HeartWeb

Foreword
by Alistair Royse

It is usually said that most patients who might otherwise survive severe trauma, die because of bleeding or as a direct or indirect result of bleeding. And the mainstay of early resuscitation is directed towards the prevention of further bleeding and the restoration of a circulating blood volume.

It is most pertinent then to consider blood coagulation factors in more detail. In this, the first of three articles, James Isbister examines critical bleeding more closely. It begins with some historical considerations, most often from previous conflicts. He notes the first experience of hypotensive resuscitation in WWII and later the results of excessive resuscitation in the Vietnam War.

The “extrinsic” and “intrinsic” coagulation pathways seem now to be mostly laboratory concepts. Clinicians will often observe a coagulation deficit and treat it before or in the absence of laboratory test evidence of coagulopathy. Indeed, he cites new evidence showing a coagulopathy may occur very soon after major injury where there is tissue hypoperfusion, yet without much consumption of clotting factors. It seems this relates to the activation of the protein C anticoagulant system and finrinolysis, which would probably not be known to most involved in treating major trauma.

Also he briefly considers the issues of pre-emptive transfusion, recombinant factor VIIa (NovoSeven) and the use of fresh whole blood.

Historical background

Haemorrhage is the commonest cause of death in salvageable trauma victims and fluid resuscitation and blood transfusion play a critical part in saving lives, but questions are now being asked about what should be the optimal replacement therapies. Much of our understanding of the pathophysiological processes in trauma, hypovolaemic shock and massive haemorrhage has come from clinical experiences in the context of war1, 2. The same applies to approaches to resuscitation and therapy in general. The history of blood transfusion has many of its key advances stimulated by the demands of war, with further developments occurring during time of peace.
Blood transfusion: Allogeneic blood transfusion became a possibility during WWI (see abbreviations), but the difficulties in anticoagulating and preserving blood prevented its wide use. During WWII anticoagulation and preservation were well developed and the use of fresh whole blood donated in the UK was available for the war in Europe. Ironically, the United States Medical units used dried plasma and the early preparations of albumin developed by Edwin Cohn at Harvard. It was apparent to the US medical officers that injured soldiers resuscitated with whole blood had better outcomes than those receiving plasma and / or albumin. “Serum hepatitis” was also recognized with thousands of recipients contracting what we now know to be hepatitis B from the pooled blood products. There are also some inspiring stories of the innovative techniques used by Australian army medical officers in the Japanese prisoner of war camps. Coconut juice was uses as a sterile intravenous volume expanding and rehydration solution. Fresh red cell transfusions were prepared by defibrinating donor blood with sticks of bamboo as anticoagulants were not available. One can surmise that this defibrinated blood was probably the first “leucoreduced” blood used in transfusion medicine.
Crystalloid: The Vietnam war again raised the issues of initial fluid replacement using large volumes of crystalloid and the problems of ARDS (“Da Nang lung”). Resuscitation fluids and blood transfusion were questioned as playing a contributory role in the development of ARDS. Controversy as to the initial management of trauma, critical haemorrhage, crystalloid versus colloid, massive transfusion, blood storage lesions and coagulopathy has never abated. A scientific approach, including evidence from animal studies, has frequently subjugated to non evidence based clinical opinion. The complex and multifactorial nature of trauma has made clinical studies and clinical trials difficult.
Recent developments: In recent years there has been a reassessment of the management of the acutely haemorrhaging patient. Advances in patient retrieval, resuscitation protocols, techniques for rapid and real time diagnosis, trauma teams and early “damage control” surgery, have all improved the management of acutely haemorrhaging trauma patients. On the battlefield, there has been renewed interest in tourniquet usage to allow for earlier control of haemorrhage. Patients are now surviving and requiring larger volumes of blood transfusion.
Complications: Sepsis, acute lung injury and multi-organ failure remain major challenges and blood transfusion is increasingly being recognised as a two-edged sword and probably a contributory factor to these complications. Observational studies have identified blood transfusion as an independent risk factor for morbidity and mortality3-5. Correlation does not mean causation, but on critical assessment of the evidence, it is likely to be the case. This is leading to a reanalysis of guidelines for the management of acutely bleeding patients. Clinical practice guidelines should no longer primarily address the “management of massive blood transfusion”, but rather the “management of critical bleeding”. The transfusion strategy is now pre-emptive, instituting measures to avoid getting into the massive transfusion and the coagulopathy quagmire in which the patient spirals down into the “triad of death” - coagulopathy, acidosis and hypothermia. Figure 1 illustrates the positives and the negatives in progress in the management of critical haemorrhage and massive blood transfusion.

