Kenneth D. Boffard

Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials.

BACKGROUND Uncontrolled bleeding is a leading cause of death in trauma. Two randomized, placebo-controlled, double-blind trials (one in blunt trauma and one in penetrating trauma) were conducted simultaneously to evaluate the efficacy and safety of recombinant factor VIIa (rFVIIa) as adjunctive therapy for control of bleeding in patients with severe blunt or penetrating trauma. METHODS Severely bleeding trauma patients were randomized to rFVIIa (200, 100, and 100 microg/kg) or placebo in addition to standard treatment. The first dose followed transfusion of the eighth red blood cell (RBC) unit, with additional doses 1 and 3 hours later. The primary endpoint for bleeding control in patients alive at 48 hours was units of RBCs transfused within 48 hours of the first dose. RESULTS Among 301 patients randomized, 143 blunt trauma patients and 134 penetrating trauma patients were eligible for analysis. In blunt trauma, RBC transfusion was significantly reduced with rFVIIa relative to placebo (estimated reduction of 2.6 RBC units, p = 0.02), and the need for massive transfusion (>20 units of RBCs) was reduced (14% vs. 33% of patients; p = 0.03). In penetrating trauma, similar analyses showed trends toward rFVIIa reducing RBC transfusion (estimated reduction of 1.0 RBC units, p = 0.10) and massive transfusion (7% vs. 19%; p = 0.08). Trends toward a reduction in mortality and critical complications were observed. Adverse events including thromboembolic events were evenly distributed between treatment groups. CONCLUSION Recombinant FVIIa resulted in a significant reduction in RBC transfusion in severe blunt trauma. Similar trends were observed in penetrating trauma. The safety of rFVIIa was established in these trauma populations within the investigated dose range.

Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: Subgroup analysis from two randomized trials

IntroductionWe conducted a post-hoc analysis on the effect of recombinant factor VIIa (rFVIIa) on coagulopathic patients from two randomized, placebo-controlled, double-blind trials of rFVIIa as an adjunctive therapy for bleeding in patients with severe trauma.MethodsBlunt and penetrating trauma patients were randomly assigned to rFVIIa (200 + 100 + 100 μg/kg) at 0, 1, and 3 hours after transfusion of 8 units of red blood cells (RBCs) or to placebo. Subjects were monitored for 48 hours post-dosing and followed for 30 days. Coagulopathy was retrospectively defined as transfusion of fresh frozen plasma (FFP) (>1 unit of FFP per 4 units of RBCs), FFP in addition to whole blood, and transfusion of platelets and/or cryoprecipitate.ResultsSixty rFVIIa-treated and 76 placebo subjects were retrospectively identified as being coagulopathic. No significant differences were noted in baseline characteristics. The rFVIIa-treated coagulopathic subgroup consumed significantly less blood product: RBC transfusion decreased by 2.6 units for the whole study population (P = 0.02) and by 3.5 units among patients surviving more than 48 hours (P < 0.001). Transfusion of FFP (1,400 versus 660 ml, P < 0.01), platelet (300 versus 100 ml, P = 0.01), and massive transfusions (29% versus 6%, P < 0.01) also dropped significantly. rFVIIa reduced multi-organ failure and/or acute respiratory distress syndrome in the coagulopathic patients (3% versus 20%, P = 0.004), whereas thromboembolic events were equally present in both groups (3% versus 4%, P = 1.00).ConclusionCoagulopathic trauma patients appear to derive particular benefit from early adjunctive rFVIIa therapy.

