Clinical indications of FFP

1. Clinical indications of FFP 4C1 Ri 陳彥榮

2. Part I • Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant • British Committee for Standards in Haematology, Blood Transfusion Task Force (J. Duguid, Chairman): D. F. O’Shaughnessy (Convenor, Task Force nominee),1,* C. Atterbury (RCN nominee),2 P. Bolton Maggs (RCPCH nominee),3 M. Murphy (Task Force nominee),4 D. Thomas (RCA nominee),5 S. Yates (representing Biomedical Scientists)6 and L. M. Williamson (Task Force nominee)7 British Journal of Haematology 2004; 126:11

3. Guidelines for FFP • Single inherited clotting factor deficiencies for which no virus-safe fractionated product is available. [ex. Factor V] • Multi-factor deficiencies associated with severe bleeding (ex.DIC with bleeding) • Fresh-frozen plasma is not indicated in DIC with no evidence of bleeding. • Hypofibrinogenemia: Cryoprecipitate may be indicated if the plasma fibrinogen is less than 1 g/l, • TTP: • Single volume daily plasma exchange should ideally be begun at presentation (grade A recommendation, level Ib evidence) British Journal of Haematology 2004; 126:11

4. DIC • Treating the underlying cause is the cornerstone of managing DIC. • If the patient is bleeding, a combination of FFP, platelets and cryoprecipitate is indicated. • If there is no bleeding, blood products are not indicated, whatever the results of the laboratory tests, and there is no evidence for prophylaxis with platelets or plasma

5. Guidelines for FFP • Reversal of warfarin effect when severe bleeding: • Partial effect • Fresh-frozen plasma should never be used for the reversal of warfarin anticoagulation when there is no evidence of severe bleeding (grade B recommendation, level IIa evidence). • Vitamin K deficiency in the intensive care unit (ICU): • Fresh-frozen plasma should not be used to correct prolonged clotting times in ICU patients; • this should be managed with vitamin K British Journal of Haematology 2004; 126:11

6. Reversal of warfarin effect • Warfarin achieves its anticoagulant effect by inhibiting the vitamin K-facilitated carboxylation of FII, FVII, FIX and FX. • Withdrawing warfarin, giving vitamin K orally or parenterally; transfusing FFP, or transfusing PCC (FII, FVII, FIX and FX, or separate infusions of FII, FIX and FX concentrate and FVII concentrate). Prothrombin complex concentrate (50 units/kg) is preferred to FFP. • Makris et al (1997) showed that FFP contains insufficient concentration of the vitamin K factors (especially Factor IX) to reverse warfarin, supporting the finding that FFP is not the optimal treatment.

7. VitaminK policies in ICUs • Many patients in ICU have an inadequate vitamin K intake, particularly as parenteral nutrition for the seriously ill usually has a restricted lipid component. • Intensive care unit patients should routinely receive vitamin K: • 10 mg thrice weekly for adults 0-3 mg per kg for children (grade B recommendation,level IIa evidence).

8. Guidelines for FFP • Liver disease: • Platelet count and function, as well as vascular integrity, may be more important in these circumstances. • The response to FFP in liver disease is unpredictable. Complete normalization of the haemostatic defect does not always occur. If FFP is given, coagulation tests should be repeated. • There is no evidence to substantiate the practice in many liver units of undertaking liver biopsy only if the PT is within 4 s of the control (grade C recommendation, level IV evidence). British Journal of Haematology 2004; 126:11

9. Guidelines for FFP • Surgical bleeding: • Should be guided by timely tests of coagulation • FFP should never be used as a simple volume relacement in adults or children (grade B recommendation, level IIb evidence). • Massive transfusion: • If bleeding continues after large volumes of crystalloid, red cells and platelets have been transfused, FFP and cryoprecipitate may be given so that the PT and APTT ratios are shortened to within 1.5, and a fibrinogen concentration of at least 1.0 g/l in plasma obtained. British Journal of Haematology 2004; 126:11

10. Guidelines for FFP • Paediatric use of FFP • should only receive pathogen-reduced FFP (PRFFP) • Haemorrhagic disease of the newborn: • FFP 10–20 ml/kg + IV vitamin K.+ Prothrombin complex concentrate. • Who are about to undergo an invasive procedure, should receive FFP and vitamin K. • Routine administration of FFP to prevent periventricular haemorrhage (PVH) in preterm infants is not indicated British Journal of Haematology 2004; 126:11

