Intensive Care Med (2008) 34:700–706 DOI 10.1007/s00134-007-0976-5

Athina Lavrentieva Theodore Kontakiotis Militsa Bitzani Georgia Papaioannou-Gaki Angeliki Parlapani Olimpia Thomareis Nicolaos Tsotsolis Maria-Amalia Giala

Received: 12 February 2007 Accepted: 30 November 2007 Published online: 12 January 2008 © Springer-Verlag 2008

A. Lavrentieva (u) Hatzipanagiotidi 2, 55236 Panorama, Thessaloniki, Greece e-mail: [email protected] Tel.: +30-2310-344270 Fax: +30-2310-350240 A. Lavrentieva · M. Bitzani Burn ICU Papanikolaou General Hospital, Exochi, Thessaloniki, Greece T. Kontakiotis Aristotle University Thessaloniki, Pulmonary Department, Thessaloniki, Greece G. Papaioannou-Gaki Papageorgiou Hospital, Hematological Department, Thessaloniki, Greece

ORIGINAL

Early coagulation disorders after severe burn injury: impact on mortality

A. Parlapani · O. Thomareis · N. Tsotsolis · M.-A. Giala Aristotle University Thessaloniki, Anesthesiology Department, Thessaloniki, Greece

were observed between survivors and nonsurvivors. SOFA score distinguished between patients with overt and nonovert disseminated intravascular coagulation (DIC) during the overall investigation period. Presence of overt DIC was related to mortality (OR = 0.1). Antithrombin, protein S, plasminogen activator inhibitor 1, and SOFA score on day 3, protein C on day 5, and thrombin/antithrombin complexes on day 7 revealed a good prognostic value for ICU mortality, according to the area under ROC curves. Conclusions: Severe thermal injury is associated with the early activation of coagulation cascade, presence of DIC, organ failure, and increased mortality.

Abstract Objective: To evaluate the time course of coagulation markers in the early postburn period and clarify the role of coagulation alterations in organ failure and in mortality prognosis. Design and setting: This prospective study was conducted in the burn ICU of a tertiary hospital. Patients: 45 patients with severe thermal burn injury. Measurements and results: Clinical data and coagulation and fibrinolysis parameters were measured during the first postburn week. Keywords Burn · Coagulation facThe ICU 28-day mortality rate was tors · Disseminated intravascular 33%. Significant differences in the coagulation · Outcome assessment time course of coagulation markers

Introduction Although the management of severe burn injury has improved over the past two decades, mortality, due to early complications, remains a major threat [1]. A severe burn injury is characterized by the activation of inflammation and coagulation mediators, leading to disseminated intravascular coagulation (DIC), microvascular thrombosis,

hypoperfusion, and multiple organ failure [2–5]. Coagulation system dysfunction is characterized by activation of procoagulant pathways, enhanced fibrinolytic activity, and impairment of natural anticoagulants activity. Both thrombotic and fibrinolytic pathways are directly triggered proportionally to the extent of the burn injury [5, 6]. General physiological changes occurring immediately after burn injury are important for the initial survival of

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the patient. Microthrombi formation within the immediate vicinity of burn injury is essential for maintaining the integrity of the microvasculature surrounding the burn wound. Although this phenomenon may serve as a defense system against bleeding by burn wound vessels, the generalized systemic microthrombi formation may lead to reduction in organ perfusion and create DIC [7]. In a postmortem study Wells et al. [6] reported DIC with widespread microvascular thrombosis in major organs in about 30% of severely burned patients. The time course of coagulation system markers, the magnitude of coagulation abnormalities, and their relationship to outcome continues to be discussed in the literature [1, 5, 7]. A scoring system that uses simple tests, available in almost all hospital laboratories, has recently been established by the subcommittee on DIC of the International Society on Thrombosis and Haemostasis (ISTH) [8]. Initial validation studies show a high accuracy of this scoring system for the diagnosis of DIC [9–12], but data are insufficient in burn patients. This prospective study evaluated the early activation of coagulation and fibrinolysis in thermal injury and analyzed the correlation between coagulation status alterations and prognosis in patients with severe burn.

