Critical Care in Obstetrics: An Innovative and Integrated Model for Learning the Essentials

Transcription

1 Critical Care in Obstetrics: An Innovative and Integrated Model for Learning the Essentials

2 Massive Blood Transfusion Michael A. Belfort, MD, PhD Professor and Chairman Department of Obstetrics and Gynecology Baylor College of Medicine Obstetrician and Gynecologist-In-Chief Texas Children s Hospital Houston, TX

3 Learning Objectives Understand the pathophysiology of hemorrhage and DIC Discuss massive transfusion protocols, and their applicability to obstetrical bleeding Order and interpret laboratory testing and how often it should be repeated Understand the blood product alternatives Discuss likely complications with transfusion

4 Outline Pathophysiology Massive Transfusion Protocols Laboratory Testing Blood products Factor concentrates Antifibrinolytics Hemostatic & Metabolic Complications Transfusion Risks & Complications

5 Massive Blood Transfusion

6 Pathophysiology

7 Pathophysiology Dilutional coagulopathy Low fibrinogen Hyperfibrinolysis Activation of protein C Acidosis Hypothermia Air embolism Rapid infusers Hypocalcemia Hyperkalemia

8 Activation of Protein C (APC) Cascade PAI-1 Hyperfibrinolysis Activated protein C Thrombin & Thrombomodulin Hypoperfusion Inhibition Factor Va & VIIIa Plasminogen Activator Inhibitor-1 (PAI-1) Activated protein C thrombomodulin on endothelial cells

9 Massive Transfusion Protocols

10 Transfusion Medicine- traditional Traditionally based on ATLS guidelines Start with crystalloid followed by PRBCs Use other products based on laboratory tests Massive Transfusion (MT) Replacement of > 50% of blood volume in hours Transfusion of > 10 U PRBC in 24 hours MT protocols at many centers No FFP until 4-10 U of PRBCs given No clear guideline re: PLTs based on waiting for laboratory data to guide therapy

11 Military Approach to Coagulopathy Rapid identification Frequent use of recombinant human VIIa Rapid treatment of acidosis Avoidance of hypothermia Prompt initiation of 1:1:1 ratio RBCs, pre-thawed universal donor AB plasma, and apheresis platelets convert to fresh whole blood ASAP??WHY THIS CHANGE Hess, JR. Blood and coagulation support in trauma care. Hematology Am Soc Hematol Educ Program 2007; Holcomb et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma 2007; 62:

12 Combat Casualties & MT 246 patients US Army combat support hospital in Iraq Combat-related trauma requiring MT 1:1 FFP:RBC ratio independently associated with improved survival, primarily by decreasing death from hemorrhage Lowered absolute risk of mortality by 55% Conclusion: MT protocols should use 1:1 ratio of FFP:RBC for all hypocoagulable patients with traumatic injuries. Borgman et al.

13 Civilian Trauma & MT 2 large studies: Aggregate data 466 MT cases at 16 centers Prospective 7 center cohort study 415 cases Conclusion: FFP:PRBC ratio > 1:1.5 associated with lower mortality but higher ARDS Zink et al. & Sperry et al

14 Is the Military approach appropriate for Obstetrics? Predominance of penetrating trauma (No) Higher rate of blast injuries (No) Longer transport times (Maybe) Different resuscitative practices: Thawed FFP (Unlikely) Fresh whole blood (No) Recombinant activated Factor VII (Maybe) Cryoprecipitate (Yes)

15 1:1 Ratio 2 Big Questions (1) Do patients unnecessarily receive excessive plasma? (2) Does the additional plasma lead to fluid overload (ie, edema, abdominal compartment syndrome, respiratory compromise and ARDS) Sambasivan et al. J Trauma. 2011;71(2 suppl 3):S329-S336. C. Inaba et al. J Am Coll Surg. 2010;210(6):

16 Transfusion - RBC:FFP 1:1? - PRO Lowered absolute risk of mortality in Iraq uncontrolled area, no immediate lab access Some data in trauma here supports More recent reviews -- Insufficient evidence to support fixed ratios in MT trauma patients *Borgman, et al. J Trauma. 2007;63: **Rajasekhar, et al. Crit Care Med. 2011;39:

