Marco Verri. U.O. di Anestesia e Rianimazione Universitaria. Dip.Emergenza Az.Ospedaliero-Universitaria Ferrara

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1 Marco Verri U.O. di Anestesia e Rianimazione Universitaria Dip.Emergenza Az.Ospedaliero-Universitaria Ferrara

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3 proteina C attivata ricombinante? (Drotrecogin) 6 riconoscimento shock sett. e gravità 1 microbiologia antibioticoterapia rimozione sorgente steroidi? 5 fluidoterapia: 2 cristalloidi colloidi emoderivati supporto respiratorio sostituz.funzione renale controllo glicemico nutrizione sedazione prevenzione complicanze ecc. inotropi 4 monitoraggio 7 altro 8 vasopressori 3

4 Molecular biology of inflammation and sepsis: a primer Cinel I. and Opal S. (Crit Care Med 2009; 37: )

5 una spirale distruttiva una spirale distruttiva Infezione Infezione Infiammazione Infiammazione Coagulazione Coagulazione Infiammazione Infiammazione Coagulazione Coagulazione Infiammazione Infiammazione Coagulazione Coagulazione Disfunzione Disfunzione Endoteliale Endoteliale Ischemia Ischemia Insufficienza Insufficienza d Organo Organo Morte Morte Infiammazione Infiammazione Esmon. Immunologist. 1998;6:84. Infezione Infezione Infiammazione Infiammazione Coagulazione Coagulazione Infiammazione Infiammazione Coagulazione Coagulazione Infiammazione Infiammazione Coagulazione Coagulazione Disfunzione Disfunzione Endoteliale Endoteliale Ischemia Ischemia Insufficienza Insufficienza d Organo Organo Morte Morte Infiammazione Infiammazione Esmon Immunologist 1998; 6; 84 Infezione Infezione Infiammazione Infiammazione Coagulazione Coagulazione Infiammazione Infiammazione Coagulazione Coagulazione Infiammazione Infiammazione Coagulazione Coagulazione Disfunzione Disfunzione Endoteliale Endoteliale Ischemia Ischemia Insufficienza Insufficienza d Organo Organo Morte Morte Infiammazione Infiammazione Infezione Infezione Infiammazione Infiammazione Coagulazione Coagulazione Infiammazione Infiammazione Coagulazione Coagulazione Infiammazione Infiammazione Coagulazione Coagulazione Disfunzione Disfunzione Endoteliale Endoteliale Ischemia Ischemia Insufficienza Insufficienza d Organo Organo Morte Morte Infiammazione Infiammazione sepsi sepsi

6 Stato di coscienza alterato, confusione, psicosi Tachicardia Ipotensione CVP PAOP FR > 20 atti/m PaO2 < 70 mm Hg SaO2 < 90% PaO2/FiO2 300 Oliguria Anuria Creatinina Ittero Enzimi fl Albumina PT fl Piastrine PT/APTT fl Proteina C D-dimero SOFA?

7 SHOCK SETTICO Condizione di ipoperfusione tissutale e d organo determinata da una disfunzione cardio-circolatoria acuta SEPSI GRAVE (sepsi + disfunzione d organo) + IPOTENSIONE (PAS < 90 mmhg o PAM < 60 mmhg) refrattaria ad adeguata espansione volemica

8 trauma, pancreatite, ischemia-riperfusione,ecc. Fisiopatologia della sepsi da Fink et al. Textbook of critical care 2005

9 proteina C attivata ricombinante? (Drotrecogin) riconoscimento shock sett. e gravità microbiologia antibioticoterapia rimozione sorgente cristalloidi steroidi? fluidoterapia: colloidi emoderivati supporto respiratorio sostituz.funzione renale controllo glicemico nutrizione sedazione prevenzione complicanze ecc. inotropi vasopressori

10 Riconoscimento che qualche cosa non va alterazione del sensorio dispnea, tachipnea, alterazione della meccanica-dinamica ventilatoria SpO 2 alterazione della PA tachicardia, aritmia contrazione della diuresi Æ T alterazione degli esami ematochimici ecc. Quanto non va? Valutazione della gravità giudizio personale scale di gravità

11 Modified Early Warning Score PA sist < >200 FC < >130 FR < >=30 T C < >=38.5 AVPU Alert reagisce reagisce Non reagisce Voce Pain Unresponsive Cut-off >4 Subbe CP et al Q J Med 2001; 94:

12 Patient-At-Risk warning score SpO2 % < >=95 Diuresi no <0.5 dialisi >3 ml/kg/h PA sist < >=180 FC < >=130 FR < >=40 T C < >=38.5 GCS Alert Confuso reagisce Non reagisce voce o solo dolore Goldhill DR et al Anaesthesia 2005; 60:

13 Clinical Instability Score SpO 2 % >= >=95 FiO 2 % aria PA sist <= >=222 FC < >180 FR <= >=53 T C <= >=41 antipiretico NO SI NON CONSIDERA IL QUADRO NEUROLOGICO

14 Sequential Organ Failure Assessment (SOFA) Vincent JL, et al. Intensive Care Med 1996;22: Score SNC GCS <6 RESPIRATORIO Pa/FiO 2 (mmhg) < 400 < 300 < 200 con supporto resp < 100 CARDIOVASCOLA RE Ipotensione MAP < 70 mmhg Dopa < 5 o DObutamin a Dopa > 5 o Adr < 0,1 o Noradr < 0,1 Dopa > 15 Adr > 0,1 Noradr > 0,1 COAGULAZIONE Piastrine(10 3 /mm 3 ) < 150 <100 <50 <20 FEGATO Bilirubina(mg/dl) 1,2-1,9 2,0-5,9 6,0-11,9 >12 RENALE Creat (mg/dl) o Diur 1,2-1,9 2,0-3,4 3,5-4,9 o < 500 ml/24h > 5,0 < 200 ml/24 h

15 Riconoscimento che qualche cosa non va alterazione del sensorio dispnea, tachipnea, alterazione della meccanica-dinamica ventilatoria SpO 2 alterazione della PA tachicardia, aritmia contrazione della diuresi Æ T alterazione degli esami ematochimici ecc. quanto sopra + iper-ipotermia / leucocitosi-leucopenia infezione Quanto non va? Valutazione della gravità giudizio personale scale di gravità sepsi, sepsi grave, shock settico

16 altre possibili cause di quadri settici pancreatite infarto intestinale sindromi da ischemia-riperfusione shock chirurgia maggiore traumi ematomi infarto miocardico infarto polmonare malattia tromboembolica emorragia cerebrale (meningea) crisi tireotossica insuff.surrenalica acuta eritrodermia rigetto di trapianto malattia di Still reazioni da incompatibilità di emocomponenti sindrome maligna da neurolettici neoplasie solide, linfomi sindrome da lisi tumorale somministrazione di citochine ecc. ecc.