Materials and methods Patients and measurements Forty-five patients with severe burn injury admitted to the four-bed Burn Unit in Papanikolau General Hospital between April 2004 and December 2005 were prospectively included in our study. The study protocol was approved by the local ethics committee. Written consent from the patients or their relatives was obtained. The patients were enrolled in the study during the first 24 h after the burn injury. Only patients with extensive burn injury (total burn surface area (TBSA) > 25%) were included in our study. Patients under the age 18 years, those with hepatic and renal failure, malignancies and associated trauma, or known hematological disease affecting the coagulation system were excluded from the study (n = 9). In addition, all patients treated with early excision of burn wound (within 7 days after the injury) were excluded (n = 11). All patients were followed up for 28 days. The patients were examined for signs of infection (clinical, microbiological, and biochemical). Four patients who developed infectious complications (two pneumonia, one burn surface infection, and one catheter-related infection) were excluded from the study. The patients’ clinical management was guided by the treatment protocol of our ICU. Fluid intake was based on the crystalloid fluid infusion only on the 1st postburn day, followed by crystalloid and colloid infusion according to the clinical and laboratory findings. Insignificant

differences on fluid administration were observed between survivors and nonsurvivors. Early enteral nutrition (within 12 h after the burn injury) was provided, and no prophylactic antibiotics were used. All patients received thromboembolic prophylaxis using low molecular weight heparin. Antithrombin (AT) and protein C (PC) were not used as therapeutic agents. Standard burn wound care was performed with excision of the necrotic area within the first 15 days. The mean time between burn injury and ICU admission was 6.2 ± 2.4 h (range 3.1–7.2 h). The following admission parameters: age, sex, severity of burn injury expressed by a percentage of the TBSA, and the ABSI were recorded. The severity of the illness was determined by the (Acute Physiology and Chronic Health Evaluation (APACHE) II score and Simplified Acute Physiology Score (SAPS) II. For the diagnosis of multiple organ dysfunction the Sequential Organ Failure Assessment score (SOFA) was used. The ISTH DIC score has been validated prospectively in the burn ICU environment [8]. The presence of an underlying disorder known to be associated with DIC is a necessary condition for use of the algorithm. According to the severity of the disorder, DIC is divided into two categories, overt (decompensated) and nonovert (compensated). The panel of coagulation tests consists of decreased blood platelet count, an elevated fibrin related marker, prolonged plasma prothrombin time, and decreased plasma fibrinogen. In this system a score of 5 or more meets the definition of overt DIC. The diagnosis of nonovert DIC additionally requires analysis of other markers, such as AT, PC, and thrombin-antithrombin complex (TAT). We examined the relationship of overt vs. nonovert DIC in 28-day mortality. All biological parameters were measured within 1 h of ICU admission and daily thereafter. Coagulation parameters Coagulation inhibitors AT activity was measured in the plasma by chromogenic assay (Dade-Bering; normal values 80–120%), as was PC activity (Dade-Bering; normal values 70–130%). Free protein S (PS) was also measured by electro-immunodiffusion method (Dade-Bering; normal values 70–130%). Factors of the fibrinolysis system The plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA) antigens were measured by the microenzyme-linked immunosorbent assay (ELISA) technique (Diagnostica Stago; (normal values 4–43 ng/ml for PAI-1, 1–12 ng/ml for t-PA).

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Results

Activation of thrombin generation, fibrinolytic system, and use of the coagulation inhibitors

Clinical data, DIC score, and mortality

To assess the activation of the fibrinolytic system, thrombin generation and neutralization, and the use of the coagulation inhibitors the following markers were measured: TAT, plasmin/α2 -antiplasmin complexes (PAP), prothrombin fragment F1.2 (F1.2) and fibrin degradation product D-dimer (D-d). TAT and PAP were measured by micro-ELISA assay (normal values 1–4.1 µg/l for TAT, 120–700 µg/l for PAP). D-d was measured by a latex semiquantitative method (Diagnostica Stago; negative: less than 0.5 µg/ml). F1.2 antigen levels were measured by the enzyme-linked immunoassay (normal values 0.4–1.1nmol/l). Mortality was recorded on the 28th day after ICU admission.

