AVERT trial shows vasopressin decreases transfusion requirements.
Hemorrhage accounts for up to 72% of trauma mortality within the first 24 hours. Early hemorrhagic shock management is largely dogmatic: volume resuscitation with early use of balanced blood products and timely hemorrhage control. Historically the use of any vasoactive agent in the resuscitation of hemorrhagic shock has been frowned upon.
The AVERT-shock trial confronts the traditional trauma doctrine; Sims et. al conduct a single center Randomized Clinical Trial examining the effects of arginine vasopressin (AVP) on the early resuscitation of trauma patients with hemorrhagic shock.
Vasoactive Agents: A Historical Perspective
Vasoactive agents, particularly epinephrine and norepinephrine, are used ubiquitously in emergency departments throughout the United States. Their use for the treatment of distributive, obstructive and cardiogenic shock is well supported by evidence and has been incorporated into guidelines.[4, 5]
Recently we have also seen the advent of “push dose pressors,” a means to achieve rapid hemodynamic improvement in unstable patients and pre-emptively during intubation in patients at risk of peri-intubation arrest.
Unlike other forms of shock, vasoactive agents have traditionally been contraindicated in early hemorrhagic shock secondary because of an observed increased mortality risk. Furthermore, vasopressors are not currently endorsed by ATLS guidelines. Perhaps the best-known study was published by Sperry et al: “Early use of vasopressors after injury: Caution before Constriction.”
This secondary analysis of a prospective cohort study compared mortality rates in blunt injured adults in hemorrhagic shock. The study demonstrated an increased mortality rate in those patients receiving early vasopressors within 12 hours of injury (hazard ratio 1.81). The authors caution against early vasopressor use in this patient population stating that vasopressors ‘should be used cautiously and not in place of aggressive crystalloid resuscitation after severe blunt injury.’
However, this is a secondary analysis, and ultimately was not designed to examine the specific hypothesis tested. Given the retrospective nature of this study the use of vasopressors may represent a marker of increased severity of illness rather than a direct contributor to adverse outcomes. We have been waiting for further, ideally prospective randomized trials, to help clarify the issue.
Sims et al performed a high-quality double-blind randomized clinical trial examining the addition of low- dose vasopressin (LDV) to the early resuscitation of patients with trauma and hemorrhagic shock (the AVERT-Shock Trial). Adult trauma patients (18-65 years) who had received six or more units of blood product within 12 hours of injury, and only after definitive hemorrhage control, were randomized to AVP (initial 4U bolus followed by infusion of 0 – 0.04 U/min) or Placebo groups, with a mean BP goal of 65 mm Hg for 48 hours.
If additional vasopressors were needed, neo-synephrine, norepinephrine, and/or epinephrine were used. All vasopressor treatments were titrated and stopped before tapering the study infusion. The authors ask a clinically important question, based on knowledge of underlying pathophysiology, using well randomized groups with similar baseline characteristics.
The primary outcome of the study was total volume of blood product transfused within 48 hours of injury, and included Packed Red Blood Cells, Platelets and Fresh Frozen Plasma, but did not include cryoprecipitate in its cumulative calculation of total volume of administered blood product. Secondary outcomes included total volume of crystalloid infused, vasopressor requirement, secondary complications such as venous thromboembolism and 30-day mortality.
A total of 100 patients were enrolled (LDV 49 vs. Placebo 51), the majority of which were young males (93 vs. 7), with median age of 27 years (IQR, 22 to 25 years). The major mechanism of injury was blunt trauma (79 vs. 21).
The primary finding was that the addition of LDV resulted in significantly fewer blood products being administered in the first 48 hours with an estimated total mean difference of – 1.00 L with a secondary finding of a decreased lower deep venous thrombosis rate in the LDV group.
Minimizing total volume of blood product administration can be considered beneficial for a number of reasons. Blood products are a precious, finite, life-saving resource — any intervention that reduces their administration without detrimental morbidity and mortality effects is one we should investigate further. Additionally, blood product transfusion may have negative immunomodulatory effects, which may account for the decreased VTE (Venous thromboembolism) rate in the LDV group.
Perhaps the most pertinent finding, that challenges traditional belief, is that the addition of early vasopressor therapy did not result in higher complication rates or mortality, thus contradicting early studies. AVP appears to be safe in trauma patients with hemorrhagic shock.
There are limitations and many aspects of the study generate more questions than answers. The study was conducted at a single center, in a primarily blunt trauma cohort, which may affect result generalizability. Furthermore, a cohort of only 100 patients is underpowered to detect differences in many clinically relevant outcomes. However, the results are promising and physiologically plausible.
Vasopressin in trauma patients with hemorrhagic shock
AVP is an endogenous hormone released by the posterior pituitary gland in response to increased serum osmolality and hypotension. It has both direct vasoconstricting effects through its action at the V1 receptor found primarily on vascular smooth muscle of the systemic, splanchnic, renal and coronary circulations.
Interestingly, it can also be branded a “secondary vasoconstrictor,” enhancing the sensitivity of the vasculature to circulating peripheral catecholamine. A significant proportion of AVP stores are released during the early stages of hemorrhagic shock. As shock progresses, AVP may become depleted, losing the protective direct and indirect vasoconstrictive effects of endogenous AVP leading to catecholamine resistance, vasoplegia and increased venous capacitance.
We have seen in animal studies the positive effects of exogenous AVP on vascular tone in shock states associated with AVP deficiency (decreased bleeding, transfusion requirement and improved survival); however, optimal timing of administration and dosing remains unknown. Interestingly, in the aforementioned Sperry et al study, vasopressin was the only vasopressor not associated with increased mortality on logistical regression.
AVERT clearly demonstrates that LDV administration in patients with hemorrhagic shock is safe, significantly decreased the use of all blood products and improved fluid balance at 48 hours. AVERT will likely serve as the beginning for larger studies evaluating the role of vasopressors in hemorrhagic shock, addressing questions such as optimal dosing and timing; its application in penetrating injuries and even the role of push dose vasopressin in the peri-intubation period of a patient’s disease course.