17 riconoscimento che qualcosa non va gravità (sepsi, sepsi grave,shock settico) terapia eziologica terapia di supporto microbiologia antibioticoterapia rimozione sorgente controllo del processo infiammatorio

18 la surviving sepsis campaign e la early goal directed therapy

19 Intensive Care Med (2008) 34: 17-60

20 Riconoscere e trattare la sepsi grave e lo shock settico utilizzando raccomandazioni o suggerimenti che presentano il maggior grado di evidenza attualmente disponibile tempestività aggressività appropriatezza diagnostico-terapeutica terapeutica

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22 JAMA. 2008;299(19): Ricard Ferrer, MD Antonio Artigas, MD, PhD Mitchell M. Levy, MD, FCCM Jesu s Blanco, MD, PhD Gumersindo Gonza lez-dı az, MD, PhD Jose Garnacho-Montero, MD, PhD Jordi Iba n ez, MD, PhD Eduardo Palencia, MD, PhD Manuel Quintana, MD Marı a Victoria de la Torre-Prados, MD, PhD for the Edusepsis Study Group Improvement in Process of Care and Outcome After a Multicenter Severe Sepsis Educational Program in Spain Conclusions A national educational effort to promote bundles of care for severe sepsis and septic shock was associated with improved guideline compliance and lower hospital mortality. However, compliance rates were still low, and the improvement in the resuscitation bundle lapsed by 1 year.

23 JAMA. 2008;299(19):

24 Annales Françaises d Anesthésie et de Réanimation 26 (2007) 53 73

25 Sono un piccolo germe innocente!!!

26 proteina C attivata ricombinante? (Drotrecogin) riconoscimento shock sett. e gravità microbiologia antibioticoterapia rimozione sorgente cristalloidi steroidi? fluidoterapia: colloidi emoderivati supporto respiratorio sostituz.funzione renale controlo glicemico sedazione prevenzione complicanze ecc. inotropi vasopressori

27 Initial resuscitation (first 6 hours) Begin resuscitation immediately in patients with hypotension or elevated serum lactate >4mmol/l; do not delay pending ICU admission. (1C) Resuscitation goals: (1C) Central venous pressure (CVP) 8 12 mm Hg* Mean arterial pressure 65 mm Hg Urine output 0.5 ml.kg-1.hr-1 Central venous (superior vena cava) oxygen saturation 70%, or mixed venous 65% If venous O2 saturation target not achieved: (2C) consider further fluid transfuse packed red blood cells if required to hematocrit of 30% and/or dobutamine infusion max 20 μg.kg 1.min 1 A higher target CVP of mmhg is recommended in the presence of mechanical ventilation or pre-existing decreased ventricular compliance.

28 1.vie aeree e respirazione 2.volemia 3. perfusione 4. metabolismo Current Opinion in Infectious Diseases 2007, 20:

29 (CHEST 2006; 130: )

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31 fluid therapy

32 reintegro volemico perché come con che cosa soluzioni a disposizioni caratteristiche vantaggi e svantaggi realizzazione fluid challenge

33 vasodilatazione maldistribuzione locale microtrombi fl deformabilità eritrocitaria maldistribuzione regionale vasodilatazione H 2 O H H 2 O 2 O H 2 O edema interstiziale H 2 O H 2 O danno endoteliale H 2 O

34 come?

35 accessi venosi possibili v.basilica e cefalica

36 vene centrali

37 con che cosa?

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39 Fluid therapy Fluid-resuscitate using crystalloids or colloids. (1B) Target a CVP of 8mmHg ( 12mmHg if mechanically ventilated). (1C) Use a fluid challenge technique while associated with a haemodynamic improvement. (1D) Give fluid challenges of 1000 ml of crystalloids or ml of colloids over 30min. More rapid and larger volumes may be required in sepsis-induced tissue hypoperfusion. (1D) Rate of fluid administration should be reduced if cardiac filling pressures increase without concurrent hemodynamic improvement. (1D) Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: Indicates a strong recommendation or we recommend ; indicates a weak recommendation or we suggest

40 è ragionevole aspettarsi la medesima risposta omeostatica, qualunque sia la soluzione utilizzata (cristalloidi, colloidi artif., albumina) se il reintegro volemico è appropriato a

41 esistono differenze nell uso delle soluzioni di rimpiazzo fluidico? ( da rimpiazzo volemico) Dove? chirurgia; trauma (, cerebrale, penetrante, ); ustioni; emorragia; sepsi; ARDS; In quali condizioni? normali, senza patologie concomitanti; shock ipovolemico, emorragico, settico, cardiogeno; insufficienza d organo o di funzione (es.: renale, epatica, coagulazione) Per fare cosa? idratare, rimpiazzare volume, correggere uno squilibrio elettrolitico o acido base Con che cosa? Cristalloidi o colloidi, e quali; Come Strategia liberale o restrittiva

42 è proprio vero? esiste la soluzione ideale? fluidi di riferimento: fluido Intra-cellulare fluido Extra-cellulare fluido interstiziale plasma

43 cristalloidi basso costo efficaci pro se è infuso un adeguato volume distribuzione: plasma:interstizio fi 1:3 (1:4) rapido equilibrio con l interstizio (20-30 min) non effetti negativi sulla funzione renale contro richiedono elevati volumi 3-5 : 1 vs deficit volemico edema (x accumulo nei settori ad elevata compliance) interstiziale polmonare (fl COP) deficit di perfusione del microcircolo (eterogenea) acidosi ipercloremica (non anion-gap) alterazione della coagulazione? (ipercoagulabilità) favoriscono l espressione di molecole di adesione? favoriscono l apoptosi cellulare?

