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Three Part Question

In [trauma patients] who require [massive transfusion] is [1:1:1 component therapy better than standard practice] at [reducing mortality]?

Clinical Scenario

A shocked multiply injured patient is brought into the emergency department following a road traffic collision. There are a number of open fractures as well as chest, abdominal and pelvic injures. Furthermore, the paramedics report a great deal of blood at the scene. A trauma call is initiated and circulatory resuscitation begins immediately with transfusion of warmed universal donor blood. You have recently been to a presentation by a military surgeon who has just returned from a combat zone. You recall that mention was made of early component therapy in massive transfusion being beneficial and wonder whether you should start such therapy now.

Search Strategy

Simple: Medline using OVID interface 1996–week 1 October 2009 [massive transfusion mp.] and [trauma mp.]

Sensitive: Medline 1950–September 2009 and Embase 1980–September 2009 using the NHS Evidence interface (plasma adj5 ratio).mp. OR (blood adj5 ratio).mp. OR (platelet adj5 ratio).mp. OR (ffp adj5 ratio).mp. OR (prbc adj5 ratio).mp. OR (rbc adj5 ratio).mp. OR (prc adj5 ratio).mp. AND transfus$.mp limit to human and English language.


The Cochrane Library, Issue 3, 2009: (massive transfusion):ti,ab,kw OR (Exsanguination):ti, ab, kw 80 records no unique titles.

