Massive Hemostatic Transfusion: Implications for Trauma Resuscitation

This is a synopsis of a topic I recently reviewed for my senior medical student classmates. 

Massive transfusion is defined as ≥ 10 units of packed erythrocytes given over 24 hours, or alternatively, over the entire perioperative period. Physiologically, this is equivalent to about half of normal blood volume of an average patient. Hemorrhagic shock can produce the lethal triad of coagulopathy, hypothermia, and acidosis. Acute traumatic coagulopathy (ATC) has been reported in 25% of trauma patients (Brohi et al. 2007). Through years of basic research in animal and in vitro models, this form of coagulopathy was found to be only partially explained by crystalloid hemodilution, consumptive diathesis (i.e. DIC), normal anion gap acidosis, and hypothermia. The major risk factor for ATC was tissue hypoperfusion of target organs, leading to systemic anticoagulation and fibrinolysis. In a prospective study of 208 patients in the trauma bay (Brohi et al. 2008), ATC was found to be associated with activation of the thrombomodulin – protein C axis of anticoagulation, as well as increased fibrinolysis mediated by suppression of plasminogen activator inhibitor (PAI-1) and subsequent hyperactivity of tissue plasminogen activator (tPA).

Hyperacute resuscitation of patients in hemorrhagic shock has traditionally been directed towards repletion of intravascular volume. However, increasing recognition is dawning upon the necessity for early proactive blood product transfusion to mitigate acute coagulopathy. Blood elements relevant for hemostatic resuscitation are red blood cells (RBCs), platelets (PLTs) and plasma (FFP).  Current guidelines from the American Society of Anesthesiology published guidelines (Nuttall et al. 2006) currently advise that FFP be administered when there is laboratory evidence (INR > 2.0, aPTT > 200% ULN) of coagulopathy, or until patients have been transfused with more than one blood volume. These parameters are to be rechecked after each transfusion of five units of RBCs. Two units of FFP are to be given per cycle, as well as six units of random donor PLT (equivalent to one apheresis unit). Cryoprecipitate fraction is to be given when fibrinogen < 80 mg/dl with concurrent micovascular oozing. Taken together, this protocol amounts to a FFP:RBC:PLT ratio of 1: 2.5: 1.

We now understand that both the absolute volume and relative ratio of these products correlates with both total transfusion requirement (Kautza et al. 2012) and mortality in military and civilian theaters. It was around 2007 when retrospective data emerged from combat centers in Iraq that higher FFP:RBC ratios, approaching 1:1, were associated with lower mortality from all causes as well as hemorrhage (Borgman et al. 2007). This result is also reproduced when survival at six hours, one day, and thirty days is examined (Holcomb et al 2008). This study, and several others, also finds that a higher PLT:RBC ratio (≥ 0.5:1) is associated with significantly improved survival, and that survival predictably decreases as this ratio decreases. In three observational studies comparing prospective cohorts against historical controls, improved survival was associated with increased intra-operative use of platelets (Cotton et al. 2008), higher PLT:RBC ratio (Perkins et al. 2009), and greater absolute PLT units within the first 24 hours of resuscitation (Johansonn et al. 2009). Together, this evidence should be interpreted to mean that  equalized transfusion ratio of 1:1:1 has been shown repeatedly in retrospective series, to be correlated with lower mortality up to 30 days from the original trauma.  In addition, it was recently found in a prospective study (Tan et al. 2012) that this ratio was associated with less requirement for activated factor VII in trauma patients and less blood product requirement overall.

The data also support the notion that having thawed plasma on standby for early transfusion may be necessary to mitigate worsening coagulopathy – hence the term “damage control transfusion”. When the ASA guidelines were followed (i.e. patients receive FFP only after massive RBC transfusion), coagulopathy remained uncorrected even when patients were transferred to the intensive care unit (Gonzales et al. 2007). Finally, there is evidence to show that hemostatic transfusion therapy can be guided by real-time coagulation monitoring via thromboelastography (TEG) or rotational thromboelastometry (ROTEM)  leads to less overall blood loss (mean difference 85 mL), but does not affect mortality. This techniques can be performed at the point of care and has a much faster turnaround time than conventional analytic coagulation assays (PT, aPTT), since it is not necessary for the sample to be citrated before initiating the reaction. Furthermore, the output of the TEG assay is a global reflection of hemotasis, reflecting the net result of platelet function, coagulation, and fibrinolysis.

