Fluid Treatments in Sepsis: Meta-Analyses

Transcription

1 Fluid Treatments in Sepsis: Recent Trials and Meta-Analyses Lauralyn McIntyre MD, FRCP(C), MSc Scientist, Ottawa Hospital Research Institute Assistant Professor, University of Ottawa Department of Epidemiology and Community Medicine Centre for Transfusion Research Chinese Society of Critical Care Medicine Conference Beijing, September 14 16, 2012

2 Conflicts of Interest CSL Behring Baxter Inc Plasma Protein Therapeutics Association

3 Why may we use colloid clinically? Plasma a 3 L For Replacement ISS IC 10 L 30 L Blood Cells 2 L Iso-oncotic colloid Hyper-oncotic colloid

4 Cochrane Systematic Reviews of Fluid Resuscitation Author/yr Few Fluids Critical compared Care Trials # Studies Perel, 2011 Colloids Outdated vs Crystalloids protocols 56 Bunn, 2011 Colloid Heterogenous vs Colloidfluids 72 Different fluid comparators NEJM, 2007 Alderson 2009 Albumin vs no albumin 37 Different doses Cochrane 2010 HES Timing vs other of fluids 34 High risk of bias So why are we still talking about and studying this Safe Study Investigators, 2010 question???????

5 International Cross Sectional Study of Resuscitation Fluid Episodes in 391 ICUs Finfer, S et al Critical Care 2010; 14: 1-24

6 International Cross Sectional Study of Resuscitation Fluid Episodes in 391 ICUs Finfer, S et al Critical Care 2010; 14: 1-24

7 The type of fluid question: heightened controversy and new evidence Perner et al, NEJM 2012; 367:

8 Snap Shot: Use of Colloids Internationally Over Time Albumin Synthetic Colloids Jones, D et al, Anesthesia and Intensive Care 2010: 38;

9 What are hydroxyethyl starch (HES) fluids? Amylopectin starch (branched chain glucose molecules) Corn Potato Rapid hydrolysis via amylase (t 1/2 = 10 minutes) Hydroxyethylation at C2 and C6 carbon units (substitution)

10 What is the current evidence for hydroxyethyl starch fluids for severe sepsis and septic shock?

11 HES and requirement for renal replacement therapy in the critically ill: A meta - analysis Study Studies n No. of events HES No. of participants Control Odds ratio (95% CI) Favours Hydroxyethyl Starch Favours Control All studies Brunkhorst, /261 51/ ( ) McIntyre, /21 1/ ( ) Schortgen, /65 11/ ( ) Cittanova, /27 1/ ( ) Overall 4 106/374 64/ ( ) Subgroup analyses Patient population Severe sepsis/septic shock 3 97/347 53/ ( ) Organ transplantation 1 9/27 1/ ( ) Type of comparator Gelatin 2 22/92 12/ ( ) Crystalloid 2 84/282 52/ ( ) Odds ratio and 95% CI Zarychanski et al, Open Medicine, 2009: 3;

12 Perner et al, NEJM 2012; 367: Multi-center randomized double blind controlled trial 798 patients in ICU with severe sepsis who met eligibility criteria within the prior 24 hours Tetraspan (6% HES 130/0.42) versus Ringers Acetate Maximum daily dose 33 mls/kg Primary Outcome: Mortality or dependence on dialysis at 90 days Baseline Characteristics HES (n = 398) Ringers Acetate (n = 400) Age Median (IQR) 66 (56 75) 67 (56 76) Male No (%) 239 (60) 244 (61) SAPS II Median (IQR) 50 (40 60) 51 (39 62) Shock No (%) 366 (84) 337 (84) Acute Kidney Injury No (%) 142 (36) 140 (35) Mechanical Ventilation No (%) 240 (60) 245 (61)

13 Perner et al, NEJM 2012; 367: HES Ringers Acetate HES Ringers Acetate Relative Risk (n = 398) (n = 400) (n = 398) (n = 400) 95% Confidence Fluid 24 hours prior to 3500 ( ) 3000 Intervals ( ) randomization Median (IQR) (Q Dead or dialysis 202 (51) 173 (43) 1.17 ( ) Study dependent Fluid 90 Median days No(%) (IQR) 3000 ( ) 3000 ( ) Dead Open 90 label days synthetic No(%) colloid No(%) 201 (51) 39 (10) 172 (43) (1.01 (9.5) 1.36) Doses Dependent > protocol on dialysis maximum 90 No(%) 1 (0.25) 28 (7)* 1 (0.25) (10) days No(%) Renal replacement 87 (22) 65 (16) 1.35( ) therapy No(%) * 2 patients in the HES group received doses higher than maximum recommended from manufacturer (> 50 mls/kg/day

