Determining surgical surge capacity with a hybrid simulation exercise.

Background: To help test and improve surgical surge capacity, mass casualty incident (MCI) exercises generate valuable information. Both large scale table-top exercises (TTX) and full-scale exercises (FSX) have limitations if you want to test an organisation's capability and structure. A hybrid exercise incorporating the advantages of TTX and FSX is a possible way forward, but is no standardised exercise method, yet. This study aims at evaluating the exercise results to determine the feasibility of a hybrid TTX/FSX exercise for an organization's capability and structure. Methods: A hybrid MCI simulation using moulaged figurants and simulation cards was designed, where the emergency department of a level 1 trauma centre receives 103 casualties over 4 h. After registration and triage, all casualties are expected to be resuscitated in real time and are transferred for further treatment inside the hospital (radiology, operating theatres, intensive care unit (ICU)/postop and wards). When reaching operation theatre, ICU or ward, figurants are replaced by simulation cards. Observers ensured that those procedures performed were adequate and adhered to realistic times. Use of resources (materials, drugs etc.) were registered. Primary endpoint was average time spent in the emergency department, from time of arrival, to transfer out. Secondary endpoints were related to patient flow and avoidable fatalities. Results: The hospital managed to deal with the flow of patients without collapse of existing systems. Operating theatres as well as ICU and ward beds were available at the end of the exercise. Several details in the hospital response were observed that had not been noticed during previous TTX. Conclusion: FSX have a valuable role in training, equipping, exercising, and evaluating MCI management. Hybrid simulations combining both FSX and TTX may optimise resource utilisation and allow more frequent exercises with similar organisational benefit.

Determining the educational impact of virtual patients on trauma team training during a multinational, large-scale civil military simulation exercise.

BACKGROUND: With asymmetrical conflicts ongoing, many countries have an increasing number of major trauma events but limited capacity to cope with these events. Training for such events comprises primarily of simulations requiring significant resources and that are time-consuming and expensive. Virtual patients are defined as computer-based programs presenting authentic cases support training in trauma management. HYPOTHESIS: Assisted learning technologies augment simulated trauma team training and can improve trauma team competencies. The aim was to investigate if virtual patients increased competencies in decision making required and to identify deficiencies in care for the management of trauma patients during a multinational civil military trauma exercise. METHODS: A prospective educational intervention study with mixed methods, measuring the effects of a novel virtual patient model on trauma teams, was performed. The population consisted of surgeons, anesthesiologists, emergency department physicians, nurses, and paramedics (n = 30) and constituted six trauma teams from eight countries; three trauma teams formed the participating group, and three were allocated as control group. The participating group was exposed to virtual patients before, during, and after the live simulation exercise. Data sources were derived from individual preassessments and postassessments, evaluations made by experts in trauma, and video recordings of performance during the live simulation exercise and analyzed by the thematic analysis method. RESULTS: Using virtual patients contributed to improved individual knowledge about the management of major trauma patients and improved teamwork. Virtual patients as support for reasoning in decision making were directly correlated to level of previous knowledge and experience. Two of the three participating trauma teams showed lower levels of existing knowledge and competence in managing major trauma patients and therefore made more efficient use of the virtual patients. CONCLUSION: Results demonstrated advantages using virtual patients during a major civil military trauma live simulation exercise and appear to be supportive especially for teams who are not as experienced. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Clinical Efficacy and Safety of a Novel Antifungal, Fosmanogepix, in Patients with Candidemia Caused by Candida auris: Results from a Phase 2 Trial.

Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including fungi resistant to standard of care antifungals. This multicenter, open-label, single-arm study evaluated FMGX safety and efficacy for treatment of candidemia and/or invasive candidiasis caused by Candida auris. Eligible participants were ≥18 years, with established candidemia and/or invasive candidiasis caused by C. auris, (cultured within 120 h [for candidemia] or 168 h [for invasive candidiasis without candidemia] with accompanying clinical signs) and limited treatment options. Participants were treated with FMGX (≤42 days; loading dose: 1000 mg IV twice daily [Day 1], followed by 600 mg IV once daily [QD]). Switching to oral FMGX 800 mg QD was permitted from Day 4. Primary endpoint was treatment success (survival and clearance of C. auris from blood/tissue cultures without additional antifungals) at the end of the study treatment (EOST), assessed by an independent data review committee (DRC). Day 30 survival was a secondary endpoint. In vitro susceptibility of Candida isolates was assessed. Nine participants with candidemia (male:6, female:3; 21 to 76 years) in intensive care units in South Africa were enrolled; all received IV FMGX only. DRC-assessed treatment success at EOST and Day 30 survival were 89% (8/9). No treatment related adverse events or study drug discontinuations were reported. FMGX demonstrated potent in vitro activity against all C. auris isolates (MIC range: 0.008 to 0.015 µg/mL [CLSI]; 0.004-0.03 µg/mL [EUCAST]), with the lowest MICs compared to other antifungals tested. Thus, the results showed that FMGX was safe, well-tolerated, and efficacious in participants with candidemia caused by C. auris.

Teams managing civilian and military complex trauma: What are the competencies required in austere environments and the potential of simulation technology to address them?

Surgical training in civilian hospitals may not be sufficient for managing complex trauma in a setting where such care is not commonly practiced. Understanding the challenges that civilian teams face when moving to austere environments can inform the competencies that need to be trained. The aim of this study was to explore the competencies required in austere environments for teams managing complex trauma, and how they can be trained with simulation technologies. Ethnographic field observations were conducted, and field notes were synthesized. The field notes were structured with the elements of Activity Theory to generate the teams' competencies that need to be trained. A literature review was conducted to verify the results and identify examples of relevant simulation modalities. The analysis resulted in a structured list of competencies for civilian teams to manage complex trauma in an austere environment and recommendations which simulation technologies could be used in training of those competencies based on published studies. Our study contributes to understanding the challenges that civilian teams face when operating in an austere environment. A systematized list of competencies with suggested simulation technologies directs future research to improve quality of complex trauma training in civilian and military collaboration.

Swedish emergency hospital surgical surge capacity to mass casualty incidents.

BACKGROUND: In Sweden the surgical surge capacity for mass casualty incidents (MCI) is managed by county councils within their dedicated budget. It is unclear whether healthcare budget constraints have affected the regional MCI preparedness. This study was designed to investigate the current surgical MCI preparedness at Swedish emergency hospitals. METHODS: Surveys were distributed in 2015 to department heads of intensive care units (ICU) and surgery at 54 Swedish emergency hospitals. The survey contained quantitative measures as the number of (1) surgical trauma teams in hospital and available after activating the disaster plan, (2) surgical theatres suitable for multi-trauma care, and (3) surgical ICU beds. The survey was also distributed to the Armed Forces Centre for Defence Medicine. RESULTS: 53 hospitals responded to the survey (98%). Included were 10 university hospitals (19%), 42 county hospitals (79%), and 1 private hospital (2%). Within 8 h the surgical capacity could be increased from 105 to 399 surgical teams, while 433 surgical theatres and 480 ICU beds were made available. The surgical surge capacity differed between university hospitals and county hospitals, and regional differences were identified regarding the availability of surgical theatres and ICU beds. CONCLUSIONS: The MCI preparedness of Swedish emergency care hospitals needs further attention. To improve Swedish surgical MCI preparedness a national strategy for trauma care in disaster management is necessary.

Decision-Making in Management of the Complex Trauma Patient: Changing the Mindset of the non-trauma Surgeon.

