Massive Transfusion in 30 minutes or less

18 Oct 2010 Kate Chipperfield MD FRCPC Vancouver Coastal Health University of British Columbia

Objectives

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Definitions of MT Complications of MT VCH protocol for MT, and planned TEP MTP’s and 1:1 blood product ratios rfVIIa (Niastase™) Antifibrinolytics in Trauma

Definition of MT

Commonly used definition:

 10 or more units of PRBC given within a 24-hour period.

Retrospective

- needs a more dynamic definition:     6+ units in one bleeding episode with ongoing losses 4+ units in one hour with ongoing losses replacement 50% BV in 3 hours rate of loss ≥ 150 ml/min  etc…

Types of patients

What types of patients are likely to require MT?

 Blunt or penetrating trauma  Cardiovascular surgery/ruptured AAA  Massive GI bleeds  Catastrophic obstetrical events  Previously unrecognized bleeding diathesis  Liver transplant  Other

Physician M’ment of MT Event Flow diagram (VA and RH) RN and Technologist procedures

Cochrane Collaboration 2007 review of 55 RCTs; crystalloid vs colloid in resuscitation - no difference in survival - colloids are more expensive with no apparent benefit If you inform the blood bank of a MT, they will call Hematology lab to ensure ‘stat’ lab tests, and start thawing plasma

‘Transfusion triggers’

Blood product administration should be guided by clinical bleeding AND labs: RBCsto maintain Hb > 80; set goal as 100g/L Plasma ±Cryo Plts aim for INR and/or PTT < 1.5 x normal to maintain fibrinogen > 1.0 g/L maintain > 50-80; set goal >80 or > 100 if CNS/multi-trauma Exception – if plts dysfunctional then count not helpful (e.g. CPB, anti-plt meds, uremia)

e.g. antifibrinolytics

Does cryo have a role in MT?

Plasma  Volume 200 -250 ml   1 dose = 3-4 units All coag factors  Fibrinogen 500 mg/unit Cryoprecipitate  Volume 10 ml per unit   1 dose = pool of 10 units FVIII, vWF, FXIII and…  Fibrinogen > 1.5 g/pool Therefore 1 dose of plasma has at least as much fibrinogen as 1 dose of cryo. Cryo more useful in situations requiring fibrinogen in small volume.

Selecting red cells, and Switching Groups

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Emergency Group O red cells

 Reserve Rh neg units for children and women of child bearing age (CSA Standard) We can issue group-specific RBCs within minutes, once we have rec’d the pt sample. It does not matter how many group O units the pt may have received.

 Remaining plasma in one RBC unit is ~15 ml

Complications of MT

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Hypothermia Citrate toxicity Increased risk of transfusion errors Metabolic - altered K+ and pH;  2,3-DPG Impaired hemostasis - multifactorial Transfusion Reaction (s)

Avoiding the vicious cycle:

Coagulopathy Hemorrhage Hemodilution Hypothermia Acidosis

 A ‘stat’ INR/PTT may take >1 hour  Do we lose valuable time if we wait to transfuse plasma before labs are back?

 ‘Acute coagulopathy of trauma’ – suggestion that trauma pts who present with prolonged coags have higher mortality

Coagulopathy: Elective surgery vs trauma setting

What about a formulaic approach to MT?

 Some centres in US advocate a MT package of blood product  e.g. 1:1 RBC/plasma  e.g. 6:4:1 RBC/plasma/platelets  Historical context:   1970s: military/trauma approach to hemorrhagic shock was large volumes crystalloid + whole blood 1980s: Move away from WB to blood components – patients got crystalloid + PRBCs  Recognition of inadvertent hemodilution, respiratory distress, and compartment syndrome

Issues of AB plasma by month for the last 4 years in Canada

AB Plasma Units Shipped to Hospitals by Month 1,950 1,750 1,550 1,350 1,150

50% increase

950

Publications On 1:1

750 20 06 /J an 20 06 /M ar 20 06 /M ay 20 06 /J ul 20 06 /S ep 20 06 /N ov 20 07 /J an 20 07 /M ar 20 07 /M ay 20 07 /J ul 20 07 /S ep 20 07 /N ov 20 08 /J an 20 08 /M ar 20 08 /M ay 20 08 /J ul 20 08 /S ep 20 08 /N ov 20 09 /J an 20 09 /M ar

Retrospective chart review of 246 pts who had MT in Iraq.