11. Adverse effects of FFP • 1. Allergy resulting in urticaria has been reported in 1–3% of transfusion, whil anaphylaxis is rare. • 2.Transfusion-related acute lung injury: • 0.02% of transfusion. • Severe respiratory distress, with hypoxia, pulmonary edema, infiltrates or ‘white-out’ on chest X-ray, and sometimes fever and hypotension. • Usually develops within 4 h of transfusion. • It cannot be distinguished clinically from ARDS. British Journal of Haematology 2004; 126:11

12. Adverse effects of FFP • 3. Infection: • The freezing process inactivates bacteria. Bacterial contamination and growth, with endotoxin production, prior to freezing is unlikely, and has not been reported in the UK in the past 5 years. • However, freezing does not remove free viruses such as hepatitis A, B and C, human immunodeficiency virus (HIV) 1 + 2, and parvovirus B19. • HIV 1 + 2 :0-1 in 10 million • hepatitis C :0-2 in 10 million • hepatitis B :0-3 in 10 million. • Patients likely to receive multiple units of FFP, such as those with a congenital coagulopathy, should be considered for vaccination against hepatitis A and B. British Journal of Haematology 2004; 126:11

13. No justification for the use of FFP • 1. Hypovolemia • Crystalloids are safer, cheaper and more readily available. • 2. Plasma exchange (except for TTP) • May results in the progressive reduction of coagulation factors, immunoglobulins, complement and fibronectin. • Haemorrhage and/or infections are not encountered. • There may be a problem with pseudocholinesterase levels being low as a result of many plasma exchanges with saline/albumin if the patient then needs an anaesthetic. This can be corrected with FFP. • 3. Prolonged INR in the absence of bleeding. British Journal of Haematology 2004; 126:11

14. Part II • Albumin use in resuscitation. • A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit NEJM Volume 350, May 2004, pp 2247-2256

15. Volume expander? • A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care UnitNEJM Volume 350:2247-2256. May 27,2004. • Saline versus Albumin Fluid Evaluation (SAFE) Study in 16 ICUs in Australia and New Zealand • Total N=6997,Exculsion: Patients admitted to the ICU after cardiac surgery, after liver transplantation, or for the treatment of burns. • Double-blind, randomized trial • Two groups: similar baseline characteristics.

16. N Engl J Med 2004; 350:2247

17. N Engl J Med 2004; 350:2247

18. Results • 726 deaths/in 3497 p’t – 4% albumin • 729 deaths /in 3500 p’t- saline; • In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days. N Engl J Med 2004; 350:2247

20. N Engl J Med 2004; 350:2247

21. In our study, patients who were resuscitated with albumin received less fluid than those who were resuscitated with saline. • However, there was no significant difference in mean arterial pressure between the groups, and the differences in central venous pressure and heart rate were small. • Patients who were assigned to albumin received a significantly greater volume of PRBC during the first two days of the study. • The reasons for this difference remain speculative but may include greater hemodilution with albumin than with saline or increased blood loss with albumin due to transient alterations in coagulation .

22. Conclusion • Albumin and saline should be considered clinically equivalent treatments for intravascular volume resuscitation in a heterogeneous population of patients in the ICU. • Whether either albumin or saline confers benefit in more highly selected populations of critically ill patients requires further study. 健保規範

23. Thanks for your attention !!

28. 健保局 Human Albumin 使用規定： • 1.本保險對象因病使用Human Albumin以符合下列適應症為限： • (1)休克病人擴充有效循環血液量 • Ⅰ.休克病人至少已給生理鹽水或林格爾液等晶類溶液1000 mL後尚不能維持穩定血流動態，血比容(hematocrit)＞30 %，或血色素(hemoglobin)＞10 gm/dL須要繼續靜脈輸液時，宜優先使用合成膠類溶液，如dextran、hydroxyethylstarch、polyvinylpyrolidone等。若無上述合適製劑，可給白蛋白溶液，每一病人用量限50 gm（86/1/1）。 • Ⅱ 70歲以上老人及二歲以下幼兒或併有心衰竭的休克 病人，無法忍受太多靜脈輸液時，可一開始即使用白蛋白溶液，每一病人用量限50 gm。