17 Transfusion - RBC:FFP 1:1? - CON High volume plasma transfusion in non-mt trauma: 12-fold increase acute respiratory distress syndrome (ARDS) 6-fold increase in multiple organ dysfunction 4-fold increase in pneumonia and sepsis 1:1 strategies did not show any improvement in survival Best evidence: Stop aggressive MT of components (FFP, platelets, and cryoprecipitate) once hemostasis achieved Additional products add risk (eg, fluid overload and transfusion complications) without benefit Sambasivan et al. J Trauma. 2011;71(2 suppl 3):S329-S336. C. Inaba et al. J Am Coll Surg. 2010;210(6):

18 Massive Transfusion Protocols Pacheco et al AJOG 2011

19 Laboratory Testing

20 Laboratory Analysis in MTP Labs should be monitored q20-30 mins When you get the results, it s time to send another set Repeat MTP Panel Hgb/Hct, platelets (purple top) DIC Panel (blue top) PT/INR, PTT, Fibrinogen, D-dimer, platelet count? TEG/ROTEM ABG with metabolites (ica, K, Glu) Single draw: AGB in heparin syringe with LAB SPAN whole blood metabolic panel

21 Prothrombin Time (PT) Assesses extrinsic cascade Influenced by factors I, II, V, VII, X Ca 2+ & TF added to platelet poor plasma Normal value: seconds Most sensitive to factors: II, VII, IX, X (Vitamin K dependent)

22 Activated Partial Thromboplastin Time (aptt) Assesses the intrinsic cascade Influenced by factors I, II, V, VIII, IX, X, XI & XII Ca2+, kaolin, and partial thromboplastin added Normal value: seconds Most sensitive to factors VIII & XI

23 Handheld Analyzers Blood Gases (ph, Hgb) Electrolytes (K, ica) Chemistries Coagulation (PT) Hematology (Hgb & Hct) Glucose Cardiac markers i-stat 1 System Abbott Point of Care Inc, Princeton, NJ

24 How to use lab testing in massive hemorrhage Follow MTP Request lab testing every min Interpret the lab results critically Transfused according to the labs Principles: Volume repeletement Clotting factors Electrolyte stability

25 Lab Results & Action If INR > 1.5 Give 2 units FFP If platelet count < 100K Give 1 apheresis platelet unit (=5 pack) If fibrinogen < 200 mg/dl Give 2 jumbo cryoprecipitates (= 10 units)

26 Blood products

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28 Blood Components RBC: ml, Hct 55-65%. FFP: well balanced all coagulation factors and coagulation inhibitors Cryoprecipitate: Contains fibrinogen, Factors VIII, XIII, von Willebrand factor, and fibronectin. 1 jumbo cryoprecipitate contains 5 units 2 jumbo cryoprecipitate units (= 10 U) may be given at a time Platelets: One pheresis platelet unit at a time.

29 Blood Component Therapy WHOLE BLOOD (500 ml) Packed Red Cells (1U = ml) 1U increases Hematocrit 3% Temp (C) of product 1 to 6 o Platelets (1U = 50 ml) 6 pooled U increases platelet count 30K/uL * Plateletpheresis (1U = 6-8 pooled singles = 250 ml) 20 to 24 o Fresh Frozen Plasma (1U = ml) 1U increases fibrinogen 7-10 mg/dl -18 o Cryoprecipitate (1U = 20 ml) Factor I, VIII, XIII, vwf, fibronectin 10 pooled U increases fibrinogen 70 mg/dl -18 o

30 Factor concentrates

31 New Products -?Value Fibrinogen Concentrate (RiaSTAP): heat-treated, lyophilized fibrinogen (Factor I) powder made from pooled human plasma. Each vial contains 900 to 1300 mg fibrinogen, 400 to 700 mg human albumin Used in combination with cryoprecipitate Prothrombin Complex Concentrate (Kcentra) Factors II, VII, IX, X, protein C and S (plasma derived) Used instead of FFP - reduced risk of volume overload. Kcentra does not require thawing, blood group typing, and has a reduced risk for TRALI and allergic reactions Pharmacy cost: ~ $2500 or more per dose

