Massive Transfusion Protocol

Quick Answer

Massive transfusion is defined as replacement of greater than 10 units of packed red blood cells (PRBCs) in 24 hours, OR greater than 4 units PRBCs in 1 hour with ongoing bleeding, OR replacement of greater than 50% of total blood volume in 3 hours. [1,2] A Massive Transfusion Protocol (MTP) is a structured institutional response to provide blood products rapidly and efficiently.

MTP Activation Criteria: Use validated prediction scores:

• ABC Score: Penetrating mechanism, SBP ≤90 mmHg, HR ≥120 bpm, positive FAST (≥2 points suggests MTP required) [3]
• TASH Score: Accounts for base excess, SBP, HR, Hb, FAST, gender, injury mechanism (greater than 16 points = 50% probability of massive transfusion) [4]
• BSAD (Blood Shortage, Acidosis, Death): Clinical gestalt with biochemical markers [5]

Ratio-Based Transfusion: The PROPPR trial (PMID: 25647203) established 1:1:1 ratio of FFP:platelets:PRBCs as the target, showing improved haemostasis and reduced early death from exsanguination (9.2% vs 14.6% at 3 hours). [6]

Blood Component Targets:

• PRBCs: Haemoglobin greater than 70-80 g/L (greater than 100 g/L if TBI or ongoing haemorrhage)
• FFP: 15-20 mL/kg; target INR below 1.5
• Platelets: Maintain greater than 50 × 10⁹/L (greater than 100 × 10⁹/L if TBI or ongoing bleeding)
• Fibrinogen: Target greater than 1.5 g/L (CRYOSTAT-2 supports early cryoprecipitate) [7]
• Calcium: Ionized Ca²⁺ greater than 1.1 mmol/L (citrate toxicity prevention) [8]

Tranexamic Acid (TXA): CRASH-2 trial (PMID: 20554319) demonstrated mortality reduction from 16.0% to 14.5% when given within 3 hours of injury. Dose: 1 g IV loading over 10 minutes + 1 g IV over 8 hours. [9]

Viscoelastic Testing: TEG/ROTEM provides rapid point-of-care assessment of clot formation, strength, and fibrinolysis, enabling goal-directed transfusion that reduces blood product usage by 20-30%. [10,11]

Lethal Diamond: Extends the traditional "lethal triad" (hypothermia, acidosis, coagulopathy) to include hypocalcemia as the fourth factor contributing to mortality. [8,12]

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CICM Exam Focus

Key High-Yield Points

1. Definition of massive transfusion: greater than 10 units PRBC/24h OR greater than 4 units/1h with ongoing bleeding OR greater than 50% blood volume in 3 hours [1,2]
2. PROPPR trial: 1:1:1 ratio reduces death from exsanguination at 3 hours (9.2% vs 14.6%); overall 24-hour/30-day mortality not significantly different [6]
3. CRASH-2 trial: TXA within 3 hours reduces mortality; AFTER 3 hours, TXA increases mortality from bleeding [9,13]
4. ABC Score components: Assessment of Blood Consumption - penetrating mechanism, SBP ≤90, HR ≥120, positive FAST; ≥2 criteria activates MTP [3]
5. Fibrinogen target ≥1.5 g/L: CRYOSTAT-2 showed early cryoprecipitate improved fibrinogen levels and may reduce mortality [7]
6. Calcium replacement: Give calcium gluconate 1 g for every 4 units transfused; target iCa²⁺ greater than 1.1 mmol/L [8]
7. Hypothermia prevention: Blood warmer mandatory; target core temperature greater than 35°C [14]
8. Viscoelastic testing: FIBTEM A5/A10 for fibrinogen, EXTEM CT for factor deficiency, EXTEM ML for fibrinolysis [10,11]

Common Viva Themes

• Physiological rationale for damage control resuscitation and permissive hypotension
• PROPPR trial design, findings, and clinical implications
• CRASH-2 trial: dosing, timing, and the "TXA should be given within 3 hours" principle
• Massive transfusion complications: hypocalcemia, hypothermia, hyperkalaemia, TACO, TRALI
• Viscoelastic testing interpretation and goal-directed transfusion algorithms
• Point-of-care testing vs conventional coagulation studies in trauma
• Whole blood vs component therapy in massive haemorrhage
• Fibrinogen replacement: cryoprecipitate vs fibrinogen concentrate

Common Pitfalls

• Forgetting calcium replacement during massive transfusion (citrate toxicity)
• Giving TXA after 3 hours from injury (CRASH-2 showed harm after this window)
• Using conventional coagulation tests (PT/APTT) alone - they underestimate clotting capacity and are too slow
• Not warming blood products (exacerbates coagulopathy)
• Over-reliance on ratio-based transfusion without viscoelastic guidance when available
• Forgetting the "lethal diamond"
• hypothermia, acidosis, coagulopathy, AND hypocalcemia
• Not recognizing permissive hypotension is CONTRAINDICATED in TBI and spinal cord injury

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Key Points

• Massive transfusion: greater than 10 units PRBC/24h OR greater than 4 units/1h with ongoing bleeding [1,2]
• ABC Score ≥2 activates MTP (penetrating mechanism, SBP ≤90, HR ≥120, positive FAST) [3]
• PROPPR trial: 1:1:1 ratio (FFP:platelets:PRBC) reduces death from exsanguination at 3 hours [6]
• CRASH-2: TXA 1 g + 1 g given within 3 hours reduces mortality; harm if greater than 3 hours [9,13]
• Fibrinogen target ≥1.5 g/L; CRYOSTAT-2 supports early cryoprecipitate [7]
• Calcium gluconate 1 g for every 4 units transfused; target iCa²⁺ greater than 1.1 mmol/L [8]
• Lethal diamond: hypothermia, acidosis, coagulopathy, hypocalcemia [8,12]
• Viscoelastic testing (TEG/ROTEM) reduces blood product usage by 20-30% [10,11]
• Permissive hypotension (SBP 80-90 mmHg) EXCEPT in TBI/spinal cord injury [15]
• Temperature greater than 35°C mandatory; use rapid infusers with warmers [14]

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Definitions and Epidemiology

Definitions of Massive Transfusion

Multiple definitions exist, reflecting the challenge of capturing the clinical concept of life-threatening haemorrhage requiring massive blood product support:

The Critical Administration Threshold (CAT) definition is increasingly preferred as it identifies patients requiring massive transfusion early, allowing proactive MTP activation. [2]

Epidemiology

Incidence: Massive transfusion is required in approximately 3-5% of major trauma admissions and up to 25% of patients with penetrating torso trauma. [18,19]

Aetiology:

• Trauma: 65-80% of massive transfusions (blunt > penetrating in most civilian settings)
• Obstetric haemorrhage: 10-15% (postpartum haemorrhage, placental abruption)
• Surgical: 10-15% (vascular surgery, cardiac surgery, hepatic resection)
• Gastrointestinal bleeding: 5-10%
• Other: Ruptured AAA, coagulopathies [20]