BACKGROUND: European surgeons are frequently subspecialized and trained primarily in elective surgical techniques. As trauma leaders, they may occasionally have to deal with complex polytrauma, advanced management techniques, differing priorities, and the need for multidisciplinary care. There is a lack of expertise, experience, and a low trauma volume, as well as a lack of research, with limited support as to the decision-making and teaching challenges present. We studied what experienced trauma experts describe as the challenges that are specific to the advanced surgical decision-making required, whether civilian, humanitarian, or military. METHODS: Design-based research using combined methods including interviews, reviews of authentic trauma cases, and video-recorded resuscitations performed at a high-volume civilian academic trauma center. RESULTS: Several educational dilemmas were identified: (1) thinking physiologically, (2) the application of damage control resuscitation and surgery, (3) differing priorities and time management, (4) impact of environment, (5) managing limited resources, (6) lack of general surgical skills, (7) different cultural behavior, and (8) ethical issues. CONCLUSION: The challenges presented, and the educational domains identified, constitute a basis for improved development of education and training in complex surgical decision-making. This study contributes new knowledge about the mindset required for decision-making in patients with complex multisystem trauma and competing priorities of care. This is, especially important in countries having a low intensity of trauma in both military and civilian environments, and consequential limited skills, and lack of expertise. Guidelines focused on the same decision-making process, using virtual patients and blended learning, can be developed.

The potential of blended learning in education and training for advanced civilian and military trauma care.

INTRODUCTION: In the field of advanced care of the complex trauma patient, there is an emerging need for focused education and training. However, several hospitals do not support further education and training in this field, and the challenge of releasing time for physicians and nurses is well-known. Educational strategies using blended learning, which combines traditional classroom methods with modern computer-assisted methods and media, have not yet been widely used. This study analysed the educational challenges and areas for improvement, according to senior physicians and nurses, and investigated the potential use of blended learning. METHOD: The setting was an international course, Definitive Surgical Trauma Care (DSTC) - Military Version, part of a programme which prepares health professionals for work during extreme conditions. The sample consisted of senior physicians and nurses, participating in the course in September 2015. A survey was completed, interviews were performed and a post-course survey was conducted 18 months later in March 2017. RESULTS: The most difficult aspect of learning how to manage the complex trauma patient, was the lack of real practice. Even though the respondents were knowledgeable in advanced trauma, they lacked personal experience in managing complex trauma cases. Cases presented during the course represented significantly greater complexity of injury compared to those usually seen in hospitals and during military deployment. The following educational challenges were identified from the study: (1) Lack of experience and knowledge of advanced trauma care. (2) Lack of the use of blended learning as support for education and training. (3) Limited time available for preparation and reflection in the education and training process. (4) Lack of support for such education and training from home hospitals. (5) The unfulfilled requirement for multidisciplinary team-training in the military medical environment. CONCLUSION: Educational strategies and methods, such as blended learning can support education and training, and the learning process by unlimited practice in reasoning and decision making in virtual patients. It can also provide flexibility and mobility for senior health professionals and their home hospitals, and contribute to an improved military pre-deployment training with less time strain on the civilian home hospitals.

The challenges of military medical education and training for physicians and nurses in the Nordic countries - an interview study.

BACKGROUND: Development and use of e-learning has not taken place to the same extent in military medicine in the Nordic countries. The aim was to explore the similarities and differences in education and training in military medicine for health professionals in the Nordic countries, and more specifically to identify the specific challenges regarding education and training of military medicine, and how e-learning is used at present and the opportunities for the future. METHODS: Key educators within military medicine in the Nordic countries, as approved by the respective Surgeons General, were interviewed and the interviews were analyzed using content analysis. RESULTS: The data showed that all Nordic countries cooperate in the field of military medical training to some extent. The models of recruitment and employment of health professionals differed as well as the degree of political support. These differences affected the ability for health professionals to gain actual experience from the military environment. To improve the quality of medical education and training, attempts were made to recruit physicians. The recruitment of physicians was considered a challenge which had resulted in disruptions of courses, training programs and maintenance of accreditation. The Nordic countries were described as having commonalities in the military medical systems and common needs for international collaboration within training, but differing in the range of education and training. Gaps were identified in methods for transferring outcomes from education into practice, as well as regarding evaluation and feedback of outcomes to military medicine. The educational tradition was described as oriented towards practical skills training without requirements on pedagogical education of educators. The results confirmed previous studies showing that e-learning was underutilized. Contextual understanding and experience of healthcare were seen as crucial factors for successful e-learning development. CONCLUSIONS: Extended Nordic cooperation on military medical education and training are needed because of the limited volumes of advanced trauma cases. A key issue to the success of e-learning and blended learning is combining educational competence with contextual understanding into a strategy, of how to use digital educational methods.

