Emorragie nel paziente anticoagulato e politraumatizzato

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1 Emorragie nel paziente anticoagulato e politraumatizzato Lagundo 1 Dicembre 2012 ANNA MARIA FERRARI DIRETTORE DEU REGGIO EMILIA

2 Prevalence and outcomes associated with warfarin use in injured adults: An analysis of the National Trauma Databank L A Dossett, B A Cotton, M R Griffin, Vanderbilt University Medical Center, Nashville Journal of the American College of Surgeons, Volume 209, September 2009 RESULTS patients (36,270 warfarin users) from 402 centers were eligible for analysis. Warfarin use increased among all patients from 2.3% in 2002 to 4.0% in 2006 (p<0.001). In patients older than 65, the rate of use increased from 7.3% in 2002 to 12.8% in 2006 (p<0.001). After adjusting for age, sex, coronary artery disease, prior cardiac surgery, and ISS, warfarin use was associated with an OR of death of 1.3 (95% confidence interval [CI], ; p<0.001) in all patients and 1.2 (95% CI, , p<0.001) in patients older than 65.

3 Prevalence and outcomes associated with warfarin use in injured adults: An analysis of the National Trauma Databank L A Dossett, B A Cotton, M R Griffin, Vanderbilt University Medical Center, Nashville Journal of the American College of Surgeons, Volume 209, September 2009 CONCLUSIONS Warfarin use is common among injured patients, and its prevalence has increased each year since After adjusting for comorbidities associated with warfarin, its use is associated with a 30% increased mortality among all patients and a 20% increased mortality among patients older than 65.

4 Terapia antitrombotica e Trauma J Am Coll Surg 2010 by the American College of Surgeons

5 Terapia antitrombotica e Trauma J Am Coll Surg 2010 by the American College of Surgeons

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7 From Fabbri A et al, JNNP, 2004

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9 Prothrombin Complex Concentrates for Oral Anticoagulant Therapy-Related Intracranial Hemorrhage: A Review of the Literature Patients with OAT-related ICH have a mortality rate approaching 60%, compared to about 40% for their non-anticoagulated counterparts The poor outcome after OAT-related ICH is related a larger baseline volume of hemorrhage, as well as continued expansion of the hematoma size after admission Early growth of the hematoma occurs more frequently in anticoagulated versus non-anticoagulated patients with ICH, 54 versus 16% respectively, and later in the hospital course Furthermore, a higher initial INR predicts higher mortality in ICH patients. All of these data support a need for an early and rapid INR correction Neurocrit Care (2010) 12:

10 Emergency reversal of antithrombotic treatment Levi M., Int and Emerg Med. 2009

11 Trattamento delle Urgenze Emorragiche in corso di TAO FFP PCC Standard basato sui livelli di fattore VIII Variabilità del contenuto di fattori vit.k dipendenti ml/kg ml per ottenere INR <1.4 Sovraccarico emodinamico Tempo di preparazione Fattore II, (VII), IX, X, proteina C, S, Correzione più rapida e completa rispetto al plasma Nessun rischio di sovraccarico emodinamico

12 Neurocrit Care (2010)

13 Trattamento delle EIC in corso di TAO Linee Guida FCSA 2010 Sospensione della TAO, infusione di vitamina K 10 mg diluita in soluzione fisiologica (100 ml) in almeno 30 minuti se INR < 2,0 se INR 2,0 3,9 se INR 4,0 5,9 se INR > 6 PCC 20 UI/kg di peso corporeo PCC 30 UI/kg di peso corporeo PCC 40 UI/kg di peso corporeo PCC 50 UI/kg di peso corporeo La dose complessiva può essere infusa* in minuti Al termine controllare INR; se > 1.5 ripetere l infusione di PCC