Statistical analysis Repeated-measures analysis of variance was used to analyze continuous variables over time. The area under the receiver operating characteristic (ROC) curve (AUC) was used to assess the prognostic accuracy of mortality markers. Logistic regression modeling was used to evaluate the prognostic value of DIC on mortality rate. The corresponding odds ratio (OR) was also calculated. Differences were considered statistically significant with p-values less than 0.05. Statistical analysis was conducted with SPSS version 14.0. Table 1 Patient characteristics Age (years) Males TBSA ABSI APACHE II score SAPS II score SOFA score Inhalational burn Table 2 Coagulation and fibrinolysis parameters of survivors and nonsurvivors on admission; no statistically significant differences were observed in any of the parameters

PAP (µg/l) TAT (µg/l) D-dimer (mg/ml) PAI-1 (ng/ml) t-PA (ng/ml) F1.2 (nmol/l) AT (%) PC (%) Free PS (%) PLT (109 /l) INR PTT (s) Fibrinogen (g/l)

The 28-day mortality of the 45 patients screened was 33%. The main early causative factor of mortality was multiorgan failure syndrome. Five patients developed septic complications. None of the patients had infectious complications during the 7-day investigation period, as determined by clinical signs, microbiological, and biochemical markers (the mean procalcitonin level during the investigation period was < 0.5 ng/ml). Nonsurvivors died at a mean of 13.4 ± 4.8 days. The clinical and biological characteristics of the survivors and nonsurvivors on admission are summarized in Table 1. On admission survivors had significantly lower TBSA, ABSI, APACHE II score, SAPS II score, and SOFA score than nonsurvivors. On admission the levels of the coagulation markers did not differ significantly between the two groups. The coagulation and fibrinolysis parameters on day 1 are presented in Table 2. Six of the 30 survivors (6.7%) fulfilled the overt DIC criteria and 20 (80%) fulfilled the criteria of the nonovert DIC. Only 4 of the 30 surviving patients (13.3%) did not have a DIC diagnosis (overt or nonovert). On the other hand, the DIC diagnosis was applied to all nonsurvivors (n = 15). Especially 8 of the 15 (53.3%) had overt DIC and 7 had nonovert DIC (46.7%). The mean overt DIC score values were 4.4 ± 1.5 in nonsurvivors and 2.7 ± 1.4 in survivors (p < 0.05). On admission there were significant differences between patients with overt and nonovert DIC

Survivors (n = 30)

Nonsurvivors (n = 15)

p

37.03 ± 14.1 86.7% 33.8 ± 8% 5.9 ± 1.6 8.03 ± 2.5 21.1 ± 8 3.5 ± 1.8 16.7%

45 ± 24 73.3% 58.1 ± 23.2% 9.6 ± 1.8 13.4 ± 4.1 44.6 ± 4.4 5.2 ± 1.5 26.6%

0.078 0.124 < 0.001 < 0.001 < 0.001 < 0.001 0.035 0.066

Survivors (n = 30)

Nonsurvivors (n = 15)

Normal values

491.2 ± 296 14.6 ± 7.9 2.2 ± 1.5 95.7 ± 32.3 10.9 ± 7.7 4.2 ± 0.21 61.9 ± 27 66.1 ± 19.1 52.3 ± 17.7 210.2 ± 97 1.3 ± 0.37 34.8 ± 7.3 1.4 ± 0.4

542 ± 396 15.7 ± 2.9 2.05 ± 0.6 115 ± 77 14.9 ± 8.5 5.3 ± 3.3 44.8 ± 10.6 42.2 ± 13.2 44 ± 7.2 271 ± 127 1.5 ± 0.4 38.9 ± 7.3 1.2 ± 0.7