Penetrating Thoracic Trauma Patients with Gross Physiological Derangement: A Responsibility for the General Surgeon in the Absence of Trauma or Cardiothoracic Surgeon?

BACKGROUND: Penetrating trauma is becoming increasingly common in parts of the world where previously it was rare. At the same time, general surgeons and surgical trainees are becoming more specialized, and less comfortable operating within areas beyond their zone of specialization. OBJECTIVE: The purpose of this manuscript is to assess the technical difficulties encountered in operating on patients who have sustained penetrating trauma, and to prove to general surgeons that the technical skills and techniques required are no different to those required for abdominal surgery, and do not require additional dexterity. METHODS: This prospective study was conducted in an Academic Trauma unit over a 3-year period. All patients who were operated upon for penetrating thoracic trauma were included in the study. The pre-operative management, techniques of surgical repair and the outcome were assessed. RESULTS: One hundred and forty-five patients were included in the study over a 3-year period. There were 97 patients with stab wounds, 47 with gunshot wounds and 1 patient with an injury from an angle grinder. Mortality was six times greater in those patients with gunshot wounds, than those with stab wounds. Several patients had multiple thoracic organ injuries. There were 57 patients who were operated upon for thoracic vessel injury. There was a 3.5 % mortality overall. Eighty-eight patients sustained pulmonary injury with a 7 % mortality, and they were managed mainly by simply repair, tractotomy or stapled partial non-anatomical lobectomy. Of the 39 patients with cardiac trauma, there was 17 % mortality, and all cases were managed by simple repair. There were 5 patients with an oesophageal injury of whom 3 died (mortality of 60 %). Twenty-four patients had thoraco-abdominal injuries with 30 % mortality. CONCLUSION: Most of the injuries in the chest can be managed by simple procedures to control life-threatening bleeding. The techniques required are similar to those taught to and are practiced comfortably by general surgeons used to work in the abdominal cavity. We encourage the general surgeon who receives a grossly unstable patient with penetrating thoracic trauma to operate, instead of adding risk to the patient's physiology by a transfer to cardio-thoracic or dedicated trauma units.

Haemodialysis for post-traumatic acute renal failure - factors predicting outcome.

BACKGROUND: Post-traumatic acute renal failure requiring renal replacement therapy in an intensive care unit (ICU) is associated with high mortality. OBJECTIVE: To assess indicators of improved survival. METHODS: This was a retrospective cohort study of 64 consecutive trauma patients (penetrating and blunt trauma and burns) who underwent haemodialysis (HD) over a period of 5 years. Information on pre-hospital and in-hospital resuscitation, trauma scores and physiological scores and daily ICU records were collected. The majority of the patients were dialysed with continuous venovenous haemofiltration in the early years of the study and later with sustained low-efficiency dialysis. RESULTS: Of the 64 patients 47 died, giving an overall mortality rate of 73%. Mortality was highest in the burns patients (84%). Survival in all patients, irrespective of injury, was unrelated to the Revised Trauma Score, Injury Severity Score, Acute Physiology and Chronic Health Evaluation Score or Trauma Injury Severity Score. The duration of HD did not differ significantly between the three trauma groups, and age was not a significant predictor of survival. Patients who were polyuric at the time of the initiation of HD had a lower mortality rate than those who were oliguric, anuric or normouric, although this did not reach statistical significance (p=0.09). CONCLUSIONS: Acute renal failure in trauma patients is associated with a low survival rate. Controversial conclusions have been presented in the literature. In this study, none of the parameters previously reported to affect survival proved to be valid, although the number of patients was comparable with those in other studies. Since understanding of the predictors and course of renal failure in trauma patients is still at an early stage, there is a need for multicentre prospective studies.