Historical and Current Dilemmas

Hypotensive resuscitation: In WWI, Cannon investigating the use of intravenous sodium bicarbonate solution for hypovlaemia onserved that “if the pressure is raised before the surgeon is ready to check any bleeding… blood that is sorely needed will be lost”6. British experience at casualty Clearing Stations was similar. In WWII, studies on resuscitation of battle casualties are reported in the official US war history7. It is stated that “evidencepointed to replacement of lost blood as the only method of improving the condition….if operation could not be undertaken immediately” also noted, “it was not necessary to achieve improvement beyond a rising blood pressure of at least 80 mmHg and a warm skin of good colour”. Further bleeding might be precipitated if the blood pressure was further elevated than necessary to keep the patient out of shock. It was also observed that saline and dextrose solutions “were not effective, and they could be dangerous”. There has been a resurgence of interest in “tolerated hypotension” during initial resuscitation until damage control surgery can be undertaken 8-10.
Haemodilution and tolerance of anaemia: Physiological haemodilution following haemorrhage and the tolerance of anaemia remains a hotly debated topic. It is surprising that controversy still surrounds almost all aspects of this debate. The debate is related to the advantages and disadvantages of crystalloid vs. colloid solutions, I am reminded of the occasion that one of my colleagues made the comment, “I don’t mind what you use as long as you do it carefully!” Boldt described in a review paper - “The age-old crystalloid / colloid controversy has still not been resolved, but has been enlarged to a colloid / colloid debate. It is now widely accepted that human albumin could easily be replaced by synthetic colloids for volume replacement in trauma patients. No superiority of a specific volume replacement strategy with regard to outcome was found. However, in several studies outcome was not the major endpoint. Although showing some promising results, the importance of hypertonic solutions for volume replacement in the trauma patient is not yet defined. The choice of fluid therapy in trauma patients engenders the most controversy and an examination of the body of literature on this subject results in confusion. It is imperative to continue the search for substances that are effective in avoiding the development of post-trauma multi-organ dysfunction syndrome without detrimental side-effect”s11, 12.

