FFP Requests: Legend, Lore, and Evidence

1. FFP Requests: Legend, Lore, and Evidence Rachel LaCount August 26, 2005

2. Objectives Present data from studies on FFP: 1. Resuscitation in burn patients 2. FFP to correct INRs before procedures

3. Case # 1 Pt is a 24 yo male s/p flash burn following crash at speedway 8 hours ago. 90% total body surface area with 60% to 70% full-thickness burns.Request for 4 FFP. Pt not bleeding or going to surgery. PT: 16.3, INR: 1.3, PTT: 34.3 Surgery resident: “My attending uses FFP as a colloid fluid for resuscitation”Is this an appropriate use of FFP?What is the data supporting the surgeon’s request?

4. A little about fluid resuscitation in burns • Prevention of shock from intravascular fluid loss • Edema formation in burned/unburned tissue should be minimized to prevent complications: • Tissue hypoxia • Compartment syndrome • Intra-abdominal hypertension leading to abdominal compartment syndrome • Pulmonary edema • 50% of edema in large burns is found in nonburned tissue

5. Physiology Review • Q = Rate of fluid crossing from intra to extravascular space • Kf= Capillary filtration coefficient, ease of passage of fluid across endothelium • Pcap = capillary hydrostatic pressure • Pi = interstitial hydrostatic pressure (collagen + hyaluronic acid = densely packed and keeps water out) • σ = capillary permeability • p = plasma oncotic pressure • i = interstitial oncotic pressure

7. Changes in burn patients • Pcap = increased transiently (sympathetic discharge) • Pi = decreased; negative value (release of osmotically active particles released cause vacuum effect—”sucks” fluid from vessel) • σ = increased (marked and sustained) • p = decreased (damaged caps release proteins) • i = begins to approach plasma value • (p - i) = 2-3 mm Hg, normally 10 • All these effects = Q ↑↑

8. Time frame Edema formation in deep burn: • Maximum edema occurs at 18 hours after burn injury • Resorption starts at 24 hrs • 25% still remains at 1 week • Resorption is delayed compared to partial thickness burn (complete in 4 days)

9. Fluid resuscitation • Colloid or Crystalloid??? • Disagreement and controversy in pts with burns covering >25% BSA has been going on since the beginning of modern tx! • Lactated Ringer’s solution • Human albumin • Hydroxyethyl starch • Plasma protein fraction • FFP

10. Albumin • Cochrane Injuries Group, 1998 • Reviewed 32 RTCs pts with hypovolemia from injury, surgery, burns, and hypoproteinemia • Randomized to receive albumin vs. LR/NS • Pts given alb: Risk of death 6% higher • Burn pts: Relative risk of death—2.4 • Why? In burns, vascular permeability so increased that alb not effective

11. FFP, burns • 1960s: Most places abandoned use of FFP or other colloids in burn pts in 1st 24o • 1989: Fewer pulmonary complications and less acute wt gain (edema) in pts tx with FFP • 1991: 30 pts with partial and full skin thickness burns involving > 30% BSA • 10 pts resuscitated with LR • 10 pts with HPT (hypertonic formula) • 10 pts with FFP 75 ml/kg + LR • Results: FFP regimen = less wt gain (edema), smaller infusion volumes, normal serum protein levels, and normal plasma oncotic pressures

12. FFP, burns • 2001: Burn injury in 45 children FFP vs. crystalloid solution in 1st 36o • “Descriptive study:” • Observed fever (12o post burn) significantly higher in FFP group than crystalloid (1.3oC) • Effects of higher fever: • More RN care, more blood taken for culture • May receive unnecessary abx • Surgeries postponed • Questions not addressed: • Were there other variables (pt’s baseline vitals, nature of burn) that caused clinicians to choose the fluid they did? • How much FFP or crystalloid was given?

