In all patients, blood samples were drawn before any colloid and <500 mL crystalloids were given. Until arrival in the ED, all 50 patients received crystalloids, and 8 patients received HES as well. On average, patients received 542 ± 432 mL of crystalloids and 79 ± 222 mL of colloids between on-scene and arrival in the ED and before the second blood sample was drawn in the ED. In the ED and during the first 24 hours of hospitalization, 48 patients received crystalloids and 19 patients additionally received colloids (Table 2). More fluids were given in the ED (1076 ± 1294 mL [P = 0.007] crystalloids and 454 ± 985 mL [P < 0.001] colloids) than during the period between on-scene and arrival in the ED.
No blood products or coagulation factors were administered between the scene of injury and arrival in the ED (Table 2). In the ED, RBCs, fresh-frozen plasma, and platelets were given in 3 (6%), 2 (4%), and 3 (6%) patients, respectively, after the second blood sample was drawn. Tranexamic acid (Cyklokapron®; Pfizer Corporation Austria GmbH, Vienna, Austria) was administered in 8 patients (16%). Four-factor (II, VII, IX, and X) PCC (Beriplex® P/N; CSL Behring AG, Bern, Switzerland) was given in 3 patients (6%). Seven patients (14%) received fibrinogen (Haemocomplettan®; CSL Behring AG) and in 4 patients (8%), FXIII (Fibrogammin®; CSL Behring AG) was given. Data presented are the mean ± SD of factors or blood products of patients having received any of those products. FXIII was given with a mean of 2813 ± 2049 IU with a range of 1250 to 6250 IU. Fibrinogen 8.9 ± 4.8 g was given with a range of 4 to 18 g. Four-factor PCC was given with a mean of 2000 ± 817 IU with a range of 1000 to 3000 IU. Tranexamic acid was administered with 1.2 ± 0.4 g with a range of 1 to 2 g.
In the first 24 hours (ED, operating room, and intensive care unit), the mean ± SD (range) RBC use was 17 ± 8 (6–26) units, platelet use was 3 ± 2 (1–6) units, and fresh-frozen plasma use was 9 ± 2 (7–11) units.
Blood Gas Analysis
Significant changes (all P ≤ 0.005) between on-scene and the ED were observed for PvO2, sodium, glucose, and lactate. Twenty-four patients had a pH <7.34 on-scene, and in 2 patients, the pH was <7.20. In the ED, a pH <7.34 was measured in 27 patients and a pH <7.20 in 1 patient. Lactate values above the normal upper threshold of 1.6 mmol/L were measured in 45 patients on-scene and in 31 patients in the ED. Lactate values >4 mmol/L were measured in 11 patients on-scene and in 5 patients in the ED. Details are shown in Table 3. The pH (r = −0.27; P = 0.05, not significant), HCO3− (r = −0.30; P = 0.032, not significant), and BE values (r = −0.32; P = 0.022, not significant) measured on-scene may have correlated weakly with the ISS, but the correlation increased slightly after arrival in the ED (pH [r = −0.40; P = 0.004], HCO3− [r = −0.32; P = 0.024, not significant], and BE values [r = −0.41; P = 0.003]). After arrival, the ED lactate values may have correlated weakly with the ISS (r = 0.29; P = 0.038, not significant). Whereas a possible weak correlation for pH and lactate was found on-scene (r = 0.36; P = 0.011, not significant), the correlation was moderate and significant in the ED (r = 0.58; P < 0.001). Lactate and aPTT did not correlate on-scene (r = 0.06; P = 0.69, not significant) but may have in the ED (r = 0.42; P < 0.001); the same results were found for pH and aPTT (r = 0.05; P = 0.72, not significant on-scene and r = 0.51; P < 0.001 in the ED).
Laboratory values below the lower limit of the normal range were measured for platelets in 3 (6%), fibrinogen in 3 (6%), FV in 2 (4%), FXIII activity in 3 (6%), protein C activity in 5 (10%), and protein S in 6 patients (12%). Thirteen patients (26%) had a Quick value, and 27 (54 %) presented an aPTT below the normal range (Table 4).