Selective non-operative management of abdominal gunshot wounds: survey of practise.

BACKGROUND: There is a growing body of evidence attesting to the effectiveness and safety of selective non-operative management (SNOM) of abdominal gunshot wounds. However, much of the research which supports this conclusion has originated from a few centres, and the actual utilisation of SNOM by trauma surgeons is not known. We therefore conducted a survey to assess the acceptance of this strategy and evaluate variations in practise. METHODS: Electronic questionnaire survey of trauma surgeons in the United States of America, Canada, Brazil, and South Africa. Responses were compared using Chi(2) and Fisher's exact tests. RESULTS: 183 replies were received. 105 (57%) respondents practise SNOM of abdominal gunshot wounds, but there are marked regional variations in the acceptance of this strategy (p<0.01). Respondents who had completed trauma (p<0.01) or critical care (p<0.01) fellowships, and those who practise in a higher volume centre (defined as >50 penetrating abdominal injuries seen per year) (p<0.01) are more likely to practise SNOM of gunshot wounds. Most surgeons who practise SNOM regard peritonitis, omental and bowel evisceration, and being unable to evaluate a patient as a contraindication to attempting non-operative management. Almost all regard CT as essential. Respondents' preparedness to consider SNOM is related to injury extent. CONCLUSIONS: SNOM of abdominal gunshot wounds is practised by trauma surgeons in all four countries surveyed, but is not universally accepted, and there are variations in how it is practised.

Antimicrobial susceptibility of gram-negative pathogens isolated from patients with complicated intra-abdominal infections in South African hospitals (SMART Study 2004-2009): impact of the new carbapenem breakpoints.

BACKGROUND: The Study for Monitoring Antimicrobial Resistance Trends (SMART) follows trends in resistance among aerobic and facultative anaerobic gram-negative bacilli (GNB) isolated from complicated intra-abdominal infections (cIAIs) in patients around the world. METHODS: During 2004-2009, three centralized clinical microbiology laboratories serving 59 private hospitals in three large South African cities collected 1,218 GNB from complicated intra-abdominal infections (cIAIs) and tested them for susceptibility to 12 antibiotics according to the 2011 Clinical Laboratory Standards Institute (CLSI) guidelines. RESULTS: Enterobacteriaceae comprised 83.7% of the isolates. Escherichia coli was the species isolated most commonly (46.4%), and 7.6% of these were extended-spectrum ß-lactamase (ESBL)-positive. The highest ESBL rate was documented for Klebsiella pneumoniae (41.2%). Overall, ertapenem was the antibiotic most active against susceptible species for which it has breakpoints (94.6%) followed by amikacin (91.9%), piperacillin-tazobactam (89.3%), and imipenem-cilastatin (87.1%), whereas rates of resistance to ceftriaxone, cefotaxime, ciprofloxacin, and levofloxacin were documented to be 29.7%, 28.7%, 22.5%, and 21.1%, respectively. Multi-drug resistance (MDR), defined as resistance to three or more antibiotic classes, was significantly more common in K. pneumoniae (27.9%) than in E. coli (4.9%; p<0.0001) or Proteus mirabilis (4.1%; p<0.05). Applying the new CLSI breakpoints for carbapenems, susceptibility to ertapenem was reduced significantly in ESBL-positive E. coli compared with ESBL-negative isolates (91% vs. 98%; p<0.05), but this did not apply to imipenem-cilastatin (95% vs. 99%; p=0.0928). A large disparity between imipenem-cilastatin and ertapenem susceptibility in P. mirabilis and Morganella morganii was documented (24% vs. 96% and 15% vs. 92%, respectively), as most isolates of these two species had imipenem-cilastatin minimum inhibitory concentrations in the 2-4 mcg/mL range, which is no longer regarded as susceptible. CONCLUSIONS: This study documented substantial resistance to standard antimicrobial therapy among GNB commonly isolated from cIAIs in South Africa. With the application of the new CLSI carbapenem breakpoints, discrepancies were noted between ertapenem and imipenem-cilastatin with regard to the changes in their individual susceptibilities. Longitudinal surveillance of susceptibility patterns is useful to guide recommendations for empiric antibiotic use in cIAIs.

