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Three Part Question

In [trauma patients requiring massive transfusion] does [the administration of Factor VIIa][improve outcome]?

Clinical Scenario

Two multi-trauma patients who died were independently presented for our regular M&M meeting. Both required massive transfusion intra-operatively and both received recombinant activated factor VII (rFVIIa) in an attempt to salvage them from exanguination.
We undertook a review of our massive transfusion policy to see if there was evidence for including rFVIIa in this policy.

Search Strategy

Ovid medline 1950 to June 2008

[factor VII.mp or Factor VI] and [blood transfusion or blood component or erythrocyte transfusion or transfusion.mp.]and [trauma.mp.or (wounds and injuries)]

Search Outcome

65 papers were found 59 of which were irrelevant or of insufficient quality. Two papers used the patients from the same data base (4,6).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Boffard KD, et al 2005 Australia/Canada/France/ et al	Trauma patients recieving rFVIIa (200,100, 100mgm/kg at 0 ,1 and 3 hours)or placebo commencing imediately after 8 units of blood n=301(158 blunt and 143 penetrating trauma)	Randomised double blinded placebo. Multi-center	Survival at 48 hrs	Placebo 115/138 (83%) vs rFVIIa 114/139 (82%)	Sponsored by Novo Nordisk. 24 (8%) ruled ineligble after initial enrollment 2% lost to follow up. Multi-center variance in practice. Not clear when surgical haemostasis achieved in relation to delivery of rFVIIa. Thromboembolic events not actively screened for. Not powered to show survival difference. Many blunt trauma patients remained in hospital beyond study time window.
			Survival at 30 days	Placebo 96/136 (71%) vs rFVIIa 102/136(75%)
			Thrombo-embolic events placebo vs rFVIIa group	6 in each group
			Mean reduction in transfusion requirement of treatment groups vs placebovs placebo	Blunt trauma 2.6 units. Penetrating trauma 1 unit reduction
			Massive transfusion requirement (defined as >20 units)	Blunt trauma Placebo 20/63(33%) vs rFVIIa 8/56 (14%) Penetrating placebo 10/54(19%) vs rFVIIa 4/58(7%)
Harrison TD et al 2005 USA	Trauma patients identified from Trauma Registry who recieved rFVIIa a minimum of 40mgm/kg, n=29. 15/29 were given a second dose. One to 3 controls per study patient were matched by ISS score+/-5 and were require to have recieved at least as many units of blood up to the point of administration of rFVIIa for the study group, n=72. 62/72 were blunt trauma. 25/29 of the study group were patients as a result of blunt trauma	Retrospective case control.	Total blood units required	Control 22+/- 9.7 rFVIIa 18.3+/-7.5 p=0.036	Retrospective historical controls.
			Baseline pH in those who died	Control 7.08 +/- 0.04 rFVIIa 7.07+/- 0.05
			Baseline pH in survivors	Control 7.27+/-0.02 vs rFVIIa 7.19+/-0.03
			Mortality at 28 days	Control 29/72 (40%) rFVIIa12/29 (41%)
			Thrombo-embolic events	Control 14/71 (19%) vs rFVIIa 2/29(7%)
Grounds RM et al 2006 Germany/Canada/Austria/Czech Republic et al	Patients with major bleeding requiring >13 units blood and received rFVIIa n=45, 36 of whom were result of trauma.	Data obtained from voluntary reporting data base	Blood use (median units)	pre -rFVIIa 20 vs 2 post rFVIIa	Not restricted to trauma. Positive bias likely with voluntary reporting
			Mortality	11/35 (31%)
Perkins J G et al May 2007 USA ,Iraq	Combat trauma patients recieving >8 units blood plus rFVIIa n=117 Divided into early (rFVIIa given before 8th unit)or late (rFVIIa given after 8th unit) Median dose of 9.6 mg per patient.	Retrospective chart review	Survival at 48 hours	Early 14/17 (82%) Late 38/44 (81%)	Retrospective review. Small numbers with significant loss to follow up (8)incomplete data (56)
			Survival to 30 days	Early 10/15 (67%) Late 25/38(66%)
			Blood transfusion requirement	Early 16.7 vs late 21.7 units
Cameron P et al May 2007 Australia, New Zealand	n=108 trauma patients (blunt injury accounting for 95)recieving rFVIIa at some time during their acute management 88 had ISS >15 (7 undocumented)	Multicenter n=19 Voluntary reporting of use of rFVIIa to Australia New Zealand Haemostasis Registry Looked at transfusion requirements before and after administration of rFVIIa.	Mean units of blood in first 24 hours (Inter Quartile Range )	Pre rFVIIa 16(8-23) vs post 3(0-8)	The authors could not "guarantee that every case from each hospital is included". No controls. Difficult to differentiate association from treatment effect. Novo Nordisk sponsored Inter-center variance in practice eg non-standardised dose, lack of standardised massive transfusion policy
			Mean units of all blood products in first 24 hours (Blood, FFP/ Cryoprecipitate/Platelets	Pre rFVIIa 34(19-51) vs post 7(0-17)
			Associations with high mortality (Odds Ratios)	pH<7.05 (53.6)Temp <35 C (5.6)ISS>26 (10.1)
Spinella PC et al Feb 2008 USA, Iraq	Trauma Registry for a Combat Support Hospital,Iraq (December 2003 - October 2005. Sub-group n=124, all severe combat related trauma (ISS>15) requiring massive transfusion(>9 units blood), 49 of whom received rFVIIa. No statistical differences in baseline mechanism of injury (92% penetrating trauma), physiological parameters Injury Severity Score (ISS)	Retrospective chart review	Mean 24 hour transfusion requirement (RBC)in survivors of >24hrs	16 units in rFVIIa group vs 14 (p=0.02)	Non-randomised chart review. 33 of the original study group of 246, were lost to follow-up, a further 47 were excluded due to treatment being commenced. Median time of death in group not recieving rFVIIa suggests selection bias. Low numbers. Unclear why more blood given in in rFVIIa group of survivors >24hrs.
			Median time to administration of in rFVIIa	120 mins(84-192)
			Survival at 24 hours	42/49 (86%) in rFVIIa group vs 49/75(65%)
			Mean time of death from arrival	43 hrs(2.7-155) in rFVIIa group vs 4 hrs(1.7-24)
			Thrombo-embolic events, multi-organ failure, sepsis, ARDS	No difference

