Χορήγηση αντιθρομβίνης σε ασθενείς με βαριά εγκαύματα

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PhD thesis (EN)

2007 (EN)
Antithrombin administration in patients with severe burn injury
Χορήγηση αντιθρομβίνης σε ασθενείς με βαριά εγκαύματα

Lavrentieva, Athina V.

Ο σκοπός της παρούσας μελέτης ήταν να εξετάσει την ενεργοποίηση του πηκτικού μηχανισμού και την αξιολόγηση των διαταραχών του πηκτικού μηχανισμού στους ασθενείς με θερμική κάκωση με τη χρήση της κλίμακας DIC της ISTH, καθώς και την αποτελεσματικότητα και την ασφάλεια της χορήγησης της ΑΤ σε ασθενείς με βαριά εγκαύματα. Η μελέτη περιλαμβάνει 31 ασθενείς οι οποίοι έπασχαν από βαριά εγκαύματα και νοσηλεύτηκαν στη ΜΕΘ Εγκαυμάτων του Γενικού Νοσοκομείου «Γ. Παπανικολάου» κατά τη διάρκεια των ετών 2004-2005. Οι ασθενείς εισήχθησαν στη μελέτη κατά τη διάρκεια των 24 πρώτων ωρών μετά τον θερμικό τραυματισμό. Η βαρύτητα της κατάστασης προσδιορίστηκε με τα βαθμολογικά συστήματα: APACHE II (Acute Physiologic, Chronic Health Evaluation) και SAPS II (Systemic Acute Physiologic Score). Η βαρύτητα του εγκαύματος εκτιμήθηκε με τη βοήθεια του ABSI (Abbreviated Burn Severity Index). Για την εκτίμηση του βαθμού δυσλειτουργίας των οργάνων χρησιμοποιήθηκε η κλίμακα SOFA (Sequential Organ Failure Assessment Score). Μελετήθηκαν οι εξής παράμετροι πηκτικού μηχανισμού: Φυσικοί αναστολείς πήξης: • Αντιθρομβίνη (AT), • Πρωτεΐνη C (protein C, PrC) • Πρωτεΐνη S (protein S, PrS) Δείκτες ενεργοποίησης ινωδόλυσης: • Ιστικός ενεργοποιητής του πλασμινογόνου (tissue plasminogen activator, t-PA) • Αναστολέας του ενεργοποιητή του πλασμινογόνου (plasminοgen activator inhibitor 1, PAI-1) • Σύμπλεγμα πλασμίνης -α2 αντιπλασμίνης (plasmin/α2 antiplasmin complexes, PAP. Δείκτες ενεργοποίησης παραγωγής και αποδόμησης της θρομβίνης και κατανάλωσης των αναστολέων πήξης: • Σύμπλεγμα θρομβίνης-αντιθρομβινης (thrombin/antithrombin complexes, TAT) • Προϊόν αποδομής του ινώδους (D-διμερές, D-dimer, D-d) • Θραύσμα 1+2 προθρομβίνης (prothrombin fragment 1+2, F1+2. )Οι ασθενείς αντιμετωπίζονταν σύμφωνα με την καθιερωμένη στην ΜΕΘ Εγκαυμάτων θεραπευτική τακτική. Oι ασθενείς χωρίσθηκαν τυχαιοποιημένα σε δύο ομάδες: 1η-ομάδα μελέτης δράσης της ΑΤ (15 άτομα), 2η-ομάδα ελέγχου (16 άτομα). Στους ασθενείς της ομάδας μελέτης χορηγούνταν το σκεύασμα ΑΤ σε συνεχή στάγδην χορήγηση κατά τη διάρκεια των πρώτων 4 ημερών της νοσηλείας, έτσι ώστε να επιτευχθούν επίπεδα της AT >150%. Η ποσότητα της ΑΤ που χορηγήθηκε στους ασθενείς της ομάδας θεραπείας ήταν 64.9±11.4 u/kg/ημέρα. Οι δύο ομάδες αντιμετώπισης δεν είχαν στατιστικά σημαντικές διαφορές σε ότι αφορά τα βασικά χαρακτηριστικά τους Τα επίπεδά των δεικτών ενεργοποίησης του πηκτικού μηχανισμού δεν διέφεραν στις δύο ομάδες. Κατά την εισαγωγή οι ασθενείς είχαν χαμηλά επίπεδα της ΑΤ. Η εφαρμογή της κλίμακας DIC κατέδειξε ότι διαταραχές του πηκτικού μηχανισμού παρατηρούνται σε μεγάλο αριθμό ασθενών με βαριά εγκαυματική βλάβη (90.3%) και συνδυάζονται με ανεπάρκεια οργάνων και αυξημένη θνητότητα (παρουσία overt-DIC σχετίζεται με δυσμενή έκβαση (Fisher's exact test, p=0.038, estimated Odds Ratio= 6.8 [95% CI: 1.233, 37.497]). Παρατηρήθηκε σχετική αναστολή του ινωδολυτικού συστήματος (υψηλά επίπεδα PAI-1, χαμηλά επίπεδα του t-PA και φυσιολογικά επίπεδα PAP). Κατά συνέπεια, η ενεργοποίηση της ινωδόλυσης στα σημεία σχηματισμού και εναπόθεσης ινώδους συνυπήρχε με μια γενική αναστολή της ινωδολυτικής δραστηριότητας λόγω των υψηλών επιπέδων PAI-1. Οι ασθενείς της ομάδας χορήγησης ΑΤ παρουσίαζαν σημαντική πτώση των επιπέδων ΤΑΤ και των D-διμερών κατά την πρώιμη μετεγκαυματική περίοδο, όπως και σημαντική βελτίωση της λειτουργίας των οργάνων (μείωση των τιμών της κλίμακας SOFA). Κανένας από τους ασθενείς που έλαβε την ΑΤ δεν παρουσίασε αιμορραγικές επιπλοκές. Παρατηρήθηκε στατιστικά σημαντική διαφορά στην θνητότητα των 28 ημερών (μέθοδος Kaplan-Meier). Από τα αποτελέσματά μας φαίνεται ότι η χορήγηση της ΑΤ αναστέλλει την υπερβολικού βαθμού ενεργοποίηση της πήξης και συμβάλει στη βελτίωση της λειτουργίας οργάνων και πρώιμης θνητότητας σε ασθενείς με βαριά εγκαύματα u967 χωρίς να συνδυάζεται με την εμφάνιση σημαντικών επιπλοκών