Intraoperative Blood Salvage in Penetrating Abdominal Trauma: a Randomised, Controlled Trial

BackgroundBlood is a scarce and costly resource. Transfusion is often required after major trauma but blood may not be readily available, and concerns remain over the potential adverse consequences of allogeneic blood transfusion. Intraoperative blood salvage (IBS) is used extensively after blunt abdominal trauma, but when blood is contaminated by enteric contents its use has been considered contraindicated.MethodsThis was a randomised, controlled trial conducted with Ethical Review Board approval in an inner city trauma unit. Patients with penetrating torso injury requiring a laparotomy and who had exhibited hypotension either pre-hospital or on arrival and in whom there was considered to be significant blood loss were randomly assigned to 2 groups. The control group was given allogeneic blood transfusion at the discretion of the attending medical staff. The cell save (CS) group underwent IBS with transfusion of both allogeneic and autologous blood. All patients received prophylactic antibiotics. The primary outcome was exposure to allogeneic blood up to the first 24 hours postinjury.ResultsTwenty-three patients were entered into the control group and 21 into the CS group. The groups were equivalent in demographic details, injury patterns and injury severity. The mean volume of salvaged blood re-infused in the CS group was 1,493 ml (range 0–2,690 ml). The mean number of units of allogeneic blood transfused in the first 24 hours in the control group was 11.17 compared to 6.47 in the CS group (P = 0.008). Enteric injury had been sustained in 17/23 (75%) of the control group and 18/21 (85%) of the CS group (P = NS). Survival in the control group was 8/23 (35%) compared to 7/21 (33.3%) in the CS arm (P = NS). Patients with documented postoperative sepsis were significantly more likely to die compared to those without sepsis (P = 0.04); however, those patients in the CS arm were no more likely to develop sepsis compared to those who received allogeneic blood alone.ConclusionIn this randomised, controlled trial for patients with penetrating abdominal injuries, IBS led to a significant reduction in allogeneic blood usage with no discernable effect on rates of postoperative infection or mortality.

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.

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.

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.

Penetrating vascular trauma in Johannesburg, South Africa

An awareness that time crucially affects outcome underpins the principles of management of vascular injury. Patients with hard signs of vascular injury should undergo urgent exploration. Soft signs mandate investigation, and arteriography is still the standard of care. Noninvasive vascular imaging may prove its worth in the future. All patients with penetrating arterial injury should receive broad-spectrum antibiotic prophylaxis. Early repair of carotid artery injury provides the best likelihood of a neurologically intact survivor. There is a definite and emerging role of endovascular therapy both for difficult access injuries and for the later complications of vascular injury, such as false aneurysm and arteriovenous fistulas. The experimental and clinical evidence for the use of intraluminal shunts in peripheral vascular injury is compelling, and experience in their use is accumulating. Vascular trauma is complex and ideally is carried out by experts in a multidisciplinary environment; resuscitation and prompt revascularization are likely to lead to satisfactory outcomes. The major trauma load in South Africa represents an unparalleled experience in management of vascular injury, which seems likely to continue for the foreseeable future.

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 β-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.

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. Clinical Trials 2009; 6: 467—479. http://ctj.sagepub.com

Guideline: appropriate use of tigecycline

INTRODUCTION Tigecycline, the first of a new class of antibiotics, the glycylcyclines, was licensed in South Africa for the parenteral treatment of adult patients with complicated intra-abdominal infections (cIAIs) and complicated skin and soft-tissue infections (cSSTIs). METHODS A multidisciplinary meeting representative of the Association of Surgeons of South Africa, the Critical Care Society of Southern Africa, the Federation of Infectious Diseases Societies of Southern Africa, the South African Thoracic Society and the Trauma Society of South Africa was held to draw up a national guideline for the appropriate use of tigecycline. Background information reviewed included randomised controlled trials, other relevant publications and local antibiotic susceptibility patterns. The initial document was drafted at the meeting. Subsequent drafts were circulated to members of the working group for modification. OUTPUT The guideline addresses several important aspects of the new agent, summarising key clinical data and highlighting important considerations with the use of the drug. The recommendations in this guideline are based on currently available scientific evidence together with the consensus opinion of the authors. CONCLUSION This statement was written out of concern regarding the widespread misuse of antibiotics. Its primary intention is to facilitate heterogeneous use of antibiotics as a component of antibiotic stewardship and to highlight the appropriate use of tigecycline in particular.