44 New acid-base disturbances Hyperchloremic acidosis [Cl - ] 112 meq/l Unidentified anion excess [XA - ] 14 meq/l Dilutional acidosis [Na + ] 136 meq/l Hyperphosphatemic acidosis [Pi - ] 2 meq/l Hypochloremic alkalosis [Cl - ] 100 meq/l Concentrational alkalosis [Na + ] 148 meq/l Hypoalbuminemic alkalosis [Albumin] 35 g/l

45 mm/l NaCl 0,9% Ringer lattato Ringer acetato Reidratante III Normosol-R Sterofundin Ringer etilpiruvato Ringer bicarbonato Bilanciata Mantenimento Reidratante con glucosio e calcio Isolyte Na , K 5,4 4,0 10 5,0 4,0 4,0 4, ,5 Ca 3,7 3,0 5 2,5 2,7 3,0 3,2 2,5 Mg 3 3,0 1,0 1, Cl , Lattato 28,3 Acetato Malato 5,0 Gluconato 23 3,2 Etilpiruvato 28 Bicarbonato 25 Citrato 8 5,0 Solfato 8 Glucosio g/l Osm (mosm/l) ph 4,5-7,0 5,5-7 6,0-7, , ,6-5,4 7,0 5,0-7,0 5,0-6,0 5,0

46 colloidi pro le soluzioni colloidali generano una pressione colloido-osmotica > espansione volemica per ml di volume infuso rapporto colloidi / perdite ematiche / 1 > durata dell effetto modulazione del processo infiammatorio fl viscosità ematica fl coagulazione emodiluizione effetto diretto (fattore VIII, piastrine) reazioni anafilattiche se permeabilità ai colloidi è aumentata vanno nell interstizio aumentando l edema interstiziale; la loro rimozione attraverso i linfatici è + lenta di quella dei cristalloidi fl coagulazione emodiluizione effetto diretto (fattore VIII, piastrine) danno renale? costo contro

47 pro idrossietilamidi contro fl permeabilità vascolare fl edema intestinale fl traslocazione batterica fl funzione fagocitica deposito nel sistema reticolo-endoteliale danno tubulare renale (>>> di gelatine) costo Voluven: 7.23 /flac 500 ml

48 2007; 106:85 91 These effects are probably related to Better perfusion and oxygenation of the organs Decreased endothelial damage Decreased systemic inflammation and its consequences Conclusions: HES 130/04 decreases the circulating levels of MMP-9 in patients undergoing abdominal surgery.

49 Characteristics of different hydroxyethyl starch (HES) solutions HES HES HES HES HES HES 70/ / / / /0.5; 260/0.5 (Pentastarch) 200/ /0.7 (Hetastarch ) Concentration (%) Volume efficacy (%) Volume effect (hr) Mean molecular weight (Mw) 70, , , , , ,000 (Daltons) 260,000 Degree of molar substitution (MS) C2/C6 ratio 4:1 9:1 6:1 6:1 9:1 4.6:1 Max. dose (ml kg 1 ) Voluven Amidolite Haes Steril Pentastarch Haes Steril Pentastarch

50 Intensive Care Med (2008) 34: Frederique Schortgen, Emmanuelle Girou, Nicolas Deye, Laurent Brochard for the CRYCO Study Group A renal event occurred in 17% of patients. After adjustment on potential confounding factors and on propensity score for the use of hyperoncotic colloids, the use of artificial hyperoncotic colloids [OR: 2.48 ( )] and hyperoncotic albumin [OR: 5.99 ( )] was significantly associated with occurrence of renal event. Conclusions: This study suggests that harmful effects on renal function and outcome of hyperoncotic colloids may exist. Although an improper usage of these compounds and confounding factors cannot be ruled out, their use should be regarded with caution, especially because suitable alternatives exist.

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52 Effects of a predominantly hydroxyethyl starch (HES)- based and a predominantly non HES-based fluid therapy on renal function in surgical ICU patients Franziska Schabinski,Janaina Oishi, Fabio Tuche, Alain Luy, Yasser Sakr, Donald Bredle, Christiane Hartog, Konrad Reinhart Intensive Care Med (2009) 35: surgical ICU patients Conclusions: The incidence of ARF was similar in patients who received predominantly HES (6% 130/.04) fluid therapy and in those who received predominantly gelatin 4%. Moderate cumulative doses of modern HES or gelatin solutions maybe associated with a higher risk of ARF.

53 Conclusions: Hyperoncotic HES should not be used in patients who are at risk of developing kidney dysfunction. In patients without preexisting kidney dysfunction there seems to be no negative effects of modern HES preparations. In septic patients with reduced kidney function (serum creatinine[2.5 mg/dl) HES should be used cautiously, because studies of these patients are not available. Dissolving HES in a balanced solution further improves the safety of HES with regard to kidney function. At present, there seems to be no good reason to generally ban use of HES in our patients.

54 Conclusions: Given the complete lack of superiority in clinical utility studies (the crystalloid/colloid volume ratio was in the range of 1.6 on day 1 and 1.4 over the first 4 days) and the wide spectrum of severe side effects, the use of HES in the ICU should be stopped. The belief that four times as much crystalloid as colloid fluid volume is needed for successful resuscitation is being seriously questioned.

55 Albumina Penetra e si lega al glicocalice di superficie dell endotelio, diminuendo la permeabilità Inoltre riduce la risposta ossidativa dei neutrofili, lega mediatori dell infiammazione Elimina radicali liberi Èil principale antiossidante extracellulare (gruppi tiolici) Modesto effetto antitrombotico e anticoagulante Cochrane 1998: 6% mortalità Studio SAFE 2004 globalmente non differenze mortalità > nei traumi cranici, < nella sepsi [ ] di albumina inversamente correlata a mortalità

56 Conclusions Colloids have various nononcotic properties that may influence vascular integrity, inflammation, and pharmacokinetics, although the clinical relevance of these properties has not been elucidated. Clinical trials are needed to determine the clinical significance of basic science properties specific to individual colloids, such as modulation of vascular permeability and systemic inflammation.

