Question 16

College Answer

Medical Measures to control bleeding

Activate Massive Transfusion Protocol as per local hospital guidelines. Close liaison with surgeon and haematologist is warranted.

Local pressure including adjunctive tourniquet use to control bleeding from the left leg wound.

Target lower systolic blood pressure (e.g. 80 mmHg) until major bleeding has been stopped (absence of brain injury permits the same). Permissive hypotension is tolerated and has shown survival benefits in some studies.

Correct hypothermia and acidosis.

Packed cells transfusion to target haemoglobin concentration 70 – 90 g/L to achieve adequate tissue perfusion.

Fresh Frozen Plasma to maintain INR & APTT < 1.5 x mean control. Usual dose 15 mL/kg.

Cryoprecipitate to maintain Fibrinogen levels > 1.5 g/L. Usual dose is 3-4 g or 50 mg/kg. (Fibrinogen

concentrate is also allowed).

Platelet transfusion to keep platelets > 50 x 109/L. With multiple injuries and suspicion of micro-vascular bleeding; platelet count can be aimed at > 100 x 109/L.
Supplemental Calcium to maintain ionised calcium > 1.1 mmol/L

Fluid Resuscitation with warmed crystalloid solutions. Aggressive fluid resuscitation is no longer recommended due to risk of pulmonary oedema, worsening of thrombocytopenia and coagulopathy due to haemoduilution.

Use of ROTEM/TEG targets Tranexamic Acid (see below)

Recombinant Factor VIIa: Not indicated at this stage (prior to surgery).

b)

Tranexamic Acid (TXA) is a synthetic lysine analogue that is a competitive inhibitor of plasminogen. TXA is distributed throughout all tissues with plasma half-life of 120 minutes.

Evidence: Recently published CRASH 2 trial; a multi-centre randomised, controlled trial examined the role of TXA against placebo in trauma patients, with, or at risk of significant haemorrhage. In more than 20,000 patients; TXA demonstrated a significant reduction in all-cause mortality at 4 weeks after injury (14.5% vs. 16%; RR = 0.91, P = 0.0035) and risk of death from bleeding (4.9% vs. 5.7%; RR=0.85, p=0.00077).

The risk of precipitated thrombosis with the use of the lysine analogues has been of major theoretical concern; however, CRASH-2 showed that the rate of thrombosis, especially myocardial infarction, was lower with the use of TXA. No adverse events were described with the use of TXA in CRASH-2, although an increased rate of seizures has been described in patients receiving a high dose of TXA when undergoing cardiac surgery.

A further analysis of CRASH-2 data showed that early treatment (< 1 hour and 1-3 hour from injury) significantly reduced the death rate of bleeding but treatment administered after 3 hours; increased the risk of death due to bleeding. Hence, TXA should be administered within 3 hours of injury.

TXA should be considered as adjunctive therapy in patients with traumatic haemorrhage in the setting of overall patient management; including strict attention to the control of bleeding, physiological and metabolic parameters, coagulation and temperature maintenance.

Additional Examiners’ Comments:

Most candidates answered this question well although knowledge relating to the evidence for tranexamic acid was overall limited. Some gave a reasonable discussion of the medical management of bleeding but omitted surgical strategies.

Discussion

The mess we're in:

• Anaemia (Hb 65)
• Thrombocytopenia (plts 46)
• Coagulopathy (INR 1.9, APTT 43, Fibrinogen 1.1)
• Metabolic acidosis (pH 7.29, SBE -11)
• Hypothermia (temp = 34.7°C)

Immediate resuscitation:

• Primary survey should include the assessment of core temperature.
  • Haemostasis by direct pressure wherever this is possible
• ABG to determine the pH, lactate, haemoglobin level and ionised calcium
• Activate the massive transfusion protocol in liason with local blood bank and haematology service
• Organise transfusion: 1:1:1 FFP, platelets, PRBCs.
  • Haemoglobin level is not a valid transfusion trigger, nor can transfusion wait for haemoglobin levels to become available. 
  • Any transfused blood products should be warmed with a heater. Six units of RBCs at 4ºC will reduce the body temperature of an average 70 kg adult by 1ºC.
  • Crystalloid is to be avoided unless there is no other option and haemodynamic performance if life-threateningly poor
• Tranexamic acid 1g over 10 minutes
• Correct ionised calcium
• Commence warming the patient externally
• Practice permissive hypotension if permitted by the absence of neurotrauma

Within the first 6 hours:

• Serial repeated Hb measurements
• Coags data, plus/minus TEG or ROTEM (its utility and cost effectiveness over traditional coags is still being questioned) will guide the ongoing use of blood products.
• FFP 15ml/kg if APTT remains elevated
• Tranexamic acid 1g over 8 hours to chase the first dose (as per CRASH-2 protocol)
• Cryoprecipitate 3-4g (or, 50mg/kg) should be given if the fibrinogen level is below 1.5
• Recombinant Factor VIIa (Novoseven) should be thought about if the coags are trending towards normal, and the patient is still exsanguinating (the dose should be 90 μg/kg)

