NovoSeven In Critical Care - Evaluation

Recombinant activated Factor VII (rFVIIa; NovoSeven) usage protocol in emerging indications

This suggested rFVIIa protocol has been endeavored to assist clinicians in the appropriate use of rFVIIa in life-threatening massive bleeds, in particular coagulopathic diffuse bleeding that could occur in various traumatic, medical and surgery-related settings which has proved unresponsive to all other conventional methods of intervention. Multidisciplinary groups of clinicians from the fields of medicine, surgery, obstetrics, anesthesia, cardiac surgery, critical care and hematology specialties have evolved an opinion and rFVIIa usage protocol based on their experience, knowledge and published international literature. Ensuing information is intended to be used as a guideline though any use should be tailored to local hospital practice and resources.

Important considerations^1,2

• In massive bleeding, every attempt should be made to control bleeding by conventional measures. rFVIIa should not replace and/or delay surgery or any other methods used to control the source of bleeding, such as angiography with embolization.
• As rFVIIa arrests coagulopathic bleed rather than surgical bleed, it should be administered as an adjunctive therapy to concomitant surgical measures.
• rFVIIa should be considered only if first line treatment with a combination of blood products (RBCs, platelets, FFP and cryoprecipitate/fibrinogen) and surgical approaches fails to control bleeding.
• Efforts to achieve the correction of factors such as hypothermia, severe acidosis, low hematocrit and hypocalcemia, which may interfere with coagulation, should be made.
• Before administering rFVIIa, the patient, or the patient's next of kin, should be informed about the type of treatment that they are receiving.

Indication^2,3

Any salvageable patient suffering from massive, uncontrolled hemorrhage*in whom there is failure to arrest hemorrhage despite appropriate surgical measures and blood component replacement therapy**. Massive bleeding could occur in the context of varied clinical settings some of which are enlisted below, though the list in itself is not claimed to be complete and exhaustive.

Specific disease entities

• Polytrauma-related hemorrhage
• Postpartum hemorrhage
• Cardiac surgery bleeds
• Anticoagulant related bleeding
• Dengue hemorrhagic fever
• Liver disease-related bleeds
• Thrombocytopenia with refractory bleeding

Definitions

Massive hemorrhage^* is defined as one of the following²:

• Loss of entire blood volume within 24 h (10 U of packed RBC in a patient weighing 70 kg)
• Loss of 50% of blood volume within 3 h
• Blood loss at a rate of 150 mL/min
• Blood loss at a rate of 1.5 mL/kg/min for ≥ 20 min

Failure to arrest the hemorrhage despite²

• Application of all accepted and available surgical measures (e.g. ligation of damaged vessels, tamponading, or packing of the bleeding site, and induction of localized thrombosis).
• Appropriate replacement therapy2:**
  • Packed red blood cells (PRBCs): 8-10 U
  • Fresh frozen plasma (FFP): 10-15 mL/kg (4-6 U for a patient weighing 70 kg)
  • Cryoprecipitate: 1-2 U/10 kg (10-15 U for a patient weighing 70 kg)
  • Platelets: 1-2 U/10 kg (10-15 U for a patient weighing 70 kg)

Contraindications²

Absolute: Unsalvageable patients, as identified according to the clinical evaluation of the treating medical team.

Relative: History of thromboembolic events (e.g. pulmonary emboli, myocardial infarction, cerebrovascular accident, deep vein thrombosis) within the previous 6 months.

Administration guidelines ^2,4,5

rFVIIa is currently available in India as room temperature stable NovoSeven 1 mg and 2 mg lyophilized powder vials with corresponding dedicated diluents and a comprehensive infusion kit.