Outcomes:

• Mortality for patients requiring massive transfusion ranges from 30-50%
• Early death (below 6 hours) is primarily from exsanguination (40-50%)
• Late death (greater than 24 hours) is from multi-organ dysfunction and sepsis
• Survival has improved with damage control resuscitation principles [6,21]

Australian Context

In Australia, massive transfusion accounts for approximately 1-2% of red cell usage but 10-15% of blood product costs. The Australian National Blood Authority provides guidelines for MTP management aligned with international best practice. Major trauma centres in Australia (e.g., Alfred Hospital, Royal Melbourne, Westmead) have established MTP protocols with pre-packaged "trauma packs" containing balanced ratios of products. [22]

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Pathophysiology

Trauma-Induced Coagulopathy (TIC)

Acute traumatic coagulopathy differs fundamentally from the iatrogenic coagulopathy caused by haemodilution and hypothermia. TIC is present in 25-35% of severely injured patients on arrival to hospital and is independently associated with 4-fold increased mortality. [23,24]

Pathophysiology of TIC:

1. Tissue injury and shock: Hypoperfusion activates protein C pathway, causing:

   • Inactivation of factors Va and VIIIa
   • Inhibition of plasminogen activator inhibitor-1 (PAI-1), promoting fibrinolysis
   • Consumption of fibrinogen and other clotting factors [23]

2. Endothelial activation: Tissue injury releases damage-associated molecular patterns (DAMPs) and activates:

   • Endothelial glycocalyx shedding
   • Tissue factor pathway inhibitor release
   • Thrombomodulin-thrombin complex formation (activates protein C) [24]

3. Hyperfibrinolysis: Enhanced fibrinolysis is driven by:

   • Increased tissue plasminogen activator (tPA) release from injured endothelium
   • Reduced PAI-1 activity
   • Present in 20-30% of severe trauma patients
   • Associated with significantly increased mortality [25]

4. Platelet dysfunction: Even with normal platelet counts:

   • Platelet aggregation and adhesion are impaired
   • Contribution of catecholamines and inflammatory mediators
   • May persist despite adequate platelet transfusion [26]

The Lethal Triad and Lethal Diamond

Classic Lethal Triad (hypothermia, acidosis, coagulopathy):

Each component worsens the others in a vicious cycle:

Lethal Diamond: Recent evidence highlights hypocalcemia as the fourth critical component:

• Hypocalcemia: Calcium is essential for coagulation cascade (Factor IV)
• Ionized calcium below 1.0 mmol/L is associated with 80% mortality
• iCa²⁺ below 0.9 mmol/L independently predicts death
• Citrate in blood products chelates ionized calcium
• Must actively replace calcium during massive transfusion [8,12]

Citrate Toxicity

Blood products are anticoagulated with citrate, which chelates ionized calcium. During massive transfusion:

• Citrate load exceeds hepatic metabolism capacity
• Ionized calcium falls rapidly
• Each unit of FFP contains more citrate than PRBCs
• Cold, acidotic, shocked patients have impaired citrate metabolism [28]

Manifestations of citrate toxicity:

• Hypotension refractory to vasopressors
• Prolonged QT interval on ECG
• Perioral and extremity paraesthesias
• Muscle twitching, tetany
• Cardiac arrhythmias (severe)
• Contributes to coagulopathy (calcium required for factor activation) [8]

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MTP Activation Criteria

Prediction Scores for Massive Transfusion

Several validated scoring systems predict the need for massive transfusion, enabling early MTP activation before laboratory results return.

ABC Score (Assessment of Blood Consumption)

The ABC Score is the most widely used bedside tool for MTP activation. [3]

Interpretation:

• Score ≥2: Activate MTP (sensitivity 75-85%, specificity 85-90%)
• Score 0-1: MTP unlikely needed but reassess frequently

Advantages: Simple, no laboratory required, rapid bedside assessment. Limitations: Developed primarily for blunt/penetrating trauma; may not apply to non-trauma causes. [3]

TASH Score (Trauma Associated Severe Haemorrhage)

More complex score providing probability of massive transfusion. [4]

Interpretation:

Advantage: More accurate probability estimation. Limitation: Requires laboratory results (Hb, base excess), delaying assessment. [4]

Shock Index

A simple physiological marker: Shock Index = Heart Rate / Systolic BP

Shock Index greater than 1.4 has ~70% sensitivity and ~70% specificity for massive transfusion requirement. [29]

Practical MTP Activation

Immediate activation criteria (any one of):

• Suspected or confirmed life-threatening haemorrhage
• ABC Score ≥2
• Shock Index greater than 1.4 with obvious bleeding source
• Clinician gestalt of uncontrolled haemorrhage

MTP activation process:

1. Contact blood bank with "Code Crimson" or equivalent institutional term
2. Request first MTP pack (typically 4 PRBC, 4 FFP, 1 pool platelets)
3. Blood bank issues uncrossmatched O-negative (or O-positive for males) PRBCs immediately
4. Subsequent packs issued at defined intervals or on request
5. Group-specific blood issued once available (usually within 10-15 minutes) [30]

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Blood Components and Targets

Component Therapy Overview

Transfusion Targets in Massive Haemorrhage

Ratio-Based Transfusion

The concept of "balanced resuscitation" emerged from military experience and was tested in the landmark PROPPR trial. [6]

PROPPR Trial (PMID: 25647203):

• Design: Pragmatic RCT; 680 patients with severe trauma predicted to require massive transfusion
• Intervention: 1:1:1 (FFP:platelets:PRBC) vs 1:1:2 (lower plasma and platelet ratio)
• Primary outcome: 24-hour and 30-day mortality - no significant difference
• Secondary outcomes:
  • "More patients achieved haemostasis in 1:1:1 group (86% vs 78%, p=0.006)"
  • "Fewer deaths from exsanguination at 24 hours in 1:1:1 group (9.2% vs 14.6%, p=0.03)"
• Conclusion: 1:1:1 ratio is safe and improves early haemostasis; it does not significantly increase transfusion-related complications [6]

Practical implementation:

• MTP packs typically contain 4 PRBC : 4 FFP : 1 pool platelets (approximating 1:1:1)
• Packs issued sequentially until bleeding controlled
• Goal-directed therapy (using viscoelastic testing) should complement ratio-based approach when available [30]

Fibrinogen Replacement

Fibrinogen is the first factor to reach critical levels during massive haemorrhage. [7,34]

CRYOSTAT-2 Trial (PMID: 37307184):

• Design: RCT of early empirical cryoprecipitate vs standard care in trauma requiring MTP activation
• Intervention: 3 pools cryoprecipitate (6 g fibrinogen) given early alongside MTP
• Results:
  • Higher fibrinogen levels at 6 hours in intervention group
  • 28-day mortality reduced (25.6% vs 31.2%; not statistically significant in primary analysis)
  • Subgroup analyses suggest benefit in specific populations
• Implication: Early fibrinogen supplementation is safe and may improve outcomes; validates target fibrinogen greater than 1.5 g/L [7]

Cryoprecipitate vs Fibrinogen Concentrate:

Australian context: Cryoprecipitate is the preferred fibrinogen source in most Australian institutions due to availability and cost. Fibrinogen concentrate (RiaSTAP) is available but often reserved for specific indications. [22]

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Tranexamic Acid (TXA)

Mechanism of Action

Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation by binding to the lysine-binding sites on plasminogen. This prevents plasmin formation and inhibits fibrinolysis, stabilising formed clot. [9]

CRASH-2 Trial (PMID: 20554319)

The landmark trial establishing TXA in trauma resuscitation.