Laboratory values above the upper limit of the normal range were measured for platelets in 2 (4%), fibrinogen in 2 (4%), FV in 3 (6%), FXIII activity in 8 (16%), D-dimer >0.5 mg/L in 44 (88%), D-dimer >4 mg/L in 12 (24%), protein C activity in 3 (6%), protein S in 4 (8%), and protein S100 in 49 patients (98%) (Table 4). Quick values, aPTT, fibrinogen, FV, and FXIII activity level did not correlate with the ISS. A significant correlation with ISS was found for Hb (r = −0.37; P = 0.008), protein S100 (r = 0.67; P < 0.001), D-dimers (r = 0.72; P < 0.001), and protein S (r = −0.41; P = 0.003). Fibrinogen (r = 0.41; P < 0.001), FV (r = 0.68; P < 0.001), FXIII activity (r = 0.41; P = 0.003), protein C activity (r = 0.45; P < 0.001), and protein S (r = 0.40; P = 0.004) may have significantly correlated with the Quick value. The only value that may have had weak evidence for a correlation with the aPTT was FV (r = −0.33; P = 0.018, not significant).
In the ED
The numbers of patients having laboratory values below the lower limit of the normal range increased for platelets in 9 (18%; P = 0.013, not significant), fibrinogen in 5 (10%; P = 0.16, not significant), protein C activity in 9 (18%; P = 0.044, not significant), and protein S in 9 patients (18%; P = 0.083, not significant). Quick value and aPTT values below the lower level of the normal range were found in 12 (P = 0.32, not significant) and 18 (P = 0.013, not significant) patients, respectively. The number of patients having FXIII activity below the normal range and D-dimer levels >4 mg/L increased to 11 (P = 0.083, not significant) and 20 (P = 0.004) patients, respectively. For other measured variables, the number of patients having laboratory values above the upper limit of the normal range decreased for fibrinogen to 1 (2%; P = 0.32, not significant), protein C activity to 2 (4%; P = 0.32, not significant), and protein S to 2 patients (4%; P = 0.16, not significant). Protein S100 levels were increased in all patients and did not change.
Table 5 presents the significant changes in coagulation measurements between on-scene and arrival in the ED. D-dimers increased; Hb, Hct, and platelets decreased; and protein C activity, protein S, fibrinogen, FV, and FXIII activity, and protein S100 decreased. There was a trend for an increase of aPTT (P = 0.04, not significant). Compared with on-scene, no changes in Quick value, INR, and leukocytes were found (Table 5). The Hb (r = −053; P < 0.001), Hct (r = −053; P < 0.001), protein S100 (r = 0.69; P < 0.001), D-dimer (r = 0.72; P < 0.001), and protein S (r = −0.54; P < 0.001) were significantly correlated with the ISS. There may have been a weak correlation of FXIII activity (r = −0.34; P = 0.014, not significant) with ISS.
The correlations of fibrinogen (r = 0.51; P < 0.001), FV (r = 0.79; P < 0.001), FXIII activity (r = 0.54; P < 0.001), protein C activity (r = 0.57; P < 0.001), protein S (r = 0.45; P = 0.001), and the D-dimer (r = 0.32; P = 0.025, not significant) with the Quick value increased compared with those on-scene. Besides FV (r = −0.40; P = 0.004), protein C activity (r = −0.35; P = 0.012, not significant) and protein S (r = −0.33; P = 0.018, not significant) may have correlated weakly with the aPTT.
Changes in ROTEM variables between on-scene and after arrival the ED are shown in Table 6.
In 4 patients (8%), ROTEM variables (CT, CFT, and MCF) were below the lower limit of the normal range. In 1 patient (patient 25), an MCF above the normal range was measured for FIBTEM of the ROTEM. In 5 patients (10%), ML was >15%. All other ROTEM variables measured on-scene were within the normal range.
In the ED
When compared with on-scene, significantly more patients (n = 18, 36%) had ROTEM variables below the lower limit of the normal range (P = 0.002). In 1 patient (patient 25), an MCF above the normal range was measured for FIBTEM of the ROTEM. Compared with on-scene, an additional 3 patients (6%) had ML >15% upon arrival to the ED. Table 6 presents the significant changes in ROTEM measurements performed between on-scene and the ED. For EXTEM, INTEM, and APTEM, CT and CFT increased significantly, whereas MCF and angle α decreased significantly. For FIBTEM, CT increased significantly, MCF decreased significantly, and ML was interestingly lower in the ED.
Post hoc analysis revealed that exclusion of 3 patients who needed RBC transfusion did not significantly influence any measured variables (hemodynamics, ISS blood gas analysis, laboratory results, and point-of-care results) either on-scene or after arrival in the ED.
