Tactics versus Strategy in Trauma Resuscitation

In this issue of Anesthesiology, Lindsay et al.  present a complex secondary analysis of the ITACTIC trial, part of the Targeted Action for Curing Trauma Induced Coagulopathy (TACTIC) program, funded by the European Commission. ITACTIC was designed to settle an ongoing debate in contemporary trauma science: the clinical utility of viscoelastic testing versus conventional coagulation tests to guide administration of coagulation agents in the setting of early resuscitation with 1:1 units of erythrocytes and plasma. The target population for this prospective, randomized trial was a cohort of 396 injured patients presenting to major European trauma centers with evidence of ongoing hemorrhage. The ITACTIC investigators included some of the leading authorities in resuscitation after trauma, and the results were eagerly awaited by the international community. In defiance of expectations, the study detected no difference in 28-day mortality. 

The current article reports results from the Activation of Coagulation and Inflammation in Trauma study, which ran in parallel with ITACTIC at the two largest-enrolling centers. The goal was to gather additional laboratory data on the development and resolution of trauma-induced coagulopathy in the ITACTIC population of patients in hemorrhagic shock. The authors used the available data to explore why ITACTIC failed to show a difference in outcome, despite the prevailing belief that viscoelastic testing provides more immediate, granular, and actionable data to guide resuscitation. Their conclusion, based on the 133 patients with complete data, was that viscoelastic testing led to more, and more rapid, administration of supplemental procoagulants (e.g., fibrinogen, platelets, four-factor prothrombin complex concentrates) but not rapidly or completely enough to change outcomes. Their recommendation, based on this observation, is that “future progress in correcting [trauma-induced coagulopathy] and improving clinical outcome will require focus on the rapid delivery and administration of more effective coagulation therapeutics.”

The authors called out delays in multiple areas of resuscitation. These included failure to rapidly identify patients with life-threatening hemorrhage; delay in drawing and sending the initial lab tests (perhaps due to delays in obtaining vascular access); time taken to run the lab test and return the results to the clinical team; time taken to analyze the results and order new therapies; time to deliver specific coagulation products to the bedside; and actual time taken to administer the ordered products. As experienced clinicians know all too well, early resuscitation of exsanguinating trauma patients requires prioritization of dozens of critical tasks, including the need to move from the trauma bay to the operating room or radiology suite, often in an off-hours setting with a limited supply of personnel. In real life, logistic complications are common, including everything from infiltrated field IV lines to clotted blood samples to random equipment failures. Identifying and mitigating trauma-induced coagulopathy must compete for the anesthesiologist’s attention with other priorities such as airway management, safe patient positioning, obtaining additional lines and monitors, and even mundane but essential tasks such as nasogastric tube placement.

Average delivery of “goal-directed” resuscitation products was 90 min from diagnosis to administration, with high variability. Need for a specific product was identified more quickly in the viscoelastic testing group, indicating the utility of this approach, but this benefit was overshadowed by the time required to order, deliver, and administer the indicated product. Although 111 of 133 patients had a coagulation abnormality that should have triggered a specific intervention, only 72 actually received the indicated therapy, with a latency of 1 h in the viscoelastic group and 2 h in the conventional group. Even with viscoelastic testing, only 20% of the detected coagulopathies were corrected.

Resuscitation early after trauma—while hemorrhage remains uncontrolled—shifted in the 2000s to emphasize rapid empiric administration of red blood cells, plasma, and platelets in even amounts (“1:1:1 resuscitation”) in an effort to directly replace ongoing blood loss.  This strategy evolved in busy civilian trauma centers in the United States and was rapidly adopted by the allied military in the early years of the global war on terror.  Combat casualty data were supportive of the 1:1:1 approach, which was prospectively tested in the 2015 Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) study.  PROPPR showed earlier resolution of hemorrhage and improved laboratory results in patients receiving 1:1:1 resuscitation, although there was no significant difference in 30-day mortality. As with many trauma trials, including the current one, it is possible that PROPPR was underpowered to overcome heterogeneity in patient presentation and the confounding effects of anatomically lethal hemorrhage (patients who will not survive regardless of therapy) and traumatic brain injury.

Strategic targeting of 1:1:1 blood product administration helped overcome logistic barriers in early resuscitation, with massive transfusion protocols now in place at almost every major trauma center.  It seems obvious, however, that different patients, with different comorbidities and different injury patterns, should benefit from variations in a strict 1:1:1 approach. It was hoped that rapid, real-time viscoelastic testing could be used to adjust resuscitation on the fly to augment whatever coagulation component was most needed: fibrinogen, platelets, or specific coagulation factors. To date, this theory has not been proven, despite ever more rigorous efforts to overcome the logistic issues demonstrated in ITACTIC. Perhaps it is just too difficult to bring precision science to the highly dynamic arena of early resuscitation, in the “fog of war” that accompanies any trauma admission.

Perhaps the theory itself is flawed. It may be that tactics of resuscitation are less important than revisiting the fundamental strategy, with a greater emphasis on simplicity. Coagulation is an incredibly complex process, involving thousands of factors and reactions between vascular endothelium, red blood cells, platelets, and circulating plasma factors, with more substeps and interactions being identified all the time. Rather than the tactical pursuit of those elements we have been able to quantify to date and those laboratory studies we can perform, perhaps we should embrace the chaos and acknowledge that we can neither know nor specifically manage coagulation in real time. Instead, perhaps we should emphasize a rapid and empiric approach to providing all possible substrate as soon as possible, trusting in the patient—and thousands of years of evolution—to put the right components to work in the right way.

What does this recommendation mean to the clinician?

Clinically, this means less effort into measurement and more into simple logistics: minimize crystalloid and maximize blood, using the most holistic products available; fresh whole blood preferably  but failing that then stored low-titer type-O whole blood or 1:1:1 components; continue until hemorrhage is controlled or the patient dies; and once coagulation has occurred, send the indicated labs and make precise corrections for the long haul.

Academically, this means less study of specific factors and granular testing and more focus on overall strategy and balanced resuscitation with pleiotrophic products. Whole blood is the ultimate “bundled” therapy, and there is now a body of observational work suggesting that it can make a difference in early resuscitation; this should lead to prospective, randomized trials organized like ITACTIC but comparing, for example, whole blood to component therapy for early resuscitation. I note that there will be an important role for public-sector and philanthropic funding of these trials, given that studies of resuscitation strategy will inherently lack the profit-driven support of companies promoting specific products or tests.

In conclusion, the take-home message of the work of Lindsay et al.  for the trauma anesthesiologist is not “we need to get these details right” but rather “we need a new strategy.” Perhaps this study will point us in the right direction.