The haemostatic system and trauma / resuscitation coagulopathy

Failure of haemostasis is common in trauma patients and may be complex and multifactorial in pathogenesis. Frequently, complex tests are required for definitive diagnosis, but the urgency of the situation cannot always wait for the results, and therapy may be initiated on clinical evidence with minimal laboratory information. We now have a much better understanding of the haemostatic system and many of the inexplicable enigmas that the older models of the system proposed now make some sense. This is not to say the old models did not progress our insights as most of the hereditary and acquired coagulopathies were elucidated13. The haemostatic system is a delicately controlled component of the host defense system, the role of which is to initiate haemostasis where and when required and in adequate, but not in excessive, amounts. The system closely interacts with other components of the host defense system, including the acute stress responses, inflammation, healing and immune functions.
Initial haemostasis: The triad of vascular constriction, platelet plugging and fibrin clot formation forms haemostatic plugs and provides the framework on which haemostasis operates and healing occurs. Following injury, vascular constriction occurs initially reducing bleeding, and allowing time to initiate haemostasis. This constriction is further accentuated by vasoconstrictors released in association with platelet plug formation. Vascular endothelial cells play an active part by synthesizing substances which act at the membrane surface and / or interact with platelets and the coagulation system (eg prostacyclin, antithrombin III, plasminogen activator, Von Willebrand's factor, thrombomodulin, heparin cofactor II, and Nitric Oxide).
Following the initial vascular reactions, successful haemostasis depends on adequate numbers of functioning platelets, coagulation cascade function, and poorly understood contributions from red cells and leukocytes. Von Willebrand Factor (vWF) is a multimeric glycoprotein that plays a central role in haemostasis by mediating adhesion of platelets to the exposed subendothelium and linking the primary vascular / platelet phase with coagulation by being the carrier protein for coagulant factor VIII which dissociates from vWF to form a complex on the activated platelet surface with IXa (tenase complex) to activate factor X to Xa.
The coagulation system is triggered via the extrinsic pathway, by which damaged tissues expose tissue factor (TF) (Figure 1). Tissue factor is a membrane protein present in cells surrounding the vascular bed. Factor VII and VIIa (a small amount circulates normally in the blood) are bound to TF triggering the coagulation cascade by activating factors IX (intrinsic system) and Factor X (common pathway). The concept of the intrinsic and extrinsic systems is more of historical and laboratory significance as it is now clear that such a division is artificial. However, the concept still has value in performing and assessing haemostatic laboratory tests.
The prothombinase complex (phospholipid bound Xa and Va) converts prothrombin to thrombin. Thrombin is the potent proteolytic enzyme of the coagulation sequence converting fibrinogen to fibrin soluble monomers, which subsequently polymerize to form the fibrin clot. Fibrinogen is the bulk protein of the coagulation system and fibrin is the end-product of this cascade of proteolytic activity, in which precursor coagulation proteins are activated to potent proteolytic enzymes, with the aid of cofactors, to produce further activate precursors down the coagulation "amplifier". The polymerised fibrin is further acted on by factor XIII to form a stable fibrin clot.

The contact phase of the haemostatic system (factors XII and XI of the conventional intrinsic coagulation system) is responsible for activation of the other plasma proteolytic systems, the fibrinolytic, kinin, and complement systems. These may be activated in concert with coagulation, depending on the stimulus.
Fibrinolysis: Parallel to and within the coagulation system, are complex feedback mechanisms to ensure fine-tuning and protection against inappropriate and excessive activation (eg disseminated intravascular coagulation (DIC) or venous thromboembolism). There are several inhibitory proteins, including antithrombin III, thrombomodulin, protein C and protein S, tissue factor pathway inhibitor as well as the fibrinolytic system, which are all important in controlling the degree and site of fibrin formation. Thrombin itself acts as either a procoagulant or anticoagulant depending on context. Massive activation, as may be seen in trauma and severe infections, can precipitate systemic activation, but in general, the system is well controlled and activity is localized to the area of the stimulus. Perturbations in this complex defence system can produce a wide range of clinical disorders from excessive arterial or venous thrombosis, microvascular obstruction and atheroma to haemostatic failure.

