Basic Outline Related to the Diagnostic Procedures and Therapeutic Approach in Patients with Trauma and Massive Hemorrhage

1. Introduction

Trauma can be defined as an injury caused by external mechanical forces ranging from physical, chemical, biochemical, or physchological [1,2].The Injury Severity Score (ISS), the most used scoring system for polytrauma patients, is established on the Abbreviated Injury Scale (AIS) [3,4]. ISS can be stratificated in several groups: 15-24; 25-40; 41-49 and 50-74 [5].AIS is an anatomical scoring system that converts the injury into a numeric scale of 0-6 in 6 body areas(head, neck, face, chest, abdomen, limbs, and surface-based injuries) [6,7]. Based on the AIS, Category 1 is considered minor, while Category 2 is moderate. This category is broken down into three parts: a mild and a severe one, with an intermediate level referred to as a third-degree burn. Category 4 represents severe injuries, while Category 5 represents injuries that could be fatal. Last of all, the 6 category of injury is fatal [7,8].

The Berlin definition of Polytrauma (2014) notes that Polytrauma can be defined as an injury to at least two organ systems whose injury severity on the Abbreviated Injury Scale (AIS) is greater than or equivalent to 3, with at least one of the followingcriteria: hypotension, defined as systolic blood pressure below 90 mmHg; altered consciousness, indicated by a Glasgow Coma Scale (GCS) score of 8 or lower, acidosis, with a base excess (BE) of -6 or less; coagulopathy, characterized by an International Normalized Ratio (INR) of 1.5 or higher or an Activated Partial Thromboplastin Time (APPT) of 40 seconds or longer; and advanced age, defined as 70 years or older [9].

In this review article we summerize all current recommendations related to the diagnostic procedures and therapeutic approach to patients with trauma, based on a review of the literature and current guidelines for the patients with massive bleeding in trauma.

2. Advanced Trauma Life Support

Advanced Trauma Life Support (ATLS) represents the most widely and generally used guide for initial in-hospital management of polytraumatized patients. It contains basic procedures for securing the airway, establishing and maintaining hemodynamic stability, and adequately assessing injuries based on diagnostic tests [10,11,12].

Several factors are essential in defining the patient’s hemodynamic status when evaluating circulation. These are skin color, heart rate, blood pressure, and response to a fluid bolus. Periodically, any internal bleeding or accumulation of fluid can be determined through ultrasound with the help of eFAST (Focused Assessment with Sonography for Trauma). It is also necessary to consider the presence of a pelvic fracture, the evaluation of diuresis, and the straightforward/dark-amber test indicating renal perfusion and function.If hemodynamic compromise is seen, blood transfusion components can be needed. Hemostasis may require to be supported with tranexamic acid (TXA) or agents that moderate bleeding levels. Nevertheless, in essential acute trauma or continued bleeding, other damage control surgery will be required to prevent further finalization of the patient [13].

ATLS protocol [11] for the intrahospital care of polytraumatized patients assesses the patient’s response to therapy in three categories: favorable therapeutic outcome, short-term improvement, and nonresponsive to treatment.Patients with excellent therapeutic responses display changes in their nominal pattern of vital status. Their blood loss estimate is low, ranging from 10- 20%. These patients demand small amounts of crystalloid and do not require issuance of blood transfusion. Sequencing the blood group type and carrying out crossmatch tests is required for blood transfusion preparation. A surgeon should be consulted.

Even patients who experience transient changes in their therapy usually show only slight variations in their vital signs. Estimates suggest that blood loss is relatively low, ranging from 20% to 40%. These patients will likely require low to moderate amounts of crystalloids and a moderate to high level of blood transfusion. For transfusion preparation, only the blood type is necessary. In such cases, surgery can proceed, and a surgeon should be on standby. Non-responder patients who do not have changes in vital signs during therapy further had a blood loss rate exceeding 40%. Their requirement for crystalloids is moderate to high, and crystalloids are utilized before other forms of products. These patients require a blood transfusion, and O-negative blood should be given without waiting for typing orcrossmatching. The early management should include the administration of 1000 ml of isotonic crystalloid solution or 20 ml/kg of body weight (see Table 1) [11].