Recombinant activated factor VII safety in trauma patients: results from the CONTROL trial.

BACKGROUND: Safety data on recombinant activated factor VII (rFVIIa, NovoSeven; Novo Nordisk A/S, Bagsværd, Denmark) in actively hemorrhaging trauma patients are limited. We present detailed safety data from a large multicenter, randomized, placebo-controlled phase III study (the CONTROL trial). METHODS: Data from 560 patients were analyzed. Subjects were monitored for adverse events (AEs) after rFVIIa or placebo administration. Incidences, timing, and presence of risk factors were reported by site investigators, supported by external study monitors and overseen by an independent Data Monitoring Committee. RESULTS: There were no differences in overall mortality, organ system failure, or AEs, serious AEs, or medical events of special interest. Arterial and venous thromboembolic (TE) events and their risk factors were similar in both groups. The greatest risk factor for TE events was a chest injury requiring mechanical ventilation >3 days (86%). There were four site investigator-reported myocardial infarctions in the rFVIIa group of which only one met diagnostic criteria preestablished by the Data Monitoring Committee. There were no reported myocardial infarctions in the placebo group. Troponins were increased in 30% of all patients. The rate of acute respiratory distress syndrome was lower in the rFVIIa (3.0%) than in the placebo (7.2%) group (p = 0.022). CONCLUSIONS: This represents the largest placebo-controlled dataset of rFVIIa use in trauma patients to date. In this prospective study of critically bleeding trauma patients, rFVIIa use was associated with an imbalance of investigator-reported Acute myocardial infarction/non-ST segment elevation myocardial infarction (AMI/NSTEMI), but was not associated with an increased risk for other AEs, including TE complications.

[24 hours at Johannesburg Hospital Trauma Unit]. / En dag på en traumeenhed i Johannesburg.

This paper describes the hectic work as a doctor at the Trauma Unit of Charlotte Maxeke Johannesburg Academic Hospital, a highly regarded and well-visited trauma unit worldwide. A trauma junior doctor is followed on a 24-hour-call through a full casualty to urgent operations and complicated postoperative management of the trauma patient. In a diary fashion the paper describes the evidence-based guidelines of management of certain trauma cases brought into the trauma unit during the 24-hour-shift.

Guideline for the assessment of trauma centres for South Africa.

INTRODUCTION: Trauma is a well-known leading cause of unnatural death and disability in South Africa. Internationally the trend is moving toward systematised care. AIM: To revise the Trauma Centre Criteria of the Trauma Society of South Africa and align these with the terminology and modern scope of emergency care practice, using best-care principles as a prelude to the development of trauma systems in South Africa. METHODOLOGY: Revision of existing documents of the Trauma Society of South Africa, the Emergency Medicine Society of South Africa and the Critical Care Society of Southern Africa, where these are relevant to the care of trauma. The committee attempted to harmonise these criteria with the goals of the World Health Organization essential trauma care guidelines for trauma centres and trauma systems. Wide expert consultation was undertaken to refine the criteria before final compilation. RESULTS AND RECOMMENDATIONS: Four levels of trauma care facility are outlined, with the criteria focusing on the trauma-specific requirements of the facilities and their place in the greater trauma system. Accreditation of hospitals according to the criteria will allow for appropriate transfer and designation of patient destination for trauma patients and will improve the quality of care provided. The criteria address structural, process and human resource requirements and medical aspects for the accreditation of various level of trauma centre. CONCLUSION: There is a great opportunity to apply best practice criteria to improve the care of trauma in South Africa and improve patient outcome.

Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage.