The Management of critical haemorrhage: The practicalities

The nature and management of haemostatic defects in trauma victims at presentation and secondary to massive blood loss and transfusion remains poorly understood. Further aggravation of the complications of massive blood transfusion can be avoided or minimized if correctable defects in the haemostatic system are identified.
Whole blood: Some degree of haemostatic failure is inevitable if stored whole blood is used for resuscitation. The labile factors V and VIII are not well preserved beyond 3-4 days; platelets are aggregated and non-functional, some coagulation factors may be activated during cooling and storage; and microaggregates and degenerate cells may be responsible for aggravating or initiating DIC and / or MOF. With blood component therapy, stored whole blood is now rarely used in the modern approach to resuscitation.
Pre-emptive transfusion: There has been an ongoing debate as to whether a pre-emptive approach to management in an attempt to avoid the “secondary” coagulopathy should be practiced. The more tradition approach and that advocated by most haematologists has been to treat haemostatic system depletion when identified by laboratory testing. In my view the later approach is not support by logic or common sense and needs to be challenged. Now there is improving understanding of the haemostatic system and the acquired coagulopathic states seen in trauma and massive blood transfusion it make more sense to take a more pre-emptive approach. With a focus to fibrinogen levels, the first clotting factor to fall significantly in acute haemorrhage, global “near patient testing” and the structure and stability of the haemostatic plug, it is logical to ensure that coagulation factors, especially fibrinogen, and platelets do not fall to dysfunctional levels14. There is now good evidence that adequate fresh frozen plasma needs to be administered and fibrinogen level should be maintained at least above 50% of normal levels15-18. Platelet concentrates should probably be considered if the platelet count falls below 75 x 109/L, but definitely if less than 50 x 109/L19. Increasing near patient testing, including thromboelastography (TEG) will have an important part to play. Real time management of haematological parameters is probably as important as the other real time measurements available in the critical care setting. Obviously, knowledge, experience and interpretation of the results is a challenge for those in the trauma surgery.
Correlation between laboratory tests and clinical haemostasis: Haemostatic failure at presentation correlates poorly with the initial resuscitation fluids, but better with the degree of hypovolaemia, tissue hypoxia and time to resuscitation. Trauma patients with major coagulopathy usually have abnormal laboratory parameters prior to massive blood transfusion. Except for severe abnormalities, haemostatic laboratory parameters correlate poorly with clinical evidence of haemostatic failure. Traumatic coagulopathy was thus thought to be caused by tissue trauma, fluid administration, acidosis and hypothermia. However it is important to differentiate between a “primary” coagulopathy at presentation in trauma victims with critical bleeding and hypovolaemic shock, prior to extensive resuscitation and the “secondary” coagulopathy that develops in connection with continuing bleeding, fluid therapy and massive blood transfusion.
Early coagulopathy: There have been interesting new insights into the nature of this primary coagulopathy of shock and / or hypoxia which appears to be Nature’s mechanism for ensuring fluidity of the blood at times of hypoperfusion, shock, hypoxia or transient cessation of the circulation. It appears that early coagulopathy in trauma victims is restricted to patients in whom there has been tissue hypoperfusion and is not associated with significant consumption of the coagulation factors20. The mechanism relates to activation of the protein C anticoagulant system and finrinolysis. Elevated thrombomodulin and low protein C levels have been associated with increased mortality, transfusion requirements, acute renal impairment, and increased assistant ventilation days.
Secondary coagulopathy: Following continuing bleeding and massive blood transfusion thrombocytopenia and impaired platelet function are the most consistent significant haematological abnormalities, correction of which may be associated with control of microvascular bleeding. Coagulation deficiency from massive blood loss is initially confined to factors V and VIII. APTT, PT and fibrinogen assay should be performed, but the urgency of the situation does not usually allow for other specific factor assays, and FFP should be infused if the test results are abnormal. A case can be made for prophylactic FFP in infusions in patients with massive blood loss which has been replaced with red cell concentrates and plasma substitutes. Hypothermia must be avoided, recognised and treated rapidly. The current challenge is to focus on the primary setting of critical bleeding and develop therapies on the basis of our better understanding of the pathophysiology of the host responses to trauma and hypovolaemic shock. A prime aim of these therapies should be to avoid getting into or at least minimising the massive blood transfusion and coagulopathy syndrome. Figure 3a and 3b illustrate this suggested change to the current management of critical bleeding paradigm.
With ongoing bleeding with associated microvascular oozing various approaches may be taken. Having ensured that all identifiable haemostatic defects have been corrected questions arise as to the role of fresh blood and, and more recently recombinant activated factor VII.