32 Recombinant Activated Factor VIIa Originally developed for treatment of Hemophilia A or B & Inhibitors to Factor VIII or IX Promotes thrombin generation Significant concerns raised about lack of efficacy and potential for harm Administration Dose 60 ug/kg IV bolus Pharmacy cost ~ $1,000 per dose

33 Activated Factor VIIa usage Efficacy of rfviia depends on: levels of other coagulation factors present patient temperature ph (acidosis) Maximal effectiveness: platelet count (>50,000/mm 3 ) fibrinogen level (>50 to 100 mg/dl) near normal temperature, ph, and calcium levels Major sources of bleeding should be controlled and major deficiencies corrected before rfviia given Rossaint et al. Crit Care 2010; 14:R52.

34 Factor Concentrates Off-Label Use - Summary Prothrombin complex concentrate (Kcentra ): Factors II, VII, IX, and X. Coagulopathy while waiting for FFP units/kg Fibrinogen concentrate (RiaSTAP ) Low fibrinogen < mg while waiting for cryoppt 70 mg/kg or [250-current fibrinogen]/1.7 = mg/kg Factor VIIa (Novoseven ) Truly last option d/t possible thrombotic complications* Fibrinogen has to be >200 mg/dl in order to work mg/kg (1 mg/vial) *Callum and Rizoli. Hematology 2012, ASH

35 Antifibrinolytics

36 Antifibrinolytics- Amicar (E-aminocaproic acid) Synthetic derivatives of amino acid lysine Competitively inhibits the activation of plasminogen to plasmin Prevents the formation of plasmin which prevents the degradation of fibrin and the formation of FDPs Dosing: Adults: 5 g over min, g/hour until bleeding stops No more than 30 g per day Half life 2 hours, decrease dose in renal dysfunction.

37 Antifibrinolytics

38 Antifibrinolytics- Tranexamic acid (TXA) Brands: Cyklokapron, Transamin Newer molecule than Amicar 8x the anti-fibrinolytic activity Elective CS, EBL reduction (unlabeled use): I.V.: 1-2 g over 5-15 minutes at least 10 min prior to skin incision 1 mg/kg/hour during surgery (? Use in percreta) Half life 3 hours Cleared in urine (Gungorduk, 2011)

39 Antifibrinolytics- Amicar or Tranexamic Acid (TXA) Study of PPH > 800cc after vaginal delivery RCT, open label, 72 in each group 4g over 1 hr, then 1g/hr for 6 hours Slight improvement in EBL, decreased procoagulants NO SAFETY DATA Theoretical thrombosis risk There is evidence that TXA reduces blood loss at C-section Ongoing RTC World Maternal Antifibrinolytic (WOMAN) Multicenter, RCT - 15,000 sample size TXA vs. placebo. *Shakur, et al. Trials. 2010;11:40. **Roberts and Ker. Int J Gynaecol Obstet. 2011;11: Shakur et al. The WOMAN Trial. Trials. 2010;11:40. Roberts I,et al. Int J Gynaecol Obstet. 2011;115(3): Ducloy-Bouthors et al Crit Care. 2011;15(2):R117.

40 Antifibrinolytics- Aprotinin (Trasylol) Anti-fibrinolytic derived from bovine lung Inhibits trypsin, chymotrypsin, kallikrein + plasmin Action on kallikrein inhibits formation of Factor XIIa Blocks both intrinsic coagulation + fibrinolytic pathways Action of plasmin slows fibrinolysis Major safety concerns and drug withdrawn: Myocardial infarction Stroke Renal failure Anaphylaxis (1:200) DO NOT USE IN PPH

41 Hemostatic & Metabolic Complications

42 Hemostatic & Metabolic Complications Rapid changes in volume status Maintenance of tissue oxygen Control of bleeding at the source Coagulation factors which? Ionized calcium & potassium Acid-base balance