57 realizzazione

58 Aggressive Fluid Resuscitation Fluid challenge in 30 min Adulto: ml di cristalloidi ml di colloidi Bambino: Boli di 20 ml/kg in 5-10 min Initial resuscitation usually requires ml/kg, but more may be required Ripetere sulla base della risposta e della tollerabilità occhio agli stravasi

59 miglioramento di sintomi e segni dello shock PA, FC, sensorio, respiro (FR), diuresi (> 0.5 ml/kg/h) colore, temperatura, marezzatura, sudore, riempimento capillare (< 2 sec); riempimento vene collo e periferiche (SvO 2 o SvcO 2 ) lattati SaO 2

60 valutazione del reintegro: infusione di 600 ml di cristalloidi o 200 ml di colloidi in 10 se PVC 2 mmhg (o PAOP 3 mmhg) : continuare infusione se PVC > 2 mmhg 5 mmhg (o PAOP > 3 mmhg 7 mmhg) arrestare l infusione finchè l è 2 mmhg (PAOP 3) e poi ricominciare l infusione se PVC > 5 mmhg (o PAOP > 7 mmhg) : arrestare l infusione R

61 Fluid therapy in resuscitated sepsis: less is more. Durairaj L, Schmidt GA. Iowa City, USA. Chest Jan;133(1): Fluid infusion may be lifesaving in patients with severe sepsis, especially in the earliest phases of treatment. Following initial resuscitation, however, fluid boluses often fail to augment perfusion and may be harmful. In this review, we seek to compare and contrast the impact of fluids in early and later sepsis; show that much fluid therapy is clinically ineffective in patients with severe sepsis; explore the detrimental aspects of excessive volume infusion; examine how clinicians assess the intravascular volume state; appraise the potential for dynamic indexes to predict fluid responsiveness; and recommend a clinical approach. After the initial fluid resuscitation, many septic patients who have traditional indications for a fluid challenge will not actually respond. Such fluid challenges may be not only ineffective, but harmful.

62 The point to emphasize is that what is beneficial early(more fluids) is not necessarilybeneficial later in the course of critical illness. Initial resuscitation transforms a hypovolemic, hypodynamic circulation into one where oxygen transport is normal or high, at least at the wholebodylevel, in most septic adults. The authors concluded that the hemodynamic effect of a typical fluid bolus was surprisinglysmall. Similarlymodest responses to a fluid bolus have been reported byothers.

63 Crystalloid or colloid fluid loading and pulmonary permeability, edema, and injury in septic and nonseptic critically ill patients with hypovolemia* Melanie van der Heijden, MSc; Joanne Verheij, MD, PhD; Geerten P. van Nieuw Amerongen, PhD;A. B. Johan Groeneveld, MD, PhD, FCCP, FCCM Crit Care Med 2009 Vol. 37, No. 4 Conclusions: Pulmonary edema and LIS are not affected by the type of fluid loading in the steep part of the cardiac function curve in both septic and nonseptic patients. Then, pulmonary capillary permeability may be a smaller determinant of pulmonary edema than COP and CVP. Safety factors may have prevented edema during a small filtration pressure-induced rise in pulmonary protein and thus fluid transport.

64 The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock Claire V. Murphy, PharmD; Garrett E. Schramm, PharmD; Joshua A. Doherty, BS; Richard M. Reichley, RPh; Ognjen Gajic, MD, FCCP; Bekele Afessa, MD, FCCP; Scott T. Micek, PharmD; and Marin H. Kollef, MD, FCCP

65 Da Murphy et al: The Importanceof Fluid Management in Acute Lung Injury Secondaryto Septic Shock. Chest 2009; 136:

66 Da Murphy et al: The Importanceof Fluid Management in Acute Lung Injury Secondaryto Septic Shock. Chest 2009; 136:

67 Da Murphy et al: The Importanceof Fluid Management in Acute Lung Injury Secondaryto Septic Shock. Chest 2009; 136:

68 proteina C attivata ricombinante? (Drotrecogin) riconoscimento shock sett. e gravità microbiologia antibioticoterapia rimozione sorgente cristalloidi steroidi? fluidoterapia: colloidi emoderivati supporto respiratorio sostituz.funzione renale controlo glicemico sedazione prevenzione complicanze ecc. inotropi vasopressori

69 Vasopressors Maintain MAP 65mmHg. (1C) Norepinephrine or dopamine centrally administered are the initial vasopressors of choice. (1C) Epinephrine, phenylephrine or vasopressin should not be administered as the initial vasopressor in septic shock. (2C) Vasopressin 0.03 units/min maybe subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone. Use epinephrine as the first alternative agent in septic shock when blood pressure is poorly responsive to norepinephrine or dopamine. (2B) Do not use low-dose dopamine for renal protection. (1A) In patients requiring vasopressors, insert an arterial catheter as soon as practical. (1D) Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: Indicates a strong recommendation or we recommend ; indicates a weak recommendation or we suggest

70 Vasopressin, an endogenously released peptide hormone, has emerged as an adjunct to catecholamines for patients who have severe septic shock. The rationale for its use is the relative vasopressin deficiency in patients with septic shock and the hypothesis that exogenously administered vasopressin can restore vascular tone and blood pressure, thereby reducing the need for the use of catecholamines. JA Russel et al. (Vasopressin And Septic Shock Trial)

71 proteina C attivata ricombinante? (Drotrecogin) riconoscimento shock sett. e gravità microbiologia antibioticoterapia rimozione sorgente cristalloidi steroidi? fluidoterapia: colloidi emoderivati supporto respiratorio sostituz.funzione renale controlo glicemico sedazione prevenzione complicanze ecc. inotropi vasopressori