14 EMORRAGIA INTRACRANICA Trattamento se TC positiva per emorragia E d obbligo l immediato ripristino di normali livelli di coagulazione A questo scopo e per non perdere tempo in attesa di ricevere il risultato dell INR immediata infusione di 20 UI/kg di peso corporeo di Complesso Protrombinico Concentrato (PCC) in minuti seguita da infusione di vitamina K 10 mg diluita in soluzione fisiologica (100 ml) in almeno 30 minuti

15 EMORRAGIA INTRACRANICA Una volta ottenuto il risultato dell INR completare la normalizzazione della coagulazione infondendo CPC secondo il seguente schema se INR < 2,0 nulla se INR 2,0-4,0 ulteriori 10 UI/kg di peso corporeo se INR > 4,0 ulteriori 30 UI/kg di peso corporeo

16 REVERSE EMORRAGICO NEI DEA ITALIANI ( ) Vitamina K 40,5% Plasma fresco 21,6% CCP 6% rf VIIa 2,6% Ricoagulato 1 paziente su 3 Baldi G. et al. Cerebrovasc. Dis. 2006; 22: /10/12

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18 GESTIONE DEL TRAUMA IN CORSO DI TRATTAMENTO CON I NUOVI ANTICOAGULANTI ORALI

19 Dabigatran Rivaroxaban Apixaban Nome commerciale Pradaxa Xarelto Eliquis Meccanismo d azione Inibitore fattore IIa Inibitore fattore Xa Inibitore fattore Xa Profarmaco Sì No No Ore per la Cmax Emivita (ore) Eliminazione 80% renale 20% biliare 1/3 renale 1/3 renale, inattivo 25% renale 75% biliare Interazioni P-Glycoprotein P-Glycoprotein CYP3A4 Interferenza cibo Nessuna Ritardato assorbimento Legame con proteine 35% 90% 87% P-Glycoprotein and CYP3A4 Non riportato Dosaggio Due somm. al dì Una somm. al dì Due somm. al dì

20 Rischio stroke emorragico NAO

21 Rischio emorragie maggiori

22 Gestione del sanguinamento/ reverse con i nuovi anticoagulanti orali Nessun antidoto validato Emivita dipendente dalla funzione renale Incerta utilità di plasma o farmaci emostatici

23 Potenziali metodi di reverse con i nuovi anticoagulanti orali Agenti emostatici non specifici - Plasma fresco congelato - PCC - FVIIa ricombinante - Antifibrinolitici (acido tranexamico) L impiego di farmaci emostatici non è validato e il loro uso deve sempre tener conto del potenziale rischio pro-trombotico

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25 Potenziali metodi di reverse con i nuovi anticoagulanti orali Rimozione dell anticoagulante - Emodialisi (Dabigatran si, Rivaroxaban no) - Emoperfusione - Plasmaferesi

26 Algoritmo di gestione dell evento emorragico van Ryn J et al. Thromb Haemost 2010 Pazienti in trattamento con dabigatran con emorragia Emorragia lieve Emorragia moderata o severa Emorragia grave con pericolo di vita Posticipare la successiva somministrazione o interrompere il trattamento Trattamento sintomatico Compressione meccanica Intervento chirurgico Idratazione e supporto emodinamico Trasfusione di emoderivati Somministrazione di carbone orale * (se dabigatran etexilato è stato assunto 2 ore prima) Emodialisi Valutazione del fattore rfvlla o PCC* Filtrazione di carbone * *Raccomandazione basata solo su dati non clinici, non c è esperienza su volontari o pazienti. PCC = concentrato di complessi di protrombina (non-attivata o attivata ); rfviia = Fattore VII attivato ricombinante

27 Rivaroxoban emergenze e reversal strategy <<Rivaroxaban Practical Guide V1 0_ pdf>>

28 COAGULOPATIA NEL PAZIENTE CON TRAUMA GRAVE

29 Fibrinolysis Consuption of clot factor Prova prova Hypothermia Modificato da: Clinical and cellular effects of hypothermia, acidosis and coagulopathy in major injury- Thorsen et AL- British Journal of Surgery 2011