A major thorn of controversy exists as to whether the apparent survival benefit of balanced transfusion is confounded by survivor bias; that is, whether the improved survival amongst high-ratio cohorts is simply due to the administration of plasma products at later times during the resuscitation effort, when patients with worse baseline characteristics would be lost from analysis. In a retrospective study that treated FFP:RBC ratio as a time-dependent variable (Snyder et al. 2009), there was a trend towards better survival for higher ratios, but it no longer reached statistical significance (RR – 0.87). When surviving patients at 24 hours were analyzed in cross section, patients receiving a higher ratio had a statistically significant survival advantage (RR = 0.37, CI: 0.22 – 0.64). In a meta-analysis of fifteen studies in which survival bias was minimized by excluding early deaths, it turned out that ten of them showed a survival advantage for high-ratio transfusion. Unfortunately, it is impossible to truly assess causality between transfusion ratio and survival without a randomized prospective study. To date, there is only one such study (Nascimento et al, 2011) investigating the effect of a balanced (1:1:1) transfusion ratio. Only 18 patients have been enrolled, and no data have been published so far due to logistic challenges in attaining rapid access to fresh plasma.

In patients determined to have submassive transfusion requirements (< 10 units in 24 hours), a retrospective study found that high-ratio therapy did not affect mortality during hospital stay or total length of stay. Ratios higher than 1:2 (relatively more plasma) were associated with longer ICU care and more days spent on a ventilator (Sambasivan et al. 2011). This study was flawed by the poor matching between comparison groups. Patients in the high-ratio cohort were more likely to be younger, have better mental status (lower GCS), and more severe injuries (higher ISS). The authors speculated the correlation with increased ICU stay may have been due to well-known complications of massive plasma transfusion, including TRALI and ARDS, bacteremia, allergic reactions, and volume overload. However, this result may simply be due to the ICU being the most frequent setting for massive transfusion.

In summary, massive transfusion in trauma patients is still in its infancy as an evidence-based practice. The preponderance of data is derived from retrospective series at multiple centers. Patients who have non-massive blood loss are at less risk of traumatic coagulopathy, and may not benefit from non-massive 1:1:1 transfusion ratios. In contrast, patients with massive injury are at high risk of acute traumatic coagulopathy (ATC). In such cases, the consensus is that plasma, red blood cells, and platelets should be provided in as close to a 1:1:1 ratio as possible. There are no guidelines on optimal monitoring of coagulation parameters, but it appears that bedside thromboelastography is essentially non-inferior to standard laboratory testing. These conclusions are based on tenuous evidence, but are leading to a widespread revolution in the management of hemorrhagic shock and coagulopathy, in which a higher emphasis is placed on pre-emptive repletion of plasma and platelets.

 

SELECTED REFERENCES

  1.  Brohi et al. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C  pathway? Ann Surg. 2007 May; 245(5):812-8.
  2. Holcomb et al. Increased platelet:RBC ratios are associated with improved survival after massive transfusion. J Trauma. 2011 Aug;71(2 Suppl 3):S318-28.
  3. Sambasivan et al. High ratios of plasma and platelets to packed red blood cells do not affect mortality in nonmassively transfused patients. J Trauma. 2011 Aug; 71
  4. Snyder et al. The relationship of blood product ratio to mortality: survival benefit or survival bias? J Trauma. 2009 Feb; 66(2):358-62
  5. Tan et al. A Massive Transfusion Protocol Incorporating a Higher FFP/RBC Ratio Is Associated With Decreased Use of Recombinant Activated Factor VII in Trauma Patients. Am J Clin Pathol. 2012 Apr; 137(4):566-71.
  6. Borgman et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007 Oct; 63(4):805-13.

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