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Three Part Question

In [adult trauma patients requiring massive transfusion or activation of the major haemorrhage protocol] does [early fibrinogen replacement (in the form of cryoprecipitate or fibrinogen concentrate) in addition to standard care, compared to standard care alone] improve [survival]?

Clinical Scenario

A 30-year-old motorcyclist is brought to a major trauma centre following a road traffic collision. He has multiple injuries with clinical evidence of haemorrhagic shock. You activate the major haemorrhage protocol, and wonder whether early cryoprecipitate would be beneficial in this patient.

Search Strategy

Medline 1946-May week 3, 2016 and EMBASE 1974-May week 3, 2016: [(exp ADULT/) AND ((trauma* OR “major trauma”).ti,ab OR exp WOUNDS AND INJURIES/ OR (“blood loss” OR bleeding).ti,ab) AND (“major transfusion” OR “massive transfusion” OR “major haemorrhage” OR “major hemorrhage” OR “massive haemorrhage” OR “massive hemorrhage”).ti,ab AND (cryoprecipitate OR “fibrinogen replacement” OR “fibrinogen concentrate”).ti,ab AND (survival OR mortality OR death).ti,ab]

Search Outcome

29 papers found, of which 28 were not directly relevant to the research question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Curry et al. 2015 United Kingdom	43 adult trauma patients with active bleeding and requiring activation of the major haemorrhage protocol at two UK major trauma centres. Patients were randomly allocated to standard major haemorrhage therapy (n=22) or standard haemorrhage therapy plus two early pools of cryoprecipitate (n=21).	Unblinded RCT, level 2b evidence.	Administration of cryoprecipitate at 90 minutes (feasibility of process)	Primary outcome achieved in 85% (95% CI: 69-100%) Median time to administration of cryoprecipitate was 60 min (IQR: 57-76) compared to 108 min (67-147), CRYO and STANDARD arms, respectively (P=0.002).	This RCT was conducted to determine the feasibility of administering cryoprecipitate early in major trauma. It was insufficiently powered to definitively evaluate clinical outcomes. Subjects in the standard arm were older, more severely injured and had a greater number of head injuries.
			Fibrinogen (Fg) concentration	During active haemorrhage mean Fibrinogen (Fg) concentrations were higher in the cryoprecipitate arm (2.5 versus 1.7 g litre-1 at the 4 unit time point). Fg values remained >1.8 g litre-1 at all times during active bleeding in the cryoprecipitate arm (versus 0.6 g litre-1 in the standard arm).
			Safety of early cryoprecipitate (Incidence of adverse events)	7 serious adverse events in the cryoprecipitate arm (3 sepsis, 1 multi-organ failure, 3 other); 11 in the standard arm (1 ARDS, 6 other, 4 thromboembolic). No thrombotic events were seen in the cryoprecipitate arm; no unexpected events or transfusion adverse events related to cryoprecipitate occurred.
			28 day all-cause mortality	Two subjects died in the cryoprecipitate arm and six died in the standard arm. All-cause mortality was 10.0% and 28.6% respectively (p=0.14).
			ICU/Hospital days	On average, standard arm patients remained on ICU for 7 days longer, but there was no difference in total hospital stay (30 days vs 31 days, respectively).

Comment(s)

Although this study establishes that the process of early cryoprecipitate administration is feasible (1), it remains undetermined whether this intervention is beneficial to survival in major traumatic haemorrhage. A separate cohort study conducted across two UK major trauma centres identified an independent association between higher fibrinogen levels and improved survival (2). There are no studies that compare the differential effects of cryoprecipitate and fibrinogen concentrate in this setting. There are 4 ongoing RCTs and 1 recently completed small RCT evaluating fibrinogen concentrate in trauma (NCT01475344), (NCT02203968), (NCT02344069), (NCT01545635), (EudraCT2015 - 000875-28), aiming to recruit 300 patients in total. All use surrogate outcomes and none evaluate mortality. There is an urgent requirement to perform a large randomised control trial to evaluate the effect of early cryoprecipitate (or fibrinogen replacement) on mortality.

Clinical Bottom Line

There is currently insufficient evidence to support the use of early cryoprecipitate in trauma.

References

1. Curry N, Rourke C, Davenport R, et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth. 2015, Jul;115(1):76-83
2. Rourke C, Curry N, Khan S, et al. Fibrinogen levels during trauma haemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012; 10(7):1342-51