13. FFP, burns • May 2005, Journal of Trauma • Hypothesis: Plasma resuscitation may be protective from abdominal compartment syn--leading to decreased mortality • Pts: 31 pts with 25% or greater TBSA burn • Study design: Prospective, randomized trial: • FFP+ LR vs LR for 48 hrs • All volumes titrated for goal urine output • FFP dose: 75 ml/kg/hr • After 48 hrs pts all on maintenance fluids • Measured parameter: Intra-abdominal pressure measured by urinary bladder pressure x 5 d

14. Results • Greater rise in IAP in patients who died in both groups • Plasma = 3 deaths; crystalloid = 4 deaths • Linear relationship between volume infused and IAP, no matter what fluid used • Pts given plasma were given total less volume (12.3 L vs. 22.1 L; p = 0.02)

15. Results, cont… • Plasma pts: • Able to give more fluid early (before weight gain and intra-abdominal pressures rose to unmanageable levels) • Lower mean peak IAP • Maintained IAP below threshold of complications of intra-abd HTN • End-organ derangement: • Peak BUN/Cr not significantly different between the groups

16. Conclusion: Reduced volume regimen may decrease morbidity & plasma allowed for reduced volume • Problems with study: • Resuscitation prior to admission • At scene, during transport, at outside hospitals: No details given on fluid received and whether study groups differed significantly • Study claim: Lower IAP decreases M & M, yet they did not have this outcome • Similar numbers died; no difference in end organ derangement • (Other literature: IAH is associated with malperfusion of the gut, liver, and kidneys as well as with cardiac and pulmonary dysfunction. IAH can lead to ACS which is 100% fatal). • Outcomes beyond 5 d not evaluated: • To study long term survival, 900 patients would have to be evaluated to have a power of 80% and 10% difference in survival

17. CAP • 1994: Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets • “The use of FFP as a volume expander or to enhance wound healing is contraindicated.”

18. British Committee for Standards in Haematology • 2004: Blood transfusion task force • “Fresh-frozen plasma should never be used as a simple volume replacement in adults or in children. Crystalloids are safer, cheaper and more readily available.”

19. Case #1 • Should you approve the FFP? • The most recent study indicates it may be helpful in preventing a 100% fatal complication • Not formally accepted as a use for FFP

20. Case #2 • 55 yo female with unexplained elevated LFTs presents for percutaneous liver bx • Her INR is I.6 and IR is requesting 2 units of FFP • Your guidelines state that INR >1.5 justifies giving the FFP • Is there any evidence that FFP will prevent bleeding in this or any patient given FFP prophylactically?

21. How common is this request? Data from Mass General physician order entry: Feb to April, 2003

22. Questions 1. Is there data that mild-moderate abnormalities in PT/APTT increase the risk for bleeding during procedures? 2. Does FFP correct these abnormalities and lead to better pt outcomes?

23. CAP (1994) FFP indications: • Hx or clinical course suggestive of a coagulopathy due to a congenital or acquired deficiency of coagulation factors, with active bleeding, or prior to an operative or other invasive procedure • Documented by at least one of the following: • PT > 1.5 times the midpoint of nl range (usually >18 sec) • APTT > than 1.5 times top of nl range (usually >55 to 60 sec) • Fib >100 mg/dL • Coagulation factor assay of less than 25% activity • But…what’s the data???

24. 1st question PT, APTT • Is there data that mild-moderate abnormalities in PT/APTT increase the risk for bleeding during procedures? • ie: Pts with PT/APTT either at 1.5 x the midpoint/top of normal range or slightly greater? • PT > 1.5 times midpoint of nl range (usually >18 sec) • APTT > 1.5 times top of nl range (usually >55 to 60 sec)

25. Increased bleeding risk?Study #1: • 1981, Digestive Diseases and Sciences • Subjects: 200 patients undergoing laparoscopic liver bx • Study design: Prospective study to determine relationship between: • Liver bleeding time (LBT) • PT • Whole blood clot time • Plt count • Length of bx cylinder • Liver histopath • Bleeding after liver biopsy did not correlate with indices of peripheral coagulation • Normal LBT even with highly abnormal clotting indices

26. Increased bleeding risk?Study #2: • 1990, Am J Clin Path • Subjects: 177 patients who had percutaneous liver bx in whom they had the following data: • PT or APTT and plt count within 10 days of procedure • Hb measured 48 hrs before and 5-48 hrs after • Notes on pt status • Excluded if had the procedure but not the above data • Excluded if had received FFP or active bleeding unrelated to procedure • Study design: Retrospectively looked at the difference between: • Bleeding (Hb decrease of  2 g/dL) or average Hb difference • & PT/APTT and plt count