120–700 1–4.1 < 0.5 4–43 1–12 0.4–1.1 80–120 70–130 70–130 150–350 0.9–1.2 30–34 2–4

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Fig. 2 Time course of antithrombin (AT)

Fig. 1 Sequential Organ Failure Assessment score in patients with overt and nonovert disseminated intravascular coagulation (DIC)

in TBSA (33.4 ± 13.6% vs. 66.5 ± 25.1%, p < 0.01), in the ABSI (6.37 ± 1.8 vs. 9.5 ± 2.6, p < 0.05) and in APACHE II score (8.82 ± 2.8 vs. 15.2 ± 7.7, p < 0.01). No differences were noted in SAPS II score or in the percentage of patients with inhalational injury (32.1 ± 9.2% vs. 39.8 ± 9.3% and 20% vs. 20%, respectively). SOFA score differed significantly between patients with overt and nonovert DIC during the overall investigation period (Fig. 1). The diagnostic accuracy of overt DIC diagnosis was assessed in relation to outcome using logistic regression. The outcome was modeled using overt DIC, age, APACHE II, TBSA, and ABSI as possible predictors. All five predictors when assessed as independent factors were found to be significantly related to mortality on day 28 (p < 0.05). Overt DIC was significantly related to mortality (β = –2.30, SE = 0.6, p < 0.0001, OR = 0.1, 95% CI = 0.31–0.33). Time course of coagulation markers activation in early postburn period Natural coagulation inhibitors: AT, PC, and PS On admission all patients had acquired reduction in all the above parameters. Normalization of coagulation inhibitors levels in survivors was observed on day 5 for AT (83.2 ± 16%) and for PC (75.7 ± 22%) and on day 7 for PS (75.3 ± 27%). AT and PS differed significantly between the two groups from day 3 (78.3 ± 21% vs. 51.8 ± 15%, p < 0.05, and 53.4 ± 14% vs. 38.9 ± 7.4%, p < 0.05, respectively) and PC from day 5 (75.7 ± 22% vs. 48.6 ± 12%). The levels of all three coagulation inhibitors increased significantly in the early postburn

Fig. 3 Time course of protein C (PC)

Fig. 4 Time course of protein S (PS)

period in survivors (p < 0.05) but remained at low levels in nonsurvivors (Fig. 2, 3, 4).

Factors of fibrinolytic system: t-PA and PAI-1 t-PA levels decreased significantly on day 7 vs. day 1 returned to normal levels after day 5 only in survivors. On the other hand, t-PA levels did not change significantly in nonsurvivors during the investigation period. A statistically significant difference in t-PA between survivors and nonsurvivors was observed only on day 7. On admission PAI-1 was above the normal level in both survivors and nonsurvivors. However, in survivors the level on day 7 was significantly lower than on admission. PAI-1 levels did not change significantly in nonsurvivors. There were statistically significant differences between the two groups from the 3rd postburn day (Table 3).

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Table 3 Time course of t-PA, PAI-1, TAT, PAP, F1.2, and D-dimer

Day 1 t-PA (ng/ml) Survivors Nonsurvivors PAI (ng/ml) Survivors Nonsurvivors TAT (µg/l) Survivors Nonsurvivors PAP (µg/l) Survivors Nonsurvivors F1.2 (nmol/l) Survivors Nonsurvivors D-dimer (µg/ml) Survivors Nonsurvivors

