In this clinical practice guideline, we highlight the current evidence for management of bleeding ICU patients and areas for further research. |
Introduction
Scope and objectives of this guideline
Methods
Taskforce membership
Conflict of interest
Sponsorship
Question development and outcome prioritization
Search strategy and study inclusion
Data abstraction and risk of bias assessment
Data analysis and rating of evidence
Evidence summaries and formulation of recommendations
Transfusion support in massively bleeding, critically ill adults
Part 1: massively bleeding patients
1. Transfusion ratios
Recommendation | |
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We suggest use of high-ratio transfusion strategies (at least one unit plasma per two units of packed red blood cells) vs. low-ratio transfusion strategies in critically ill patients with massive bleeding due to trauma (Conditional recommendation, low certainty of evidence). | |
We make no recommendation regarding the use of fixed high-ratio transfusion strategies in critically ill patients with non-traumatic massive bleeding (No recommendation, very low certainty evidence). |
Evidence summary
Justification
Implementation issues
2. Platelets
Recommendation | |
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We make no recommendation regarding the use of cryopreserved or cold-stored platelets in bleeding patients with massive or non-massive hemorrhage (No recommendation, very low certainty of evidence). |
Evidence summary
Justification
3. Prothrombin complex concentrate and plasma
Recommendation | |
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We make no recommendation for the use of PCC versus plasma alone in massively bleeding patients due to very low certainty of evidence from observational studies only (No recommendation, very low certainty of evidence). |
Evidence summary
Justification
Research priorities
4. Fibrinogen
Recommendation | |
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We make no recommendation regarding the use of early empiric fibrinogen replacement in critically ill patients with massive hemorrhage due to trauma (No recommendation, low certainty evidence). |
Evidence summary
Justification
Implementation issues
5. Point of care testing
Recommendation | |
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We suggest for either for viscoelastic or conventional coagulation assays to guide transfusions in massively bleeding trauma critically ill patients (Conditional recommendation, low quality of evidence). |
Part 2: transfusion support in non-massively bleeding critically ill adults
1. RBC transfusion
Recommendation | |
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In patients with non-massive bleeding after vascular surgery, we suggest restrictive (7.5–8 g/ d/L) red blood cell transfusion threshold (Conditional recommendation, low certainty). |
Evidence summary
Justification
Implementation issues
Recommendation | |
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In patients with non-massive postpartum hemorrhage, we suggest restrictive transfusion, guided by presence of shock and symptoms potentially attributable to anemia (e.g. dyspnea, syncope, tachycardia, angina, neurological symptoms) or hemoglobin < 6 g/dL, rather than at a liberal target hemoglobin of 9 g/dL (Conditional recommendation, low certainty). |
Evidence summary
Justification
Implementation issues
Recommendation | |
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In patients with non-massive gastrointestinal bleeding, we suggest restrictive (7 g/dL) transfusion vs. liberal (9 g/dL) red blood cell transfusion threshold (Conditional recommendation, moderate certainty). |
Evidence summary
Justification
Implementation issues
2. Platelets
Recommendation | |
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We make no recommendation for the use of a restrictive vs a liberal platelet transfusion threshold in non-massively bleeding patients with thrombocytopenia (No recommendation, very low certainty evidence). |
Evidence summary
Justification
Implementation issues
Recommendation | |
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We suggest using a restrictive platelet transfusion strategy (no transfusion) in patients with intracranial hemorrhage (spontaneous or traumatic intracerebral hemorrhage) who are on antiplatelet therapy (Conditional recommendation, moderate certainty evidence). | |
We make no recommendation for the use of a restrictive (no transfusion) vs liberal platelet transfusion strategy in critically ill patients with non-massive bleeding who are on antiplatelet therapy (No recommendation, very low certainty of evidence). |
Evidence summary
Justification
Implementation issues
3. Fibrinogen
Recommendation | |
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We suggest the empiric use of fibrinogen concentrate in critically ill patients with non-massive bleeding after cardiac surgery, using either fixed dose (2–4 g) or titrated to FIBTEM clot firmness, to maintain a fibrinogen level over 1.5 g/dL necessary for clot formation and platelet aggregation, after giving the empiric fibrinogen dose if available [55] (Conditional recommendation, low certainty of evidence). | |