The main findings early after injury are (1) Quick values were pathologic in at least 13% of the patients (95% CI, 13%–35%) and aPTT in at least 26% (95% CI, 26%–52%), but only aPTT increased significantly after admission in the ED; (2) D-dimer levels were increased in 88% (44 of 50 patients D-dimer >0.5) of the patients and increased significantly until arrival at the ED; (3) Hb, platelet, fibrinogen, FV and FXIII activity, protein C activity, and protein S100 values were significantly decreased from on-scene to ED arrival (Table 5); (4) ROTEM variables were abnormal in 8% of the patients (reduced MCF) on-scene but in 36% of patients after arrival in the ED; (5) protein S100 levels were increased in 98% of the patients on-scene but decreased significantly until admission in the ED (4.14 ± 1.49 to 2.37 ± 4.66; P < 0.001); and (6) on-scene 70% of the patients developed lactate levels above the upper limit of the normal range, and half of these patients presented with lactic acidosis.
Data describing changes in the coagulation status of patients are sparse in the early period after trauma. Only 1 study has performed standard coagulation tests and measurements of FV, protein C activity, and antithrombin III on-scene and after admission in the ED of the hospital.14 Floccard et al.14 found abnormal coagulation in 56% of their patients on-scene and in 60% on hospital admission. The on-scene coagulopathy was spontaneously normalized in 2 patients, whereas others had the same or a poorer coagulopathy status, which are quite similar findings to ours.
In our study, blood samples were taken directly at the location of the injury and as soon as possible after admission to the ED. In addition, we evaluated coagulation by using several approaches: standard and advanced laboratory coagulation tests, ROTEM, blood gas analysis, and protein S100 as a brain trauma marker.
Several studies have shown that systemic hypoperfusion itself plays a central role in the pathogenesis of early traumatic coagulopathy.21,22 A dose-dependent association between the degree of coagulopathy after admission to the ED measured with the Quick value and aPTT, and the severity of tissue hypoperfusion has been reported.23,24 White et al.25 demonstrated in a swine model that traumatic shock itself significantly reduced the fibrinogen concentration and the clot strength as measured by the maximum amplitude of thromboelastography. The high proportion of patients on-scene with metabolic acidosis and lactate concentrations above the upper limit of the normal range in this study supports the suggestion that significant hypoperfusion states are present very early after severe trauma. Nearly half (n = 23; 46%) of these patients initially developed lactic acidosis (pH <7.34, lactate >1.6 mmol/L) as the result of extensive hypoperfusion of tissues. Six of these patients demonstrated a hypocoagulable state (INR >1.2, Quick value <70%). The other 17 patients still had coagulation variables within the normal range. Another 7 patients were hypocoagulable and had high lactate levels with a pH still in the normal range. Even though lactate concentrations decreased after initial intravascular volume resuscitation until reaching the ED, the degree of acidosis remained the same. A decrease of lactate and remaining acidosis might be explained by only limited volume replacement in the initial period between on-scene and arrival the ED, which is in agreement with previously reported results and recommendations in the latest update of the European trauma treatment guidelines.11,26,27 Although acidosis itself may affect coagulation, adverse effects of acidosis on extrinsic and intrinsic coagulation pathways and on platelet function are not generally seen until the pH decreases <7.2.28 In our study, only 2 patients had a pH <7.2 and both died. These patients developed massive hemorrhage due first to the major injury itself and second to the disturbed coagulation system.
At the scene of trauma, we found a Quick value <70% in 26%, a shortened aPTT in 54%, and an increased D-dimer in 88% of patients. In one-quarter of the patients, the D-dimer concentration was >4 mg/L. The combination of normal Quick value, decreased aPTT, and pathologic high levels of D-dimer suggests a massive activation of coagulation factors (hypercoagulable) leading to their consumption and simultaneously to an activated fibrinolytic system early after trauma. ROTEM analysis found an ML >15% in only 8 patients, showing a systemic hyperfibrinolysis, whereas our other results suggest a local hyperfibrinolysis/fibrinolysis that seems to play a role in the early phase of trauma. The shortened aPTT might be explained by a sudden increase of FVIII in the context of a severe trauma.