Design:

• Double-blind RCT; 20,211 adult trauma patients with significant bleeding or risk of bleeding
• Intervention: TXA 1 g IV over 10 minutes, then 1 g IV over 8 hours vs placebo
• Setting: 274 hospitals in 40 countries

Results:

• All-cause mortality reduced from 16.0% to 14.5% (RR 0.91, 95% CI 0.85-0.97; p=0.0035)
• Death due to bleeding reduced from 5.7% to 4.9% (RR 0.85, 95% CI 0.76-0.96; p=0.0077)
• No increase in vascular occlusive events (PE, DVT, MI, stroke)
• NNT = 67 to prevent one death [9]

Timing is Critical

CRASH-2 Subgroup Analysis (PMID: 21435709) revealed the critical importance of timing:

Critical teaching point: TXA given after 3 hours from injury INCREASES mortality from bleeding. The mechanism is unclear but may relate to stabilisation of abnormal thrombus or prothrombotic effects in the later phase of coagulopathy. [13]

TXA Dosing Protocol

Standard trauma dose:

• Loading dose: 1 g IV over 10 minutes (ideally within 1 hour of injury)
• Maintenance dose: 1 g IV over 8 hours

Practical considerations:

• Give in pre-hospital setting if possible
• Do NOT give if greater than 3 hours from injury
• No evidence for repeat doses beyond the standard protocol
• Can be given with other blood products (compatible)

TXA in Other Settings

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Viscoelastic Testing

Overview

Viscoelastic haemostatic assays (VHAs) provide point-of-care assessment of whole blood clot formation, strength, and breakdown. The two main platforms are:

• TEG (Thromboelastography): Haemonetics system
• ROTEM (Rotational Thromboelastometry): Werfen/Instrumentation Laboratory

Both provide similar information using different nomenclature and reagent systems. [10,11]

ROTEM Parameters and Interpretation

TEG Parameters and Interpretation

Goal-Directed Transfusion Algorithms

Viscoelastic-guided algorithms enable targeted replacement therapy:

If FIBTEM A5/A10 low (fibrinogen below 1.5 g/L):

• Give cryoprecipitate (2 pools = ~5 g fibrinogen) OR fibrinogen concentrate 4 g

If EXTEM CT prolonged (factor deficiency):

• Give FFP 15-20 mL/kg

If EXTEM A10 low but FIBTEM A10 normal (platelet contribution low):

• Give platelets 1-2 pools

If EXTEM ML greater than 15% (hyperfibrinolysis):

• Give TXA 1 g IV (if not already given)

Evidence for Viscoelastic-Guided Transfusion

ITACTIC Trial (PMID: 33652024):

• RCT of VHA-guided vs conventional coagulation testing in trauma
• VHA-guided arm had lower 24-hour mortality (7.6% vs 8.8%) but not statistically significant
• VHA allowed earlier and more targeted therapy [38]

Cardiac surgery meta-analysis:

• VHA-guided algorithms reduce blood product transfusion by 20-30%
• Reduce mortality and major complications [11]

Practical benefit: VHA results available in 10-15 minutes vs 45-60 minutes for conventional PT/APTT. This time advantage is critical in massive haemorrhage. [10]

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Complications of Massive Transfusion

Metabolic Complications

Hypocalcemia (Citrate Toxicity)

• Mechanism: Citrate anticoagulant chelates ionized calcium
• Risk factors: Rapid transfusion rate, hypothermia, liver dysfunction, shock
• Incidence: Up to 90% during massive transfusion if not actively replaced
• Treatment: Calcium gluconate 1 g IV for every 4 units transfused; target iCa²⁺ greater than 1.1 mmol/L
• Monitoring: Check iCa²⁺ every 30 minutes during active transfusion [8]

Hyperkalaemia

• Mechanism: Stored blood potassium increases with storage duration (up to 50 mmol/L in older units); cellular lysis releases intracellular K⁺
• Risk factors: Older blood products, rapid transfusion, renal impairment, hypothermia (impairs cellular uptake)
• Paradox: Hypokalaemia may develop after resuscitation as citrate is metabolised to bicarbonate and cells take up K⁺
• Treatment: Standard hyperkalaemia management if symptomatic; often self-corrects with resuscitation [39]

Acid-Base Disturbances

• Initial: Metabolic acidosis from stored blood (lactic acid, hypoperfusion)
• Later: Metabolic alkalosis as citrate is metabolised to bicarbonate (delayed effect)
• Management: Avoid sodium bicarbonate initially; correct with resuscitation [27]

Hypothermia

• Mechanism: Blood products stored at 4°C; rapid infusion without warming
• Impact: Temperature below 35°C impairs clotting factor activity by 10% per °C; platelet dysfunction; increased oxygen-haemoglobin affinity
• Prevention: Mandatory blood warming (rapid infuser systems with warming capability)
• Target: Core temperature greater than 35°C [14]

Immune/Inflammatory Complications

Transfusion-Related Acute Lung Injury (TRALI)

• Definition: New ALI/ARDS within 6 hours of transfusion; no other ALI risk factor OR new ALI with risk factor (possible TRALI)
• Incidence: 1:5,000 to 1:190,000 transfusions; higher with plasma products
• Mechanism: Anti-HLA or anti-HNA antibodies in donor plasma activate recipient neutrophils → pulmonary endothelial injury
• Risk reduction: Male-only plasma donors (reduces anti-HLA antibody exposure); platelet additive solutions [40]
• Treatment: Supportive (lung-protective ventilation); usually resolves within 48-72 hours
• Mortality: 5-10%

Transfusion-Associated Circulatory Overload (TACO)

• Definition: Acute pulmonary oedema within 6 hours of transfusion from volume overload
• Incidence: 1-8% of transfusions; higher in elderly, cardiac disease, renal impairment
• Risk factors: Large volume transfusion, rapid infusion rate, pre-existing cardiac/renal disease
• Distinguishing from TRALI: TACO has elevated BNP, responds to diuretics, positive fluid balance
• Prevention: Judicious transfusion; slow rates in at-risk patients; diuretics if needed [41]

