Critical Care 2006, 10:218

Whether it is the primary reason for admission or a complication of critical illness, upper gastrointestinal bleeding is commonly encountered in the intensive care unit. In this setting, in the absence of endoscopy, intensivists generally provide supportive care (transfusion of blood products) and acid suppression (such as proton pump inhibitors). More recently, octreotide (a somatostatin analogue) has been used in such patients. However, its precise role in patients with upper gastrointestinal bleeding is not necessarily clear and the drug is associated with significant costs. In this issue of Critical Care, two expert teams debate the merits of using octreotide in non-variceal upper gastrointestinal bleeding.

Critical Care 2006, 10:R104

Recombinant activated factor VII (rFVIIa) has been used as adjunctive therapy in trauma patients with severe bleeding. However, its pharmacokinetics profile remains unknown.

Methods
In two placebo-controlled studies in patients with blunt and penetrating trauma, the pharmacokinetics of rFVIIa given at an initial dose of 200 µg.kg^-1 after transfusion of eight red blood cell units, followed by additional doses of 100 µg.kg^-1, one and three hours later, have been studied, based on the FVII coagulant activity assay. Both non-compartment and population pharmacokinetic analyses were performed. A two-compartment, population pharmacokinetic model was used to estimate a population profile for the rFVIIa dosing regimen. Data are population means (percent coefficient of variation (CV)).

Results
Based on the two-compartment population model, the estimated pharmacokinetic parameters were: clearance 40 (30% CV) ml.kg^-1.h^-1; central volume of distribution 89 (32% CV) ml.kg^-1; inter-compartmental clearance 24 ml.kg^-1.h^-1; and peripheral compartment volume 31 ml.kg^-1. Baseline FVII coagulant activity was estimated at 0.29 (39% CV) U.ml^-1, initial half-life was 0.6 (34% CV) hours, and terminal half-life 2.4 (50% CV) hours. High intra- and inter-patient variability was noted in volume of distribution and clearance, which was in part correlated with the transfusion requirements as the single significant covariate. The non-compartmental analysis led to almost identical estimates of key parameters.

Conclusion
A high intra- and inter-patient variability was noted in the volume of distribution and clearance of rFVIIa in trauma patients with severe bleeding, mainly related with the transfusion requirements and thus blood loss and/or bleeding rate.

Critical Care 2006, 10:R120  http://ccforum.com/content/10/4/R120

Our aim was to develop consensus guidelines for use of recombinant activated factor VII (rFVIIa) in massive hemorrhage.

Methods
A guidelines committee derived the recommendations using clinical trial and case series data identified through searches of available databases. Guidelines were graded on a scale of A-E according to the strength of evidence available. Consensus was sought among the committee for each recommendation.

Results
A recommendation for use of rFVIIa in blunt trauma was made (grade B). rFVIIa might also be beneficial in post-partum hemorrhage (grade E), uncontrolled bleeding in surgical patients (grade E) and bleeding following cardiac surgery (grade D). rFVIIa could not be recommended for use: in penetrating trauma (grade B); prophylactically in elective surgery (grade A) or liver surgery (grade B); or in bleeding episodes in patients with Child-Pugh A cirrhosis (grade B). Efficacy of rFVIIa was considered uncertain in bleeding episodes in patients with Child-Pugh B and C cirrhosis (grade C). Monitoring of rFVIIa efficacy should be performed visually and by assessment of transfusion requirements (grade E), while thromboembolic adverse events are a cause for concern. rFVIIa should not be administered to patients considered unsalvageable by the treating medical team.

Conclusions
There is a rationale for using rFVIIa to treat massive bleeding in certain indications; however, only adjunctively to the surgical control of bleeding once conventional therapies have failed. Lack of data from randomized, controlled clinical trials, and possible publication bias of the case series data, limits the strength of the recommendations that can be made.

J Trauma 2005;59:8–18

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 ug/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.

Health Technol Assess 2005;9(49).

Objectives
The objectives of this study were to assess the benefits in terms of reductions in the risks of deep vein thrombosis (DVT) and of pulmonary embolism (PE), and hazards in terms of major bleeding, of: (i) mechanical compression (graduated compression stockings, intermittent pneumatic compression, footpumps); (ii) oral anticoagulants; (iii) dextran; and (iv) regional anaesthesia (as an alternative to general anaesthesia) in surgical and medical patients.