Floccard et al.14 reported similar results but used the scoring system proposed by the International Society on Thrombosis and Haemostasis. They reported that 50% of patients on-scene and 60% of the patients after arrival to the ED experienced trauma-associated coagulopathy and that D-dimer levels were increased both on-scene and after admission to the ED. In our investigation, the platelet count, aPTT, fibrinogen, FV, FXIII activity, protein C activity, and protein S on-scene were in the normal range and thus gave no indication of the current coagulation state during trauma-associated bleeding. This observation is in agreement with previous findings that procoagulant coagulation factors are critically reduced in the late stages of blood loss.29,30 Mittermayr et al.29 and Innerhofer30 hypothesized that most factors are needed at low concentrations and short half-life times. These hypotheses, however, are based only on investigating the procoagulant and anticoagulant coagulation factors after admission to the hospital. Interestingly, in our study, fibrinogen, FV, FXIII activity, protein C activity, and protein S all decreased and aPTT increased between on-scene and the ED. The decrease in coagulation factors is unlikely to have been attributable to dilutional coagulopathy because only small volumes of crystalloids (1076 ± 1294 mL) and in particular colloids (454 ± 995 mL) were infused between on-scene and arrival the ED. The use of colloids such as HES further predisposes to a coagulopathy which is difficult to reverse.31 No or little volume (no colloids) given before the first blood drawn is unlikely to have influenced the results of the measurement of this study because the amount of colloids given was 79 ± 222 mL and the amount of crystalloids 542 ± 432 mL before the second blood drawn in the ED are considered low. One possible explanation is that trauma induces a massive coagulation response, including increased protein C activity, which thus leads to a decrease of fibrinogen, FV, FXIII activity, protein C activity and protein S, and an increased aPTT. Because we measured protein C activity based on the not yet protein C activity, our results presented in Table 4 are correct because less unactivated protein C is available in the late phase of trauma due to earlier activation. Data from the German Trauma Registry of 8724 patients show a clear relationship between early coagulopathy and the volume of fluids administered.12 The registry reported an incidence of early coagulopathy at >40%/>50% and >70% with fluid volumes of >2000, 3000, and 4000 mL, respectively.12 In contrast, a retrospective study of 1088 traumatized patients by Brohi et al.27 demonstrated that the incidence of early coagulopathy was not related to preclinical fluid administration but clearly associated with the severity of injury. This shows that there are actually 2 completely opposite ways to explain coagulopathy in trauma patients.
In addition to standard laboratory evaluation, our study included ROTEM measurements both on-scene and after arrival in the ED. On-scene in 8% of the patients, the MCF of the ROTEM was reduced, presenting reduced clot strength and 10% presented an ML >16%. After arrival in the ED, 36% of the patients had abnormal ROTEM parameters, including increases in CT and CFT of EXTEM, INTEM, and APTEM and decreases in angle α and MCF compared with on-scene values. In addition, FIBTEM CT was prolonged and the MCF reduced. These data suggest an early deficiency or loss of activity of coagulation factors such as fibrinogen, FXIII, and platelets and were supported by simultaneously determined platelet count and changes in FV, FXIII activity, protein C activity, and protein S. Davenport et al.32 hypothesized that traumatic coagulopathy is characterized by reduction in clot strength and has a specific thromboelastometric signature, which can be diagnosed by the clot amplitude at 5 minutes. Although our study was too small to test this possibility, reduced clot strength was seen in more than one-third of the patients in the ED. Another reason for the development of impaired clot formation measured with ROTEM might be a dilutional coagulopathy caused by intravascular volume resuscitation during patient transport to the ED. In an in vitro study, Haas et al.33 reported significant worsened clot formation after diluting blood samples by using 60% lactated Ringer’s solution. In this investigation, the crystalloid volume replacement was only 542 ± 432 mL, and colloid was only given to 8 patients. We thus believe it unlikely that the worsened coagulation and clot formation were caused by dilution. In cases in which clearly pathological values of ROTEM are identified, early treatment as suggested by the European Trauma Guidelines26 might be useful, and administration of factor concentrates has been suggested to treat traumatic coagulopathy by Theusinger et al.20
Some limitation of this study should be noted. The study sample size was small. Hence, subgroup analysis for different ISS classes or for patients with significant hypoperfusion states was not performed because of insufficient power. For ethical reasons, blood samples on-scene and in the ED were always performed without disturbing life-sustaining treatment. Therefore, it cannot be ensured that blood samples were drawn before the first dose of volume replacement. In addition, samples for blood gas analysis were performed from a second venous access site and not cooled on ice during transportation to the ED. However, several studies have demonstrated that blood samples remain stable over a long period of time at 21°C temperature, so we do not believe these values distort our analysis.16,17 We also did not measure body temperature of our patients on arrival to the ED. Hypothermia may have also altered our measurement of coagulation status. Blood loss was neither calculated nor was it estimated because the data were not available for the days after trauma. In only 8 patients, ML >15% indicated systemic hyperfibrinolysis. These results might suggest that in an early phase of trauma, hyperfibrinolysis could be a local phenomenon because high D-dimers show the presence of fibrinogen split products.
In the urban setting with transport times <1 hour, coagulation values measured on arrival to the ED change drastically from those measured at the scene of trauma. On-scene measurements thus do not provide clinically relevant information that leads to an acute specific laboratory variable-based therapeutic intervention in most trauma patients. For 1 hour after injury, significant activation and consumption of fibrinogen, FV, FXIII, protein C activity, and protein S were observed. Markers such as increasing D-dimers indicate a progressive fibrinolysis even if not shown by an increased ML in ROTEM. Routine coagulation tests may not indicate the diagnosis of ongoing coagulopathy. Thromboelastometry promises to be a useful tool for early detection of traumatic coagulopathy.