Febrile Non-Haemolytic Transfusion Reaction

• Definition: Temperature rise ≥1°C during or within 4 hours of transfusion
• Incidence: 0.5-1% of transfusions
• Mechanism: Cytokines in stored products; recipient antibodies against donor leukocytes
• Treatment: Pause transfusion; paracetamol; investigate for haemolytic reaction

Allergic Reactions

• Incidence: 1-3% of transfusions (mild urticaria); anaphylaxis rare (1:20,000-50,000)
• Mechanism: Recipient IgE against donor plasma proteins
• Treatment: Mild - antihistamines and continue; severe - stop transfusion, adrenaline, standard anaphylaxis management

Infectious Complications

Modern blood product screening has dramatically reduced infectious transmission. Current residual risks in Australia per unit transfused:

Bacterial contamination of platelets is the highest residual infectious risk due to room-temperature storage. [42]

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Permissive Hypotension and Damage Control Resuscitation

Damage Control Resuscitation (DCR) Principles

DCR represents a paradigm shift from traditional aggressive crystalloid resuscitation:

Permissive Hypotension

Concept: Accept lower than normal blood pressure until surgical haemorrhage control is achieved, to avoid:

• Disrupting early clot formation
• Dilutional coagulopathy from crystalloid
• Increased hydrostatic pressure promoting bleeding [15]

Target: SBP 80-90 mmHg (or MAP 50-60 mmHg) OR presence of radial pulse

Evidence:

• Bickell et al. (PMID: 7492753): Delayed fluid resuscitation in penetrating trauma improved survival
• Multiple observational studies support lower transfusion triggers and reduced crystalloid
• Limited RCT evidence; ethical challenges in conducting trials [43]

CONTRAINDICATIONS to permissive hypotension:

• Traumatic brain injury (TBI) - target SBP greater than 100 mmHg to maintain CPP
• Spinal cord injury - target MAP greater than 85 mmHg for cord perfusion
• Pregnancy (relative) - consider fetal perfusion
• Pre-existing hypertension (relative) [15]

Damage Control Surgery

Surgical approach aligned with DCR principles:

Phase 1: Initial abbreviated surgery (30-60 minutes)

• Control haemorrhage (packing, ligation, shunting)
• Control contamination (bowel stapling, drainage)
• Temporary abdominal closure

Phase 2: ICU resuscitation (24-48 hours)

• Correct coagulopathy, acidosis, hypothermia
• Optimise physiology
• Organ support as needed

Phase 3: Definitive surgery

• Return to theatre when physiology corrected
• Definitive repair, anastomosis, closure [44]

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Whole Blood Transfusion

Resurgence of Whole Blood

Fresh whole blood (FWB) and cold-stored whole blood (WB) have regained interest as an alternative to component therapy:

Advantages of whole blood:

• Contains all blood components in physiological ratios
• Reduced total volume for equivalent haemostatic effect
• Lower storage lesion effects
• Simpler logistics (one product vs multiple components)
• Favourable military experience [45]

Current evidence:

• Observational data suggest improved outcomes compared to component therapy
• STORHM trial (ongoing): Randomising whole blood vs component therapy in haemorrhagic shock
• Cold-stored whole blood (14-21 day storage) increasingly available at trauma centres

Australian context: Low-titre O-positive whole blood programs being developed at major trauma centres. O-negative whole blood may be used for female patients of childbearing age. [22,45]

Low-Titre Group O Whole Blood

• Low-titre: Anti-A and anti-B titre below 256 to reduce haemolytic risk
• O-positive: For males and females beyond childbearing age
• O-negative: For females of childbearing age (Rh sensitisation prevention)
• Storage: Up to 21 days refrigerated; some centres use 14-day limit

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Special Populations

Trauma in Pregnancy

Unique considerations:

• Physiological anaemia of pregnancy (Hb normally 100-120 g/L)
• Hypercoagulable state (increased fibrinogen, factors VII, VIII, X, vWF)
• Uterus is highly vascular; massive haemorrhage can be rapid
• Two patients (maternal and fetal considerations)
• Rhesus status and Kleihauer-Betke testing

Management modifications:

• Aggressive transfusion to maintain fetal oxygenation
• Early obstetric involvement
• Perimortem caesarean section if cardiac arrest greater than 4 minutes
• Rhesus-negative blood for Rh-negative mothers; Anti-D immunoglobulin if Rh-positive blood given [46]

Patients Refusing Blood Products

Jehovah's Witness patients:

• Respect autonomy if documented refusal
• Discuss acceptable interventions (cell salvage may be acceptable if continuous circuit)
• Maximise pre-operative haemoglobin (iron, erythropoietin)
• Meticulous surgical haemostasis
• TXA acceptable
• Advance care planning and documentation essential [47]

Paediatric Massive Transfusion

Volume calculations:

• Total blood volume: ~80 mL/kg (neonates 90 mL/kg)
• Massive transfusion: greater than 50% blood volume in 3 hours OR greater than 100% in 24 hours

Product dosing:

• PRBC: 10-15 mL/kg
• FFP: 10-15 mL/kg
• Platelets: 10-15 mL/kg
• Cryoprecipitate: 5-10 mL/kg

Special considerations:

• Higher metabolic rate; faster citrate metabolism but smaller reserves
• Risk of hypoglycaemia (check BSL)
• Temperature maintenance critical
• CMV-negative products for neonates/immunocompromised [48]

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ICU Management Post-MTP

Ongoing Resuscitation Endpoints

Monitoring in ICU

Laboratory monitoring (post-MTP, every 4-6 hours until stable):

• FBC, coagulation profile (PT/INR, APTT, fibrinogen)
• Electrolytes (particularly potassium, ionized calcium, magnesium)
• Blood gas (lactate, base excess)
• Renal function

Clinical monitoring:

• Ongoing haemorrhage assessment (drains, surgical sites)
• Urine output
• Vasopressor/inotrope requirements
• Temperature

Complications to Anticipate

Early (below 24 hours):

• Ongoing coagulopathy
• Hypocalcemia requiring ongoing replacement
• Hypokalaemia (as acidosis corrects)
• Hypothermia (requires active rewarming)

Intermediate (24-72 hours):

• TRALI/TACO
• Abdominal compartment syndrome (if damage control surgery)
• Acute kidney injury
• ARDS

Late (greater than 72 hours):

• Multi-organ dysfunction syndrome
• Infection/sepsis
• Venous thromboembolism (transition from coagulopathy to prothrombotic state) [49]

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MTP Logistics and Organisation

MTP Pack Contents (Typical Australian Configuration)

Pack 1 (Emergency):

• 4 units O-negative PRBC (or O-positive for males)
• Available within 5-10 minutes

Pack 2 (Balanced):

• 4 units group-specific PRBC
• 4 units FFP
• Available within 15-20 minutes

Pack 3 and Subsequent:

• 4 units PRBC
• 4 units FFP
• 1 pool platelets (or apheresis platelets)
• Cryoprecipitate (2 pools) often added to every second pack

Blood Bank Communication

Essential information for blood bank:

• Patient identification
• Location
• Urgency (Code Crimson / MTP activated)
• ABO/Rh if known (otherwise O-negative/O-positive)
• Products requested
• Single point of contact for transfusion coordination

Transfusion Safety During MTP

Even in emergencies, core safety principles apply:

• Two-person patient identification check (or emergency identification band)
• Blood product verification (two-person check if possible)
• Document all products transfused
• Monitor for transfusion reactions (may be masked by haemorrhagic shock)
• Blood bank notification of any adverse events [30]

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CICM Exam Practice

SAQ 1: Massive Transfusion Physiology

Question: A 28-year-old male is brought to the emergency department following a motorcycle collision. He has an open pelvic fracture, is hypotensive (SBP 70 mmHg), tachycardic (HR 135 bpm), and a positive FAST examination. Massive transfusion protocol is activated.