We make no recommendation regarding the empiric use of fibrinogen concentrate in other critically ill patients with non-massive bleeding (No recommendation, low certainty of evidence). |
Evidence summary
Justification
Implementation issues
4. Plasma
Recommendation | |
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We make no recommendation for a restrictive plasma versus a liberal plasma transfusion strategy for non-massively bleeding patients with or without coagulopathy (No recommendation, low certainty evidence). |
Evidence summary
Justification
5. Point of care vs. conventional coagulation testing
Recommendation | |
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We suggest either viscoelastic testing or conventional coagulation testing to guide transfusions in massive and non-massively bleeding cirrhotic patients, liver transplant patients or critically ill trauma patients (Conditional recommendation, low certainty evidence). |
Evidence summary
Justification
Recommendation | |
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We suggest either viscoelastic testing or conventional coagulation testing to guide transfusions in bleeding cardiac surgery patients (Conditional recommendation, very low certainty of evidence). | |
We suggest using either viscoelastic testing or conventional coagulation testing to guide transfusion in extra corporeal membrane oxygenation (ECMO) patients with non-massive bleeding (Conditional recommendation, very low certainty evidence). |
Evidence summary
Justification
Implementation issues
Part 3. Tranexamic acid (TXA) in bleeding critically ill adults
TXA in patients with traumatic intracranial hemorrhage
Recommendation | |
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We recommend the use of early (< 3 h from trauma) TXA in critically ill patients with bleeding or suspected bleeding due to trauma (Strong recommendation, high certainty). |
Evidence summary
Justification
Implementation issues
Recommendation | |
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We suggest the use of TXA in critically ill patients with acute traumatic brain injury and bleeding due to trauma (Conditional recommendation, moderate certainty). |
Evidence summary
Justification
Implementation issues
Recommendation | |
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We make no recommendation regarding the use of TXA in critically ill patients with subarachnoid hemorrhage (No recommendation, low certainty evidence). |
Evidence summary
Justification
Implementation issues
TXA in patients with non-traumatic intracranial hemorrhage.
Recommendation | |
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We make no recommendation regarding the use of TXA in critically ill patients non-traumatic intracranial hemorrhage (No recommendation, moderate certainty). |
Evidence summary
Justification
Implementation issues
Recommendation | |
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We suggest not using high-dose IV TXA in critically ill patients with gastrointestinal bleeding (Conditional recommendation, high certainty evidence). | |
We make no recommendation regarding the use of low-dose IV TXA or enteral TXA in critically ill patients with gastrointestinal bleeding (No recommendation, moderate certainty evidence). |
Evidence summary
Justification
Implementation issues
Recommendation | |
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We suggest the early use of TXA in critically ill patients with postpartum hemorrhage (Conditional recommendation, high certainty). |
Evidence summary
Justification
Implementation issues
Recommendation | |
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We recommend the use of TXA in critically ill patients with bleeding post-cardiac surgery (Strong recommendation, high certainty). |
Evidence summary
Justification
Implementation issues
Discussion
Section | Research priorities |
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Transfusion ratios in massive bleeding | More high-quality, randomized data of massive transfusion protocols including high-ratio transfusion vs. low-ratio transfusion are required in trauma and non-trauma patients with massive bleeding More RCT data on impacts of massive transfusion protocols guided by empiric transfusion ratios vs. guided by point of care testing |
Cold-stored platelets | RCTs involving conventional and cold-stored platelets are needed in patient populations where rapid control of hemorrhage is vital, such as trauma-associated or obstetric hemorrhage. Key outcomes include clinical and blood product use, effects on measured hemostatic parameters, and patient-important outcomes |
Prothrombin complex concentrate in massive bleeding | RCT data demonstrating the effects of prothrombin complex concentrate (± fibrinogen concentrate) vs. conventional massive transfusion protocols are needed in both trauma and non-trauma populations with massive bleeding |
Early fibrinogen replacement in massive bleeding | Large-scale trials, including clear fibrinogen testing strategies, targets, products (cryoprecipitate vs concentrate), and populations are needed to guide decisions on the role of fibrinogen early in resuscitation |
