How do I use early plasma in the ED?

Logistics of use are complicated, but future options are even more promising.

A Case for Plasma:

A 46-year-old male unrestrained driver is brought in by EMS to your emergency department following a collision in which he struck a tree at highway speed. The patient was extricated from the vehicle and complains of severe 8/10 abdominal pain. His forehead is lacerated and he has a prominent mark from a seat belt on his lower abdominal wall. On initial assessment, the patient’s vital signs are pulse 118, BP 74/46, SpO2 92% and GCS 15. The bleeding from the patient’s head laceration was controlled. The paramedic has started a peripheral IV and has administered 1L of NS.

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Despite this intervention, the patient remained hypotensive (84/50) and they diverted to your emergency department as the nearest trauma center is 45 minutes away. After performing your primary survey, you continue IV fluid administration for the hypotension and complete a secondary survey remarkable for a distended and painful abdomen. Your FAST is positive. You call for a helicopter and arrange for transfer to the closest trauma center. No surgeon is available locally. What else could you do to resuscitate this patient? Do you give more saline? Do you administer blood products? Which product?

What Makes the Perfect Solution?

The ideal resuscitative fluid would be easily available, act as a volume expander, preserve blood function (carrying capacity and coagulation), minimize metabolic derangement (isotonic and neutral pH), free of transmissible diseases and inexpensive. We have been seeking such a product for nearly 200 years.

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Resuscitation from hemorrhage began in 1825 when Dr. James Bundell transfused fresh whole blood into a woman exsanguinating from post-partum hemorrhage.(¹⁾ In 1941, Cohn first fractionated plasma from blood. This new product deployed on the battlefield the following year and saved thousands of lives in WWII. In the subsequent years, fear of transmissible diseases and storage issues diminished the use of blood products in acute resuscitation. Emphasis shifted to inexpensive, ubiquitous, crystalloid solutions, but at what cost? Bickell first suggested that delaying large volume crystalloid fluid resuscitation until after hemorrhage control results in increased survival.(²⁾  Subsequent studies demonstrate that large volume crystalloid resuscitation in acute hemorrhage is associated with increased mortality.(³⁾

Crystalloid solutions may contribute to poor outcomes in hemorrhage through disrupting existing clot, dilutional coagulopathy, acidosis, hypothermia, endothelial dysfunction and reperfusion injury. Studies of colloids and hypertonic solutions also failed to show benefit.(⁴⁾ Conversely, early blood transfusion is associated with improved survival from traumatic hemorrhage, but several questions remain.(^5,6)  Which blood products should be used? Uncross matched Packed Red Blood Cells (PRBCs) are most readily available, but also lack clotting factors and platelets. Should plasma be incorporated into early resuscitation? What about platelets? Which should be given first?

The Evidence for Plasma:

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Observational studies demonstrate that early use of plasma improves acidosis, mitigates coagulopathy and decreases the need for fluid resuscitation.(^7,8) Animal studies suggest that plasma may repair endothelial damage, reducing inflammation and fluid redistribution.(⁹⁾ Among patients requiring massive transfusion, survival is associated with high ratios of plasma to PRBCs.(^10,11) The Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study identified an association between high ratios of platelet and plasma transfusion and decreased mortality in patients with traumatic hemorrhagic shock (THS).(¹²⁾ The Pragmatic Randomized Optimal Platelet and Plasma (PROPPR) study is a randomized controlled trial that demonstrated early plasma and platelet administration in THS improved hemostasis and decreased mortality from exsanguination at 24 hours.(⁸⁾

Applications in Trauma Patients with Acute Hemorrhagic Shock:

In 2018, two separate trials implemented early plasma administration for the treatment of hemorrhagic shock with divergent results. The Control of Major Bleeding After Trauma (COMBAT) trial enrolled 125 patients with THS transported by ground ambulance in an urban setting. Patients were randomized to receive plasma or standard crystalloid resuscitation. There was no difference in survival between the groups that were characterized by 50% penetrating trauma and very short prehospital times.(¹³⁾ In contrast, the Prehospital Air Medical Plasma (PAMPer) enrolled 501 patients with THS and demonstrated a 10% absolute reduction in mortality at 30 days among the patients who received plasma. These patients were transported by air, were primarily blunt trauma and had long prehospital times.(¹⁴⁾

When and How to Use Plasma:

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While this data is encouraging, several questions remain. Studies support the use of limited crystalloid resuscitation and early use of blood products. They also suggest that among patients with THS, early plasma use decreases mortality and may particularly benefit patients with blunt injury and longer prehospital times. Should we be using plasma in the emergency department? The location of use may be less relevant then the need to resuscitate prior to definitive surgical care. How do we incorporate plasma into our resuscitation? Does early plasma mean plasma first? Should we administer plasma to support coagulation and “plug the whole” before other products?