• rFVIIa could be considered if there is no response to transfusion of 8-10 U of PRBCs, conventional replacement therapy and surgical interventions
• Appropriate timing of rFVIIa usage is critical as its usage as a 'last resort' could minimize the chances of consistent positive clinical outcomes
• An initial dosage of 90-100 mcg/kg could be considered for most of the clinical situations; nevertheless specific dosage for relevant disease entities are mentioned in the ensuing pages; dosage usually rounded to a nearest vial and administered as a slow IV bolus over 2-5 minutes
• If bleeding persists beyond 20 minutes, a second dose could be repeated up to a maximum of total 3 doses
• Before considering the third dose, hypocalcemia to be corrected along with empirical replacement therapy
• Preferably rFVIIa should be used soon after reconstitution as slow IV bolus over 2-5 min. It should not be mixed with infusion solutions
• Response to rFVIIa should be assessed on clinical grounds (i.e. reduction or cessation of hemorrhage)

Preconditions for rFVIIa administration^2,4,5

All standard measures for the management of massive hemorrhage will have to be undertaken before the potential use of rFVIIa including

• Adequate correction of hypovolemia
• Achieving hematological parameters which include
  • Fibrinogen levels of ≥50 mg/dL (preferably 100 mg/dL)
  • Platelet levels of ≥50 000 X 109 per L (preferably 100 000 X 109 per L - for head trauma or neurosurgery) desirable; haemostatic response to rFVIIa however has been documented even with lower platelet counts.
  • Hemoglobin > 80 g/L (to optimize hemostasis)
  • Hematocrit of 0.24 (to facilitate clot formation)
• Attempts to correct acidosis (aim for pH =7.20 or higher as poor response to rFVIIa is seen if pH ≤7.1)
• Attempts to prevent and/or correct hypothermia (not mandatory for functioning of rFVIIa though)

Algorithm for use of rFVIIa

Note: *General dosage recommended in majority of indications is about 90-100 mcg/kg; however in anticoagulant-related bleeds, lower doses of 60-90 mcg/kg are preferred; doses of 20-40 mcg/kg have been used for non-emergent anticoagulant reversal.⁶

NICE Data: According to188 cases reviewed at NICE-review meet held on Mar28-29, 2009, the median dose for majority of the indications was 60mcg/kg though the median dose for DHF was 90mcg/kg and those for ICH, Cardiac surgery and Thrombocytopenia respectively were 44, 40 and 45mcg/kg.

Specific disease entities

Indications	Recommendation	Suggested doses*
Polytrauma - related bleed1,6,7	Ongoing bleeding and coagulopathy despite surgical intervention and replacement therapy - Appropriate6 Level of recommendation - Grade B1	Initial dose of 90 - 100 mcg/kg IV bolus If bleeding persists: Consider II and III dose after 1 h and 3 h respectively following administration of I dose7
Postpartum hemorrhage1,6,8	Attempted significant clotting factor replacement; Prior to hysterectomy - Appropriate 6,8 Level of recommendation - Grade E1	Initial dose of 90 mcg/kg IV bolus If bleeding persists: Consider II dose after 20 mins If bleeding persists after 2 doses - Consider hysterectomy
Cardiac surgery bleed1,6,9,10	Intractable nonsurgical bleeding unresponsive to attempted significant clotting factor replacement - Appropriate6 Level of recommendation - Grade B9	Initial dose of 70-90 mcg/kg IV bolus If bleeding persists, repeat dose up to 3 times
Anticoagulant-related bleed6,11	Non-traumatic intracranial bleeding6 < 4 hours since symptom onset On anticoagulant therapy - Appropriate Isolated traumatic head injury with evidence of expanding bleeding6 Taking anticoagulant therapy - Appropriate Level of recommendation - Grade B	Initial dose of 60 - 90 mcg/kg IV bolus If bleeding persists, repeat up to 3 doses
Dengue hemorrhagic fever12,13	Adjunctive therapy to significant blood component transfusion for controlling active bleeding - Appropriate Level of recommendation - Grade C	Initial dose:100 mcg/kg repeated at 15-30 mins interval (usually 1-2 doses) till reduction of bleeding Repeat dose: 100 mcg/kg, repeated at 2-4 intervals (usually 2-4 doses) till cessation of bleeding Final dose: 100 mcg/kg after bleeding completely stops
Liver disease-related bleeds1,11	Ongoing hemorrhage despite attempted significant clotting factor replacement in patients with liver disease (variceal, non-variceal and liver transplantation related bleed) - Inappropriate Level of recommendation - Grade B1	Not applicable
Thrombocytopenia with refractory bleeding14	Severe bleeding despite attempted significant clotting factor replacement - Could be appropriate Level of recommendation - Grade E	Initial dose of 50-100 mcg/kg Dose to be repeated if necessary