Thromboelastography vs conventional coagulation testing in massive bleeding | Trials comparing the use of thromboelastography to conventional coagulation testing protocols are needed to demonstrate the effects and economic impacts of implementing thromboelastography across a variety of patient populations with massive bleeding; these should incorporate transfusion protocols (eg. ratios, alternative blood products) |
Red blood cell transfusion | More research is needed on transfusions in patients undergoing vascular surgery, and other surgical populations at risk for significant bleeding and with cardiovascular comorbidities More research is needed on guiding transfusions in low-risk patients with bleeding, such as healthy postpartum women, and surgical patients with few comorbidities |
Restrictive vs. liberal platelet transfusion in non-massive bleeding | More studies are needed to examine the difference in the transfusion practice of a restrictive versus a liberal platelet transfusion practice in terms of outcomes, effects, patient values and preferences, as well as resources required to implement such strategies |
Restrictive vs liberal platelets in patients on antiplatelet medications | Further research is required to define the platelet transfusion strategy with the restrictive strategy being no platelet transfusion in other subgroups of patients with non-major bleeding patients This is an important research question as gastrointestinal bleeding is common and patients with cardiovascular diseases requiring antiplatelet therapy are increasing |
Fibrinogen in non-massive bleeding | Research is needed on which which triggers should be used for “early” or “empiric” fibrinogen administration in patients with bleeding, and specific targets for replacement (fixed dose vs. use of viscoelastic testing) |
Plasma in non-massive bleeding | Future research should focus on 1) targeted personalized trial of using any point of care testing to assess presence and type of coagulopathy and determine transfusion requirements compared to transfusing patients based on clinical presentation; 2) restrictive versus liberal plasma transfusion strategies in non-massively bleeding critically ill patients with a coagulopathy and 3) exploring the correction of coagulopathy versus non-correction of coagulopathy in non-massively bleeding critically ill patients |
Point of care vs conventional in non-massive bleeding | RCTs comparing transfusion strategies guided by point of care testing vs. conventional coagulation testing, with and without fixed ratio blood product transfusions are needed to determine whether thomboelastography improves patient outcomes and impacts blood product use in critically ill patients |
TXA in trauma and traumatic brain injury | More research is required to identify subgroups most likely to benefit from the use of TXA and the role of individualized patient use guided by thromboelastometry and conventional coagulation tests |
TXA in subarachnoid hemorrhage | More research is needed on the role of TXA in specific patient populations, eg. those with delayed or challenging aneurysm securement |
TXA in intracranial hemorrhage | Given residual uncertainty around the effects of TXA on patient-important outcomes of mortality and functional recovery, further research is required. Other trials are planned or ongoing (NCT03385928, NCT02625948, NCT03044184, NCT02866838,ChiCTR1900027065), and will assist in addressing this area of uncertainty |
TXA in gastrointestinal bleeding | More evidence is required evaluating the role of enteral and low-dose intravenous TXA, and the potential role of TXA as rescue therapy in refractory hemorrhage |
TXA in postpartum | More research is needed on identifying which patients with PPH are most likely to benefit from TXA. For instance, it may be more helpful in patients with PPH after vaginal rather than caesarean delivery [38]. |
PICO | Trial details | Participants | Comparisons | Primary Outcome(s) | Most recent status | |
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Intervention | Control | |||||
Transfusion ratios | Evaluation of a transfusion therapy using whole blood in the management of coagulopathy in patients with acute traumatic hemorrhage (T-STORHM) NCT04431999 | Severe trauma patients requiring initiation of MHP, based on standardized criteria n = 200 | Whole blood for 1st and 2nd pack; then 3 PRBC, 3 plasma, 1 platelet | 3 PRBC, 3 plasma, 1 platelet | Noninferiority of coagulopathy correction (6 h); Mortality (day 2, 30); Mortality/ morbidity (24 h); Time to blood; Time to infusion; Coaguloapthy evolution; Cost | Not yet recruiting (Feb 9, 2021) |
Prothrombin complex vs plasma | Factor replacement in surgery (FARES) NCT04114643 | Patients undergoing cardiac surgery with or without CBP, who require coagulation factor replacement in the OR n = 103 | PCC | FFP | Treatment response (4 h, 24 h); number of transfusions (24 h); number who do not receive RBC transfusion | Active, not recruiting (November 3, 2020) |
PCC vs FFP | PCC vs FFP for post-cardiopulmonary bypass coagulopathy and bleeding NCT02557672 | Adults undergoing cardiac surgery with CPV, excessive microvascular bleeding n = 100 | PCC 15 u/kg | FFP 10–15 mL/kg | Blood loss (24 h); blood transfusions (24 h) | Enrolling (January 27, 2021) |