BACKGROUND: Traumatic coagulopathy contributes to early death by exsanguination and late death in multiple organ failure. Recombinant Factor VIIa (rFVIIa, NovoSeven) is a procoagulant that might limit bleeding and improve trauma outcomes. METHODS: We performed a phase 3 randomized clinical trial evaluating efficacy and safety of rFVIIa as an adjunct to direct hemostasis in major trauma. We studied 573 patients (481 blunt and 92 penetrating) who bled 4 to 8 red blood cell (RBC) units within 12 hours of injury and were still bleeding despite strict damage control resuscitation and operative management. Patients were assigned to rFVIIa (200 µg/kg initially; 100 µg/kg at 1 hour and 3 hours) or placebo. Intensive care unit management was standardized using evidence-based trauma "bundles" with formal oversight of compliance. Primary outcome was 30-day mortality. Predefined secondary outcomes included blood products used. Safety was assessed through 90 days. Study powering was based on prior randomized controlled trials and large trauma center databases. RESULTS: Enrollment was terminated at 573 of 1502 planned patients because of unexpected low mortality prompted by futility analysis (10.8% vs. 27.5% planned/predicted) and difficulties consenting and enrolling sicker patients. Mortality was 11.0% (rFVIIa) versus 10.7% (placebo) (p = 0.93, blunt) and 18.2% (rFVIIa) versus 13.2% (placebo) (p = 0.40, penetrating). Blunt trauma rFVIIa patients received (mean ± SD) 7.8 ± 10.6 RBC units and 19.0 ± 27.1 total allogeneic units through 48 hours, and placebo patients received 9.1 ± 11.3 RBC units (p = 0.04) and 23.5 ± 28.0 total allogeneic units (p = 0.04). Thrombotic adverse events were similar across study cohorts. CONCLUSIONS: rFVIIa reduced blood product use but did not affect mortality compared with placebo. Modern evidence-based trauma lowers mortality, paradoxically making outcomes studies increasingly difficult.

Prolonged prothrombin time after recombinant activated factor VII therapy in critically bleeding trauma patients is associated with adverse outcomes.

BACKGROUND: In trauma patients with significant hemorrhage, it is hypothesized that failure to normalize prothrombin time (PT) after recombinant activated factor VII (rFVIIa) treatment predicts poor clinical outcomes and potentially indicates a need for additional therapeutic interventions. METHODS: To assess the value of PT to predict outcomes after rFVIIa or placebo therapy, we performed a post hoc analysis of data from 169 severely injured, critically bleeding trauma patients who had 1-hour postdose PT measurements from two randomized clinical trials. Baseline characteristics and outcome parameters were compared between subjects with 1-hour postdose PT >or=18 seconds and PT <18 seconds. RESULTS: In rFVIIa-treated subjects, prolonged postdose PT values >or=18 seconds were associated with significantly higher 24-hour mortality (60% vs. 3%; p < 0.001) and 30-day mortality, increased incidence of massive transfusion, and fewer intensive care unit-free days compared with postdose PT values <18 seconds. Recombinant rFVIIa-treated subjects with postdose PT >or=18 seconds had significantly lower baseline hemoglobin levels, fibrinogen levels, and platelet counts than subjects with postdose PT values <18 seconds even though they received similar amounts of blood products before rFVIIa dosing. Placebo-treated subjects with postdose PT >or=18 seconds had significantly increased incidence of massive transfusion, significantly decreased intensive care unit-free days, and significantly lower levels of fibrinogen and platelets at baseline compared with subjects with postdose PT values <18 seconds. CONCLUSIONS: The presence of prolonged PT after rFVIIa or placebo therapy was associated with poor clinical outcomes. Because subjects with postdosing PT >or=18 seconds had low levels of hemoglobin, fibrinogen, and platelets, this group may benefit from additional blood component therapy.

The treatment of bleeding is to stop the bleeding! Treatment of trauma-related hemorrhage.