Day 3

10.9 ± 7.7 14.9 ± 8.5

11.2 ± 5.6 15.2 ± 9.9

95.7 ± 32.3 115 ± 77

35.5 ± 6.5** 101 ± 62.1

14.6 ± 7.9 15.7 ± 2.9

8.2 ± 5.5 14.5 ± 4.7

491.2 ± 296 542 ± 396

411 ± 189 493 ± 268

Day 5

Day 7

7.1 ± 2.1 12.3 ± 8.5

3.3 ± 2.4* 10.9 ± 9.2

31.2 ± 25** 85.4 ± 39

19.3 ± 14** 80.9 ± 30.4

7.8 ± 4.5 11.9 ± 5.7

6.2 ± 4.9* 11.4 ± 4.5

515.4 ± 284 678.9 ± 374

564 ± 215 3.3 ± 0.45

4.2 ± 0.21 5.3 ± 3.3

4.8 ± 1.1 5.27 ± 3.5

3.7 ± 0.8 5.4 ± 1.2

5.5 ± 2.3 5.5 ± 2.3

2.15 ± 1.5 2.05 ± 0.6

2.3 ± 1.7 1.93 ± 0.5

1.7 ± 1.1 1.96 ± 0.4

2 ± 1.05 2.7 ± 0.7

* p < 0.05; ** p < 0.01 vs. nonsurvivors

Markers of the activation of thrombin generation and neutralization, activation of fibrinolytic system, and the use of the coagulation inhibitors: TAT, PAP, and F1.2 TAT levels were above the normal value on the 1st postburn day in both groups of patients and remained elevated throughout the investigation period. levels decreased significantly in both groups from day 1 to day 7. Survivors had significantly lower levels than nonsurvivors on day 7 postburn. PAP levels were within the normal range in both survivors and nonsurvivors on the first postburn day, and there were no significant differences between the groups during the investigation period (Table 3). F1.2 levels were permanently elevated throughout the investigation period, and there were no statistically significant differences between survivors and nonsurvivors (Table 3). Fibrin degradation products: D-d D-dimer levels were also elevated during the first postburn week in all patients, but no significant differences between survivors and nonsurvivors were observed during the first 7 postburn days (Table 3). None of the coagulation markers on admission proved to be independently associated with 28-day mortality. AT, PS, PAI-1 and SOFA score on day 3, PC on day 5, and TAT on day 7 revealed a good prognostic value for ICU mortality, according to ROC AUC (Table 4).

Discussion Coagulation system homeostasis is frequently impaired in burn patients. Thermal injury initiates the systemic inflammatory response syndrome that is mediated by the acti-

vation of numerous mechanisms (e. g., coagulation, fibrinolysis, complement). While controlled activation of the coagulation system is an essential part of the wound healing process, uncontrolled activation of the coagulation mediators, often seen in patients with severe thermal injury, leads to an increased morbidity and mortality [6, 7, 13]. Severe burn injury frequently promotes a DIC syndrome. DIC is a complex disorder characterized by the activation of coagulation and fibrinolytic pathways, consumption of coagulation factors, and depletion of coagulation regulatory proteins [14]. There is good experimental and clinical evidence that the activation of coagulation and fibrin deposition contributes to multiple organ dysfunction and mortality in critically ill patients [15–19]. The ISTH DIC score has recently been studied in a few studies of critically ill patients with a clinical suspicion of DIC, but, to our knowledge, it has not been validated in burn patients. DIC has been shown to be a strong and independent predictor of mortality in patients with sepsis. Patients with sepsis and overt DIC, according to this scoring system, have a mortality of more than 40%, compared with about 27% in patients without DIC. For each DIC point in the system the odds ratio for mortality is 1.29, whereas, in comparison, for each APACHE point, the odds ratio for mortality is 1.07 [18]. Our study revealed that a high percentage of patients (41 of 45, 91.1%) with severe burn injury fulfilled the DIC criteria. Nonsurvivors had significantly higher percentage of overt and nonovert DIC diagnoses than survivors (overt DIC 53.3% vs. 6.7% and nonovert DIC 80% vs. 46.7%). Only a small number of survivors (4 of 45) had no DIC criteria. Overt DIC patients had significantly higher SOFA score than patients with nonovert DIC. According to logistic regression analysis, the presence of overt DIC diagnosis was related to mortality (p = 0.000, odds ratio 0.1, 95% CI = 0.31–0.33).