72 Inotropic therapy Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output. (1C) Do not increase cardiac index to predetermined supranormal levels. (1B) Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: Indicates a strong recommendation or we recommend ; indicates a weak recommendation or we suggest

73 Apparato cardiovascolare: cuore In 35 pazienti con shock settico, ventilati, TEE al ricovero mostra: nel 46% disfunzione sistolica del LV e LVEF ridotta nel 10% dilatazione del LV nel 20% disfunzione diastolica del LV Tali alterazioni risultano scomparse dopo la sospensione delle amine Etchecopar-Chevreuil C et al Intensive Care Med 2008

74 Apparato cardiovascolare: cuore In sepsi severa/shock settico la Troponina I(TnI), marker di danno miocardico, aumenta Turner ACrit Care Med 1999; Fernandes CJ Intensive Care Med 1999 Arlati S et al Intensive Care Med 2000 Lo stesso non accade nel volontario sano Van Bockel EAP et al Intensive Care Med 2003;29: Su 37 pazienti, alta TnI presente nel 43%, associata a alte dosi di farmaci vasoattivi, maggiori anormalità alla TTE valori minori di frazione di eiezione maggior mortalità Mehta NJ et al Int J Cardiol. 2004;95:13-7

75 inotropi In pazienti con portata cardiaca ridotta nonostante adeguata infusione di liquidi Dobutamina inotropo di prima scelta in infusione 5-20 mg/kg/min Associare a vasopressori per mantenere PAM 65 mm Hg

76 proteina C attivata ricombinante? (Drotrecogin) riconoscimento shock sett. e gravità microbiologia antibioticoterapia rimozione sorgente cristalloidi steroidi? fluidoterapia: colloidi emoderivati supporto respiratorio sostituz.funzione renale controlo glicemico sedazione prevenzione complicanze ecc. inotropi vasopressori

77 Steroids Consider intravenous hydrocortisone for adult septic shock when hypotension remains poorly responsive to adequate fluid resuscitation and vasopressors. (2C) ACTH stimulation test is not recommended to identify the subset of adults with septic shock who should receive hydrocortisone. (2B) Hydrocortisone is preferred to dexamethasone. (2B) Fludrocortisone (50μg orally once a day) may be included if an alternative to hydrocortisone is being used which lacks significant mineralocorticoid activity. Fludrocortisone is optional if hydrocortisone is used. (2C) Steroid therapy may be weaned once vasopressors are no longer required. (2D) Hydrocortisone dose should be 300 mg/day. (1A) Do not use corticosteroids to treat sepsis in the absence of shock unless the patient s endocrine or corticosteroid history warrants it. (1D)

78 Nov.2008 Steroids Negli ultimi decenni l uso dei corticosteroidi nello shock settico è risultato controverso Pro: miglioramento emodinamico con più rapida sospensione dei vasopressori > rapidità di risoluzione della disfunzione d organo < mortalità (?) Con: mortalità tra responder e non responder = rapidità nella sospensione dei vasopressori > superinfezioni debolezza neuromuscolare intolleranza glucidica

79 Steroids Annane D, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288: Sì steroidi nello shock settico che richiede vasopressori SprungCL, et al. The CORTICUS randomized, double-blind, placebocontrolled study of hydrocortisone therapy in patients with septic shock. N Engl J Med 2008;358: NO steroidi nello shock settico

80 Steroids Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine Crit Care Med 2008; 36: Recommendation 6: Hydrocortisone should be considered in the management strategy of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents. Strength of Recommendations: 2B

81 Corticosteroids in the Treatment of Severe Sepsis and Septic Shock in Adults Annane D, Bellissant E, Bollaert PE, et al. JAMA. 2009; 301: day mortality was modestly reduced (relative risk [RR] = 0.84, P =.05) and was also modestly reduced in the subset of studies reporting prolonged corticosteroid administration (RR = 0.84, P =.02). Treatment increased the proportion of patients achieving reversal of shock and reduced the length of intensive care unit stay without a detectable increase in gastrointestinal bleeding, superinfection, or neuromuscular complications. Corticosteroids did increase the risk for hyperglycemia and hypernatremia. The authors concluded that the prolonged use of corticosteroids safely reduces short-term mortality in patients with severe sepsis or septic shock. Until a definitive clinical trial answers this question, corticosteroid use will continue to be highly variable and at the discretion of intensivists worldwide

82 proteina C attivata ricombinante? (Drotrecogin) riconoscimento shock sett. e gravità microbiologia antibioticoterapia rimozione sorgente cristalloidi steroidi? fluidoterapia: colloidi emoderivati supporto respiratorio sostituz.funzione renale controlo glicemico sedazione prevenzione complicanze ecc. inotropi vasopressori

83 Recombinant human activated protein C (rhapc) Consider rhapc in adult patients with sepsis-induced organ dysfunction with clinical assessment of high risk of death (typically APACHE II 25 or multiple organ failure) if there are no contraindications. (2B, 2C for post-operative patients) Adult patients with severe sepsis and low risk of death (e. g.: APACHE II<20 or one organ failure) should not receive rhapc. (1A) Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: Indicates a strong recommendation or we recommend ; indicates a weak recommendation or we suggest

84 Recombinant Human Activated Protein C (rhapc)) (Drotrecogin( alpha attivato) Azione anticoagulante, modula il processo infiammatorio ( citochine proinfiammatorie) e l immunità naturale ( infiltrazione e adesione leucocitaria), riduce l apoptosi delle cellule endoteliali Nella sepsi: produzione epatica proteina C attivazione della proteina C da parte dell endotelio (attivazione da parte del complesso trombomodulina-trombina collocato sulla superficie endoteliale e dal recettore endoteliale per la proteina C) disponibilità della proteina S ( cui si lega il complesso attivato, inibendo il fattore V e VIII attivati e la sintesi dell attivatore del plasminogeno)