3. The Damage Control Strategy

This is a multidisciplinary approach to the polytraumatized patient, including Damage control resuscitation and Damage control surgery. This approach demands good communication between surgeons, anesthesiologists, and other team members. It should be applied when clinical parameters indicate massive hemorrhage and/or the possibility for massive transfusion or when no response is recorded after initial fluid resuscitation (systolic arterial pressure < 90 mmHg) [11].

Damage control resuscitation includes permissive hypotension and restrictive fluid resuscitation until bleeding control is accomplished, with early use of blood components.

Permissive hypotension applies to maintain a systolic arterial pressure between 80 and 90 mmHg or a mean arterial pressure (MAP) greater than 65 mmHg to reduce blood loss. It is contraindicated in brain and spinal cord injuries (MAP > 80 mmHg) [13,14].

The use of vasopressors is desired to maintain permissive hypotension over aggressive volume compensation to avoid hemodilution, dilutional coagulopathy, and increased blood flow at the bleeding site [11,15].

Peripheral IV lines are inserted, and blood samples are taken for a complete blood count, glucose levels, and arterial blood gas analyses. If required, a blood transfusion and blood components are requested, and point-of-care tests are performed to assess hemostasis. Intravenous fluid resuscitation is initiated to stabilize the patient, and a urinary catheter is inserted to monitor urinary output.

A head-to-toe examination is conducted to identify any other injuries. Surgical consultations are obtained froma general surgeon, neurosurgeon, and orthopedic surgeon. Additional diagnostic imaging, such as X-rays and CT scans, may also be requested to further evaluate the patient’s condition [16].

4. Recognize Signs of Shock in the Patient

In the emergency room management of a polytraumatized patient, several critical steps are taken to guarantee comprehensive care. Initially, all clothing and jewelry are removed from the patient. Monitoring devices are placed (ECG leads, non-invasive blood pressure cuffs, and pulse oximetry sensors). Circulatory status is evaluated by monitoring blood pressure, skin color, and capillary refill time [16,17].Blood typing and cross-matching are done, and possibly, the transfusion of blood and blood products is initiated [18].

5. Steps in the Initial Management of Hemorrhage

The Initial Hemorrhage Management Steps are, first and most importantly, controlling the bleed source (damage control surgery), maintaining permissive hypotension and adequate fluid resuscitation (Damage control resuscitation), providing coagulation support and treating/reversing trauma-induced coagulopathy, and finally, initiating empirical therapy.

Fluid resuscitation should be aimed at 20 ml/kg body weight quickly over a few minutes up to 15 minutes, with isotonic crystalloid solution (ideally heated to 37⁰C), which avoids hemodilution and deepening coagulopathy. Further measures should be taken, such as using Tranexamic Acid of 1g within the first 3 hours of injury, following the level 1A recommendation. Adittinlay, administration of Fibrinogen Concentrate in doses 3-4g or 15-20 units of cryoprecipitate 1-2 doses of cryprecipitateper 10 kg body weight - level 2C recommendation. Furthermore,packed red blood cells (PRBC) at target Hgb level 70-90g/L followedthe level 1C recommendation.

Support and treatment or/and reversal of Coagulation Cascade of Trauma-Induced Coagulopathy should correspondingly be treated with TXA, fibrinogen concentrate, or cryoprecipitate,blood transfusion aimed to control Hgb to 70-90g/L levels. Supportive perfusion therapy provides maintenance of adequate pH > 7,2, with monitored lactate levels. To evade a lethal triad, body temperature should be maintained above 36⁰C to prevent hypothermia. Ultimately, maintenance of electrolyte levels, especially Ca, to ensure adequate coagulation (ionized Ca>1mmol/L) [19,20].