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Table 4 Prognostic value of coagulation parameters early postburn (SE, standard error; CI, confidence interval)

Area SOFA, day 3 AT III, day 3 PS, day 3 PC, day 5 PAI-1, day 3 TAT, day 7

0.846 0.771 0.802 0.802 0.976 0.827

The correlation between activation of coagulation and severity of burn, organ failure, and prognosis is still discussed in the literature [1, 7, 10–13, 15, 20, 21]. Prior clinical studies [7, 10–13, 15, 21] indicate that antithrombotic factors such as AT III, PS, and PC levels are decreased in burn patients, and that the levels of TAT, PAP t-PA, PAI-1, and D-dimer are increased. However, studies evaluating coagulation abnormalities in burns include only a small number of patients [7, 21], and they have not demonstrated the time course of the coagulation factors [13]. Moreover, there are not sufficient data regarding the relationship of coagulation abnormalities with organ failure (estimated by the SOFA score) and the outcome in burn patients. The coagulopathy seen in burn patients is associated with the marked depletion of the endogenous regulators of blood coagulation [13, 22]. In our study the levels of coagulation inhibitors were decreased in all patients and returned to normal levels only in survivors on day 5 for AT and PS and on day 7 for PC. On admission no differences were noted in the coagulation inhibitors. The levels of TAT were significantly elevated in both survivors and nonsurvivors and remained elevated throughout the investigation period. The combined decrease in AT along with the elevated levels of TAT in our patients indicate the increased use and consumption of AT and augmented thrombogenicity. High levels of t-PA and the counterbalancing of its effect by increased levels of PAI-1 have been reported in sepsis and burn patients [19, 21]. In sepsis patients t-PA and PAI-1 levels were found to be higher in nonsurvivors and tended to normalize in survivors [23, 24]. We observed a significant elevation in PAI-1 levels in all patients on admission (about three times higher than normal values in nonsurvivors). On the other hand, we observed only a moderate increase in t-PA levels in nonsurvivors. The greater increase in PAI-1 than in t-PA can be explained by the behavior of PAI-1 as an acute-phase reactant in response to

SE 0.061 0.087 0.894 0.908 0.92 0.115

Asymptotic p

95% CI

0.002 0.020 0.029 0.015 0.05 0.05

0.727–0.966 0.941–0.601 0.990–0.595 0.982–0.621 0.599–0.985 0.601–1.053

injury stress [13, 24]. Aoki et al. [25] report that the increase in PAI-1 is more rapid than that in fibrinogen or C-reactive protein in postoperative patients. This suggests that the PAI-1 level would be a sensitive indicator of the acute response to stress. Nevertheless, the persistent production of excessive PAI-1 observed in our study may induce hypofibrinolysis and may play a pathophysiological role in the development of hypercoagulability and organ dysfunction in the early postburn period. Normal levels of plasmin-antiplasmin were also observed in our patients during the investigation period. Our observations are in agreement with those of other authors [18, 26–28] who have found that in patients with inflammation and DIC the activation of fibrinolysis is not sufficient to counteract the excessive fibrin formation and may contribute to both organ damage and mortality. The elevated plasma concentrations of F1.2 and D-dimer in our patients reflect the increased generation of thrombin and fibrin formation and its degradation. We found no differences between the survivors and nonsurvivors in these markers of coagulation. We also found no association of coagulation markers with mortality on admission. Only from day 3 (AT III and PS), and day 5 (PC) the levels of coagulation inhibitors proved to be mortality predictors as judged by AUC analysis. The PAI-1 level on day 3 and TAT level on day 7 also had a prognostic value for ICU mortality. The main limitation of our study is the relatively small number of investigated patients. Obviously more data must be analyzed for further confirmation of these findings. In conclusion, there is a high percentage of burn ICU patients that fulfill the ISTH DIC criteria. The activation of coagulation, impairment of physiological anticoagulant pathways, and depression of fibrinolysis are observed in the majority of patients with severe burn injury in the early postburn period. The presence of overt DIC in ICU burn patients seems to contribute to organ failure and mortality.

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