The aim of this prospective study was to evaluate the early activation of coagulation and fibrinolysis after severe thermal injury, to correlate the coagulation status alterations with prognosis, as well as to estimate the treatment effect of AT administration on coagulation parameters and organ failure. Thirty one patients with severe burn injury admitted to the four bed Burn Unit in "Papanikolaou" General Hospital from April 2004 to December 2005 were prospectively investigated in a randomized trial. The study protocol was approved by the local ethics committee and written consent was obtained by the patients or their closest relatives. The patients were enrolled in the study during the first 24 hours after the burn injury. Patients with known hematological disease, with hepatic and renal failure, malignancies and associated trauma were excluded from our study (n=5). AT were administered for four consecutive days after admission in the burn unit at a dose 64.9±11.4 u/kg/day to achieve the level of 150%. Patients' clinical management was guided by the written treatment protocol of our ICU. Anthropometric characteristics (age, sex) were recorded. Severity of the burn injury was estimated by the percentage of total burn surface area (TBSA) and the Abbreviated Burn Severity Index (ABSI). The severity of the illness was determined by the APACHE II score (Acute Physiology and Chronic Health Evaluation II) and SAPS II score (Simplified Acute Physiological Score II). For the diagnosis of multiple organ dysfunction or failure, the Sequential Organ Failure Assessment score (SOFA) was used. the illness was determined by the APACHE II score (Acute Physiology and Chronic Health Evaluation II) and SAPS II score (Simplified Acute Physiological Score II). For the diagnosis of multiple organ dysfunction or failure, the Sequential Organ Failure Assessment score (SOFA) was used. According to the International Society on Thrombosis and Haemostasis (ISTH) definition [18] DIC score have been validated and the value of the diagnosis of overt DIC in predicting the 28th day mortality was examined. The following coagulation parameters were evaluated on admission in the ICU and daily thereafter for four consecutive days: Antithrombin (AT) activity was measured in the plasma by chromogenic assay (Dade- Bering; normal values 80-120%), as was the protein C (PC) activity (Dade- Bering; normal values 70-130%). The free protein S levels (PS) were also measured by elecrtoimmunodiffusion method (Dade- Bering; normal values 70-130%). The plasminοgen 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 ng/ml for PAI-1, 1-12 ng/ml for t-PA). To assess the activation of the fibrinolytic system, the thrombin generation and neutralization and the use of the coagulation inhibitors, the following markers were measured: thrombin/antithrombin complexes (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 0.5μg/ml). The F1.2 antigen levels were measured by the enzyme-linked immunoassay (normal values 0.4-1.1nmol/L). The patients' mortality was recorded on the 28th day of ICU admission. ANOVA methodology was conducted for the study of continuous variable measurements over