L uso appropriato dell albumina nel trattamento del paziente settico

Transcription

1 Uso appropriato dell Albumina nella Cirrosi Epatica: le raccomandazioni AISF-SIMTI Istituto Superiore di Sanità, Roma Martedì 29 Marzo, 2016 L uso appropriato dell albumina nel trattamento del paziente settico Pietro Caironi, MD Dip. di Fisiopatologia Medico-Chiururgica e dei Trapianti Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano pietro.caironi@unimi.it

2 Appropriate use of Human Albumin in Septic Patients Rationale Biological plausibility (for efficacy) Clinical evidence (of efficacy) Absence of harm (or limited) Cost / Effectiveness The RIGHT patients for the RIGHT treatment [Sepsis is widely heterogeneous ]

3 2009 SIMTI Recommendations Appropriate indications (3) Occasionally appropriate indications (9) Inappropriate indications (13) Blood Transfus 2009;7:216-34

4 2016 AISF-SIMTI Recommendations in Cirrhosis Blood Transfus 2016;14:8-22

5 Why albumin in sepsis patients? (current guidelines and rationale) Clinical evidence in Severe Sepsis / Septic Shock Possible future developments and area of research (efficacy, appropriate use, precision medicine)

6 Type Dose, Velocity Crit Care Med 2013;41:

7 History of SSC guidelines (from 2004 to 2013) We recommend CRYSTALLOIDS be used as the initial fluid of choice?

8 Reasons from superiority of Crystalloids vs. Colloids 1 2 Limited evidence on superiority (clinically and physiologically) Evidence of potential toxicity Raghunathan K et al, BJA, 2014;113: VISEP trial HES vs. RL 2012 CRYSTMAS trial HES vs. RA S trial HES vs. RA 2012 CHEST trial HES vs. RA 2012 EARSS trial Albumin vs. NS 2013 CRYSTAL trial Coll. vs. Crys HES harmful No difference HES harmful No diff./hes harmful No difference No diff./coll. better

9 Intensive Care Med 2015;41: Cross-sectional prevalent study (6 study days, ) 2825 ICU pts screened (754 resuscitated, 254 with sepsis) Change in patterns of fluid use

10 Albumin in Critically Ill Patients in 2016 COLLOIDS Albumin (4/5% %) Hammond NE et al., Intensive Care Med 2015;41:1611-9

11 Cystein 34 SECONDARY FUNCTIONS PRIMARY FUNCTION Oncotic Pressure Transport Anti-inflammatory Anti-oxidant Endothelial stabilization Site 2 Anti-aggregant Site 1 Acid-base balance Immune system stabilization Histidine Both functions as potentially important in critically ill patients ALBUMIN AS A DRUG

12 Why albumin in sepsis patients? (current guidelines and rationale) Clinical evidence in Severe Sepsis / Septic Shock Possible future developments and area of research (efficacy, appropriate use, precision medicine)

13 The SAFE trial Prospective, randomized, double-blinded trial 6997 patients 16 ICU (Australia, New Zeland) 4% albumin vs. 0.9% NaCl Death at 28-days N Engl J Med 2004, 350:

14 SAFE study 2004 predefined subgroup analysis Treated % Control % P Trauma patients Severe sepsis patients ARDS patients

15 1800 patients with severe sepsis or septic shock Albumin + Crystalloids vs. Crystalloids 28-day and 90-day mortality Funded by AIFA N Engl J Med 2014;370:

16 From ALBIOS trial: net daily fluid balance Net fluid Balance [ml] No. at Risk Albumin Crystalloids P< Study Day Albumin Crystalloids Caironi P et al., N Engl J Med 2014;370:

17 Probability of survival Results Primary Outcome Albumin Crystalloids No. at Risk Albumin Crystalloids P = Days since Randomization Caironi P et al., N Engl J Med 2014;370:

18 Results Subgroup analysis ALBUMIN (%) CRYSTAL. (%) RR (95% CI) All patients ( ) 0.29 TIME OF ENROLLMENT 0.46 < 6 hours ( ) hours ( ) 0.20 SEPTIC SHOCK AT ENROLLMENT 0.01 Without shock With shock ( ) ( ) ALBUMIN better CRYSTALLOIDS better Caironi P et al., N Engl J Med 2014;370:

19 Albumin in SEPTIC SHOCK: rationale for a novel large RCT Authors Year of publication Delenay et al [45] Cui JY et al [46] Inclusion criteria Sepsis of any severity (Adults and Pediatrics) Predefined subgroups Sepsis of any severity (Adults) Leitch A et al [47] Severe sepsis Wiedermann et al [48] Rochwerg B et al [49] Patel A et al [50] Severe sepsis (Adults) Severe sepsis (Adults) Predefined subgroup and network metaanalysis Sepsis of any severity (Adults) Predefined subgroups Number of studies included (sample size) 17 (N=1977) 14 (N=1729) 9 (N=1435) 3 (N=3791) 14 (N=18916) 16 (N=4190) Comparison Albumin vs. Crystalloid or Colloid Albumin vs. Crystalloid or Colloid Albumin vs. Crystalloid or Colloid Albumin vs. Crystalloid Any fluid strategy compared to a different fluid strategy Albumin vs. Crystalloid or Colloid Types of studies included RCTs RCTs RCTs Large scale RCTs RCTs RCTs Primary outcomes All-cause mortality at the longest follow-up available All-cause mortality All-cause mortality at the longest follow-up available All-cause mortality at the longest follow-up available All-cause mortality at the longest follow-up available All-cause mortality at the longest follow-up available Results (OR or RR, 95% CI) Sepsis OR 0.82 ( ), P=0.047 Sepsis OR 0.87 ( ), P=0.18 Severe sepsis RR 0.90 ( ), P=0.11 Severe sepsis RR 0.92 ( ), P=0.046 Severe sepsis Albumin vs. Crystalloids OR 0.83 ( ) Sepsis RR 0.94 ( ), P=0.11 Severe sepsis without shock RR 0.95 ( ), P=0.35 [N=2070] Septic shock RR 0.92 ( ), P=0.10 [N=1962] Jiang L et al [51] Sepsis of any severity (Adults and Pediatrics) Predefined subgroups 15 (N=6998) Albumin vs. Crystalloid or Colloid RCTs All-cause mortality at the longest follow-up available Sepsis RR 0.94 ( ), P=0.15 Severe sepsis without shock RR 0.95 ( ), P=n.s. Septic shock RR 0.89 ( ), P=0.04 Xu JY et al [52] Severe sepsis (Adults) Predefined subgroup 6 (N=3658) Albumin vs. Crystalloid RCTs and parallel trials All-cause mortality (including 28-, 90- day mortality, or at other time points) Severe sepsis OR 0.88 ( ), P=0.08 Shock OR 0.81 ( ), P=0.03 Caironi P et al., Curr Opin Crit Care 2015;21:

20 Why albumin in sepsis patients? (current guidelines and rationale) Clinical evidence in Severe Sepsis / Septic Shock Possible future developments and area of research (efficacy, appropriate use, precision medicine)

21 1 90-DAY SURVIVAL according to baseline characteristics Death at 90 days (%) ALBUMIN (%) CRYSTAL. (%) RR (95% CI) P Time of enrollment < 6 hours (341) 6-24 hours (780) ( ) 0.84 ( ) Mean arterial pressure < 70 mmhg (556) 70 mmhg (565) ( ) 0.97 ( ) Lactate > 2 mmol/l (752) 2 mmol/l (334) ( ) 0.90 ( ) Central SvO 2 < 70% (333) 70% (668) ( ) 0.84 ( ) In preparation

22 2 Average albumin during the study vs. 90-day mortality Death at 90 days (%) ) Effect of treatment 2) Effect of disease severity Pts with SHOCK OR 0.93 [ ] p<0.001 (after adjustments) From ALBIOS N=1135 Pts with Septic Shock 10 P< Tertiles of average serum albumin level during the study (g/l) In preparation

23 Average albumin level during the study by treatment groups Death at 90 days (%) Average serum albumin level of the Crystalloid group as marker of disease severity P= ± vs. ±5.3 T1 Severe Hypo 23.3 ±4.8 P= vs. ±5.6 T2 Moderate Hypo 28.2 ±5.4 P= vs. ±5.8 T3 Mild Hypo Crystalloid Albumin P=0.01 P< Tertiles of average serum albumin level during the study for each study group (g/l) In preparation

24 3 Serum Albumin vs. Resolution of the Primary Infection Clinical resolution of the Primary Infection (%) Overall population N=1679 Overall study population Severe Moderate Mild HYPO-ALBUMINEMIA P< Unpublished

25 Independent role of Serum Albumin Level Serum albumin level as independently associated with the clinical resolution of the Primary Infection Average serum albumin level during the study (for each g/l increase) Overall population (n=1401) OR 1.06 ( ) P< Average serum albumin level during the study (for each g/l increase) Septic shock (n=866) OR 1.06 ( ) P= After adjustments for overall severity (SAPS II score), SOFA at baseline, age, ICU stay during the study Unpublished

26 4 Endogenous HA alterations during inflammation Interaction with immuno-system 1 2 Alteration of endogenous albumin Cys-34 Ischemia-Modified Albumin (IMA) Cobalt chelation Bernardi M. et al, J Clin Exp Hepatol 2014;3:

27 Oxidized Albumin on Cys-34: HMA, HNA-1 and HNA-2 Human Mercaptalbumin (HMA): reduced Human Non-Mercaptalbumin-1 (HNA-1): rev. oxidized Human Non-Mercaptalbumin-2 (HNA-2): irrev. oxidized 60 pts with severe sepsis 30 healthy subjects by HPLC-fluorescence [%] Healthy Subjects HMA ** Severe Sepsis Healthy Subjects HNA-1 ** Severe Sepsis Healthy Subjects HNA-2 ** Severe Sepsis From ALBIOS biobank P<0.001 for all Unpublished

28 HNA-2 / HMA ratio and 90-Day Mortality Probability of Death [%] Log-rank test: p< HNA-2/HMA 0.39 HNA-2/HMA < 0.39 From ALBIOS biobank Unpublished

29 CONCLUSIONS Albumin is not just a colloid solution, but is a physiologic drug which has many crucial properties (secondary functions). In critically ill patients with severe sepsis albumin administration is SAFE, but its not associated with an improved survival, despite hemodynamic advantages. The beneficial effect of albumin replacement in septic shock needs further confirmations (the ALBIOSS-BALANCED trial). The efficacy (and the appropriate use) of albumin in septic patients may depend on specific, yet unproven, clinical characteristics, and specific effects (hemodynamic status, serum concentration, anti-infective / immuno-modulating effect, red-ox state, etc.).