Pts grouped by the ratio of plasma to RBCs they received during their MT.

Authors’ conclusions

a 1:1 ratio of plasma to hypocoagulable with traumatic injuries.”

: “..MT protocols should utilize

RBCs for all patients who are

Limitations:

- Retrospective, some data not retrievable or inaccurate - No standardized MT protocol - Used whole blood and non-leukoreduced products - Mostly young men (median age 24; only 3 female) - 94% were penetrating injuries - Differences in baseline characteristics between groups

- Low ratio group included patients who died before plasma could be thawed

Many Many other publications …

 Civilian trauma studies  Duchesne JC et al, J Trauma 2008, 65:272-276  Retrospective review of both non-massive and massive transfusion  In MT, mortality 87.5% (less plasma) vs 26% (more plasma)  Scalea TM et al, Ann Surg 2008, 248:578-584  Prospective observational study of trauma patients  The plasma to red cell ratio did not predict survival or LOS in ICU or hospital in either MT or non-MT

Survivorship bias

Snyder et al, J Trauma 66:358-364, 2009     The authors sought to control for survivorship bias by controlling for the timing of FFP retrospective cohort study of 134 trauma patients who received ≥10 RBC in 24h In their centre, plasma is not kept thawed Divided patients into low ratio (<1:2) and high ratio (≥1:2) groups at varying time points:  (every 30 mins for the first 2 h, hourly from 2-6 h, and every 6 h until 24 h)

Snyder et al, J Trauma 66:358-364, 2009

 Median time to the first RBC was 18 min, and first FFP was 93 minutes  The start times for the first FFP ranged from 24 to 350 minutes!

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Key Finding: Over time, patients moved from low-ratio to high-ratio group

 at 90 min: 83% low-ratio; at 6 h: 53% low-ratio  Among early deaths, more occurred in the low-ratio group  Among late deaths, more occurred in the high-ratio group

Snyder et al, J Trauma 66:358-364, 2009

Snyder et al, J Trauma 66:358-364, 2009

“As component blood products are not administered uniformly and simultaneously in civilian clinical practice, and many deaths occur early, it is possible that the survival advantage observed among those receiving a higher FFP:PRBC ratio may simply reflect the fact that they lived long enough to receive the higher ratio of products.”   One question this study doesn’t address is the effect of having thawed plasma ready and available But is it feasible for Canada to have thawed AB plasma available at all times?  Thawed plasma can be stored for 24 h in the fridge; cannot be refrozen (in US they can keep thawed plasma for 5 days)  Much AB plasma in Canada still comes from female donors, therefore at increased risk of causing TRALI

Percentage of Male vs Female plasma produced by CBS by blood group

100 90 30 20 10 0 80 70 60 50 40 O A B AB Male Female

Retrospective, NonMT Trauma, 1716 pts, Excluded early deaths

One Size does not fit all!

J Am Coll Surg

Final thoughts on “1:1”

     In general, the concept of plasma earlier rather than later for coagulopathic trauma patients is supported No good evidence (yet) to suggest the optimal timing or ratio of FFP to RBC Hospital should develop own MT protocol taking into account patient pop and resources We will likely never have thawed AB plasma available 24/7 so order plasma early knowing that there will be >30 min delay for thawing Platelets are suspended in plasma!

VGH, Future Trauma Exsanguination Protocol (TEP)

 In general, the concept of plasma earlier rather than later for coagulopathic trauma patients is supported  VGH developing TEP – 2011  Criteria include:  4uRBC in and ongoing rapid Tx needs PLUS;  Poor hemodynamic response and SBP <90 mmHg  Base Deficit < -8  pH <7.25

rFVIIa (Niastase)

 Developed as a ‘bypassing agent’ for Hemophilia A and B patients with Inhibitors (antibodies to factor)  These pts no longer respond to simple factor replacement therapy  Canada: Any use outside of Hemophilia is OFF LABEL  In some countries it is also licensed for:  Congenital factor VII deficiency  Glanzmann’s thrombasthenia where plt transfusions ineffective

The Coagulation Cascade

Exogenous FVIIa bypasses the problem in hemophiliacs

Cell-Based Model of Hemostasis (Hoffman): Where does Niastase Come In?