The logistics of plasma use are complicated. Plasma is usually stored frozen in the blood bank and may take 20-30 minutes to thaw. Thawed plasma is immediately available, but has a shelf life of only five days making it impractical for most blood banks and emergency departments to keep on hand. Some centers have addressed this issue by developing processes to recycle thawed product to the operating room for immediate use at the end of its shelf life making new product available every few days. Alternatively, systems of prehospital notification for trauma, STEMI and Stroke reduce time to intervention. The blood bank can be incorporated into our prehospital notification system and selectively thaw plasma for patients with evidence of THS. The transport time can be used to thaw universal donor plasma and release it to the ED.  In patients presenting to the emergency department with THS saline should be limited and packed cells and plasma should be given to resuscitate until the patient is stabilized or damage control surgery is available.

Future Options:

Liquid plasma, that was never frozen, has a shelf life of nearly a month.(¹⁵⁾ It may allow greater flexibility for facilities wishing to incorporate plasma into their resuscitation, but not commonly available from blood banks. Freeze dried plasma, available in Europe, would be a game changer and could democratize the availability of plasma to nearly any environment.(¹⁶⁾ Freeze dried plasma is used in combat, easily stored and can be maintained outside the blood bank for as long as two years.(¹⁷⁾

The FDA is currently reviewing freeze dried plasma products. Other solutions may include the transfusion of whole blood or component therapy directed by viscoelastic hemostatic assay (thromboelastography). The combination of packed red blood cells, plasma and platelets can be achieved, but by using whole blood. While whole blood is showing promise clinically, it is a limited resource that is challenging to process and store.(¹⁸⁾  Guiding resuscitation by hemostatic assays requires time (~20 minutes) to run the test and informs which blood product to use, but is still limited by product availability.

Conclusion

Returning to the case above, the patient presenting to your emergency department is in traumatic hemorrhagic shock and definitive surgical care will be delayed. Further crystalloid resuscitation may be detrimental and blood products should be administered. In addition to packed red blood cells, thawed plasma should be administered as soon as practicable. Your institution has 2 units of thawed plasma available for immediate release. After administration of plasma, the patient’s blood pressure has improved to 100/60 and he is transported to the local trauma center for operative management. Early plasma administration reduces mortality is an important tool in the resuscitation of traumatic hemorrhagic shock.

References:

1. Baskett TF. James Blundell: the first transfusion of human blood. Resuscitation. 2002;52(3):229-233.
2. Bickell WH, Wall MJ, Jr., Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994;331(17):1105-1109.
3. Brown JB, Cohen MJ, Minei JP, et al. Goal-directed resuscitation in the prehospital setting: a propensity-adjusted analysis. J Trauma Acute Care Surg. 2013;74(5):1207-1212; discussion 1212-1204.
4. Tisherman SA, Schmicker RH, Brasel KJ, et al. Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the Resuscitation Outcomes Consortium. Ann Surg. 2015;261(3):586-590.
5. Brown JB, Cohen MJ, Minei JP, et al. Pretrauma center red blood cell transfusion is associated with reduced mortality and coagulopathy in severely injured patients with blunt trauma. Ann Surg. 2015;261(5):997-1005.
6. Shackelford SA, Del Junco DJ, Powell-Dunford N, et al. Association of Prehospital Blood Product Transfusion During Medical Evacuation of Combat Casualties in Afghanistan With Acute and 30-Day Survival. JAMA. 2017;318(16):1581-1591.
7. Gonzalez EA, Moore FA, Holcomb JB, et al. Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma. 2007;62(1):112-119.
8. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471-482.
9. Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289-1295.
10. Teixeira PG, Inaba K, Shulman I, et al. Impact of plasma transfusion in massively transfused trauma patients. J Trauma. 2009;66(3):693-697.
11. Zink KA, Sambasivan CN, Holcomb JB, Chisholm G, Schreiber MA. A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large multicenter study. Am J Surg. 2009;197(5):565-570; discussion 570.
12. Holcomb JB, del Junco DJ, Fox EE, et al. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013;148(2):127-136.
13. Moore HB, Moore EE, Chapman MP, et al. Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet. 2018;392(10144):283-291.
14. Sperry JL, Guyette FX, Adams PW. Prehospital Plasma during Air Medical Transport in Trauma Patients. N Engl J Med. 2018;379(18):1783.
15. Cardigan R, Green L. Thawed and liquid plasma–what do we know? Vox Sang. 2015;109(1):1-10.
16. Pusateri AE, Given MB, Schreiber MA, et al. Dried plasma: state of the science and recent developments. Transfusion. 2016;56 Suppl 2:S128-139.
17. Shlaifer A, Siman-Tov M, Radomislensky I, et al. The impact of prehospital administration of freeze-dried plasma on casualty outcome. J Trauma Acute Care Surg. 2019;86(1):108-115.
18. Beckett A, Callum J, da Luz LT, et al. Fresh whole blood transfusion capability for Special Operations Forces. Can J Surg. 2015;58(3 Suppl 3):S153-156.