Initial empirical therapy is a clinical assessment as follows: evaluating the patient, ISS score, emergency CBC, and initial empirical therapy are necessary for adequate trauma management with bleeding.The shift to directed therapy that is based on standa rd coagulation tests and point-of-care (POC) methods (thromboelastography - CLOTPro^®, aggregometry - MULTIPLATE^®) as soon as possible.

6. Classification of Bleeding According to the World Health Organization (WHO)

0 no bleeding

1 petechial bleeding

2 moderate blood loss, clinically relevant

3 significant blood loss requiring a blood transfusion

4 massive blood loss or bleeding in CNS, pericardial bleeding, orbital bleeding (localization) [10].

Definition of Massive Bleeding:

Bleeding requiring the replacement of one circulating volume in 24 hours (10 units of red blood cells in 24 hours) or four units of red blood cells in 1 hour, or the loss of 50% of the blood volume within 3 hours, or blood loss at a rate greater than 150 ml per minute [20,21,22,23].

7. Diagnosis and Monitoring of Bleeding-Initial Procedures

It is recommended that the Shock Index (SI) and Pulse Pressure (PP) be used to predict the need for more blood units in hypovolemic shock (MT protocol). (1C)

Common predictors of massive bleeding initiating Massive Transfusion Protocol (MT) are Injury mechanism, Anatomical injury location, Systolic pressure, Heart rate, Hemoglobin level, Lactate levels, and Positive FAST examination [19].

Addressing the bleeding site and identifying the cause of bleeding is the first and mandatory step in managing bleeding patients (1B) [19].

Mandatory blood sampling in case of a massive transfusion protocol include:

• Complete Blood Count (CBC)inclduding: Hemoglobinlevel (Hgb), Hematocrit (HCT) and platelet count;
• Coagulation Screening tests: Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT) (indicates the presence of Dabigatran), and fibrinogen level;
• Point-of-Care (POC) testing sample to determination viscoelastic haemostatictests (VET):Thromboelastogram (TEG) or Rotational Thromboelastometry(ROTEM);
• Blood Type Determination Sample (for pretransfusion testing)

Blood transfusion requests are referred to the hospital’s blood banks. When initiating the blood transfusion protocol, we must note Hgb and HCT for erythrocyte components and platelet count for platelet transfusions. The blood sample for ROTEM analysis must be specially labeled. Any information on anticoagulant or antiplatelet treatment or knowledge abouth congenital/acquired coagulopathies should be provided. Avoid transfusion therapy before sampling if possible (wait for ROTEM based recommendations) [19,21,24,25].

8. Hemoglobin Level

The current guidelines require us to repeat Hgb/HCT measurements as laboratory markers of bleeding since initially measured values may be in the normal physiological range during the early stages of bleeding [19]. Resuscitation fluids and the transition of interstitial fluid to the vascular space influence Hgb value. Despite these limitations, Hgb values closely correlate with hemorrhagic shock in polytraumatized patients, more so than heart rate, blood pressure, and acidosis.With regard to current recommendation a restrictive approach is recommended in blood administration. The target value for RBC administration is Hgb ≤ 70-90g/L [19,24,26,27,28].

Note: Cochrane data analysis did not find a better treatment outcome in patients with liberal blood application (Hgb 90-100g/L) compared to the restrictive approach [26].

9. Intraoperative Blood Salvage

This measure isrecommended in case of bleeding from chest, abdominal, or pelvic cavities. Blood salvage equipment is not commonly used due to limitations, primarily potential hemodilution (loss of plasma components during washing), leading to coagulation factor loss. There is also a risk of leukoreduction during processing or possible contamination from bowel contents, potentially presenting malignant tumors. However, preliminary experimental studies suggest that autologous salvaged blood may have advantages in massive hemorrhage [19,21].