Search strategy
The strategy involved a systematic search of electronic databases (MEDLINE, EMBASE, BIOSIS, Derwent), search of the Antithrombotic Trialists’ Collaboration database, contact with trialists and manufacturers, and scrutiny of bibliographies of identified papers and reviews of thromboprophylaxis.

Selection criteria
Properly randomised trials were selected, including those reported in a non-English language, with at least one unconfounded comparison of the effect of one of the methods under review versus control, or a direct comparison between different versions of a method, or a direct comparison between a pharmacological agent (dextran or an oral anticoagulant) and low molecular weight or unfractionated heparin. Trials were included only if systematic assessment of DVT by radiological methods was planned.

Data collection and analysis
All trials identified as fitting the selection criteria were independently assessed by at least two review authors for methodological quality and the numbers of patients with primary and secondary outcomes were recorded. The primary outcomes were DVT, PE and major bleeding events, and proximal venous thrombosis (PVT) and fatal PE were secondary outcomes. Trials were subdivided into those that had assessed a method as the only means of thromboprophylaxis (‘monotherapy’) and those that had assessed the effects of adding a method to another form of thromboprophylaxis (‘adjunctive therapy’).

Main results
Mechanical compression methods reduced the risk of DVT by about two-thirds when used as monotherapy and by about half when added to a pharmacological method. These benefits were similar irrespective of the particular method used (graduated compression stockings, intermittent pneumatic compression or footpumps) and similar in each of the surgical groups studied. Mechanical methods reduced the risk of PVT by about half and the risk of PE by two-fifths.

Oral anticoagulants, when used as monotherapy, reduced the risk of DVT and of PVT by about half, and this protective effect appeared similar in each of the surgical groups studied. There was an apparently large four-fifths reduction in the role of PE, but not only was the magnitude of this reduction statistically uncertain, but also pulmonary embolism was reported by a minority of trials, so it may be subject to selection bias. Oral anticoagulant regimens approximately doubled the risk of major bleeding. Oral anticoagulant regimens appeared less effective at preventing DVT than heparin regimens [64% (standard error [SE] 8 ) greater risk of DVT], although were associated with less major bleeding [35% (10) risk reduction for major bleeds].

Dextran reduced the risk of DVT and of PVT by about half, again irrespective of the type of surgery, but too few studies had reported PE to provide reliable estimates of effect on this outcome. Dextran appeared to be less effective at preventing DVT than the heparin regimens studied. Dextran was associated with an increased risk of bleeding, but too few bleeds had occurred for the size of this excess risk to be estimated reliably.

Compared with general anaesthesia, regional anaesthesia reduced the risk of DVT by about half, and this benefit appeared similar in each of the surgical settings studied. Regional anaesthesia was associated with less major bleeding than general anaesthesia.
Conclusion
In the absence of a clear contraindication (such as severe peripheral arterial disease), patients undergoing a surgical procedure would be expected to derive net benefit from a mechanical compression method of thromboprophylaxis (such as graduated compression stockings), irrespective of their absolute risk of venous thromboembolism. Patients who are considered to be at particularly high risk of venous thromboembolism may also benefit from a pharmacological thromboprophylactic agent, but since oral anticoagulant and dextran regimens appear less effective at preventing DVT than standard low-dose unfractionated heparin or low molecular weight heparin regimens, they may be less suitable for patients at high risk of venous thromboembolism, even though they are associated with less bleeding. Whenever feasible, the use of regional anaesthesia as an alternative to general anaesthesia may also provide additional protection against venous thromboembolism. There is little information on the prevention of venous thromboembolism among high-risk medical patients (such as those with stroke), so further randomised trials in this area would be helpful.

Anaesthesia 60 (12), 1203-1212.

Recombinant activated factor VII is a safe and effective for the treatment and prevention of haemorrhage in haemophiliacs with circulating inhibitors to replacement factors, and patients with Glanzmann’s thrombasthenia refractory to platelet transfusion. By restoring thrombin generation on the surface of tissue factor bearing cells, such as activated platelets and monocytes, recombinant activated factor VII has the potential to effect haemostasis in the setting of many coagulopathic states encountered by the anaesthetist in the operating theatre or the intensive care unit. Case reports of successful rescue therapy make up the majority of the literature covering other, numerous, off-label uses of recombinant activated factor VII, although some randomised, controlled studies, mostly underpowered to address safety concerns, have been performed. However, off-label use is becoming increasingly popular judging by the number of published case reports. Additional randomised, controlled trials to determine the safe and appropriate use of this potentially valuable therapy in broader patient groups are eagerly awaited.