Haemostatic resuscitation and massive transfusion

In all of the CICM past exams, the topic of haemostatic resuscitation has only come up twice, as part (b) of Question 20 from the first paper of 2011 and Question 23 from the first paper of 2022.  In addition to this, one other SAQ (Question 10 from the first paper of 2020) had asked about the strategies one could use to decrease the PRBC transfusion requirements in an acutely bleeding trauma patient, which is essentially a question about haemostatic resuscitation.

There is a lot written on this topic- much more than an exhausted exam candidate can be expected to internalise. As always, LITFL says it best. For a good long-form review, one may turn either to Heiko Lier et al (2008) or to this 2016 dissertation by Lana Castellucci.  The Critical Bleeding/Massive Tranfusion Module from the National Blood Authority is the definitive resource for the "official position". The main message is the management of the "lethal triad" - correction of hypothermia, acidosis and coagulopathy. At the same time, it is important to limit the total amount of infused crystalloid, so as to avoid excessive organ oedema.

Definition of haemostatic resuscitation

• Rapid correction of haemostasis-impairing factors, such as hypothermia hypocalcemia and acidosis
• Resuscitation with a balanced combination of blood products, which in combination resemble the composition of whole blood, aiming to avoid dilutional coagulopathy.

Goals of haemostatic resuscitation:

• Reverse hypothermia
• Reverse acidosis
• Limit crystalloid load
• Use blood components in a proportion which resembles whole blood
• Reverse fibrinolysis associated with massive blood loss
• Achieve this whole-blood-like ratio within the first 6 hours of resuscitation

Rationale for haemostatic resuscitation

Traditional methods of trauma resuscitation were "unbalanced". Historically, vast volumes of crystalloid would be funnelled into the patient in order to restore the circulating volume, with occasional units of packed cells thrown in randomly whenever the haemoglobin result comes back low. Then, when coags become abnormal, other blood products would be used. The goal was to flog the patient with fluid boluses, with the goal being a normal arterial blood pressure. This carried on for some time, even though from the literature of the period (eg. Shoemaker at al, 1976) it seems the disadvantages of this approach were already clear.

Such unbalanced resuscitation strategies lead to depletion of coagulation factors and exacerbation of dilutional coagulopathy. The oedematous tissues would swell, limiting vascular access and creating compartment syndromes. Oedematous organs would refuse to work. Lungs would fill with oedema and become stiff; oedematous gut would refuse to perform normal peristaltic work, and oedematous anastomotic sites would break down due to poor perfusion. If non-blood colloids were used, they would either clog the kidneys (hydroxyethyl starch) or incorporate themselves into newly formed clots, degrading the clot integrity (gelofusine).

In short, the old way didn't work very well. The new paradigm of trauma resuscitation is to preserve coagulation at all costs, while keeping the cardiac output at whatever minimum is required to maintain vital organ perfusion. A summarised series of arguments for this new paradigm are offered below:

Rationale for aggressive correction of coagulopathy

• Exsanguination is a major cause of death in trauma (40% of trauma-related death in the first 24 hours is due to haemorrhage)
• Coagulopathy is common:  25% of severe trauma patients are coagulopathic at presentation
• According to retrospective cohort studies (MacLeod et al, 2003) and the coagulopathic patients have increased mortality (46%) compared to non-coagulopathic controls (11%).

Rationale for avoiding large volumes of crystalloid

• Aggressive resuscitation with crystalloid leads to haemodilution.
• Haemodilution decreases the concentration of clotting factors and leads to coagulopathy.
• 75% of the crystalloid volume load distributes into the extravascular space; organ and tissue oedema ensues, putting the patient at risk of pulmonary oedema and abdominal compartment syndrome (among other problems).
• Crystalloids do not contribute to the transport of oxygen; by diluting the blood they actually decrease its oxygen-carrying capacity.
• In the case of saline, crystalloid resuscitation may exacerbate the acidosis.

Rationale for using a balanced blood product ratio

• Transfusion of packed red cells does not restore clotting factors.
• Coagulopathy will develop if packed red cells are the sole resuscitation fluid.
• Transfused PRBCs suffer from storage lesions. Their oxygen-carrying capacity isn't very good anyway.
• The citrate in the PRBCs tends to chelate the patient's calcium; this can't be good for their clotting function.
• It stands to reason that whole blood is the best resuscitation fluid to replace whole blood which is lost by haemorrhage.
• A "balanced" ratio of blood products resembles whole blood.
• The precise ratio of platelets plasma and PRBCs is still being debated.