VIII IX

vWF

Is there any evidence that rFVIIa works in MT?

 Lots of personal anecdotal reports and case studies  ? Literature bias against negative studies  Limited number of RCTs in various bleeding situations  Some have shown small reduction in units transfused but no evidence of improved outcomes  What is the risk of giving it?

  Several RCTs have shown small increased risk of thrombosis (dose dependent) COST

2008: National Advisory Committee (NAC) reviewed published RCTs re use of rFVIIa in various bleeding scenarios.

(trauma, ICH, liver transplant, cardiac surgery, prostatectomy, SCT) Conclusions: - most are dose-finding studies that are powered to find reductions in units transfused, not reduced morbidity/mortality - studies are too small to adequately assess risk of thromboembolism - high risk pts usually excluded from studies (age >65, DIC/sepsis, Hx of thrombosis, mechanical heart valve, etc)

NAC recommendations

 The current evidence does not support the routine use of rFVIIa in MT  However its use should be part of a MT framework for use on a case by-case basis  Consider when:   Massive intractable bleeding (>8 units in 24h or >4 units in first hour with ongoing bleeding) AND all other measures to achieve hemostasis have been attempted  Dose: 20-50  g/kg and round to nearest vial  Repeat at 30 min and up to 2h (max 3 doses)

Niastase – Cost and Access (VA)

 ~$1000 per mg   1.2mg, 2.4mg and 4.8mg vials (changing to 1mg, 2mg, 5mg)  Call Blood Bank (54420) to order – hematopathologist approval  For faster approval have recent coags, pH, temperature and pt weight available to discuss with HP  There must be adequate platelets and reasonable coagulation profile  Acidosis and hypothermia must be corrected  Surgical bleeding must be excluded

VGH MT protocol….

rFVIIa is not explicitly stated but would go here

Antifibrinolytics in MT?

    CRASH-2 trial (Lancet 2010: 376:23-32) RCT of 20,211 adult trauma patients in 274 hospitals in 40 countries Randomized to receive placebo or   TXA 1 g over 10 min then infusion 1 g over 8h Treatment initiated within 8 hours of injury  Staff blinded to treatment arm How did TXA reduce mortality? Suppression of plasmin proinflammatory effects? Results:  All cause mortality sig reduced in TXA arm (14.5% vs 16.0%)   Death due to bleeding sig reduced in TXA arm (4.9% vs 5.7%) Vascular occlusive events did not differ (1.7% vs 2.0%)  Blood transfusion rate not different (50.4% vs 51.3%)

 Questions about Massive Transfusion?

 VCH TM Intranet site: http://vchconnect/programs_services/transfusion_medicine/page_29666.htm

References

        Stanworth et al. Recombinant fVIIa for the prevention and treatment of bleeding in patients without hemophilia. Cochrane Database of Systematic Reviews 2007, Issue 2. April 18.

Mathew, P et al. How we manage requests for rfVIIa. Transfusion 2007;47:8-14.

Boffard K et al. Recombinant fVIIa as adjunctive threapy for bleeding control in severely injured Trauma Patients: Two parallel randomized, placebo-controlled, double blind clinical trials. Journal of Trauma 2005 59 (1)8-18.

Webert et al.Letters to the Editor. Journal of Trauma 2006;60(1):242-3.

Teixeira et al, Impact of plasma transfusion in massively transfused trauma patients. J Trauma 66:693-697, 2009 Link, K et al. 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 197, 565-570, 2009 Snyder, CW et al, The relationship of blood product ratio to mortality: survival benefit or survival bias. J Trauma 66:358-364, 2009 CRASH-2 trial (Lancet 2010: 376:23-32)

Other references: See Physician Management of Massive Transfusion Event, VCH TM Intranet site