10. Initial Blood and Blood Components Administration

For patients expected to undergo massive transfusion, the application of blood components or products and haemostatic agents are necessary. In first line Cryoprecipitate (Cryo) or Fibrinogen Concentrate (FIB CONC) and Packed Red Blood Cells (PRBC). The application of FIB CONC and Tranexamic Acid (TXA), as initial therapy is based on the frequent fibrinogen deficiency and reduced clot firmness and stability observed in polytraumatized patients. The application of Fresh Frozen Plasma (FFP) and PRBC in a 1:2 ratio is recommended. Higher PRBC to platelet ratio is additionally recommended. Blood and blood components including PRBC, Platelets (PLT) and FFP can be applied using these two modelstransfusion packages: FFP:PLT:PRBC = 1:1:1 and FFP:PLT:PRBC = 1:1:2 [12,27,28,29].

The PROPPR study examined two fixed ratio transfusion packages. The study’s outcome showed that the first model of “whole blood” led to faster hemostasis and fewer fatal outcomes [29].

It is recommended that blood and blood component therapy be based on results from standard coagulation and VEt point of care tests (ROTEM, TEG). VES tests mimic the coagulation process and provide a broader and comprehensive picture of the coagulation status. They are better at detecting clot stability, assessing adequate fibrinogen and platelet involvement in coagulation, identifying hyperfibrinolysis, and diagnosing dilutional coagulopathy [30,31,32,33,34].Therapy based on ROTEM parameters:

The Critical Bleeding ROTEM Transfusion Algorithm, delivers a structured approach for managing trauma-related coagulopathies. The algorithm include four steps, commences with Step 1: Hyperfibrinolysis, where if the FIBTEM CT is more significant than 300 seconds and the EXTEM A5 is less than 35 mm, the recommendation is to administer TXA (1 g) along with FIB CONC (4g). Additionally, if Maximum Lysis (ML) is greater than or equal to 5%, this suggests ongoing fibrinolysis that requires further treatment.Step 2: Fibrinogen Deficiency is considered when the FIBTEM A5 is less than 10 mm, and the EXTEM A5 is greater than or equal to 35 mm. In this case, the patient should receive FIB CONC (4g). Alternatively, Cryocan be administered.In Step 3: Platelet Deficiency, if the EXTEM A5 is less than 35 mm and the FIBTEM A5 is greater than or equal to 10 mm, it suggests the need for platelet transfusion, and a pool of 1 Plateletconcentrate (typically 4-6 units) should be given.

Lastly, factor deficiency is addressed in the fourth step when the EXTEM A5 is less than 10 mm, and the EXTEM CT is greater than 80 seconds, indicating the need for clotting factors. In this case, the protocol suggests the administration of Prothrombin Complex Concentrate (PCC) at a dose of 30-50 IU/kg.

An essential part of this algorithm is to constantly repeat ROTEM tests 10 minutes after treatment to evaluate the effectiveness of the administered therapies. This algorithm targets specific deficiencies: hyperfibrinolysis, fibrinogen, platelets, and coagulation factors, using tailored interventions such as TXA, FIB CONC, Cryo, FFP, PLT, and PCC, guaranteeing that the physiological targets of trauma-related coagulopathy management are achieved effectively [19,21,25,32,33,34,35,36,37]. Summary- therapy based on ROTEM Parameters is shown in Table 2).

11. SupportuveTransfusion Therapy

Fresh frozen plazma (FFP) contains about 70% of the donor’s plasma coagulation factors, but it lacks standardized coagulation factor values. FFP with Cryo contains all coagulation factors and inhibitors, including labile factors (FV and FVIII). So,1 mL of FFP contains approximately one unit of coagulation factor activity. One unit of FFP increases the concentration of most coagulation factors by approximately 2.5%. The dosage should be 10-15mL per kilogram of body weight. FFP application should be based on standard coagulation tests and VET testing [38,39]. Table 3 shows the values of the PT and APTT ratio and VET tests (CT in EXTEM) that indicate the need for the application of FFP.

The choice of the FFP with tegardto the blood type (ABO) of the donor and recipient in relation to the first or second choiseis shown in the Table 4.