Prothrombin complex & fibrinogen vs plasma | factor in the initial resuscitation of severe trauma 2 patients (FiiRST-2) NCT04534751 | Severly injured adult trauma patients (age > 16) with massive hemorrhage protocol within first hour of hospital arrival n = 350 | PCC 2000 IU & fibrinogen concentrate 4 g in first and second MHP packs | FFP | Composite of total number of allogenic blood products within 24 h; total PRBCs transfused; thrombotic events (venous or arterial); ventilator-free days | Recruiting, April 5, 2021 |
Thromboelastography; PCC vs FFP | Patient blood management for massive obstetric hemorrhage NCT03784794 | Patients with severe obstetric hemorrhage of any cause n = 100 | Thromboeslastography guided transfusion of RBC, fibrinogen,PCC, platelets, RBCs | Conventional coagulation test driven tranfusion with RBC, platelet, FFP, cryoprecipitate | Number of transfusions (24 h), types (24 h); hospital mortality, bleeding control; ICU LoS, surgical intervention, TACO, TRALI, infection | Recruiting (March 3, 2020) |
Fibrinogen replacement | Transfusion of red blood cells, tranexamic acid and fibrinogen concentrate for severe trauma hemorrhage at prehospital phase of care. (PRETIC) NCT03780894 | Adults with severe trauma, bleeding/high bleeding suspicion, predicted need for transfusion n = 60 | 2 g fibrinogen concentrate; 1 g TXA; 2 RBCs prehospital phase of care | Standard care (TXA 1 g) | Coagulopathy as measured with TEG; mortality (1 h, 6 h, 24 h, 30d); Transfusions (24 h); VTE (30d); fluids, fluid balance; ventilator-free days | Recruiting (January 18, 2020) |
A multi-center, randomized, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma hemorrhage requiring major hemorrhage protocol (MHP) activation NCT04704869 | Adults with severe traumatic injury with ongoing active hemorrhage and requiring activity of MHP n = 1500 | Early Cryoprecipitate + Massive Transfusion Protocol (RBCs, Plasma, Platelets, Whole Blood) | Massive Transfusion Protocol (RBCs, Plasma, Platelets, Whole Blood) | Mortality (6 h, 24 h, 6 months, 12 months); death from bleeding (6 h, 24 h); transfusion requirements; QoL; ventilation, ICU, and hospitalization duration | Recruiting (January 12, 2021) | |
Transfusion of red blood cells, tranexamic acid and fibrinogen concentrate for severe trauma hemorrhage NCT04149171 | Adults with severe trauma and bleeding or high suspicion of bleeding n = 30 | RBC, Fibrinogen concentrate, TXA | Crystalloids, TXA | RBCs delivered, transfused | Recruiting (November 4, 2019) | |
Adjusted fibrinogen replacement strategy (AdFIrst) NCT03444324 | Adults with spine surgery and expected major blood loss, intra-op blood loss > 1L with need for FFP n = 200 | BT524 human fibrinogen concentrate | FFP | Intra-op blood loss; transfusion requirements; correction of fibrinogen; 24 h blood loss; re-bleed; hospital length of stay; mortality (hospital); adverse events; VTE | Recruiting (July 25, 2019) | |
Fibrinogen concentrate in isolated traumatic brain injury NCT03304899 | Severe isolated TBI with serum fibrinogen less than 200 mg/dL n = 50 | Weight based fibrinogen concentrate | No fibrinogen | Mortality; progression of intracranial hemorrhage, serum fibrinogen levels, VTE, myocardial infarction, transfusions | Unknown (February 27, 2019) | |
Fibrinogen in Haemorrhage of Delivery (FIDEL) NCT02155725 | Adult women with vaginal delivery, PPH requiring IV administration of prostaglandins n = 448 | 3 g fibrinogen concentrate IV | Placebo | Change in Hb > 4 g/dL or transfusion 2 PRBC; | Completed (September 25. 2020) | |
Pilot randomized trial of fibrinogen in trauma haemorrhage NCT02344069 | Adult trauma patient with need for transfusion, predicted need for MHP n = 40 | Fibrinogen concentrate | Placebo | TEG, transfusions, time to transfusion, need for surgery, VTE, anaphylaxis, mortality (24 h, 30d) | Completed (April 2017) | |
Thromboelastography | Use of ROTEM intraoperatively in women with placenta accreta (ROTEM) NCT02729974 | Women with placenta accrete with scheduled delivery by caesarian section n = 40 | ROTEM-guided transfusion | Conventional coagulation testi-guide transfusion | Transfusions (up to day 10); length of stay (ICU, hospital); surgical site infection; readmissions | Enrolling (January 21, 2020) |
TXA in PPH | NCT03475342 (Recruiting); NCT04350645 (Active, not recruiting); NCT03069859 (Recruiting); NCT03364491(Recruiting); NCT04707950 (Recruiting); NCT04427618 (Recruiting); NCT04733157 (Not yet recruiting); NCT04274335 (Recruiting); NCT04518163 (Recruiting); NCT02797119 (Recruiting); NCT04463966 (Recruiting); NCT03778242 (Recruiting); NCT03774524 (Recruiting); NCT03777878 (Recruiting); NCT03863964 (Active not recruiting); NCT03287336 (Active, not recruiting) | |||||
TXA in ICH | NCT04742205 (Not yet recruiting); NCT03044184 (Recruiting)l NCT03385928 (recruiting); NCT02866838 (Recruiting) | |||||
TXA in cardiac surgery | BCT04290884 (Recruiting) | |||||
TXA in SDH | NCT03353259 (Recruiting); NCT03582293 (Recruiting); NCT02568124 (Recruiting) | |||||
TXA in GI bleeding | NCT04489108 (Recruiting) | |||||
TXA in trauma | NCT02187120 (Recruiting) |