BACKGROUND: The secret with any alternative to transfusion is to minimize the need for transfusion in the first place. This can be done by reducing the volume of blood loss. The volume of blood being lost can be reduced by direct methods where possible (i.e., hemostasis at the point of bleeding), or by improving the coagulation profile of the patient, thereby improving the extrinsic coagulation. Recombinant activated factor VII (rFVIIa) offers theoretical possibilities of improving the coagulation profile. STUDY DESIGN AND METHODS: The efficacy and safety of rFVIIa for the treatment of bleeding in patients with severe blunt and penetrating trauma has been investigated in two double-blind, placebo-controlled studies within a single trial-one on patients with blunt injury and the other in similar patients with penetrating injury. RESULTS: In patients with blunt trauma alive at 48 hours, treatment with rFVIIa effected a significant reduction in the primary endpoint of 48-hour red blood cell (RBC) transfusion requirement (p = 0.02), and the safety of the dosing regimen was established. Similar trends were observed in patients with penetrating injuries. Across both studies and treatment arms, the 48-hour mortality rate ranged from 16 to 19 percent. In the blunt trauma study, this equated to 13 patients from each arm who died before the benefits of treatment could be adequately assessed. Analysis of data for the 117 blunt trauma patients who survived at least 48 hours after receiving study treatment shows that, in addition to reducing RBC requirement, rFVIIa significantly reduced the need for massive transfusion over 48 hours (>20 RBC units) (relative risk reduction of 56% [95% confidence interval: 9%-79%]; p = 0.03), and the fresh-frozen plasma (p = 0.036), platelet (p = 0.023), and cryoprecipitate (p = 0.053) requirements within 48 hours, and was associated with a significant reduction in the 30-day risk of acute respiratory distress syndrome (ARDS) (p = 0.05) and multiple organ failure and/or ARDS (p = 0.05). CONCLUSION: Treatment with adjunctive rFVIIa significantly reduces transfusion requirements in the 48 hours after severe injury and these procoagulant effects may improve clinical outcome at 30 days.

Scientific and logistical challenges in designing the CONTROL trial: recombinant factor VIIa in severe trauma patients with refractory bleeding.

BACKGROUND: Clinical research in trauma patients poses multiple challenges in study design. These reflect the heterogeneity of injury and treatment, the paucity of acceptable study endpoints aside from mortality, and the difficulties inherent in obtaining informed consent in acutely ill populations. A current example of this problem is the study of recombinant factor VIIa (rFVIIa), which has attracted considerable interest as a systemic procoagulant agent for use in trauma patients with exsanguinating hemorrhage. PURPOSE: To report on the implementation of an international trial - CONTROL - intended to assess the efficacy and safety of rFVIIa in trauma, and discuss trauma research study design in light of this experience. METHODS: The CONTROL trial international steering committee confronted a number of barriers in the design of the CONTROL trial. They addressed methodologies for (1) standardizing entry criteria for trauma patients suffering inherently heterogeneous injuries, (2) obtaining informed consent in an acutely injured population with altered levels of consciousness, (3) avoiding futile care, while recruiting subjects with incompletely diagnosed injuries, (4) standardizing trauma intensive care across different investigating sites and countries, and (5) establishing study endpoints that were both clinically relevant and convincing to regulatory authorities. The resulting study methodology is reported. RESULTS: The CONTROL trial began active recruitment in October 2005, and was halted on June 11, 2008 because the observed mortality in the 576 enrolled patients was so far below expectations that the study would lack sufficient statistical power at the planned number of subjects to demonstrate a benefit. The utility of the endpoints selected for study will not be known until completion of data analysis. LIMITATIONS: Any clinical trial in trauma patients must cope with the urgency of care required, issues of patient heterogeneity, standardization of care across multiple centers, and the difficulties of obtaining informed consent. CONCLUSION: Research in acutely hemorrhaging trauma patients presents numerous scientific and ethical challenges. The methodology of the CONTROL study is presented as an example of how some of these challenges can be approached and managed, and of the pitfalls that may arise.