30 IMPATTO Coagulopathy in trauma patients, and specifically acute traumatic coagulopathy (ATC), is associated with higher transfusion requirements longer intensive care unit and hospital stays more days requiring mechanical ventilation and a greater incidence of multiorgan dysfunction

31 IMPATTO Injury to brain tissue may predispose to acute traumatic coagulopathy and about one-third of patients with traumatic brain injury (TBI) have a coagulopathy

32 ~1800 pts HEMS admissions ~1 in 4 pts admitted with coagulopathy Independent of fluid administration Significant association with mortality ATC = ACoTS (acute coagulopathy of trauma-shock)

33 ATC correlates with ISS

34 Pathophysiology ATC DIC Tissue/endothelial injury and hypoperfusion Increased endogenous anticoagulants Fibrinolysis and hyperfibrinolysis

35 HYPERFIBRINOLYSIS Thr thrombin, Tm thrombomodulin, apc activated protein C, PS protein S, PAI 1 plasminogen activator inhibitor 1, t-pa tissue plasminogen activator Hypoperfusion causes increased endothelial expression of thrombomodulin. The thrombin thrombomodulin complex activates protein C, which (together with protein S) inhibits the accelerators FVa and FVIIa. Additionally, larger quantities of apc decrease plasminogen activator inhibitor, the most essential antagonist for tissue plasminogen activator. Together with decreased plasmin levels, hyperfibrinolysis is triggered. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Ann Surg (2007) Coagulation management in multiple trauma: a systematic review. H. Lier B. W. Bo ẗtiger J. Hinkelbein H. Krep M.Bernhard Intensive Care Med (2011)

36 INJURY HAEMORRHAGE COAGULOPATHY HYPOPERFUSION EXPOSURE ACIDOSIS HYPOTHERMIA

37 IPOTERMIA T corporea < 35 C Lieve C Moderata Severa < 30 NEL TRAUMA < 32 C SEVERA Cause: Esposizione alle basse temperature (accidentale) Infusione di fluidi freddi (trasfusioni) Infusione di farmaci (spt anestetici)

38 IPOTERMIA C è la temperatura ideale per le reazioni enzimatiche dei fattori della coagulazione e per la funzione piastrinica.

39 L attività dei fattori della coagulazione si riduce del 10% per ogni grado di riduzione della temperatura

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41 Le piastrine sono molto più sensibili alla temperatura

42 PIASTRINA Reazione critica per adesione piastrinica, temperatura dipendente GpIb vwf ENDOTELIO ENDOTELIO ENDOTELIO ENDOTELIO SUB-ENDOTELIO COLLAGENE

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44 ACIDOSI L acidosi è secondaria a ipotensione e ipovolemia con ipoperfusione ed ipossia tissutale ed incremento del metabolismo anaerobio. L acidosi può essere in questo setting aggravata dalla infusione di soluzioni saline e anche dalla trasfusione massiva di EC : 1 U di GR ha un ph basso che si riduce progressivamente con la conservazione, per effetto della produzione da parte dei GR di acido lattico

45 L attività dei fattori della coagulazione si riduce del 90% per valori di PH inferiori a 7.1

46 The effect of temperature and ph on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patient. Meng ZH, Wolberg AS, Monroe DM 3rd, Hoffman M. J. Trauma 2003 A coagulation factor complex with normal activity at ph 7.4 has 50% of normal activity at ph % at ph % of normal activity at ph 6.8

47 Thrombin generation rate in blood samples measured as thrombin-antithrombin III (TAT) complex concentration. The TAT concentration was measured in sample aliquots at time 0 (sample withdrawal) and at 1-min intervals thereafter to determine thrombin generation with time in each sample. *P < 0.05, different from normal value at the same quench time point. J Trauma 2005;58

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49 Fibrinolysis Consuption of clot factor Prova prova Hypothermia Modificato da: Clinical and cellular effects of hypothermia, acidosis and coagulopathy in major injury- Thorsen et AL- British Journal of Surgery 2011