Comment(s)

Red cell transfusion along with fresh frozen plasma, platelets and surgical control of bleeding are mainstay measures in the management of traumatic haemorrhage. In the setting of massive transfusion, rFVIIa has been shown to reduce ongoing requirement for blood products. One paper showed a non-significant mortality benefit at 28 days. It seems possible this may be partly due to the lower ongoing requirement for blood products. If used, best practice would appear to require early enough delivery of rFVIIa to avoid hypothermia, acidosis, coagulopathy during and after surgical control of bleeding. In June 2008 Novo-Nordisk discontinued a phase III multi centred double blinded placebo controlled trial of rFVIIa in trauma due to lack of mortality benefit. 550 of a planned 1502 patients were recruited. The original power calculation for the study over-estimated the overall mortality. Data from the study is yet to be published. The off-lable use of rFVIIa in trauma may result in under reporting of thrombo-embolic events.

Editor Comment

Older papers at Factor VIIa for intractable blood loss in trauma - http://www.bestbets.org/bets/bet.php?id=371

Clinical Bottom Line

The administration of rFVIIa reduces the requirement for ongoing RBC transfusion in trauma patients requiring massive transfusion. A clear mortality benefit has not been demonstrated. Local guidelines should be followed.

References

1. Boffard KD, Riou B, Warren B et al Recombinant Factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients:two parallel randomized, placebo-controlled, double blind clinical trials Journal of Trauma Injury Infection and Critical Care July 2005 59:8-18
2. Harrison TD, Laskosky J, Jazaeri O et al Low dose recombinant activated factor VII results in less blood and blood product use in traumatic hemorrhage The Journal of Trauma Injury,Infection and Critical Care July 2005 59(1)150-54
3. Grounds RM, Seebach C, Knothe C et al Use of recombinant activated Factor VII( Novoseven) in trauma and surgery: analysis of outcomes reported to an international registry Intensive Care Medicine 2006 21(1) 27-39
4. Perkins JG, Schreiber MA, Wade CE et al Early versus late recombinant Factor VIIa in combat trauma patients requiring massive transfusion Journal of Trauma Injury Infection and Critical Care May 2007 62(5) 1095-1101
5. Cameron P, Phillips L Balogh Z et al The use of recombinant activated factor VII in trauma patients: Experience from the Australian and New Zealand haemostasis registry Injury,Int J Care Injured 2007 38,1030-38
6. Spinella PC, Perkins JG McLaughlin DF et al The effect of recombinant activated Factor VII on mortality in combat-related casualties with severe trauma and massive transfusion Journal of Trauma Injury Infection and Critical Care Feb 2008;64:286-94