Rationale for correction of acidosis

• Nonsurvivors of trauma are more likely to have been acidotic than survivors
• Acidosis in trauma is largely the consequence of raised lactate
• The lactate is generated not only by tissue anaerobic metabolism, but also by the β-agonist adrenergic effects of endogenous catecholamines.
• The main problems with acidosis in trauma is its influence on coagulopathy and haemodynamic performance (Lier et al, 2008). In fact, acidosis seems to be more important for coagulopathy than the hypothermia (Hoffman et al, 2004)
• Coagulopathy due to acidosis is the result of multiple pathophysiological processes:
  • The main problem is impaired thrombin generation. The thrombin generation rate during the propagation phase is impaired by 50%  at a pH of 7.10.
  • Platelet structure changes at a pH below 7.4: they assume a spherical shape, and lose their pseudopodia.
  • Clotting factors function poorly -particularly Factors V, VIIa and X- because the interaction between the clotting factors and negatively charged phospholipids is impaired at low pH (Hess et al, 2006).
  • Clotting factors which require iCa²⁺ have a decreased affinity for it at a low pH.
• The haemodynamic effects of metabolic acidosis are also counterproductive, particularly if the pH is below 7.10:. Specific problems are listed as follows.
  • Decreased cardiac output
  • Increased propensity to arrhythmias
  • Decreased systemic vascular tone and arterial vasodilation
  • Decreased responsiveness to catecholamines
  • Pulmonary vasoconstricition

Rationale for correcting hypothermia

• Hypothermia seems to have a real impact on trauma outcomes: in a retrospective analysis of trauma patients (Jurkovich et al, 1987), the temperature was associated with the following mortality rates:
  • Presenting temperature of over 34°C = mortality of 7%;
  • 33-34°C = mortality of 40%;
  • 32-33°C = mortality of 67%,
  • Under 32°C = mortality of 100%,
• The pathophysiological factors which influence mortality due to hypothermia in trauma are listed as follows:
  • The enzymes of the coagulation cascade function poorly at low temperature (more on this in the chapter on the physiological effects of hypothermia)
  • In short, at 33°C the clotting activity is suppressed to the point where it resembles a 50% reduction in clotting factor concentration (even when the actual concentration is normal). Interestingly, recombinant Factor VIIa (Novoseven) still retains its activity at 34°C (+/- 2.5°C).
  • Platelet activity is also impaired at low temperature;Each 1°C decrease in temperature results in a 15% decrease in the rate of thromboxane B2 production (thus, platelet activation is impaired).
  • LITFL also report that at low temperatures, platelets are sequestered in the liver and spleen

Rationale for correction of fibrinolysis with tranexamic acid

• One of the effects of trauma is to induce a hyperfibrinolytic state
• The major source of this seem to be increased serum levels of thrombomodulin and tPA (Brohi et al, 2008)
• It would therefore make sense to give a tPA inhibitor such as tranexamic acid or eta-aminocaproic acid
• This is backed by some evidence; how robust that evidence is remains the subject of debate (see below)

Rationale for the use of hypertonic saline

• After the resuscitation of trauma, massive tissue injury and ischemia/reperfusion produces an exaggerated systemic inflammatory response syndrome (SIRS) .
• Extravasation and sequestration of neutrophils into vital organs is one of the main mechanisms of organ damage in this context
• Hypertonic saline is said to have immunomodulatory effects, specifically affecting neutrophil migration (Angle et al, 2000) and decreasing the permeability of the blood-brain barrier.
• As a hyperosmolar solution, it should theoretically expand the volume of extracellular fluid by osmotically "borrowing" water from the intracellular compartment-

Problems with haemostatic resuscitation

• The ideal resuscitation fluid would of course be whole blood. Unfortunately, this is usually not available. One may try to recombine stored blood products to achieve an end result which resembles whole blood, but it is never quite the same due to lesions of processing and storage.
• All blood products suffering storage lesions are cold (contributing to hypothermia) and acidic (because of cellular metabolism in storage, as well as due to citrate-based storage media)
• The infusion of massive amounts of blood products exposes the patient to risks of massive transfusion which are not trivial, and it is debatable whether these risks outweigh the risks of massive crystalloid load
• Tranexamic acid may have prothrombotic effects which increase the risk of DVT in already DVT-prone trauma patients. Furthermore, the methodology of the major trial in support of its use makes it difficult to generalise its finding to the ICU setting (see below)
• Hypertonic saline can theoretically increase the risk of bleeding by causing some sort of platelet function impairment (fortunately studies have demonstrated that one would need to replace 10% of their blood volume with hypertonic saline before one experiences any of these effects).

Evidence in support of specific haemostatic resuscitation strategies

Evidence regarding correction of the "lethal triad"

Many studies are available; this is merely a selection of famous representatives.