85 Recombinant Human Activated Protein C (rhapc)) (Drotrecogin( alpha attivato) PROWESS (2001): mortalità assoluta (6%) e relativa (19%) soprattutto nei paz gravi (APACHE II > 25) e > 1 insuff.organo e con recente chirurgia; emorragia 3% (non trattati 2%); emorragia intracranica 0.2% (non trattati 0.1%); ENHANCE (2005): studio aperto osservazionale: > outcome nei trattati (mortalità 26% nei trattati); emorragia 6%; emorragia intracranica 1.5% ADDRESS (2005): arruolamento di pz. con bassa probabilità di morte: 1) sostanziale non di mortalità (lievemente > nei trattati) 2) non beneficio nei pz gravi e con > 1 insuff.organo e con recente chirurgia; emorragia 4% (non trattati 2%); emorragia intracranica 0.5% (non trattati 0.2%)

86 Recombinant Human Activated Protein C Altre: (rhapc)) (Drotrecogin( alpha attivato) di comorbilità presenti (tra trattati e non trattati nei diversi studi) di eziologia (> efficace in batteriemia e pneumonia, < in infezioni urinarie e addominali) di gravità del processo infiammatorio non rilevabile dagli indici di gravità < gravità, più tardivo inizio del trattamento (es.in ADDRESS) sanguinamenti importanti probabilmente sottostimato dai trial (probabile 10%) bambino (RESOLVE): non differenze, ma > emorragie (anche intracraniche) non raccomandato

87 Recombinant Human Activated Protein C (rhapc)) (Drotrecogin( alpha attivato) Humanrecombinant activatedproteinc for severe sepsis (Review) Martí-Carvajal AJ, Salanti G, Cardona-Zorrilla AF a Cochrane review, prepared and maintained bythe Cochrane Collaboration and published in The Cochrane Library 2008, Issue 4 Implications for practice Our original review (Martí-Carvajal 2007 ) was updated in response to comments (See Comments and criticisms section).this updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. Additionally, APC seems to be associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.

88 Conclusions In the PROGRESS registry, DrotAA-treated patients were younger, more severely ill, and had fewer comorbidities than patients not treated with DrotAA. After adjustment for group differences, a significant reduction in the odds of death was observed for patients that received DrotAA compared with those that did not. Early Use of Drotrecogin Has Benefits in Severe Sepsis retrospective analysis of the Canadian ENHANCE cohort confirm. This analysis, the authors explain in their report posted online May 20 in the journal Critical Care, suggests that, "when indicated, treatment with drotrecogin alfa should be initiated as soon as possible, regardless of age."

89 Reversal of refractory septic shock with drotrecogin alpha (activated) A. Vieillard-Baron, V. Caille, C. Charron, G. Belliard, P. Aegerter, B. Page, F. Jardin Intensive Care Med (2009) 35: Identification of a subgroup of patients with refractory septic shock and a 100% risk of death. Refractory shock was defined as persistent circulatory failure despite adequate circulatory support, associated with persisting lactic acidosis despite 6 h of CVVHDF. The objective of this study was to investigate whether early administration of drotrecogin alpha (activated) (DrotAA) to this selected subgroup of septic patients at extremely high risk of death would significantly improve prognosis. Patients selected by this strategy received DrotAA infusion for four days. The 28-day mortality rate of the 23 patients was 39%. Conclusion: in patients with refractory septic shock, our study showed that early use of DrotAA, combined with adequate vasopressor support and early CVVHDF, was associated with unexpectedly high 28-day survival.

90 Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock Jean-Francois Dhainaut Massimo Antonelli Patrick Wright Arnaud Desachy Jean Reignier Sylvain Lavoue Julien Charpentier Mark Belger Michael Cobas-Meyer Cornelia Maier Mariano A. Mignini Jonathan Janes Intensive Care Med (2009) 35: DAA treatment did not result in a difference in the primary outcome of time to resolution of vasopressor-dependent hypotension versus placebo (P = 0.419). However, few patients reached resolution (DAA 34%, placebo 40%) as most continued to require vasopressor support after 72 additional hours of treatment. Treatment did not reduce 28- day all-cause mortality and inhospital mortality or improve organ function compared with placebo, although there was a lower percentage change in D-dimers (P\0.001) and increases in protein C levels were numerically greater on extended infusion. There was no difference in serious adverse events including bleeding events. Conclusions: Extended DAA treatment did not result in more rapid resolution of vasopressor-dependent hypotension, despite demonstrating anticipated biological effects on D-dimer and protein C levels.

91 Editors comments on a new trial of activated protein C for persistent septic shock Jordi Mancebo, Massimo Antonelli Intensive Care Med (2008) 34: Finfer S, Ranieri V, Thompson B, Barie P, Dhainaut J, Douglas I, Gardlund B, Marshall J, Rhodes A (2008) Design, conduct, analysis and reporting of a multi-national placebo controlled trial of activated protein C for persistent septic shock. Intensive Care Med.

92 sono guarito!!!

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94 monitoraggio macrocircolazione Swan-Ganz: classico con SvO2 con RVEF e RVEDV PiCCO LiDCO Vigileo monitoraggio continuo della CO mediante Doppler monitoraggio in continuo della CO mediante parziale rebreathing della CO2 cardiografia impedenziometrica ecocardiografia TTE e TEE ecc.

95 Nov 2008 monitoraggio

96 Measurement of Tissue Perfusion v Gastrointestinal tonometry (gastric and sigmoid) v Laser Doppler flowmetry v Microdialysis catheters v Near-infrared spectroscopy v Reflectance spectroscopy v Transcutaneous oxygen measurements v Tissue CO2 measurements v Tissue ph monitors v Lactate measurements

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98 Indici clinici utilizzati per la terapia fluidica variazione del polso durante ventilazione Systolic and Pulse Pressure Variation Valori predittivi di risposta al riempimento vascolare SP: 10 mmhg o 9 % down: 5 mmhg PP: % Elevazione passiva delle gambe Aumento di PP: 10 % Aumento del flusso aortico: 10 %