Search Outcome

Ninety-nine papers were found with the simple search and 567 with the complex search. Thirteen were of sufficient quality and relevance but two were excluded as they presented no new data. The remaining 11 papers are shown in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Borgman et al, 2007, USA/Iraq	246 combat casualties admitted to combat hospital in Baghdad, Iraq, November 2003 to September 2005 who were given ≥10 units RBCs (PRBCs or fresh whole blood) in first 24 h. Three groups analysed according to low (0:12–1:5), intermediate (1:3.0–1:2.3) and high ratio (1:1.7–1:1.2) of units of FPP:PRBCs. Overall mortality 28%.	Registry Review	Survival of high vs intermediate vs low ratio of FFP:PRBC	131/162 (81%) vs 35/53 (66%) vs 14/31(45%)	Retrospective. Fresh whole blood was viewed as 1:1:1 PRBCs:FFP:PLT. Unlikely to reflect community setting with high degree of penetrating trauma and highly focused prehospital care. rFVIIa administered to 32% of patients. Higher incidence of thoracic trauma in low ratio group. This group died early. Haemoglobin lower in low ratio group. Selected patients received rFVIIa Those who rapidly exsanguinate have little time for damage control therapy.
			Median time to death for high vs intermediate vs low ratio. rFVIIa used in 81 patients	38 h vs 4 h vs 2 h.61/81 (75%) of patients survived.
Maegele et al, 2008 Germany	n=713 ISS>16 received >10 units packed RBC Grouped according to FFP:PRBC ratios. Overall mortality 42%	Registry review.	Overall survival according to FFP:PRBC ratio High(>1:1) vs Low(<1:2)	153/229 (67% ) vs 262/484 (54%)	Open to selection bias.
Duchesne et al, 2008, USA	135 massively transfused trauma patients receiving >10 units PRBCs. Patients not receiving FFP were excluded. 55% mortality	Retrospective chart review.	Survival FFP:PRBC ratio 1:1 vs 1:4	52/71 (73%) vs 8/64 (12.5%)	Retrospective. Slightly different criteria for massive transfusion (>10 units).
Kashuk et al, 2008, USA	n=133 trauma patients receiving >10 units PRBC in first six hours. 56% mortality.	Retrospective review of prospectively entered data over 5 year period.	Survival probability according to ratio of FFP:PRBCs 1:1 vs1:2 -1:3 vs ≥1:5	Approximately 43% vs 72% vs 9%	Subject to bias of retrospective study. Probabilities generated based on small numbers, raw survival data not provided.
Gunter et al, 2008, USA	259 trauma patients. Pre-Trauma Exsanguination Protocol (TEP) vs post TEP protocol. Overall mortality 56%.	Retrospective cohort study	30 day survival FFP:PRBC≥1:1.5 vs <1:1.5	38/64 (59%) vs 74/195 (38%)	Data for post-TEP group gathered prospectively while pre-TEP group data all retrospective. TEP protocol initiated by trauma surgeon upon arrival. Selection bias (discretionary decision-making unavoidable). More penetrating injury in pre-protocol group (61%) vs 48% in post-protocol group.
			30 day survival PLT:PRBC ≥1:1.5 vs 1:<1.4	39/63 (62%) vs 76/196 (39%)
			30 day survival for pre-TEP vs post TEP groups	37/140 (53%) vs 61/119 (61%)
Holcomb et al, 2008, USA	466 trauma patients who received ≥10 units of PRBCs in first 24 h. 65% blunt injury. Patients divided into groups according to FFP:PRBCs and subgroups according to FFP:platelets:PRBCs. Overall mortality 41%.	Multicentre retrospective	30 day survival by ratio FFP:PRBC High (≥1:2) vs < Low (1:2)	165/252 (66%) vs 112/214 (52%)	Retrospective.
			30 day survival by ratio Platelets :PRBC High (≥1:2) vs Low (<1:2)	166/234 (71%) vs 111/232 (48%)
			30 day survival platelets & FFP: PRBC high vs low	110/151 (73%) vs 56/131 (43%)
Sperry et al, 2008, USA	415 trauma patients transfused ≥8 units in first twelve hours divided into high (≥1:1.5) and low (<1:1.5) FFP:PRBCs ratios. Identified from collaborative data base. Median transfusion of 14 units PRBCs Overall mortality 33.5%	Multicenter prospective data entry retrospective review.	Survival according to ratio of FFP:PRBC ≥1:1.5vs <1:1.5	72/102 (71%) vs 203/313 (65%)	Open to selection bias- severe trauma group received high ratio component therapy. rVIIa used variably. Data collated from study with different primary objective. Higher cryoprecipitate administration in high ratio group.
			Multi organ failure high vs low ratio	64% vs 54%
			Infection rate. High vs low ratio	58% vs 43%
			ARDS	47% vs 24%
			24hr PRBC transfusion requirement	16+/-9 vs 22+/-17
Teixteira et al, 2009, USA	383 trauma patients receiving 10 or more units PRBCs in first 24 hours. All severe head injuries excluded. 42% mortality.	Retrospective review of cross referenced data bases.	Survival to discharge low ratio(≤1:8) vs medium ratio FFP:PRBC (>1:8-≤1:3) high ratio (>1:3)	6/62 (10%) vs 48/95 (51%) vs 58/226 (74%)	Retrospective. Open to selection bias. 6 year duration.
Perkins et al, USA/IRAQ, 2009	Trauma patients in military hospital Bagdad receiving ≥10 units PRBC’s and variable units of apheresis platelets in first 24 hrs. n=456	Retrospective review of records of patients admitted to combat hospital January 2004-December 2006	Survival to 24 hrs days aPLT: PRBC ratio (≥1:8) vs n=96 vs medium (1:16-<1:8) n=151 vs low ratio(<1:16) n=209	91/96 (95%) vs 131/151 (87%) vs 134/209 (64%)	Military combat setting (skewed to young male penetrating trauma) may not apply to civilian. More use of adjuvant therapy (FFP, cryoprecipitate and rFVIIa) in medium to high ratio group. Large numbers lost 30 day survival follow-up
			Survival to 30 days high vs medium vs low ratios	45/60 (75%) vs 51/85 (60%) vs 64/150 (43%)
Dente et al, USA, 2009	Trauma patients received to urban level 1 trauma hospital for twelve months from February 2007 receiving ≥ 10 units PRBC’s	Prospective trauma cases with massive transfusion protocol (MTP) activation n=73 vs historical controls n=84	30 day survival pre vs post MTP	64% vs 83%	Limitations of historical cohort. Possible that early aggressive use of components may be more important than ratio.
			Ratio FFP:PRBC pre vs post MTP	1:3 vs 1:1.9
			First 6 hours use of components pre MTP vs post MTP	5.5 vs 13.7 units FFP. 14.1 vs 9.2 units PLT
			Crystalloid use pre vs post MTP	9.4 L vs 6.9 L
			24 hr survival for post MTP ‘successes’ FFP:PRBC ratio <1:2 vs post MTP violations (>1:2-2.9 and >1:3 )	43/50 (66%%) vs 3/16(81%) vs 4/7(43%)
Risken et al, 2009, USA	77 trauma patients requiring >10 units PRBC in first 24 h.	Retrospective review comparing cohorts 2 years pre- and post- initiation of MTP.	Survival rate pre vs post MTP.	22/40 (55%) vs post MTP 30/37 (81%).	Retrospective non-blinded review of notes
			Ratio PRBC:FFP pre and post MTP.	1.8:1 vs 1.8:1.
			Time to first cross-matched PRBC.	115 vs 71 min.