(a) Outline the criteria you would use to predict the need for massive transfusion. (4 marks) (b) Describe the pathophysiology of trauma-induced coagulopathy. (4 marks) (c) List the components of the "lethal diamond" and explain the importance of each. (4 marks)

Model Answer:

(a) Criteria for predicting massive transfusion (4 marks):

ABC Score (Assessment of Blood Consumption): This patient scores 4/4:

• Penetrating/significant mechanism (1 point)
• SBP ≤90 mmHg - present (1 point)
• HR ≥120 bpm - present (1 point)
• Positive FAST - present (1 point)

Score ≥2 indicates high probability of massive transfusion requirement; MTP should be activated.

Alternative scoring systems:

• TASH Score: Incorporates base excess, haemoglobin, gender, fracture type. Score greater than 16 indicates 50% probability of massive transfusion.
• Shock Index (HR/SBP): greater than 1.4 suggests high likelihood of massive transfusion. This patient has SI = 135/70 = 1.93 (severely elevated).

Clinical triggers:

• Clinician gestalt of uncontrolled haemorrhage
• Unstable vital signs despite initial resuscitation
• Obvious exsanguinating injury

(b) Pathophysiology of trauma-induced coagulopathy (4 marks):

Trauma-induced coagulopathy (TIC) is present in 25-35% of severely injured patients on arrival and differs from iatrogenic coagulopathy.

Mechanisms:

1. Tissue injury and shock (primary driver):

   • Hypoperfusion activates protein C pathway
   • Activated protein C inactivates Factors Va and VIIIa
   • Also inhibits PAI-1, promoting fibrinolysis

2. Endothelial glycocalyx shedding:

   • Tissue injury releases DAMPs (damage-associated molecular patterns)
   • Glycocalyx breakdown releases anticoagulant molecules
   • Exposes endothelial tissue factor pathway inhibitor

3. Hyperfibrinolysis:

   • Injured endothelium releases excess tPA
   • PAI-1 is inhibited by activated protein C
   • Present in 20-30% of severe trauma patients
   • Strongly associated with mortality

4. Platelet dysfunction:

   • Despite normal platelet count, function is impaired
   • Catecholamine surge and inflammatory mediators contribute
   • May persist despite platelet transfusion

5. Factor consumption and dilution:

   • Secondary to haemorrhage and resuscitation
   • Fibrinogen is first factor to reach critical levels

(c) Components of the "lethal diamond" (4 marks):

The lethal diamond extends the classic lethal triad to include hypocalcemia as the fourth critical factor:

Clinical implications:

• Each component worsens the others in a vicious cycle
• Active rewarming is mandatory (blood warmers, warming blankets)
• Avoid excessive crystalloid (worsens acidosis, dilution)
• Actively replace calcium: 1 g calcium gluconate per 4 units transfused
• Target: Temperature greater than 35°C, pH greater than 7.2, fibrinogen greater than 1.5 g/L, iCa²⁺ greater than 1.1 mmol/L

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SAQ 2: CRASH-2 and Viscoelastic Testing

Question: A 45-year-old female is admitted to ICU following emergency laparotomy for a ruptured ectopic pregnancy with massive haemoperitoneum. She has received 8 units of PRBC and is continuing to bleed from surgical sites.

(a) Discuss the evidence for tranexamic acid use in this patient. Include dose, timing, and mechanism. (5 marks) (b) Outline how you would use viscoelastic testing (ROTEM/TEG) to guide transfusion therapy. (5 marks) (c) Describe the complications of massive transfusion you would monitor for in ICU. (2 marks)

Model Answer:

(a) Tranexamic acid evidence (5 marks):

Mechanism of action:

• Synthetic lysine analogue
• Competitively binds to lysine-binding sites on plasminogen
• Prevents plasminogen activation to plasmin
• Inhibits fibrinolysis, stabilising formed clot

Evidence from CRASH-2 trial (PMID: 20554319):

• Landmark RCT: 20,211 trauma patients with significant bleeding
• Intervention: TXA 1 g IV over 10 minutes, then 1 g IV over 8 hours
• Results:
  • All-cause mortality reduced from 16.0% to 14.5% (RR 0.91)
  • Death due to bleeding reduced from 5.7% to 4.9%
  • No increase in thrombotic complications
  • NNT = 67 to prevent one death

Critical timing consideration:

• Subgroup analysis (PMID: 21435709) showed:
  • "TXA within 1 hour: RR 0.68 (strong mortality benefit)"
  • "TXA 1-3 hours: RR 0.79 (moderate benefit)"
  • "TXA after 3 hours: RR 1.44 (INCREASED mortality)"

Application to this patient:

• WOMAN trial (obstetric haemorrhage) supports TXA use: mortality reduced from 1.9% to 1.5%
• Dose: 1 g IV over 10 minutes, can repeat after 30 minutes if still bleeding
• Timing: Give as early as possible; ideally within 3 hours of haemorrhage onset
• If greater than 3 hours from initial haemorrhage onset, TXA is NOT recommended

(b) Viscoelastic-guided transfusion (5 marks):

ROTEM provides point-of-care assessment of clot formation, strength, and breakdown within 10-15 minutes (vs 45-60 minutes for conventional coagulation tests).

