Podcast #216 - Vasopressin in Trauma?

On our last blog and podcast, part of the ATLS series, we covered shock.  In that last post, it was briefly mentioned how vasopressin could be used in hemorrhagic shock.  We want to build on that discussion today with a more detailed review on using vasopressin (and other vasopressors) in such a situation.

It is worth noting that there is not a lot of literature on this topic and we may find with time that there are better alternatives or that there is no true role in vasopressors including vasopressin in hemorrhagic shock.  Additionally, such medications do not replace the rest of shock management in trauma including blood products and definitive control of the bleeding.  This was also emphasized in the previous post.  We have also mentioned why crystalloids are not great in trauma.

Where It May Be Used:
Vasopressors may have a role in the resuscitation of hemorrhagic shock when blood pressure cannot be maintained by blood products alone.  Adequate tissue perfusion must be maintained.  In certain circumstances, such as in rural or austere settings, there may be little to no blood products available prior to transferring the patient to definitive care.  There may also be periods of time where there are simply not enough blood products to keep up with the body's demand to maintain adequate perfusion such as during periods of time where more blood products have not arrived from the blood bank.  Most studies on the subject have used either norepinephrine or vasopressin.

Pathophysiology of Hemorrhagic Shock:
We should quickly discuss the pathophysiology to hemorrhagic shock and how this plays a role in the thought process with vasopressors.  Catecholamines such as epinephrine and norepinephrine are released at 10-40 times their normal levels during hemorrhage.  There is also a delayed activation of the renin-angiotension system.  This leads to vasoconstriction which allows for blood pressure to be maintained even with as much as 30% of blood volume being lost before signs and symptoms of shock appear.  The vasoconstriction can also lead to end-organ ischemia and impaired oxygen delivery which leads to anaerobic metabolism that will lead to metabolic acidosis.  In turn, the acidosis can down-regulate vasopressor receptors.  

Remember the citric acid cycle or tricarboxylic acid cycle?  Maybe you remember it as the Krebs Cycle?  It is actually useful to think about here for a moment.  Digging way back to your studies, the citric acid cycle and oxidate phosphorylation produces 38 adenosine triphosphate (ATP) molecules.  That ATP is the main source of energy for cellular activity.  However, in oxygen-deprived tissue pyruvate remains within the cytoplasm and converts to lactate in the process known as anaerobic glycolysis which only produces 2 ATP making it much less efficient.

If hemorrhagic shock persists, the cellular membrane loses the ability to maintain its integry leading to cellular damage, edema, and death.  A variety of vasodilatory mediators (leukotrienes, interleukins, thromboxane, prostaglandin, prostacyclins, tumor necrosis factor, and complements) resulting from ischemia-reperfusion injury may be released.  Decompensation follows with vasodilation and hypotension which will not respond to crystalloid fluids or blood products.  This will eventually lead to end-organ damage and multiple-organ dysfunction syndrome.

Norepinephrine:
Over the years, norepinephrine has become widely used for a variety of conditions such as septic shock.  It is a sympathomimetic agent acting on alpha adrenergic receptors in both veins and artery.  Increased vasoconstriction on artery increases the blood pressure directly.  Venoconstriction, especially in the splanchnic circulation, causes a shift of venous blood volume into systemic circulation, increasing the circulating blood volume in the central compartment, thus maintaining blood flow to the vital organs.  In addition, venous return is increased due to decreased venous resistance caused by the stimulation of beta adrenergic receptors.  Norepinephrine can also improve the cardiac index and coronary perfusion.  It will increase cerebral perfusion pressure (CPP) but does not improve cerebral oxygenation until there is a transfusion of blood products.  Renal perfusion is also increased with an improvement in creatinine clearance.

We only have animal studies to rely off of including rats and pigs demonstrating that norepinephrine can decrease the amount of fluids needed to achieve a target blood pressure with lower blood loss and significantly improved survival.  A study in mice also found that the microcirculation was preserved when using norepinephrine to the same extent as those receiving fluids alone arguing against the concerns for tissue ischemia due to excessive arteriolar vasoconstriction during hemorrhagic shock.