Endpoint goals within the first 6 hours:

• No further haemorrhage
• SBP = 80-90
• MAP = 50
• Temperature >35.0°C
• pH >7.30
• Hb >70
• INR <1.5
• APTT <40
• Fibrinogen >1.0
• Platelets >50 (100 if there has been intracranial haemorrhage)
• iCa²⁺ >1.10 mmol/L

Use of ROTEM or TEG:

• No clear advantage to their use (Sankarankutty et al, 2011)
• Positive experience with both systems has been reported
• Slightly different transfusion strategies will result, depeding on which modality is used
• A major advantage over traditional coags is immediate access to fibrinolysis data

Evidence for the use of tranexamic acid in trauma

• CRASH-2 Trial (2010):  multi-centre international RCT; 20,211 patients in total. The trial-based dosing regimen was 1g of tranexamic acid within the first 3 hrs, followed by an infusion of 1g over the following 8 hours.
  • The all-cause mortality improvement was small (14.5% vs 16%) but reached significance because of the truly massive number of enrolled patients.
  • Similarly, the improvement in mortality from bleeding was also small (4.9% vs 5.7%)
  • The greatest improvement in mortality was seen in patients who received it earlier: 1 hour after the trauma was ideal. 
  • Analysis of cost-benefit had concluded that tranexamic acid was a very cheap way of saving many lives (Roberts et al, 2013).
  • Concerns regarding the increased risk of thrombosis were not supported by the analysis (in fact the tranexamic acid group had a lower rate of thrombosis and myocardial infarction)
• MATTERS study (2012): single centre observational study, 896 admissions with combat injury to a surgical hospital in southern Afghanistan. Mortality was improved in the intervention group (17.4% vs 23.9%) and the benefit was greatest among those who had massive transfusion
• MATTERS II study (2013)-  also a military retrospective observational study; 1332 patients over 5 years. Looking at whether administering tranexamic acid together with fibrinogin (cryoprecipitate) has any influence on mortality. Mortality was lowest in the tranexamic acid + cryoprecipitate group (11.6%), then the tranexamic acid group (18.2%), then the  cryoprecipitate alone group (21.4%) and finally the "nothing" group (23.6%).

Criticism of this evidence

• Reduction of fibrinolysis was the proposed goal, but no attempt to measure fibrinolysis was made.
• Tranexamic acid has an anti-inflammatory effect, which may account for some of the mortality difference (Volpi et al, 2015).
• In the CRASH-2 trial, doctors could choose to randomize or not randomize based on treatment certainty. Also, of the dead patients, only approximately 5% had bleeding as a cause of death. Approximately half of the patients in the trial did not even require a transfusion. in short, there are serious methodology concerns.
• Much of the trial intervention occurred in the pre-hospital environment, which makes it difficult to generalise the findings.
• If  the tranexamic acid was given later than 3 hours after the injury, it was associated with an increased risk of death from bleeding.
• The CRASH-2 trial did not find much evidence of increased risk of thrombosis, but the observational MATTERS study (2012),  which was conducted among "proper" trauma patients,  demonstrated that DVT/PE rates among patients who received tranexamic acid were 9 and 12 times higher (for PE and DVT respectively)

Sankarankutty, Ajith, et al. "TEG® and ROTEM® in trauma: similar test but different results." World J Emerg Surg 7.Suppl 1 (2012): S3.

Shoemaker, William C. "Comparison of the relative effectiveness of whole blood transfusions and various types of fluid therapy in resuscitation." Critical care medicine 4.2 (1976): 71-78.

El Sayad, Mohamed, and Hussein Noureddine. "Recent Advances of Hemorrhage Management in Severe Trauma." Emergency medicine international 2014 (2014).

Castellucci, Lana Antoinette. Evaluating Risk of Delayed Major Bleeding in Critically Ill Trauma Patients. Diss. University of Ottawa, 2016.

Stensballe, Jakob, and John B. Holcomb. "Hemostatic resuscitation is neither hemostatic nor resuscitative in trauma hemorrhage—But did they in fact test the effect of hemostatic resuscitation?." Journal of Trauma and Acute Care Surgery 78.6 (2015): 1237.

MacLeod, Jana BA, et al. "Early coagulopathy predicts mortality in trauma." Journal of Trauma and Acute Care Surgery 55.1 (2003): 39-44.

Lier, Heiko, et al. "Preconditions of hemostasis in trauma: a review. The influence of acidosis, hypocalcemia, anemia, and hypothermia on functional hemostasis in trauma." Journal of Trauma and Acute Care Surgery 65.4 (2008): 951-960.