Comment(s)

Hypothermia, acidosis, coagulopathy and hypotension and failure to control surgical bleeding all contribute to mortality in trauma patients. Emphasis on damage control resuscitation and damage control surgery may have contributed to improved survival. Attention has refocused on optimising the ratio of component therapy in patients requiring massive transfusion. The aim here is to find evidence based on improved patient outcomes to develop best practice administration of massive transfusion.

In all, 3367 patients were studied. There is considerable heterogeneity between studies. Mortality varies from 56% to 29% in a community setting to 28% in a combat environment. Varying definitions were used for massive transfusion ranging from ≥8 units in 12 h to >10 units in the first 6 h and varying ratios of component therapy were examined. Several studies did not control for the use of adjuvant therapy such as cryoprecipitate and rFVIIa. Five papers were pure chart reviews, four of which gave little detail of the methods used. Five studies used data that had been prospectively gathered. Two comparative cohort studies used a combination of prospectively entered data and chart review for the historical comparison group. All of these studies compared ratios of packed red blood cells (PRBCs) to fresh frozen plasma (FFP). Four studies examined or included PLT:PRBC ratios. Five studies occurred over time periods of 42 months to 6 years.

Owing to the nature of severe trauma requiring high-volume blood product resuscitation, significant survivor bias is highly likely. Within these limitations, the available literature demonstrates a clear survival benefit associated with early delivery of FFP and platelets in exsanguinating trauma. It should be noted that high ratio therapy may be associated with a higher incidence of organ failure, ARDS and infection. One group showed that incremental benefit may be reversed in ratios of FFP:PRBs higher than 1:2–3.

Editor Comment

FFP = Fresh frozen plasma PRBC = Packed red blood cells PLT = Platelets aPLT = Apheresis platelets rFVIIa = Recombinant factor VIIa

Clinical Bottom Line

Early use of component therapy of PRBC:FFP:PLT ratios approaching 1:1:1 is supported by the best available literature. Clearly a massive transfusion protocol has significant resource implications on hospital blood banks. Local guidelines should be followed.

References

1. Borgman MA, Spinella PC, Perkins JG et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusion at a combat support hospital. Journal of Trauma October 2007;63:(4) 805-813.
2. Maegele M, Paffrath T, Tjardes T et al. Red blood cell to plasma ratios transfused during massive transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the trauma registry of the Deutsche. Gesells Vox Sanguinis June 2008;95: 112-119.
3. Duchesne JC, Hunt JP, Wahl G et al . Review of current blood transfusions strategies in mature level 1 trauma center: were we wrong for the last 60 years? Journal of Trauma August 2008: 272-276.
4. Kashuk JL, Moore EE, Johnson JL et al. Postinjury life threatening coagulopathy: Is 1:1 fresh frozen plasma:packed red blood cells the answer? Journal of Trauma August 2008;65:(2) 261-70.
5. Gunter OL, Au BK, Isbell JM et al. Optimizing outcomes in damage control resuscitation:identifying blood product ratios associated with improved survival. Journal of Trauma Sept 2008;65:(3) 527-34.
6. Holcomb JB, Wade CE, Michalek JE et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Annals of Surgery September 2008;248:(3) 447-456.
7. Sperry JL, Ochoa JB, Gunn SR et al. An FFP:PRBC transfusion ratio ≥1:1.5 is associated with a lower risk of mortality after massive transfusion. J.Trauma November 2008;65:(5) 986-993.
8. Teixteira PGR, Inaba K, Sculman I et al. Impact of plasma transfusion in massively transfused trauma patients. Journal of Trauma March 2009;66:(3) 693-97.
9. Perkins JG, Andrew CP, Spinella PC et al. An evaluation of the impact of apheresis platelets used in the setting of massively transfused trauma patients. Journal of Trauma April Supplement 2009;66:(4) s77-s84.
10. Denete CJ, Shaz BH, Nicholas JM et al. Improvements in early mortality and coagulopathy are sustained better in patients with blunt trauma after institution of a massive transfusion protocol in a civilian level I trauma center. Journal of Trauma June 2009;66:(56) 1616-1624.
11. Riskin DJ, Tsai TC, Riskin L, et al. Massive transfusion protocols: the role of aggressive resuscitation versus product ratio in mortality reduction. J Am Coll Surg 2009;209: (2)198–205.