was independently associated with injury severity score (P < 0.01), shock (P < 0.001), and prehospital fluid volume (P < 0.001). Fibrinogen supplementation during transfusion maintained but did not augment fibrinogen levels. Administration of cryoprecipitate was associated with improved survival. ROTEM parameters correlated with fibrinogen level, and ex vivo fibrinogen administration reversed coagulopathic ROTEM parameters. Fibrinogen level was an independent predictor of mortality at 24 h and 28 days (P < 0.001). CONCLUSIONS: Fibrinogen level is decreased in injured patients on admission and is associated with poor outcomes. ROTEM is a rapid means of assessing hypofibrinogenemia. Earlier administration of specific fibrinogen replacement may improve outcomes, and prospective controlled trials are urgently needed.

What's new in resuscitation strategies for the patient with multiple trauma?

The last decade has seen a sea change in the management of major haemorrhage following traumatic injury. Damage control resuscitation (DCR), a strategy combining the techniques of permissive hypotension, haemostatic resuscitation and damage control surgery has been widely adopted as the preferred method of resuscitation in patients with haemorrhagic shock. The over-riding goals of DCR are to mitigate metabolic acidosis, hypothermia and coagulopathy and stabilise the patient as early as possible in a critical care setting. This narrative review examines the background to these changes in resuscitation practice, discusses the central importance of traumatic coagulopathy in driving these changes particularly in relation to the use of high FFP:RBC ratio and explores methods of predicting, diagnosing and treating the coagulopathy with massive transfusion protocols as well as newer coagulation factor concentrates. We discuss other areas of trauma haemorrhage management including the role of hypertonic saline and interventional radiology. Throughout this review we specifically examine whether the available evidence supports these newer practices.

Acquired factor V inhibitor in a critically ill patient.

Acquired inhibitor of factor V is a rare condition with a variety of clinical manifestations, from extremely mild to life threatening haemorrhage. We present a case from our intensive care unit as a reminder of the less common causes of elevated prothombin and activated partial thromboplastin times, and how knowledge of the variable presentation may aid management.

Achievement of immune tolerance in a patient with haemophilia B and inhibitory antibodies, complicated by an anaphylactoid reaction.

We describe a young boy with severe haemophilia B who developed inhibitory antibodies and an anaphylactoid reaction to factor IX. Immune tolerance was achieved by desensitisation with escalating doses of factor IX followed by the Malmö regimen.

The multi-disciplinary evaluation of a national agri-environment scheme.

With an increasing amount of public funds being spent on agri-environmental schemes effective methods have to be developed to evaluate them. As many schemes have multiple objectives there is a need for a multi-disciplinary approach to any evaluation. A method was developed to assess the degree to which ecological, landscape, historical and access objectives for the Countryside Stewardship Scheme (CSS) in England have been met. The method used a sample of 484 agreements for which data were collected from surveys, a desk study and an interview with the agreement holder. These data were then evaluated by an expert team of an ecologist, landscape architect, landscape historian, and a social scientist specializing in rural affairs. The team were subsequently brought together with a Chair to discuss their findings for each agreement, allocating scores for each of five criteria: agreement negotiation; appropriateness, environmental effectiveness, compliance and side effects. The additionality that each agreement was likely to provide was also assessed. The results of this process suggest that in the majority of cases the CSS agreements should maintain or enhance the environment in terms of ecology, landscape, and landscape history and increase public enjoyment of the countryside. Thirty-six percent of agreements showed high additionality and 38% medium additionality which demonstrates that the CSS is likely to provide a benefit to society. Agreement negotiation, predicted environmental effectiveness and predicted compliance all improved significantly over the period 1996-98. Recommendations made from this project have been implemented by the Government department to improve the CSS. The multi-disciplinary method was successful and, with further development, could be used for assessment of any agri-environment scheme, or potentially any conservation project or broader 'rural development' scheme encompassing environmental, economic and social objectives. A key to success is the need for the criteria to be tailored for the project concerned and clearly established at the beginning.