99 Systolic and Pulse Pressure Variation Variations in systolic blood pressure and pulse pressure with positive pressure ventilation are a useful method of predicting circulatory responses to a fluid challenge Tavernier B, Makhotine O, Lebuffe G, et al. Systolic pressure variation as a guide to fluid therapy in patients with sepsisinduced hypotension. Anesthesiology 1998;89: Together with continuous measurement of CO, on-line monitoring of SVV might help to guide and optimize fluid therapy to avoid unnecessary and potentially harmful volume overloading in high-risk patients after cardiac surgery Reuter Daniel A. Usefulness of left ventricular stroke volume variation to assess fluid responsiveness in patients with reduced cardiac function. Crit Care Med 2003; 31: The analysis of the arterial blood pressure curve may remain the simplest way to predict fluid responsiveness because most patients with acute circulatory failure are instrumented with an arterial line, allowing the automatic calculation of the arterial pressure variation by bedside monitors in the near future Michard f. Changes in Arterial Pressure during Mechanical Ventilation. Anesthesiology 2005;103: Systolic pressure variation (SPV) and stroke volume variation (SVV) have been demonstrated to be good predictors of preload responsiveness Grocott, Michael P. W. Differentiating Volumetric Preload Monitoring and Assessing Fluid Responsiveness Anesth Analg. 2006; 102(2): 652

100 Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? Intensive Care Med (2008) 34: Conclusion: In ICU resuscitated patients, targeting only ScvO2 may not be sufficient to guide therapy. When the 70% ScvO2 goal value is reached, the presence of a P(cv-a)CO2 larger than 6 mmhg might be a useful tool to identify patients who still remain inadequately resuscitated. At T0, T6 and T12, CI and P(cv-a)CO2 values were inversely correlated (P\0.0001).

101 Passive leg raising for predicting fluid responsiveness: importance of the postural change To summarize, when PLR started from the supine position, its increasing effects on cardiac preload and cardiac index were lower than if it started from the semirecumbent position. Moreover, the same cut-off value could not be used interchangeably for the two PLR methods. This strongly suggests that the PLRSEMIREC should be preferred for assessing fluid responsiveness in patients with septic circulatory failure Interestingly, the difference in cardiac preload and cardiac index changes found between the two postural maneuvers corresponded to those induced by transferring the patient s trunk from the semirecumbent to the supine position before performing theplrsupine, suggesting that PLRSEMIREC induced the additional recruitment of the vast splanchnic reservoir.

102

103 Arterial pressure changes during the Valsalva maneuver to predict fluid responsiveness in spontaneously breathing patients Thirty patients without mechanical ventilation and equipped with a radial arterial catheter for whom the decision to give fluids was taken due to suspected hypovolemia. Pulse pressure changes during the Valsalva maneuver (DVPP) were calculated as the difference between maximal pulse pressure during phase 1 and minimal pulse pressure during phase 2 of the Valsalva maneuver divided by the mean of the two values and expressed as a percentage. Valsalva changes in systolic pressure (DVSP) were calculated in similar way. Conclusions: Arterial response during the Valsalva maneuver is a feasible tool for predicting fluid responsiveness in patients without mechanical ventilatory support. The present study demonstrates that arterial pressure waveform variations induced by a VM reliably predict fluid responsiveness in spontaneously breathing patients. A DVPP value of 52% was predictive with a high sensitivity and specificity of an increase by more than 15% in SVi after volume administration in patients with spontaneous respiratory efforts.

104 a set 2009

105 The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360: Patients in ICU commonly have hyperglycemia, which is associated with increased morbidity and mortality. In 2001, Van den Berghe et al reported that in a study of over 1500 surgical-icu patients, intensive glucose control reduced mortality. However, three subsequent studies in medical- and general-icu patients did not demonstrate a mortality benefit with tight glucose control. Average blood glucose was 115 mg/dl with intensive control and 144 mg/dl with conventional control. Among patients who received intensive vs conventional blood glucose control, 90-day mortality was higher (27.5% vs 24.9%; odds ratio 1.14; p=0.02), as was severe hypoglycemia (6.8% vs 0.5%). Length of stay in the ICU or hospital, time spent on mechanical ventilation, and need for dialysis were similar in the two groups.

106 The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360: The study showed that lowering blood glucose levels below about 140 to 180 mg/dl for patients in a general ICU did not provide added benefit, and levels below this may cause harm, they note. This does not imply that efforts to optimize glucose control should be abandoned. "Until further evidence becomes available, it would seem reasonable to continue our attempts to optimize the management of blood glucose in our hospitalized patients, especially to avert the extremes of hyperglycemia (which have acute effects on renal function, hemodynamics, and immune defenses) and also hypoglycemia (with its own, often more immediate and serious, consequences),".

107 Michael Joannidis Intensive Care Unit, Department of Internal Medicine I, Medical University Innsbruck, Austria Seminars in Dialysis Vol 22, No 2 (March April) 2009 pp This study reviews the role of continuous renal replacement therapy (CRRT) in sepsis with acute kidney injury (AKI) and septic shock with multiple organ failure. In addition to the conventional aim of replacing renal function in AKI, CRRT is often used with the concept of modulating immune response in sepsis. With the intention of influencing circulating levels of inflammatory mediators like cytokines and chemokines, the complement system, as well as factors of the coagulation system, several modifications of CRRT have been developed over the last years. These include high volume hemofiltration, high adsorption hemofiltration, use of high cut-off membranes, and hybrid systems like coupled plasma filtration absorbance. One of the most promising concepts may be the development of renal assist devices using renal tubular cells for implementing renal tubular function into CRRT. High Adsorption Hemofiltration, High Volume Hemofiltration (HVH), High Cut-Off (HCO) Hemofiltration or Hemodialysis, Coupled plasma filtration adsorption (CPFA)

108 Anne-Corne lie J. M. de Pont, MD, PhD Adult Intensive Care Unit Academic Medical Center University of Amsterdam Amsterdam, The Netherlands The improvement of blood purification techniques and membranes has generated new opportunities for the use of extracorporeal techniques in sepsis. Removal of both pro- and anti-inflammatory mediators by means of these new techniques is feasible and might add to the restoration of homeostasis by controlling excessive cytokine production (the so-called peak concentration hypothesis). Whether this approach will result in a better clinical outcome for patients with severe sepsis remains to be investigated.