• Duchesne et al (2010): retrospective cohort, 196 patients; a survival benefit was reported in the haemostatic resuscitation group (73.6% vs 54.8%) and shorter ICU stay (11 vs 20 days)
• Cotton et al (2011): retrospective cohort,  390 patients; again a survival benefit was reported at 30 days (86% vs 76%)
• Duchesne et al (2011): retrospective cohort, 196 patients; odds ratio of death was almost halved (OR = 0.40) and length of stay in hospital was decreased by 13.2 days.
• Morrison et al (2013) have demonstrated that correction of the lethal triad is possible intraoperatively (in a retrospective cohort of severely injured survivors of military explosion-based Rambo-style trauma, which unfortunately excluded surgical non-survivors).

Criticism:

• The lethal triad of trauma (hypothermia, acidosis, and coagulopathy) may be an overly  simplistic model, and most of the expert recommendations on this issue are based on associations from observational databases (Theusinger et al, 2015)
• In all the abovementioned studies, the "lethal triad" was corrected as a part of a greater trauma care package, which changed many aspects of trauma care. This package included permissive hypotension and damage control surgery.  One may just as easily attribute the survival advantage to these measures.

Evidence regarding 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:

• 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)

Evidence regarding specific massive transfusion ratios

• PROMMTT study (2013): multicentre prospective cohort study; 905 patients enrolled. This was a time-varying study: the authors did not direct therapy, but merely observed what happened. What happened was the early death of patients who received more red cells than platelets and plasma within the first 6 hours. For these people, mortality was increased 3-4 times. On the other hand, those who received 1:1 transfusion of plasma or platelets and red cells tended to survive more. Furthermore, the survival benefit was concentrated in the first six hours: of the patients who survived the first 24 hours, there was no difference in mortality at 30 days, regardless of what transfusion ratio was used.
• Khan et al (2014): a prospective cohort study of ROTEM and lactate measurements. 106 patients were enrolled; samples were taken after every 4 units of PRBCs. The authors found the ROTEM data and lactate kept getting worse in spite of "haemostatic resuscitation", and were forced to conclude that it was neither haemostatic nor resuscitative. However critics responded (Stensballe and Holcomb, 2015) with the criticim that Khan et al did not use enough platelets (1 unit to every 8 bags of PRBCs) nor enough FFP (0.5 units per every bag PRBCs), and thus were not practicing "proper" haemostatic resuscitation.
• PROPPR trial (2015): multicentre RCT, 680 patients randomised to receive plasma, platelets and red cells in a 1:1:1 or 1:1:2 ratio. There was no difference in mortality. Or rather, the difference was small (4% improvement in absolute mortality, favouring the 1:1:1 group) but the study was not powered to detect this.  The major difference between groups was death by exsanguination within the first 24 hours (much better in the 1:1:1 group, 9.2% vs 14.6%).
• CRYOSTAT trial (2015):  feasibility study; no 28-day mortality difference, whether or not you receive 2 units of cryoprecipitate early.

Criticism:

• ‘Survivor bias’: sure, the higher ratio works best;  patients that were going to live long enough to receive the extra blood products (and therefore achieve the expected ratio) were always going to be more likely to survive. The patients that were not going to survive did not achieve the ratio because they died of their severe injuries within the first few hours.
• The studies were largely observational cohorts.
• The settings were mainly American; penetrating trauma was highly prevalent (33% in PROMMTT) which is difficult to generalise in the relatively gunshot-free environment of -lets say even Western Sydney, where your trauma is likely to be in the form of a stoned cyclist vs. parked vehicle.
• The one RCT (PROPPR) was underpowered, unblinded, and of the groups the majority never even achieved their transfusion ratio targets.
• Even when the targets are met, the 1:1:1 ratio is nothing like whole blood. UpToDate reports that this cocktail represents whole blood which only has 65% of the normal concentration of coagulation factors, a platelet count of 88, and a relatively dilute haematocrit of 0.29. If you sampled such blood from a trauma patient, you would be tempted to transfuse them.
• RebelEM and LITFL contain rich deposits of links for high-quality EBM evaluations of the PROMMTT and PROPPR studies, as practically every ED physician in the land seems to have blogged an opinion on this topic.

Evidence regarding the use of hypertonic saline

• Rizoli et al (2006): single centre RCT; a single 250ml dose of hypertonic slurry (7.5% NaCl plus 6% dextran) was given to 13 of the total 27 enrolled patients. Primary outcomes were nerdy immunochemical parameters, such as measures of neutrophil activation and inflammatory cytokines. The hypothesis was that the slurry would have some sort of magical anti-inflammatory effect. In factm it did: TNF-α production was supressed, while anti-inflammatory IL-1ra and IL-10 production was increased. Hypertonic saline may prevent post-resuscitation multi-organ-system failure, the authors concluded.
• Bulger et al (2008): single centre RCT; again a single shot of 7.5% saline plus dextran was being used to resuscitate blunt trauma. 209 patients were enrolled; 28-day survival without ARDS was the primary endpoint. No difference was found, although there was some trend towards benefit in the group of patients who received 10 or more units of PRBCs. 
• Bulger et al (2011): multicentre RCT; 853 patients randomised into  three groups ( 7.5% saline plus dextran, vs. 7.5% saline alone, vs. normal 0.9% saline). 28-day mortality was the primary outcome measure. The study was stopped early, at 23% of proposed sample size, "for futility and potential safety concern". Within the limitations of a prematurely aborted trial, the hypertonic fluid groups seem to have had a poorer survival if the patients did not receive any PRBCs in the first 24 hours (10% mortality vs. 4.8 with normal saline).