27. Study # 2, cont… • Results: No difference in bleeding between normal & mildly prolonged PT/APTT or plt count • Prolonged mild: PT/APTT 1.1 to < 1.5 x nl • 14% of pts had moderately abnl APTT > 43.6, but their rates of bleeding were not significantly different than normals • Problems with study: • No patients with PT > 1.5 x nl analyzed & they do not state why • Pts given FFP prophylactically were excluded--perhaps these pts had PTs > 1.5 x nl, but not stated

28. Increased bleeding risk?Study #3: • 1991, Transfusion • Subjects: 608 patients who had undergone paracentesis and thoracentesis in whom they had the following data: • PT or APTT and plt count within 10 days of procedure • Hb measured 48 hrs before and 6-48 hrs after • Notes on pt status • Excluded if had the procedure but not the above data • Study design: Retrospectively looked at the relationship between: • Bleeding (Hb decrease of  2 g/dL) or average Hb difference & PT, APTT and plt count • No patient had received prophylactic FFP or RBCs

29. Study #3, cont… • Results: No difference between bleeding or average Hb difference among pts with normal PT/APTT, those with mildly or moderately prolonged PT/APTT or plt count • Prolonged mild: PT/APTT 1.1 to < 1.5 x nl • Prolonged moderate: 1.5 to < 2.0 x nl • Side note: Found a 7 fold increase in average blood loss in pts with Creatinine > 6 • Problems with study: • Needle and bore length variable or not recorded • Generalization to other pt populations? • This study = AIDS, pancreatitis, malignancies, EtOH liver dz, viral hepatitis, renal failure, CHF

30. Increased bleeding risk in Angiography: • Angiography (Radiology, 1996): • Abnormal PTs, APTTs, plt # do not correlate with postangiographic hematoma • 1000 pts included in study: Mean Min Max PT 12.5 8.8 20.8 PTT 30.0 18.3 150.0 PLT 288.8 17 1,170

31. Increased bleeding risk in central line placement, study #1: • Central venous catheter placement (2000) • 88 pts w/hemostatic abnormalities not corrected prior to procedure: Median Min Max INR 1.8 1.2 3.5 PTT 54 22 100 PLT 95 12 330 • Bleeding (intervention other than digital pressure nec.) only in 3% • Plts < 50 was associated with bleeding • INR/APTT not associated with bleeding

32. Line placement, study #1… • Problems: • They do not state the rate of bleeding complications in the normal population at their institution, ie control data • Inaccurate/underreporting reporting of complications? • Who placed the lines? (level of training)

33. Increased bleeding risk in central line placement, study #2: • 1996: Transfusion • Study design: Retrospective chart review of 938 catheter insertions • Labs: 24 hrs before procedure • Hct, PT/APTT, Plt #, cr • Pts given a hemostatic defect score (admittedly arbitrary), ie: PT of 15 sec = 1 pt, APTT of 50 sec = 3 pts, creatinine of 2.0 = 0 points, plt of 85 = 1 pt. • Notes on comments about bleeding • Per policy in ICU all lines examined q8hr • Pts categorized according to who did the line (medical, surgical, trauma)

34. Line placement, study #2… • Results: • 17% of patients had no lab data • Of those who did, 41% had at least one abnl value prior to line, 1/3 with serious defects (score >7) • 37% had transfusions to correct plt # or coags prior • Complication rate by hemostatic score • 0 = 0.25% • 1-7 = 2.87% • >7 = 22% • 75% of bleeding complications and only 15% of lines = medical service

35. Line placement, study #2… • Conclusion: In patients with hemostatic scores of 7 or less, no blood should be given • A policy of not correcting mild-mod defects should be established • Medicine = 75% of complications • These residents have less experience: Experienced operator may be of even more importance than correcting mild-moderate abnormalities • Problems: • Which patients were given transfusions and how did this influence outcomes? • Hemostatic score was arbitrary but influences conclusions drawn

36. Line placement, study #3 • 1999: Intensive care medicine • Study: Prospective audit of 658 central line placements in pts with: • Liver dz + INR >1.5 and/or PLT <150K • Mean INR 2.4, PLT 81K • Also recorded: level of physician training, PTT, number of passes through vein, if a transfusion was given what the INR & Plt were afterwards

37. Line placement, study #3… • Results: • INR >1.5 in 580, plts <150 in 531, both in 453 • 1 major complication (hemothorax) • Independent risk factors for minor complications (hematoma, oozing): • INR > 5.0 (n = 137) • Plts < 10K (n = 146) • IJ site and more than 1 puncture with introducer • Conclusion: Complications low in patients with raised PT/INR due to liver dz; it may be beneficial to correct platelet levels if very low. • Only experienced practitioners should cannulate pts with coagulopathy • There is little evidence that FFP should be transfused beforehand

38. Get to the point already!!! Question # 1: Is there data that mild-moderate abnormalities in PT/APTT increase the risk for bleeding during procedures? Answer: Not that I could find!