Recombinant activated factor VII (rVIIa, NovoSeven®) This drug is being widely used off label and there is controversy as to its benefits and risks21. rFVIIa is effective for the prevention or treatment of bleeding in patients with inhibitors to factor VIII and Factor IX. Current insights into haemostatic mechanisms have resulted in a better understanding of the central role FVII/FVIIa has in the localization and initiation of haemostasis. Consequently this has lead to the wider use of rFVIIa as a haemostatic agent. There are numerous numbers of case reports and series published on the use of rFVIIa in critical life-threatening haemorrhage21, 22. In many cases, control of critical bleeding is possible with surgical haemostasis and the replacement of blood products to support the underlying coagulopathy. Patients with uncontrolled critical bleeding and coagulopathy, despite large transfusions and surgical intervention have significant mortality rates and most case reports and case series have described the use of rFVIIa in these salvage type clinical situations. However, there is increasing interest in the early use of rFVIIa, especially in high risk cardiac surgery cases and trauma (especially in Iraq)23, 24.

Fresh whole blood
The use of freshly collected whole blood remains a controversial subject needing some comment25-27. The provision of fresh whole blood can present logistic, ethical and safety problems needing consideration. Many transfusion medicine specialists categorically state there is never an indication for fresh whole blood. Such dogma can be difficult to defend in the clinical setting of the massive haemorrhage and transfusion syndrome where pathophysiology remains poorly understood and specific blood component therapy may be ineffective or unavailable.
The following statements reasonably summarise the current status of “super fresh” whole blood transfusion:-