time. Multivatiative logistic regression was used to evaluate the prognostic influence of DIC on mortality rate. The corresponding Odds Ratios were also calculated. Kaplan-Meier survival trend was used and statistically significant difference was evaluated according to Log Rank (Mantel-Cox) test between AT-treated and control groups. Results were considered statistically significant for p-values less than 0.05. Statistical analysis was conducted with SPSS 14.0. The levels of coagulation system markers did not differ significantly between 2 groups of patients on admission. Nine patients (29%) fulfilled the criteria of overt DIC, and 19 (61.3 %) had non-overt DIC. Only the small number of the survivors (three) had no criteria of DIC diagnosis. The forward stepwise multivariative logistic regression analysis revealed that the presence of overt DIC is significantly related to the outcome (p=0.002, OR=0.021, 95% CI = 0.002-0.251). On admission all patients had severe acquired deficiency of AT, PC and PS. With the supplementation of AT its levels were increased, but never achieved the desirable levels (>150%). The t-PA levels were within the physiological range in both groups of patients on admission and were decreased significantly at day four compared to day one values only in the AT-treated group. PAI-1 was increased above the physiological levels at day 1 after burn injury both in the control and in the AT treated group. There was statistically significant decrease in PAI-I levels in both groups of patients from the first day to the fourth day. The levels of TAT were above the physiologic range during the investigation period in both groups of patients. The TAT levels decreased significantly in the AT treated groups from day one to day four. PAP levels were within physiological range in the AT-treated and the control groups during the first postburn day and there were no statistically significant difference between two groups of patients during the investigation period. The levels of F1.2 were elevated during the first day and were decreased significantly in both groups of patients from day one to day four. D-d levels were also elevated permanently during the first postburn days in all patients, and changed in the opposite direction for the two groups from day one to day four (elevated in control group and decreased in AT - treated group). AT-treated patients showed a decrease in SOFA score in day three and four compared to the admission SOFA. On the contrary, the control group patients didn't change their SOFA score in the same period. AT- treated patients had an absolute reduction in 28-day mortality of 25% compared to control group (p=0.004). No treatment related side effects were observed. None of the patients who received AT showed hemorrhagic complication. Activation of coagulation mediators was detected in ICU patients with severe burn injury. Most of these patients fulfilled the criteria of DIC syndrome. The diagnosis of DIC was related to mortality. Treatment with AT seems to decrease hypercoagulation (decresed TAT and D-d). Improvement of organ function and mortality was observed in patients after AT administration

PhD Thesis / Διδακτορική Διατριβή

Burns and scalds
Διάχυτη ενδοαγγειακή πίεση
Disserminated intravascular coagulation
Coagualation abnormalities
Συστηματική φλεγμονώδης αντίδραση
Systemic Inflammatory Response
Διαταραχές πήξης

Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης (EL)
Aristotle University of Thessaloniki (EN)



Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης, Σχολή Επιστημών Υγείας, Τμήμα Ιατρικής

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