50 Coagulopathy: Its Pathophysiology and Treatment in the Injured Patient Brandon H. Tieu, John B. Holcomb, Martin A. Schreiber. World J Surg (2007) 31 HEMODILUTION Hemodilution of coagulation products can have a profound effect on the development of coagulopathy. Direct loss of coagulation factors through hemorrhage can quickly reduce the body s small stores of fibrinogen (10 g) and platelets (15 ml). Dilutional coagulopathy can then develop when these losses are replaced with fluids that do not contain clotting factors. Dilution often starts in the pre-hospital setting when crystalloids are given en route to the trauma center, followed by prbcs in the trauma bay before laboratory test results become available.

51 Breaking the Bloody Vicious Cycle Prevent hemodilution Coagulopathy Hemorrhage Hemodilution and Hypothermia Resuscitation Treat coagulopathy Control hemorrhage Use best possible resuscitation products Prevent hypothermia

52 Damage Control Resuscitation 3 essential components: Damage control surgery Haemostatic resuscitation Permissive hypotension Cotton BA et al Ann Surg 2011

53 1. Damage Control surgery Unstable patients with major trauma do not survive prolonged definitive surgery Normalise physiology at expense of anatomy Stop haemorrhage (Packing, clamping, resection +/- IR) Minimise contamination Limb saving procedures Good wash out of cavities Drains and low threshold for Laparostomy Definitive surgery another day Optimise lethal triad on the ICU

54 2. Haemostatic resuscitation Aggressive and simultaneous management of the lethal triad and ATC in major trauma Minimise Crystalloid transfusion, NO COLLOID. PRBC - HCT~0.5-6 & K mmol/L. Important for oxygen carriage and volume. FFP FII, V, VII-XII, fibrinogen, vwf and ATIII Platelets Cryoprecipitate fibrinogen, FVIII, FXIII and vwf Ideal PRBC:FFP:platelet ratio not clear but should be <2:1:1 Use of adjunctive therapies Tranexamic acid (Crash 2) Calcium vital for clotting

55 Permissive hypotension The end points for resuscitation will depend on age, premorbid autoregulatory state and acute pathology Rule of thumb resuscitation end points: Penetrating trauma - maintain cerebration or central pulse or SBP~60mmHg Blunt trauma maintain radial pulse or SBP >80mmHg Head injury maintain temporal pulse or SBP >100mmHg

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57 Coagulopathy: Its Pathophysiology and Treatment in the Injured Patient Brandon H. Tieu, John B. Holcomb, Martin A. Schreiber. World J Surg (2007) 31 Diagnosis and treatment strategies of coagulopathy in trauma patients with hemorrhagic shock. It is imperative to continually assess the patient for the resolution of coagulopathy, acidosis, and hypothermia after the initiation of treatment. Implementation of more invasive maneuvers may be required if standard procedures fail.

58 The coagulopathy of trauma is a discrete disease which has a decisive influence on survival. Diagnosis and therapy of deranged coagulation should start immediately after admission to the emergency department. A specific protocol for massive transfusion should be introduced and continued. Loss of body temperature should be prevented and treated. Acidaemia should be prevented and treated by appropriate shock therapy.

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60 This randomised controlled trial was undertaken in 274 hospitals in 40 countries adult trauma patients with, or at risk of, significant bleeding

61 All-cause mortality was significantly reduced with tranexamic acid (1463 [14 5%] tranexamic acid group vs 1613 [16 0%] placebo group; relative risk 0 91, 95% CI ; p=0 0035) The risk of death due to bleeding was significantly reduced (489 [4 9%] vs 574 [5 7%]; relative risk 0 85, 95% CI ; p=0 0077)

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63 Thrombelastography R : Reaction Time Clotting Factors SP a : Clot Formation Time Fibrinogen MA : Maximum Amplitude Platelets G : Clot Strength EPL : Percent Lysis Platelet - Fibrin Interaction Fibrinolysis

64 Grazie dell attenzione