43 Hyperkalemia in Massive Transfusion Normal range: meq/l >10 U PRBC s MUST assume increased K + Arrhythmias when K + >6.5 meq/l Ventricular fib when K + >7.5 meq/l K + goes up more after rapid transfusion Acidosis contributes to hyperkalemia

44 Hyperkalemia in Massive Transfusion K + in supernatant increases linearly from 2 to 45 meq/l) over 2 to 42 days of RBC unit storage Irradiation causes a rapid increase in K + Sufficient K + in RBC packs to lead to hyperkalemia with large volumes ~5mEq per 300cc PRBC s Usually transient due redistribution of the K + load Hyperkalemic cardiac arrests are reported

45 ECG Changes in Hyperkalemia MT patients should be kept on EKG monitoring for: Peaked T wave (tall tented T wave) Decreased P wave

46 Hyperkalemia: Cardiac Arrest 16 transfusion-associated hyper K + cardiac arrests Cancer, major vascular, and trauma Mean K+ was 7.2 +/- 1.4 meq/l ( meq/l) Nearly all patients were acidotic, hyperglycemic, hypocalcemic, hypothermic at the time of arrest Transfusion factors: Number of RBC units before cardiac arrest: 1-54 Fourteen (87.5%) received RBC via CVP line Commercial rapid infusion devices (pumps) used in 73% RBC units were rapidly administered (pressure bags, syringe pumped) in all patients. The in-hospital survival was 12.5% Smith et al. Anesth Analg 2008

47 Hyperkalemia Treatment Prevention: RBC washing, in-line K+ filter Treatment for hyperkalemia > 5 meq/l Remove K from circulation: D10 (glucose) 500 ml + regular insulin 10 U over 60 min. OR bolus of regular insulin 10 U Block of the affects of K Calcium infusion -1g CaCl 2 slow IV infusion Correct acidosis by bicarbonate

48 MT and HYPOkalemia Watch for hypokalemia in the hours after massive transfusion Once citrate is metabolized: Increase in HCO 3 leading to alkalosis which leads to loss of K +

49 Hypocalcemia and Hypomagnesemia Citrate in blood components chelates both calcium and magnesium Monitor EKG for the QT interval Prolonged QT low calcium and magnesium Hypomagnesemia can cause Torsades de Pointes No easy way to measure ionized Mg +2 Monitor ionized calcium at baseline and q15 min. during MT Prophylaxis: 10% Ca gluconate (1g/10ml) g over 2-3 minutes IV for every 4 U PRBC s

50 Hypomagnesemia - Torsades de Pointes

51 Hypocalcemia and Cardiac Arrest Normal calcium mmol/l Hypocalcemia of <0.77 mmol/l has linear; concentration-dependent relationship with mortality More important than lowest fibrinogen concentration, acidosis and lowest platelet count in predicting mortality OR = 1.25 per 0.1 mmol/l decrement, CI: 1.04 to 1.52; P = 0.02 Aggressively treat any ionized calcium < 1 (normal) high risk of cardiac arrest 10% CaCl -1g (1g/10ml vial CaCl2 in 100cc saline over 2-5 minutes via central line) Elmer et al 2013; Ho and Lenard. 2011

52 Transfusion Risks & Complications

53 Intra Operative Blood Loss Treatment Avoid dilutional coagulopathy!!!!!! check Hct/plts/PT/PTT/fib/ABG q 15 min Use cryoprecipitate/fibrinogen concentrate/pcc if coagulopathic FFP is not enough to normalize very low fibrinogen! Transfuse FFP/cryoprecipitate/platelets early in heavy bleeding Avoid acidosis, hypocalcemia, hyperkalemia Consider Factor VIIa (last resort & only if criteria met)

54 Intra Operative Blood Loss treatment Avoid hypothermia Warmed products & IV fluids Beir hugger, room warming, warm irrigation Stop & wait for reversal of coagulopathy if possible Pelvic pressure, aortic occlusion, pack Do not hesitate to use staged procedure with pressure pack placement

55 Rapid Transfusion Devices More questions than answers regarding use in obstetrics What is the optimum flow rate? Vascular damage from rates >700cc/min Hemodynamic response to MT?