This information has led to European guideline formulated by multidisciplinary Task Force for Advanced Bleeding Care in Trauma to recommend the use of norepinephrine as the primary agent to be used to maintain target blood pressures (often 80-90 mmHg systolic) in the absence of a response to fluid therapy.  However, they also acknowledged that cardiac dysfunction could be altered due to a cardiac contusion, pericardial effusion, or from intracranial hypertension and recommended in such situations to use an inotropic agent such as dobutamine or epinephrine.

Arginine Vasopressin:
The use of vasopressin is growing thanks to some new evidence, but we should start with the basics.   It is an endogenous neurohypophyseal hormone, which acts on v1 receptors in blood vessels and shunts blood from skin, splanchnic, and skeletal areas to heart and brain thus maintaining perfusion of vital organs.  It also restores blood to kidney and liver and decreases the mesenteric and portal blood flow.  This may be useful with intra-abdominal bleeding given its decreased mesenteric perfusion which would limit blood flow to the involved area.  Additionally, vasopressin may improve hemostasis by enhancing platelet function and thus augmenting clot formation.  When given in a physiologic dosage (0.04 U/min or less), it does not augment blood pressure in healthy volunteers and only acts as a vasopressor in deficient states.

Multiple pig studies exist that have found benefits with vasopressin.  In one study, vasopressin resulted in a higher mean arterial pressure (MAP) and survival with full recovery compared to fluid resuscitation or placebo. Another study found a higher MAP and improved organ blood flow without aggravating further blood loss in the vasopressin group compared to fluid resuscitation or placebo.  A third study found that vasopressin was better than epinephrine in hemorrhagic shock and cardiac arrest with all the pigs in the epinephrine group dying within 60 minutes and all treated by vasopressin survived.  While this evidence had been enough to help support the recommendation of using vasopressin in hemorrhagic or hypovolemic shock when deemed necessary for Canadian emergency departments by the Critical Care Practice Committee of the Association of Emergency Physicians, there is now even stronger evidence of its use.

A randomized control trial (RCT) in humans was published last year known as the AVERT Shock trial that was published by Sims et al. in JAMA Surgery.  They randomized 100 adult trauma patients in hemorrhagic shock to receive either vasopressin as a bolus and as an infusion versus placebo.  They had a positive primary outcome by demonstrating that vasopressin significantly reduced the volume of blood products transfused in the first 48 hours.  None of the secondary outcomes including 30 day mortality were different between the two groups.  Interestingly, there was no difference in adverse events except a significantly reduced rate of DVTs (20% versus 39%) in favor of the vasopressin group.  The dosing of vasopressin was a 4 unit bolus of vasopressin followed by a 0.04 U/min infusion that could be titrated down to 0 to maintain a MAP of 65 or higher for 48 hours following surgical control of bleeding.

The AVERT Shock trial has been very well critiqued by other free and open access medical (FOAMed) sources including The Bottom Line, St. Emlyn's, EAST Traumacast, andREBEL EM.  This was a well done study that has supported the use of vasopressin in humans. A systematic review that was written prior to the AVERT Shock trial supported the need for RCTs to better define the role of vasopressors in the setting of hemorrhagic shock. 

Conclusion (For Now):
We need to see more, and larger, well done RCTs to help look for when managing hemorrhagic shock should include the use of vasopressors.  The AVERT Shock trial was not powered to show a survival benefit or to show a difference in complications.  This would require larger studies.  Additionally, we need to see more evidence regarding timing of giving such medications, dosing, and other parameters that may impact the effectiveness of this treatment.  One important aspect yet to be studied is how resource limited settings may (or may not) benefit from vasopressors in hemorrhagic shock where massive transfusion protocols may not exist or blood products may not be available.

For now, in hemorrhagic shock the main goals continue to be the control of bleeding and administration of blood products.  If the patient is still in hemorrhagic shock without adequate tissue perfusion, it appears that vasopressin may be the more appropriate first-line agent given the current evidence.  However, norepinephrine may be a reasonable alternative when vasopressin is not available or not adequate.  It is also worth remembering that inotropes such as dobutamine or epinephrine could be beneficial if there is cardiac dysfunction.  However, evidence is extremely limited in regards to inotropes in trauma.

Let us know what you think by giving us feedback here in the comments section or contacting us on Twitter or Facebook.  Remember to look us up on Libsyn and on Apple Podcasts.  If you have any questions you can also comment below, email at [email protected], or send a message from the page.  We hope to talk to everyone again soon.  Until then, continue to provide total care everywhere.

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