Key parameters and interpretation:

Goal-directed algorithm for this patient:

1. If FIBTEM A5 below 8 mm or FIBTEM A10 below 10 mm:

   • Fibrinogen deficient
   • Give cryoprecipitate 2 pools (~5 g fibrinogen) OR fibrinogen concentrate 4 g
   • Recheck after 15 minutes

2. If EXTEM CT greater than 80 seconds:

   • Factor deficiency
   • Give FFP 15-20 mL/kg
   • Recheck after 15 minutes

3. If EXTEM A10 low but FIBTEM A10 normal:

   • Platelet contribution deficient
   • Give 1-2 pools platelets
   • Note: Platelet function may be impaired despite normal count

4. If EXTEM ML greater than 15%:

   • Hyperfibrinolysis present
   • Give TXA 1 g IV if not already given
   • Consider repeat dose

Advantages of viscoelastic-guided approach:

• Faster results (10-15 min vs 45-60 min)
• Whole blood analysis (reflects in vivo conditions better)
• Reduces unnecessary transfusion by 20-30%
• Identifies specific defect for targeted therapy

(c) Complications to monitor in ICU (2 marks):

Immediate/early (below 24 hours):

• Hypocalcemia (citrate toxicity) - check iCa²⁺ every 2-4 hours, replace to greater than 1.1 mmol/L
• Hyperkalaemia (initially) → hypokalaemia (as acidosis corrects)
• Hypothermia (active rewarming, target greater than 36°C)
• Ongoing coagulopathy (monitor ROTEM/coagulation studies)
• Metabolic acidosis → later metabolic alkalosis

Intermediate (24-72 hours):

• TRALI (new hypoxaemia, bilateral infiltrates within 6 hours of transfusion)
• TACO (pulmonary oedema from volume overload)
• Acute kidney injury

Late (greater than 72 hours):

• Multi-organ dysfunction syndrome
• Infection/sepsis
• Venous thromboembolism (prothrombotic state after initial coagulopathy)
• Abdominal compartment syndrome (if massive resuscitation)

---

Viva Scenarios

Viva 1: PROPPR Trial and Ratio-Based Transfusion

Examiner: Tell me about the PROPPR trial and its implications for massive transfusion practice.

Candidate response:

The PROPPR trial (Pragmatic Randomized Optimal Platelet and Plasma Ratios) was a landmark multi-centre RCT published in JAMA in 2015 (PMID: 25647203) that compared transfusion ratios in severe trauma.

Study design:

• 680 patients at 12 Level 1 trauma centres in North America
• Included patients predicted to require massive transfusion
• Randomised to 1:1:1 (FFP:platelets:PRBC) versus 1:1:2 ratio
• Primary outcome was 24-hour and 30-day mortality

Key findings:

• No significant difference in 24-hour mortality (12.7% vs 17.0%, p=0.12) or 30-day mortality (22.4% vs 26.1%, p=0.26)
• However, 1:1:1 group had significantly more patients achieving haemostasis (86% vs 78%, p=0.006)
• Fewer deaths from exsanguination at 24 hours in 1:1:1 group (9.2% vs 14.6%, p=0.03)
• No difference in transfusion-related complications between groups

Examiner: Why might the overall mortality not have been significantly different despite better haemostasis?

Candidate response:

Several factors may explain this apparent paradox:

1. Sample size and power: The trial may have been underpowered for overall mortality, particularly if the effect size was smaller than anticipated.

2. Late deaths: Improved early haemostasis prevents exsanguination deaths, but patients who survive the initial phase may die from other causes (TBI, multi-organ failure, sepsis) that are not affected by transfusion ratio.

3. Competing risks: Patients saved from bleeding death may succumb to other complications.

4. Crossover effect: In the 1:1:2 arm, clinicians may have deviated toward higher plasma/platelet ratios based on clinical assessment.

Examiner: How would you translate this evidence into your MTP protocol?

Candidate response:

Based on PROPPR and supporting evidence:

1. Protocol design: Pre-packaged MTP packs approximating 1:1:1 ratio (typically 4 PRBC : 4 FFP : 1 platelet pool)

2. Early balanced resuscitation: Start with balanced products from the beginning rather than PRBC-heavy initial resuscitation

3. Complement with viscoelastic testing: When available, use TEG/ROTEM to guide ongoing therapy and identify specific deficiencies

4. Fibrinogen supplementation: Add cryoprecipitate early (CRYOSTAT-2 supports this)

5. Avoid excessive crystalloid: Limit crystalloid to prevent dilutional coagulopathy

6. Adjuncts: TXA within 3 hours, calcium replacement, active warming

---

Viva 2: Viscoelastic Testing Interpretation

Examiner: A trauma patient has received 10 units of PRBC. Their ROTEM shows: EXTEM CT 95 seconds, EXTEM A10 35 mm, FIBTEM A10 8 mm. How do you interpret this and what would you do?

Candidate response:

Let me systematically interpret each parameter:

EXTEM CT 95 seconds (normal 38-79 seconds):

• This is prolonged, indicating factor deficiency
• Suggests need for FFP

EXTEM A10 35 mm (normal greater than 43 mm):

• This is reduced, indicating clot strength is suboptimal
• Could be due to low fibrinogen OR low platelet contribution

FIBTEM A10 8 mm (normal greater than 10 mm):

• This is at the lower limit, indicating fibrinogen contribution is borderline insufficient
• FIBTEM isolates the fibrinogen component by inhibiting platelets with cytochalasin D

Interpretation: The EXTEM A10 of 35 mm with FIBTEM A10 of 8 mm suggests both fibrinogen deficiency and likely platelet deficiency contributing to reduced clot strength.

Platelet contribution ≈ EXTEM A10 - FIBTEM A10 = 35 - 8 = 27 mm (reduced)

Management approach:

1. Address factor deficiency (prolonged EXTEM CT):

   • Give FFP 15-20 mL/kg (~4 units for 70 kg patient)

2. Address fibrinogen deficiency (borderline FIBTEM A10):

   • Give cryoprecipitate 2 pools (~5 g fibrinogen)
   • Alternatively, fibrinogen concentrate 4 g

3. Consider platelets (reduced calculated platelet contribution):

   • Check platelet count; if below 100 × 10⁹/L with ongoing bleeding, give 1 pool platelets
   • May need platelets even if count normal due to functional platelet dysfunction in trauma

4. Recheck ROTEM in 15-20 minutes to assess response

5. Ensure ongoing supportive measures:

   • Calcium replacement (check iCa²⁺)
   • Temperature greater than 35°C
   • TXA if within 3 hours and not yet given

Examiner: The EXTEM ML is 25%. What does this mean?

Candidate response:

EXTEM ML (Maximum Lysis) of 25% indicates significant hyperfibrinolysis (normal below 15%).

This means the clot that forms is being broken down too rapidly by plasmin. This is seen in approximately 20-30% of severe trauma patients and is strongly associated with mortality.

Management:

• Give TXA 1 g IV immediately if not already given
• TXA inhibits plasminogen activation and will reduce fibrinolysis
• Can consider repeat TXA dose if ongoing evidence of hyperfibrinolysis
• Ensure adequate fibrinogen levels for clot substrate

This finding reinforces the importance of early TXA administration in trauma as recommended by CRASH-2.

---

References

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22. National Blood Authority. Patient Blood Management Guidelines: Module 1 - Critical Bleeding/Massive Transfusion. Canberra: National Blood Authority; 2011.