Monitoring

Currently, the best available indicator of rFVIIa efficacy is the arrest of hemorrhage judged by visual evidence, hemodynamic stabilization and a reduced demand for blood components.²

*rFVIIa Dosage as per NICE Data:

According to188 cases reviewed at NICE-review meet held on Mar28-29, 2009, following are the dosages (mcg/kg) used in clinical hemorrhage of various etiologies. The median dose for majority of the indications was 60mcg/kg though the median dose for DHF was 90mcg/kg and those for ICH, Cardiac surgery and Thrombocytopenia respectively were 44, 40 and 45mcg/kg.

References

1. Vincent et al. Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding - a European perspective. Critical Care. 2006;10(4):R120. Available online http://ccforum.com/content/10/4/R120.
2. Martinowitz U, et al. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force. Journal of Thrombosis and Haemostasis. 2005;3: 1-9.
3. IAP Guidelines 2006 on recombinant activated factor VIIa (rFVIIa). 2006:258-268.
4. Moltzan CJ, et al. The evidence for the use of recombinant factor VIIa in massive bleeding: development of a transfusion policy framework. Transfusion Medicine.2008;18:112-120.
5. Activated Factor Viia Working Group Northern Ireland Advisory Committee On Blood Safety. Regional Guidelines for off-licence use of Recombinant Factor VIIa (Eptacog-alfa; NovoSeven®) in acquired coagulopathy. 2007:1-13. Available at http://www.dhsspsni.gov.uk/recombinantfactorviiaguidelines.pdf.
6. Shander, et al. Consensus recommendations for the off-label use of recombinant human factor VIIa (NovoSeven) therapy. P&T. 2005;30(11):644-658.
7. Spahn DR, et al. Management of bleeding following major trauma: a European guideline. Critical Care. 2007;11:R17. Available online http://ccforum.com/content/11/1/R17.
8. Welsh A, et al. Guidelines for the use of recombinant activated factor VII in massive obstetric haemorrhage. Australian and New Zealand Journal of Obstetrics and Gynaecology 2008; 48: 12-16.
9. Ferraris, et al. Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists Clinical Practice Guideline. Ann Thorac Surg 2007;83:S27-86.
10. Dunkley S, et al. Recombinant Activated Factor VII in Cardiac Surgery: Experience From the Australian and New Zealand Haemostasis Registry. Ann Thorac Surg 2008;85:836-44.
11. Recombinant factor VIIa in non-haemophiliac conditions. A position statement of the NSW Therapeutic Advisory Group Inc. June 2007:1-56. Available online http://www.ciap.health.nsw.gov.au/nswtag/publications/posstats/Eptacog_FINALaddendum0907.pdf.
12. Chuansumrit A, et al. Control of bleeding in children with Dengue hemorrhagic fever using recombinant activated factor VII: a randomized, double-blind, placebo-controlled study. Blood Coagulation and Fibrinolysis 2005, 16:549-555.
13. Chuansumrit A and Tangnararatchakit K. Pathophysiology and management of dengue hemorrhagic fever. Transfusion alternatives in transfusion medicine. 2006;8(Suppl 1):3-11.
14. Combination therapy with rFVIIa and platelets for hemorrhage in patients with severe thrombocytopenia and alloimmunization. Available online http://www3.interscience.wiley.com/cgi-bin/fulltext/112456266/PDFSTART.