56 Rapid Transfusion devices OK Now we are really transfusing! The Belmont Rapid Infuser High flow rates (up to 1000 ml/min Pressure restricted (300mmHg) Warms fluid Detects air

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58 Abdominal Compartment Syndrome (ACS) Pressure from bowel edema, ascites, ileus, blood products leads to: Decreased venous return, lower CO, lower BP Decreased renal perfusion and oliguria Diaphragm dysfunction with atelectasis, AV shunting, higher pressures and hypoxemia Bladder pressure >20 mmhg = ACS 25 ml in NaCl in bladder, clamped, measure mmhg Abdominal hypertension > 12 mmhg Normal = 0 10 mmhg (non-pregnant)

59 Summary

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61 Massive Blood Transfusion Conclusions PPH is a major cause of maternal mortality Most deaths due to PPH are preventable Many preventable deaths are due to inadequate blood component therapy Lethal Triad - coagulopathy, hypothermia, & acidosis MT protocols are rapidly evolving after recent observational reports from military & civilian trauma centers This experience may be applicable to the L&D setting in MT for PPH This topic remains highly debated and RCTs are much needed

62 Evidence

63 Evidence Borgman et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007;63(4): Zink 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 2009;197(5): Pacheco et al AJOG 2011 Rajasekhar, et al. Crit Care Med. 2011;39: Sperry et al & Inflammation the Host Response to Injury Investigators. An FFP:PRBC transfusion ratio >/=1:1.5 is associated with a lower risk of mortality after massive transfusion. J Trauma 2008 Nov;65(5):

64 Evidence Hess, JR. Blood and coagulation support in trauma care. Hematology Am Soc Hematol Educ Program 2007; Holcomb et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma 2007; 62: Burtelow et al. How we treat: management of life-threatening primary postpartum hemorrhage with a standardized massive transfusion protocol. Transfusion 2007;47: Hematol Oncol Clin North Am. 1998:12; Rossaint et al. Crit Care 2010; 14:R52. Callum and Rizoli. Hematology 2012, ASH Shakur et al. The WOMAN Trial. Trials. 2010;11:40. Roberts I,et al. Int J Gynaecol Obstet. 2011;115(3):

65 Evidence Ducloy-Bouthors et al Crit Care. 2011;15(2):R117. Sambasivan et al. J Trauma. 2011;71(2 suppl 3):S329-S336. C. Inaba et al. J Am Coll Surg. 2010;210(6): Smith et al. Anesth Analg 2008 Ho and Lenard Elmer et al 2013

66 Thank You for Your Attention! Planning Committee Mike Foley, Director Shad Deering, co-director Helen Feltovich, co-director Bill Goodnight, co-director Loralei Thornburg, Content co-chair Deirdre Lyell, Content co-chair Suneet Chauhan, Testing Chair Mary d Alton Daniel O Keeffe Andrew Satin

67 Supplemental

68 Protein C and Protein S Systems Hematol Oncol Clin North Am. 1998:12;

69 Intra Operative Blood Loss Mix Monitoring of coagulation: Thromboelastogram (TEG) A = reaction time B = clotting time a = alpha angle (A, B and a reflect clotting factor function) C = max. amplitude (reflects platelet function) D = Rate of decay of clot (reflects fibrinolysis) Obstetric hemorrhage has enhanced fibrinolysis when compared with other types of hemorrhage May indicate need for EACA or tranexamic acid Pacheco et al. AJOG 2011

70 Principle of ROTEM

71 Massive Transfusion Postpartum Hemorrhage Stanford Univ Med Ctr Blood products 6 U PRBC 4 U FFP or LP 1 U aplt Lab assessment CBC & PLT PT / PTT / Fibrinogen Recombinant Factor VIIa Burtelow et al. How we treat: management of life-threatening primary postpartum hemorrhage with a standardized massive transfusion protocol. Transfusion 2007;47:

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74 Kcentra FII (units/ml) FVII (units/ml) FIX (units/ml) FX (units/ml) Cost $1.26/uni t $630/vial INR >6 Units/kg Max dose Dosing Guidelines

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77 TEMogram aka TEM