39. 2nd question Does FFP correct abnormalities in the PT/APTT and lead to better pt outcomes?

40. Question #2: FFP efficacy • BHJ, 2004 • Systematic review of RTCs to answer the question “Is FFP clinically effective” • 57 studies included • Liver dz (6) • Cardiopulmonary bypass • Reversal of warfarin • DIC and massive transfusion • HUS/TTP • FFP in neonatal medicine • Other--GBS, pancreatitis, burns

41. FFP efficacy, cont… • Conclusion: 37 studies showed no significant differences with use of FFP compared with the comparator intervention for the outcomes measured • 4 showed possible benefit (most for plasma exchange in TTP/HUS) • Some outcomes measured: • Bleeding • Reduction of transfusion requirements • Coagulation testing correction • Mortality

42. FFP efficacy, cont • Quality of the studies: • Few RTCs compared FFP with no FFP • Most compared FFP to different types of FFP (pathogen-inactivated forms) • Presupposes that the clinical effectiveness of one of the interventions has been demonstrated • Size of trials small, often < 30 • Few studies discussed methods of blinding

43. FFP efficacy, cont… • Conclusions: • RTC evidence for use of FFP is limited • Lack of evidence does not mean intervention is ineffective, just that there is insufficient RTC evidence to support or refute the efficacy • The strongest evidence = FFP is not significantly or consistently effective in a broad range of clinical situations

44. FFP efficacy, cont… • It seems intuitive that replacing plasma proteins should prevent bleeding • FFP for prophylaxis before invasive procedures accounts for a substantial amount of the 3 mil units of FFP transfused each year

45. Ok, what’s the bottom line??? • Question #2: Does FFP correct abnormalities in the PT/APTT and lead to better pt outcomes? • Not that any data proves!

46. AABB • “ FFP is often given prophylactically to patients with mild to moderate prolongation of the PT or APTT before invasive procedures, but there is little or no evidence that this prevents bleeding complications.” • “Because these tests do not accurately predict the risk of bleeding when mildly prolonged, there is little logic for a transfusion intended to “improve” the results.”

47. British Committee for Standards in Haematology • “Many liver units will only undertake liver bx if the PT is no more than 4 sec longer than the upper limit of normal. There is no evidence to substantiate this.” • PLT count and fnx may be more important • “The response to FFP is unpredictable. More work needs to be conducted to establish the role, if any, of FFP in patients with liver dz to correct the bleeding tendency prior to bx.”

48. British Committee for Standards in Haematology • FFP in liver dz + PT > 4 s longer than control: Level C recommendation • Level C = • Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality (evidence level IV)

49. Conclusions • We give out a considerable amount of FFP for common “indications” without any really good data • But, good RTC data will be hard to obtain (Who wants to randomize patients with abnormal coags to receive no FFP prior to surgery?) • Experience may be more important than normal coags

50. References British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. British Journal of Haematology. 2004;126:11-28. Childs, C., et al. The acute febrile response to burn injury in children may be modified by the type of intravenous fluid used during resuscitation--observations using fresh frozen plasma (FFP) or Hartmann’s solution. Burns. 2001;27:386-388. Cochrane Injuries Group. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. British Medical J. 1998 July;317:235-240. College of American Pathologists. Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets. JAMA. 1994;271:777-781. Darcy, M., el al. Evaluation of coagulation tests as predictors of angiographic bleeding complications. Radiology. 1996;198:741-744. DeLoughery, TG., et al. Invasive line placement in critically ill patients: do hemostatic defects matter? Transfusion. 1996;36:827-831. Demling, RH. The burn edema process: current concepts. J of Burn Care and Rehabilitation. 2005;26:207-227. Dzik, W., et al. Why do physicians request fresh frozen plasma? Transfusion. 2004 Sept;44:1393-4.