In relation to the choice of FFP based on blood type the PROPPR study has shown that using incompatible A plasma in patients with B or AB blood type during a massive transfusion protocol did not increase mortality in these patients [42].

12. Cryoprecipitate (Cryo)

Cryo contains FVIII, WF, F XIII, fibrinogen and fibronectin. All of these components areimportant for achieving hemostasis in bleeding patients. Each Cryounit contains at least 150 mg of fibrinogen and at least 80 IU of factor VIII. It is used to treat bleeding associated with fibrinogen deficiency. This component may be useful for the treatment of bleeding after cardiac surgery, other surgical bleeding, and massive hemorrhage. One unit of Cryo contains about 200 mg of fibrinogen and infusion of 10 units of Cryo (2 g of fibrinogen) should increase serum fibrinogen levels by an average of about 0.7 g/L in an adult.Standard dose of Cryo is 1-2 units per 10 kg of body weight [40,41].

13. Platelets

Platelet administration is recommended for bleeding patients when platelet count is < 50x${10}^9$/L, whilefor severe traumatic brain injuries, the threshold is< 100x${10}^9$/L. Initial platelets dose is 4-6 single donor platelet concentrates. One therapeutic dose of platelets contains about 3-4x${10}^{11}$ platelets, leading to an increase in platelet count by about 30x${10}^9$/L.

Note: Routine use POC testing for platelet function is not recommended for polytraumatized patients with suspected platelet dysfunction or antiplatelet therapy. Namely, early resuscitation, a drop in platelet counts, and changes appearing in TIC influence the objectivity of the results in POC testing for platelet function [19]. In disorders of platelet function (acquired disorders, uremia), Desmopressin (DDVAP) in doses 0.2-0,3µg/Kg can be used [42,43,44].

14. Trauma Induced Coagulopathy (TIC)

TIC is a frequent complication in polytraumatized patients observed in 30% of them. TIC is characterized by accelerated fibrinogen consumption and increased fibrinolytic activity, followed by reduced coagulation factor levels. Administration of TXA is recommended in the first 3 hours for traumatized patients as a 1g bolus dose. Further therapy can continue with 1g TXA every 8 hours. FIB CONC/Cryo is recommended when fibrinogen level is < 1.5g/L or VET tests indicate fibrinogen deficiency obtained with ROTEM test: MCF in FIBTEM test < 9mm). It is suggested dose of 3-4gFIB CONC or 15-20 units of Cryo. In TIC, a deficit in FXIII, known for its’ stabilization activity of formed clots, has been noted. The current recommendation is application of FXIII or Cryo in patients with values of FXIII < 30%. In relation to the new multimodal algorithms for the management of hemorrhagic shock a value of FXIII above 60 should be achieved by applying substitution [25,45,46,47,48,49,50,51].

15. Recombinant FVIIa

The use of recombinant FVIIa (rFVIIa) is not recommended as first-line therapy in hemorrhage. rFVIIa can be used once conventional methods have shown no success in controlling hemorrhage (off-label use).A prerequisite for the application of rFVII is maintaining the level of Fibrinogen > 1.5 g/L; Platelets > 50x${10}^9$/L; pH > 7.2 and Ca> 0.8 mmol/L.

Note: In 1-2% of patients, administration of recombinant rFVIIa can lead to thromboembolism [52].

16. Prothrombin Complex Concentrate

PCC is a highly purified, concentrated preparation of coagulation factors prepared from a pool of plasma, and may contain various combinations of factors. There are two forms on the market with three factors (II, IX and X) or with four factors (II, VII, IX and X). Initially, its use was in the treatment of patients with hemophilia B [53]. Today, its use is indicated for:

▪

persons who have overdosed on inhibitors of vitamin K-dependent factors (oral anticoagulants, VKA) and, as a result, suffered major or life-threatening bleeding; or in the case of the need for rapid reversal of VKA in case of emergency surgery. It is given in a dose of 25 to 50 IU/kg. When using it, INR monitoring is necessary;

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in the case of DOAC reversion (in the absence of a specific antidote);

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large bleedings with a determined lack of vitamin K-dependent factors and this is indicated by ROTEM (EXTEM);

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for the treatment and prophylaxis of congenital deficiency of vitamin K-dependent coagulation factors (II or X) [54].