Criticism:

• The available RCTs are either small or were aborted early
• Of the larger studies, many patients were not "major trauma" by definition (eg. Bulger et al, 2011 - many patients didn't even require transfusion).
• At least in the prehospital environment, resuscitation with hypertonic saline (specifically, 250ml of 7.5% NaCl) seems to worsen hypocoagulability and hyperfibrinolysis (Delano et al, 2015). In this study, the blood pressure of the hypertonic-resuscitated patients was certainly better on arrival to hospital than that of patients who got isotonic fluids. However there was no diference in total fluid requirement between these two groups, which debunks the idea that hypertonic saline is somehow "volume-sparing", i.e. useful for reducing the total resuscitation fluid volume.

Practical approach to haemostatic resuscitation

A suggested approach to the medical management of haemostasis in trauma

The following suggestions are concocted from lots of sources, none of which are directly credited, but which include LITFL, UpToDate and the abovelisted trial/cohort evidence.

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 is 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.
• Tranexamic acid 1g over 8 hours to chase the first dose (as per CRASH-2 protocol)
• Cryoprecipitate 3-4g should be given if the fibrinogen level is below 1.0
• 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)

Use of ROTEM or TEG:

• No In brief, one can say that there is no clear (Sankarankutty et al, 2011) advantage to their use, as a recent (2011) meta-analysis could not make a firm recommendation in their favour.

Endpoint goals of medical haemostasis in trauma

These are being offered as a reasonable-sounding list of goals, on the basis of the evidence above, as well as using the college answer to Question 7 from the second paper of 2015. These goals should be achieved at the end of the first six hours of resuscitation

• 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

Strategies to minimise transfusion requirements

Question 10 from the first paper of 2020 asked the exam candidates about how they would "reduce the red cell transfusion requirements in an actively bleeding multiple trauma patient". Without having thought about this previously, this answer would have been quite difficult to approach. One could conceivably separate it into two main components: stop the bleeding, and stop transfusing. An excellent article by Tinmouth et al (2008) supports this section, even though it was written about ICU patients in general, rather than trauma patients.

Prevent further haemoglobin loss:

• Minimise acute bleeding
  • Achieve haemostasis early:
    • Potentially, laparotomy prior to CT
    • Damage control surgery rather than primary definitive management
    • Early reduction and control of fractures, eg. pelvic binder and long bone fracture reduction
    • Use of invasive haemostatic devices/techniques such as REBOA is controversial but appears effective
  • Prevent coagulopathy:
    • Correct ionised calcium
    • Correct hypothermia
    • Correct acidosis
    • Correct factor deficiency by proactively transfusing blood products including plasma, platelets and fibrinogen sources
    • Proactively correct pro-fibrinolytic states with tranexamic acid
    • Enhance platelet activity with desmopressin
  • Prevent blood loss by other mechanisms:
    • Practice "permissive hypotension"
  • Avoid the use of crystalloids, which dilute the clotting factors and decrease the oxygen carrying content of the blood
• Over the medium term:
  • Use paediatric blood tubes and rationalise blood tests to decrease the iatrogenic blood loss rate
  • Use point-of-care microanalysis where possible, to decrease the sampled blood volume

Prevent wasteful use of blood products:

• Encourage the use of intraoperative aoutotransfusion, eg. cell saver technology
• Change local transfusion practice
  • Avoid haemoglobin "targets"; aim for clinical endpoints rather than numeric Hb concentration values
  • Avoid the use of empiric massive transfusion protocols; aim to use TEG or ROTEM-guide blood product administrationm 
• Distributive justice decisonmaking
  • Engage with trauma team during the resuscitation, identify unsalvageable patients early, and share the moral responsibility for the decision to stop treatment.

Support haemopoiesis:

• Optimise protein nutrition: ensure appropriate daily protein intake
• Iron infusion may be necessary
• Replace haematinics like folate and B12
• Erythropoietin may be necessary (though this has its own disadvantages)

Exotic techniques

• Artifical oxygen carriers are available:
  • Modified haemoglobin substitutes
  • Perfluorocarbon
• Hyperbaric oxygen
• Increased cardiac output to maintain oxygen delivery in spite of poor oxygen carrying capacity