References

1.         Pinkerton PH. Canadian surgeons and the introduction of blood transfusion in war surgery. Transfusion medicine reviews 2008;22(1):77-86.
2.         Kendrick DB. Blood Program in World War II: The Evolution of the Use of Whole Blood in Combat Casualties. 1964;   http://history.amedd.army.mil/booksdocs/wwii/blood/default.htm.
3.         Charles A, Shaikh AA, Walters M, Huehl S, Pomerantz R. Blood transfusion is an independent predictor of mortality after blunt trauma. The American surgeon 2007;73(1):1-5.
4.         Robinson WP, 3rd, Ahn J, Stiffler A, et al. Blood transfusion is an independent predictor of increased mortality in nonoperatively managed blunt hepatic and splenic injuries. The Journal of trauma 2005;58(3):437-45.
5.         Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. The Journal of trauma 2003;54(5):898-905; discussion -7.
6.         Cannon WB, Fraser J, Cowell EM. The preventive treatment of wound shock. JAMA 1918;70:618-21.
7.         Beecher HK. Resuscitation of men severely wounded in battle. In: De Bakey ME, ed Surgery in World War II, Vol II General Surgery Washington DC Office of the Surgeon General: Department of the Army 1955:3-39.
8.         Bickell WH, Wall MJ, Jr., Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. The New England journal of medicine 1994;331(17):1105-9.
9.         Rafie AD, Rath PA, Michell MW, et al. Hypotensive resuscitation of multiple hemorrhages using crystalloid and colloids. Shock (Augusta, Ga 2004;22(3):262-9.
10.       Hai SA. Permissive hypotensive resuscitation--an evolving concept in trauma. Jpma 2004;54(8):434-6.
11.       Boldt J. Fluid choice for resuscitation of the trauma patient: a review of the physiological, pharmacological, and clinical evidence. Canadian journal of anaesthesia 2004;51(5):500-13.
12.       Boldt J. The balanced concept of fluid resuscitation. British journal of anaesthesia 2007;99(3):312-5.
13.       Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am 2007;21(1):1-11.
14.       Fries D, Innerhofer P, Reif C, et al. The effect of fibrinogen substitution on reversal of dilutional coagulopathy: an in vitro model. Anesthesia and analgesia 2006;102(2):347-51.
15.       Lauzier F, Cook D, Griffith L, Upton J, Crowther M. Fresh frozen plasma transfusion in critically ill patients. Critical care medicine 2007;35(7):1655-9.
16.       Ketchum L, Hess JR, Hiippala S. Indications for early fresh frozen plasma, cryoprecipitate, and platelet transfusion in trauma. The Journal of trauma 2006;60(6 Suppl):S51-8.
17.       Stinger HK, Spinella PC, Perkins JG, et al. The Ratio of Fibrinogen to Red Cells Transfused Affects Survival in Casualties Receiving Massive Transfusions at an Army Combat Support Hospital. The Journal of trauma 2008;64(2):S79-S85.
18.       Spinella PC, Perkins JG, Grathwohl KW, et al. Effect of Plasma and Red Blood Cell Transfusions on Survival in Patients With Combat Related Traumatic Injuries. The Journal of trauma 2008;64(2):S69-S78.
19.       Grottke O, Henzler D, Rossaint R. Use of blood and blood products in trauma. Best Pract Res Clin Anaesthesiol 2007;21(2):257-70.
20.       Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Annals of surgery 2007;245(5):812-8.
21.       Isbister J, Phillips L, Dunkley S, Jankelowitz G, McNeil J, Cameron P. Recombinant activated factor VII in critical bleeding: experience from the Australian and New Zealand Haemostasis Register. Internal medicine journal 2008;38(3):156-65.
22.       von Heymann C, Jonas S, Spies C, et al. Recombinant activated factor VIIa for the treatment of bleeding in major abdominal surgery including vascular and urological surgery: a review and meta-analysis of published data. Crit Care 2008;12(1):R14.
23.       Karkouti K, Yau TM, Riazi S, et al. Determinants of complications with recombinant factor VIIa for refractory blood loss in cardiac surgery. Canadian journal of anaesthesia = Journal canadien d'anesthesie 2006;53(8):802-9.
24.       Spinella PC, Perkins JG, McLaughlin DF, et al. The effect of recombinant activated factor VII on mortality in combat-related casualties with severe trauma and massive transfusion. The Journal of trauma 2008;64(2):286-93; discussion 93-4.
25.       Spinella PC, Perkins JG, Grathwohl KW, et al. Fresh whole blood transfusions in coalition military, foreign national, and enemy combatant patients during Operation Iraqi Freedom at a U.S. combat support hospital. World J Surg 2008;32(1):2-6.
26.       Spinella PC, Perkins JG, Grathwohl KW, et al. Risks associated with fresh whole blood and red blood cell transfusions in a combat support hospital. Critical care medicine 2007;35(11):2576-81.
27.       Repine TB, Perkins JG, Kauvar DS, Blackborne L. The use of fresh whole blood in massive transfusion. The Journal of trauma 2006;60(6 Suppl):S59-69.

Abbreviations

WWII        World War II
ARDS      Adult respiratory distress syndrome
vWF         von Willebrand Factor
TF            Tissue factor
DIC          Disseminated intravascular coagulation
SIRS         Systemic inflammatory response syndrome
MOF        Multi organ failure
APTT       Activate partial thromboplastin time
PT            Prothrombin time
FFP          Fresh frozen plasma
rVIIa, NovoSeven® Activated factor VII

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Trauma and Critical Bleeding - Part 1

Download the Newsletter in PDF format (Adobe 7)

James P. Isbister

Foreword
by Alistair Royse

Historical background

Historical and Current Dilemmas

The haemostatic system and trauma / resuscitation coagulopathy

The Management of critical haemorrhage: The practicalities

References

Abbreviations

Disclaimer

Trauma and Critical Bleeding - Part 1 Download the Newsletter in PDF format (Adobe 7)

James P. Isbister

Foreword by Alistair Royse

Historical background

Historical and Current Dilemmas

The haemostatic system and trauma / resuscitation coagulopathy

The Management of critical haemorrhage: The practicalities

References

Abbreviations

Disclaimer

Trauma and Critical Bleeding - Part 1

Download the Newsletter in PDF format (Adobe 7)

Foreword
by Alistair Royse