In addition to the beneficial effects, the use of PCC rarely shows side effects such as: allergy, alloantibody formation, elevated temperature, DIK and thromboembolic complications (microvascular thrombosis and myocardial infarction). Monitoring of PCC application is enabled by the use of ROTEM (EXTEM) and PT (INR) [53,54].

Note: Correct hypothermia, acidosis and hypocalcemia in order to achive optimal therapeutic response in trauma patients.

17. The Lethal Triad and Massive Transfusion Protocol

The lethal triad of trauma— the trinity of hypothermia, acidosis, and coagulopathy—frequently occurs together in severely injured and polytraumatized patients, further associated with a high risk of mortality.

Hypothermia appears frequently in trauma patients because they lose significant amounts of blood and encounterexternal environmental conditions. The condition interferes with enzymatic coagulation mechanisms, which results in worsened hemostasis and reduced blood clotting ability. Hypoperfusion occurring from severe trauma and significant blood loss forces the body to shift its metabolic processes toward anaerobic pathways. The buildup of lactic acid and acidosis develops because of this process. Acidosis causes detrimental effects on blood clotting through its impact on clotting factor activities and platelet operational abilities [1]. The combination of tissue damage along with shock and systemic inflammation causes trauma-induced coagulopathy (TIC). The body’s natural clotting processes become disrupted, producing an unstable condition. During different phases of care, patients show alternating hypo-coagulable and hyper-coagulable states [55].

The Lethal triad intensifies hemorrhagic shock while creating major difficulties in the resuscitation process. The Massive Transfusion Protocol,or MTP,provides an organized approachto blood transfusions. Itallocates blood products at specific ratios thatwork against Lethal triad effects furthermoreenhance trauma outcomes [56,57].

Initially, MTPs dictate pre-transfusion heat therapy for blood products to maintain patient temperature stability. Maintainingnormothermia is essential,as hypothermia can intensify both acidosis and coagulopathy [58]. Perfusion and oxygen delivery are established through quick and adequate administrationofblood products in MTPs, which work to reduce theprogressionofmetabolic acidosis. Successful acid-base disturbance treatment demands equal transfusion ratios between red blood cells (RBCs) and platelets with plasma components,simultaneously addressing TIC [59]. This approach is superior to a single RBC transfusion, as balancing blood products enhances patient coagulation functions while decreasing traumatic mortality statistics [59,60].

Easterday et al. 2024 research study note that MTP success depends on precise plasma-to-red blood cell (FFPR) and platelet-to-red blood cell (PLTR) ratios—the FFPR at a 1:2 ratio and PLTR at a 1:12 rate, providing significantly better inpatient survival statistics. The research showed protective results with odds ratios of 0.451 and 0.402 when these ratios were used [58].A 2021 study by Matthay et al. performed for the Eastern Association for the Surgery of Trauma demonstrated that patients receiving ultra-massive transfusions with balanced RBC/FFP and RBC/PLT ratios below 1.5:1 showed better survival outcomes when defined as receiving ≥20 units of RBCs in 24 hours. Unbalanced blood transfusion ratios consistently produced elevated patient death rates [59].

18. Conclusions

In the approach to treating trauma patients, an important place is occupied by understanding the mechanism of trauma coagulopathy and the use of rapid diagnostic methods (POC) that enable the application of individual treatment. Also, it is necessary to have well-trained teams including trauma surgeons, anesthesiologist and critical care physicians trained in damage control resuscitation and surgery. Regarding the timely inclusion of supportive therapy, we emphasize the importance of good communication between the trauma center and the hospital blood bank. In order to achieve best outcomes in the treatment of trauma patients hospitals need to provide adequate training and establish local guidelines or algorithmsfor the treatment of trauma patients.