23. Brohi K, Cohen MJ, Ganter MT, et al. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg. 2007;245(5):812-818. PMID: 17457176

24. Johansson PI, Stensballe J, Ostrowski SR. Shock induced endotheliopathy (SHINE) in acute critical illness - a unifying pathophysiologic mechanism. Crit Care. 2017;21(1):25. PMID: 28178967

25. Raza I, Davenport R, Rourke C, et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost. 2013;11(2):307-314. PMID: 23176206

26. Kutcher ME, Redick BJ, McCreery RC, et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg. 2012;73(1):59-66. PMID: 22743373

27. Martini WZ, Pusateri AE, Uscilowicz JM, et al. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma. 2005;58(5):1002-1009. PMID: 15920416

28. Dzik WH, Kirkley SA. Citrate toxicity during massive blood transfusion. Transfus Med Rev. 1988;2(2):76-94. PMID: 3154132

29. Vandromme MJ, Griffin RL, Kerby JD, et al. Identifying risk for massive transfusion in the relatively normotensive patient: utility of the prehospital shock index. J Trauma. 2011;70(2):384-388. PMID: 21307738

30. Dzik WH, Blajchman MA, Fergusson D, et al. Clinical review: Canadian National Advisory Committee on Blood and Blood Products--Massive Transfusion Consensus Conference 2011: report of the panel. Crit Care. 2011;15(6):242. PMID: 22188866

31. Carson JL, Guyatt G, Heddle NM, et al. Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA. 2016;316(19):2025-2035. PMID: 27732721

32. Yuan S, Ferrell C, Chandler WL. Comparing the prothrombin time INR versus the APTT to evaluate the coagulopathy of acute trauma. Thromb Res. 2007;120(1):29-37. PMID: 16887171

33. Stanworth SJ, Walsh TS, Prescott RJ, et al. A national study of plasma use in critical care: clinical indications, dose and effect on prothrombin time. Crit Care. 2011;15(2):R108. PMID: 21466676

34. Rourke C, Curry N, Khan S, et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10(7):1342-1351. PMID: 22519961

35. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10084):2105-2116. PMID: 28456509

36. HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927-1936. PMID: 32563378

37. Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018;391(10135):2107-2115. PMID: 29778325

38. Baksaas-Aasen K, Gall LS, Stensballe J, et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial. Intensive Care Med. 2021;47(1):49-59. PMID: 33652024

39. Smith HM, Farrow SJ, Ackerman JD, et al. Cardiac arrests associated with hyperkalemia during red blood cell transfusion: a case series. Anesth Analg. 2008;106(4):1062-1069. PMID: 18349174

40. Toy P, Popovsky MA, Abraham E, et al. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005;33(4):721-726. PMID: 15818095

41. Narick C, Triulzi DJ, Yazer MH. Transfusion-associated circulatory overload after plasma transfusion. Transfusion. 2012;52(1):160-165. PMID: 21762464

42. Kuehnert MJ, Roth VR, Haley NR, et al. Transfusion-transmitted bacterial infection in the United States, 1998 through 2000. Transfusion. 2001;41(12):1493-1499. PMID: 11778062

43. Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994;331(17):1105-1109. PMID: 7935634

44. Stone HH, Strom PR, Mullins RJ. Management of the major coagulopathy with onset during laparotomy. Ann Surg. 1983;197(5):532-535. PMID: 6847272

45. Spinella PC, Perkins JG, Grathwohl KW, et al. Warm fresh whole blood is independently associated with improved survival for patients with combat-related traumatic injuries. J Trauma. 2009;66(4 Suppl):S69-76. PMID: 19359972

46. Pacheco LD, Saade GR, Costantine MM, et al. An update on the use of massive transfusion protocols in obstetrics. Am J Obstet Gynecol. 2016;214(3):340-344. PMID: 26656180

47. Lawson T, Ralph C. Perioperative Jehovah's Witnesses: a review. Br J Anaesth. 2015;115(5):676-687. PMID: 26385662

48. Neff LP, Cannon JW, Morrison JJ, et al. Clearly defining pediatric massive transfusion: cutting through the fog and friction with combat data. J Trauma Acute Care Surg. 2015;78(1):22-28. PMID: 25539199

49. Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37(12):3124-3157. PMID: 19773646

50. Holcomb JB, del Junco DJ, Fox EE, et al. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013;148(2):127-136. PMID: 23560283

51. Gonzalez E, Moore EE, Moore HB, et al. Goal-directed Hemostatic Resuscitation of Trauma-induced Coagulopathy: A Pragmatic Randomized Clinical Trial Comparing a Viscoelastic Assay to Conventional Coagulation Assays. Ann Surg. 2016;263(6):1051-1059. PMID: 26720428

52. Schöchl H, Nienaber U, Hofer G, et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care. 2010;14(2):R55. PMID: 20374650

53. Kashuk JL, Moore EE, Sawyer M, et al. Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg. 2010;252(3):434-442. PMID: 20739843

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Additional Viva Scenarios

Viva 3: Transfusion Complications

Examiner: A 35-year-old male received 15 units of PRBC over 4 hours following a ruptured spleen. He now has new bilateral pulmonary infiltrates on chest X-ray and hypoxaemia. How do you approach this?

Candidate response:

This presentation raises concern for a transfusion-related complication. The main differential diagnoses are:

Primary differentials:

1. Transfusion-Related Acute Lung Injury (TRALI)
2. Transfusion-Associated Circulatory Overload (TACO)
3. ARDS from underlying trauma/shock

Distinguishing features:

My approach:

1. Immediate assessment:

   • ABG (severity of hypoxaemia, PaO2/FiO2 ratio)
   • Fluid balance calculation
   • Central venous pressure if available
   • BNP or NT-proBNP level
   • Echocardiography (LV function, IVC size and collapsibility)

2. If TACO suspected:

   • Stop or slow transfusion
   • Diuresis (furosemide 40-80 mg IV)
   • Upright positioning
   • Respiratory support as needed (NIV, intubation if severe)
   • Usually resolves within 24-48 hours with treatment

3. If TRALI suspected:

   • Stop transfusion immediately
   • Supportive management (oxygen, NIV, mechanical ventilation if needed)
   • AVOID diuretics (patients often hypovolaemic)
   • Notify blood bank (implicated donors tested for HLA antibodies)
   • Usually resolves within 48-72 hours
   • Mortality approximately 5-10%

4. Blood bank notification:

   • Mandatory reporting of all suspected transfusion reactions
   • Enables donor testing and deferral if TRALI confirmed

Examiner: What measures reduce the risk of TRALI?

Candidate response:

TRALI risk reduction strategies include:

1. Male-only plasma donors: Women with prior pregnancies develop HLA antibodies; using male-only plasma for transfusion has reduced TRALI incidence by 50-80%

2. Platelet additive solutions: Reduce plasma content in platelet products, decreasing antibody exposure

3. Transfusion indication discipline: Transfuse only when clearly indicated (restrictive transfusion thresholds)

4. Avoid old blood: Although TRALI is primarily antibody-mediated, storage lesion effects may contribute to two-hit hypothesis

5. Leukoreduction: Reduces cytokine accumulation in stored products; standard practice in most countries

6. HLA-matched products: For patients with documented HLA antibodies (reduces alloimmunisation risk)

---

Viva 4: Hypocalcaemia During MTP

Examiner: You are called to ED where a trauma patient receiving massive transfusion becomes hypotensive and bradycardic despite ongoing blood product administration. ECG shows prolonged QT interval. What is your assessment?