Name: Oliver M. Theusinger, MD.
Contribution: This author designed the study, conducted the study, analyzed the data, and wrote the manuscript.
Attestation: Oliver M. Theusinger approved the final manuscript.
Conflicts of Interest: Oliver M. Theusinger has received honoraria or travel support for consulting or lecturing from the following companies: CSL Behring Schweiz, Zurich, Switzerland; Vifor SA, Villars-sur-Glâne, Switzerland; Roche Pharma (Schweiz) AG, Reinach, Switzerland; Pentapharm AG, München, Germany; and TEM International GmbH, München, Germany.
Name: Werner Baulig, MD.
Contribution: This author helped conduct the study, and write and edit the manuscript.
Attestation: Werner Baulig approved the final manuscript.
Conflicts of Interest: Werner Baulig has received honoraria or travel support for consulting or lecturing from the following companies: CSL Behring Schweiz, Zurich, Switzerland; Fresenius-Kabi AG, Bad Homburg, Germany; B. Braun Melsungen AG, Melsungen, Germany; OrPha Swiss GmbH, Küsnacht, Switzerland; and SenTec AG, Therwil, Switzerland.
Name: Burkhardt Seifert, PhD.
Contribution: This author conducted the statistical analysis, and helped write the manuscript.
Attestation: Burkhardt Seifert approved the final manuscript.
Conflicts of Interest: This author has no conflicts of interest to declare.
Name: Stefan M. Müller, MD.
Contribution: This author helped conduct the study, and write the manuscript.
Attestation: Stefan M. Müller approved the final manuscript.
Conflicts of Interest: This author has no conflicts of interest to declare.
Name: Sergio Mariotti, MD.
Contribution: This author helped conduct the study, and write the manuscript.
Attestation: Sergio Mariotti approved the final manuscript.
Conflicts of Interest: This author has no conflicts of interest to declare.
Name: Donat R. Spahn, MD, FRCA.
Contribution: This author designed the study, conducted the study, and wrote the manuscript.
Attestation: Donat R. Spahn approved the final manuscript.
Conflicts of Interest: Donat R. Spahn’s academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland (grant numbers: 33CM30_124117 and 406440-131268); the Swiss Society of Anesthesiology and Reanimation (SGAR), Berne, Switzerland (no grant numbers are attributed); the Swiss Foundation for Anesthesia Research, Zurich, Switzerland (no grant numbers are attributed); Bundesprogramm Chancengleichheit, Berne, Switzerland (no grant numbers are attributed); CSL Behring, Berne, Switzerland (no grant numbers are attributed); and Vifor SA, Villars-sur-Glâne, Switzerland (no grant numbers are attributed). Dr. Spahn was the chairman of the ABC Faculty and a member of the ABC Trauma Faculty, both of which are managed by Thomson Physicians World GmbH, Mannheim, Germany, and sponsored by an unrestricted educational grant from Novo Nordisk A/S, Bagsvärd, Denmark. In the past 5 years, Dr. Spahn has received honoraria or travel support for consulting or lecturing from the following companies: Abbott AG, Baar, Switzerland; AstraZeneca AG, Zug, Switzerland; Bayer (Schweiz) AG, Zürich, Switzerland; Baxter S.p.A., Roma, Italy; B. Braun Melsungen AG, Melsungen, Germany; Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland; Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France; CSL Behring GmbH, Hattersheim am Main, Germany and Bern, Switzerland; Curacyte AG, Munich, Germany; Ethicon Biosurgery, Somerville, New Jersey; Fresenius SE, Bad Homburg v.d.H., Germany; Galenica AG, Bern, Switzerland (including Vifor SA, Villars-sur-Glâne, Switzerland); GlaxoSmithKline GmbH & Co. KG, Hamburg, Germany; Janssen-Cilag AG, Baar, Switzerland; Novo Nordisk A/S, Bagsvärd, Denmark; Octapharma AG, Lachen, Switzerland; Organon AG, Pfäffikon/SZ, Switzerland; Oxygen Biotherapeutics, Costa Mesa, California; Pentapharm GmbH (now Tem Innovations GmbH), Munich, Germany; Roche Pharma (Schweiz) AG, Reinach, Switzerland; and Schering-Plough International, Inc., Kenilworth, New Jersey.
This manuscript was handled by: Avery Tung, MD.
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© 2015 International Anesthesia Research Society
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