29. 健保局 (2)病危、有腹水或水腫併有血清白蛋白濃度偏低病人 I 血清白蛋白濃度低於 2.5 gm/dL • i. 肝硬化症(有相當之腹水或併發水腫)每日最多用量限25 gm。 • ii. 腎病症候群(嚴重蛋白尿致血清白蛋白下降)，每日最多用量限25 gm。 • iii 嚴重燒燙傷。 • iv 肝移植。 Ⅱ血清白蛋白濃度低於 3.0 gm/dL • i呼吸衰竭使用人工呼吸器超過三天，仍無法脫 離。 • ii嚴重肺水腫。 • iii大量肝切除（＞40 %） • Ⅲ開心手術用於維持體外循環液，用量限 37.5 gm。 2.注意事項 • (1)血清白蛋白濃度檢驗日期限最近三天以內，如係多次注射，限上次注射後，最近三天內之結果。

30. TRALI • According to some authors, TRALI develops in two steps (Silliman et al, 2003). • First, a predisposing condition: • surgery or active infection. • ->cause cytokines releasing and neutrophils attaching to the vascular endothelium particularly in the pulmonary capillaries. • The second step: • lipid and other cytokines, or human leucocyte antigen or granulocyte alloantibodies (found in 80% of the donors in some series, most of whom are women who have been pregnant) • ->cause further neutrophil priming, activation and pulmonary damage. British Journal of Haematology 2004; 126:11

31. Cryosupernatant • The current established treatment of thrombotic thrombocytopenic purpura (TTP) is plasma exchange with fresh frozen plasma (FFP). With this treatment, there is a 49% response after seven exchanges and a 78% survival at 1 month. Although the exact cause of TTP is unknown, the presence of von Willebrand factor (VWF) multimers has been implicated in the disease. Accordingly, it has been suggested that cryosupernatant (plasma from which cryoprecipitate has been removed), which is relatively deficient in VWF multimers, might be an effective replacement fluid during plasma exchange. • British Journal of HaematologyVolume 94 Page 383  - August 1996

32. Complications of therapeutic plasma exchange [UpToDate] • Therapeutic plasma exchange (TPE, plasmapheresis) is an extracorporeal blood purification technique designed for the removal of large molecular weight substances from the plasma. This topic review will discuss the complications associated with this procedure; the prescription and technique of TPE are discussed separately. (See "Prescription and technique of therapeutic plasma exchange"). • COMPLICATIONS — A review of the reported complications from over 15,000 plasma exchange treatments found that adverse reactions were substantially more common with fresh frozen plasma (FFP) than with albumin replacement (20 versus 1.4 percent) [1]. The most frequent problems are citrate-induced paresthesias (due to binding of free calcium to citrate), muscle cramps, and urticaria [2]. More serious complications, such as severe anaphylactoid reactions, typically follow the administration of FFP and other plasma-containing replacement fluid [3]. The overall incidence of death is 0.03 to 0.05 percent (see below) [1,3].

33. Complications of therapeutic plasma exchange [UpToDate] • Hypotension — TPE can lead to a reduction in blood pressure that is usually due to a decrease in intravascular volume. A certain proportion of whole blood must necessarily be extracorporeal during the procedure. With continuous flow technology, the extracorporeal volume is usually no more than 15 percent of the patient's intravascular volume; however, instrumentation which utilizes discontinuous flow technology may have higher extracorporeal volumes. Infusing additional intravascular fluid or increasing the return rate can return the blood pressure toward the baseline level.If a fall blood pressure is accompanied by a decrease in pulse rate, diaphoresis, and/or syncope, it is likely that a vasovagal reaction is occurring. Lowering the patient's head, using ammonium salts, and stopping the procedure temporarily are the appropriate responses to this type of reaction. • Dyspnea — The development of shortness of breath or dyspnea suggests the presence of pulmonary edema due to fluid overload. Noncardiogenic edema can rarely occur and, if the blood components being reinfused are not adequately anticoagulated, massive pulmonary emboli can ensue. The latter is a rare occurrence, since state-of-the-art blood cell separators control and monitor anticoagulant volumes.