Candidate response:

This presentation is highly concerning for severe hypocalcaemia secondary to citrate toxicity.

Pathophysiology:

• Citrate anticoagulant in blood products chelates ionized calcium
• Normal hepatic metabolism clears citrate (metabolised to bicarbonate)
• During rapid transfusion, citrate load exceeds metabolic capacity
• Ionized calcium falls precipitously
• Risk factors: rapid transfusion rate (greater than 1 unit per 5 minutes), hypothermia, shock, liver dysfunction

Clinical features of severe hypocalcemia:

• Cardiovascular: Hypotension refractory to vasopressors, bradycardia, prolonged QT, cardiac arrest
• Neuromuscular: Tetany, muscle twitching, perioral paraesthesias
• Coagulopathy worsening: Calcium is Factor IV in coagulation cascade

Immediate management:

1. Confirm with blood gas: Check ionized calcium (iCa²⁺)

   • Critical threshold: below 0.9 mmol/L associated with severe complications
   • Target: greater than 1.1 mmol/L

2. Calcium replacement:

   • If peripheral access only: Calcium gluconate 10% 10-20 mL (1-2 g) IV over 5-10 minutes
   • If central access available: Calcium chloride 10% 10 mL (1 g) IV - provides 3x more elemental calcium
   • May need to repeat every 10-15 minutes during active transfusion

3. Slow transfusion rate if clinically possible (may not be possible with ongoing haemorrhage)

4. Empiric calcium replacement protocol:

   • Give 1 g calcium gluconate for every 4 units of blood products transfused
   • FFP has higher citrate content than PRBC - give more calcium with FFP-heavy transfusion
   • Monitor iCa²⁺ every 30 minutes during active MTP

5. Rewarming:

   • Hypothermia impairs citrate metabolism
   • Ensure active warming strategies in place

6. Address liver function:

   • If liver injury or dysfunction suspected, be more aggressive with calcium replacement
   • Consider citrate accumulation in context of hepatic failure

Examiner: What is the "lethal diamond" and why is it important?

Candidate response:

The lethal diamond extends the classic lethal triad (hypothermia, acidosis, coagulopathy) to include hypocalcaemia as the fourth critical component:

Clinical importance:

1. Each component perpetuates the others in a vicious cycle
2. Hypocalcaemia specifically impairs:
   • Factors VII, IX, X activation (vitamin K-dependent factors require calcium)
   • Platelet aggregation
   • Fibrinogen to fibrin conversion
3. iCa²⁺ below 0.9 mmol/L independently predicts mortality in trauma
4. Hypocalcaemia contributes to refractory hypotension (impairs cardiac contractility and vascular tone)
5. Often under-recognised during resuscitation focus on other elements

Key teaching point: The diamond must be addressed simultaneously - correcting coagulopathy without addressing hypocalcaemia is unlikely to succeed.

---

Clinical Pearls and Practical Tips

Blood Product Administration

Infusion rates:

• Standard: 1 unit PRBC over 2-4 hours in stable patients
• Massive transfusion: 1 unit every 5-15 minutes as needed
• Rapid infuser devices can deliver up to 750 mL/min when warmed

Warming:

• All blood products should be warmed during massive transfusion
• Standard blood warmers: 37°C with flow rates up to 150 mL/min
• Rapid infuser systems (Level 1, Belmont): 37°C at flows up to 750 mL/min
• Never use microwave or hot water bath (causes haemolysis)

Compatibility:

• ABO-compatible blood preferred
• Emergency: O-negative for females of childbearing age; O-positive for others
• Rh-negative blood for Rh-negative females to prevent sensitisation
• FFP: Any ABO type acceptable in emergency; AB is universal donor
• Platelets: ABO-compatible preferred but any type acceptable in emergency

Laboratory Monitoring During MTP

Common Dosing Quick Reference

MTP Termination Criteria

Consider stopping MTP when:

• Surgical/procedural haemorrhage control achieved
• Vital signs stabilising (HR below 100, SBP greater than 100 mmHg without vasopressors)
• Lactate clearing
• Coagulation normalising (INR below 1.5, fibrinogen greater than 1.5 g/L, platelets greater than 50)
• Urine output greater than 0.5 mL/kg/hr
• No ongoing clinical evidence of bleeding

Transition to standard transfusion practice:

• Continue individual product ordering based on laboratory results
• Maintain close monitoring for 24-48 hours
• Watch for delayed complications (TRALI, TACO, DIC)

---

Summary Algorithm: MTP Management

MASSIVE HAEMORRHAGE IDENTIFIED
           |
           v
+------------------------------+
|   ACTIVATE MTP               |
|   ABC Score ≥2 OR            |
|   Shock Index greater than 1.4 OR        |
|   Clinical gestalt           |
+------------------------------+
           |
           v
+------------------------------+
|   IMMEDIATE ACTIONS          |
|   - TXA 1g IV (within 3h)    |
|   - Request MTP Pack 1       |
|   - Start rapid infuser      |
|   - Active warming           |
|   - Send group & screen      |
+------------------------------+
           |
           v
+------------------------------+
|   DAMAGE CONTROL             |
|   RESUSCITATION              |
|   - 1:1:1 ratio transfusion  |
|   - Permissive hypotension   |
|     (SBP 80-90) unless TBI   |
|   - Minimise crystalloid     |
|   - Target temp greater than 35°C        |
+------------------------------+
           |
           v
+------------------------------+
|   MONITOR & REPLACE          |
|   - iCa²⁺ every 30 min       |
|     (target greater than 1.1 mmol/L)     |
|   - Ca gluconate 1g/4 units  |
|   - ROTEM/TEG if available   |
|   - Fibrinogen greater than 1.5 g/L      |
+------------------------------+
           |
           v
+------------------------------+
|   GOAL-DIRECTED THERAPY      |
|   Based on ROTEM/TEG:        |
|   - Low FIBTEM → Cryo/Fib    |
|   - Prolonged CT → FFP       |
|   - Low A10 + normal FIBTEM  |
|     → Platelets              |
|   - High ML → TXA            |
+------------------------------+
           |
           v
+------------------------------+
|   REASSESS CONTINUOUSLY      |
|   - Haemostasis achieved?    |
|   - Lactate clearing?        |
|   - INR/fibrinogen normal?   |
|   → TERMINATE MTP            |
+------------------------------+

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Key Trials Summary Table

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Appendix: ROTEM Reference Values

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Appendix: Calcium Replacement Guide

Conversion: 10 mL 10% Ca gluconate = 0.22 mmol elemental Ca; 10 mL 10% Ca chloride = 0.68 mmol elemental Ca (3x more)