109 Impact of Continuous Venovenous Hemofiltration on Organ Failure During the Early Phase of Severe Sepsis: A Randomized Controlled Trial Didier Payen, MD, PhD; Joaquim Mateo, MD; Jean Marc Cavaillon,PhD; FrançoiFraisse, MD; Christian Floriot, MD; Eric Vicaut, MD, PhD In summary, we report the results of a multicenter trial on the use of early hemofiltration in severe sepsis aiming at limitation of organ failure. Contrary to our expectations, early HF resulted in worse outcomes and prolongation of organ support. Although hemofiltration has not proved its therapeutic efficacy in sepsis, it remains an extrarenal purification technique of choice in acute renal failure, particularly indicated in hemodynamically unstable intensive care patients. New techniques in the area of extrarenal purification are currently being developed, based on the regeneration of high ultrafiltrate volume after passing over resins that absorb excess inflammatory mediators. If practical application of the technique can be achieved, and if it remains financially viable, very highflux techniques may eventually exert a beneficial effect on the evolution of severe sepsis and septic shock. To conclude, in septic patients, hemofiltration with an ultrafiltration rate of 2 L/hr did not limit organ failure. Whether high-volume hemofiltration is able to limit organ failure in these patients remains to be investigated.

110 altro (Pub Med ultimo anno) Continuous hemodiafiltration with PMMA Hemofilter in the treatment of patients with septic shock. Mol Med May-Jun;14(5-6): The present findings suggest that cytokine-oriented critical care using PMMA- CHDF might be an effective strategy for the treatment of septic shock. Implementation and outcomes of a severe sepsis protocol in an Australian tertiary hospital. Crit Care Resusc Sep;10(3): Implementation of a sepsis protocol led to a change in the delivery of care with no reduction in mortality in patients with severe sepsis and septic shock admitted to a Level III ICU in a tertiary hospital. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med Mar;34(3): The proposed three-level system, by using objectively defined criteria for risk of mortality in sepsis, could be used by physicians to stratify patients at ICU admission or shortly thereafter, contributing to a better selection of management according to the risk of death.

111 altro (Pub Med ultimo anno) Using transcutaneous oxygen pressure measurements as selection criteria for activated protein C use. J Trauma Jul;65(1):30-3. Withholding APC did not result in an increase in mortality from severe sepsis in those patients who demonstrated adequate PtcO2 values. The transcutaneous oxygen measurement may be a useful adjuvant in addition to the other selection criteria for better identification of patients who may benefit from APC Diastolic arterial blood pressure: a reliable early predictor of survival in human septic shock. J Trauma May;64(5): Septic shock survival increases when dose of 0.5 mug/kg/min of norepinephrine continuously improves vascular tone within the first 48 hours, or when diastolic arterial pressure (>50 mm Hg) is restored. Norepinephrine has beneficial effects on renal function. Predictive value of LODS score on day 3 is demonstrated, while SAPS II is confirmed as the only reliable predictive factor in first 24 hours. Cerebral perfusion in sepsis-associated delirium. Crit Care. 2008;12(3):R63. In this small group of patients, cerebral perfusion assessed with transcranial Doppler and near-infrared spectroscopy did not differ between patients with and without sepsis-associated delirium. However, the state of autoregulation differed between the two groups. This may be due to inflammation impeding cerebrovascular endothelial function. Further investigations defining the role of S- 100beta and cortisol in the diagnosis of sepsis-associated delirium are warranted.

112 altro (Pub Med ultimo anno) Vascular endothelial growth factor in severe sepsis and septic shock. Anesth Analg Jun;106(6): VEGF concentrations are increased in patients with severe sepsis. Low concentrations are associated with hematological and renal dysfunction. VEGF concentrations were lower in nonsurvivors than in survivors, but did not adequately predict hospital mortality in patients with severe sepsis. Randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor in patients with septic shock. Crit Care Med Feb;36(2): G-CSF does not improve outcomes in patients with septic shock, excluding melioidosis. Increased hepatic dysfunction and higher peak troponin levels in patients receiving G-CSF have not been reported in previous clinical trials and warrant further investigation. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med Dec;35(12): Polyvalent immunoglobulins exert a significant effect on mortality in sepsis and septic shock, with a trend in favor of IgGAM.

113 altro (Pub Med ultimo anno) Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med Dec;35(12): This meta-analysis demonstrates an overall reduction in mortality with the use of ivig for the adjunctive treatment of severe sepsis and septic shock in adults, although significant heterogeneity exists among the included trials and this result was not confirmed when only high-quality studies were analyzed. These data warrant a welldesigned, adequately powered, and transparently reported clinical trial. Early intravenous unfractionated heparin and mortality in septic shock. Crit Care Med Nov;36(11): Early administration of intravenous therapeutic dose unfractionated heparin may be associated with decreased mortality when administered to patients diagnosed with septic shock, especially in patients with higher severity of illness. Prospective randomized trials are needed to further define the role of this agent in sepsis and septic shock.

114 altro (Pub Med ultimo anno) The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial. Intensive Care Med (2009) 35: Statin therapy may be associated with a reduction in the levels of inflammatory cytokines in patients with acute bacterial infections. Large controlled trials will determine if this reduction will translate into a clinical benefit.trial. SCCM 2009: High-Dose Statins Reduce Mortality in Sepsis Patients Shah A. Since statins are not without toxicity and little is known about the metabolism of statins in sepsis, dosing will have to be considered carefully. For now, I would not recommend that statins be initiated in a septic patient, but it is reasonable to continue statins in a septic patient previously taking astatin. Statins for All: The New Premed? BJA Z. L. S. Brookes; C. C. McGown; C. S. Reilly Published: 08/18/2009 The use of statins is widespread and many patients presenting for surgery are regularly taking them. There is evidence that statins have beneficial effects beyond those of lipid lowering, including reducing the perioperative risk of cardiac complications and sepsis... However, the evidence for the prophylactic use of statins perioperatively is weak and lacks prospective controlled studies.