14 Insert our updated forrest plot of all HES RCTs to date, CHEST Trial results to come

15 ALBUMIN Human plasma protein Derived from pooled plasma Molecular weight of 66 Kd Synthesized in the liver Negatively charged Most common plasma protein (60%) Concentration in plasma 40 g/l Available: Iso oncotic (4 5%) Hyper oncotic (20 25%) Responsible for 75-80% oncotic pressure Oncotic effect of albumin due to: Direct effect of albumin: 60% Gibbs-Donnan effect: 40% Quinlan, GJ et al, Hepatology, 2005: 41;

16 What are albumin s functions? Maintenance of colloid oncotic pressure Transport protein Binds inflammatory mediators Anti-oxidant effects Vincent, JL Best Practise and Research Clinical Anesthesiology 2009; 23:

17 What is the evidence for albumin as a volume resuscitation fluid? Are colloid fluids better maintained in the Are colloid fluids better maintained in the intravascular space as compared to crystalloids in critical illness?

18 RCT/Yr Population Fluid Comparators SAFE/04 Critically ill N = % albumin vs normal saline Ratio Colloid/Crystalloid 1:1.4 VISEP/08 Severe Sepsis/Septic Shock N = % HES vs ringers lactate 1:1.4 McIntyre/08 Septic Shock N=40 10% HES vs 0.9% saline 1:1.1 McIntyre/12 Septic Shock N = 50 5% albumin vs 0.9% saline 1:1.4 Perner/12 Severe Sepsis and shock N = 800 tetraspan vs ringers acetate 1:1.1

19 Finfer et al, NEJM 2004; 350:

20 Finfer et al, NEJM 2004; 350:

21 N = 460 GCS 3 12 and an abnormal CT scan Myburgh J et al, NEJM 2008; 357:

22 SAFE TBI: Baseline Characteristics Albumin (n=231) Normal Saline (n=229) Age Median (IQR) 37 (23-55) 35 (23-50) Male (%) *APACHE II 20.4± ±6.4 *AISS 28.6± ±10.5 *MAP mm Hg 82.5± ±13.7 *CVP mm Hg 7.3± ±3.8 *GCS 7 (4-9) 7 (5-9) *ICP 15.0± ±7.2 2 Hypotension (%) * mean±sd Myburgh J et al, NEJM 2008; 357:

23 Survival in SAFE TBI sub-group Survival 28 Days Survival 24 Months 20.4% Mortality Severe TBI (N = 290) RR and 95% CI: 1.88 (1.31 to 1.70) 33.2%

24 Predefined sub-group with severe sepsis n = 1218 Finfer et al, Intensive Care Medicine, published on line, October 6, 2010

25 Baseline Characteristics CVP missing n=707 (58%) Finfer et al, Intensive Care Medicine, published on line, October 6, 2010

26 Fluids and Co-Interventions Finfer et al, Intensive Care Medicine, published on line, October 6, 2010

27 MAP HR CVP ALB

28 SAFE Severe Sepsis: 28 day mortality No differences in renal injury between the fluid groups Finfer et al, Intensive Care Medicine, published on line, October 6, 2010

29 What is the evidence for use of albumin for patients who are hypoalbuminemic?

30 Albumin levels are decreased in the critically ill.. Altered production Increased degredation Increased losses Leak from capillaries Vincent, JL Best Practise and Research Clinical Anesthesiology 2009; 23:

31 Single center, non-blinded RCT pilot study in Brussels, Belgium. 100 patients with serum albumin < 30 g/l 300 mls of 20% albumin on day 1 followed by 200 mls/day if serum albumin 30 g/l versus ringers lactate as standard therapy Primary Outcome: change SOFA score baseline to day 7 Albumin Control P Value Delta SOFA 3.1 (1.0) 1.4 (1.1) 0.03 Fluid Gain mls (Mean (SD)) (1101) (1156) Caloric intake Kcal (Median, IQR) (935, 1158) (571, 1077) Dubois et al. Crit Care Med. 2006; 34:

32 6045 patients from SAFE trial Baseline serum albumin levels < 25 versus 25 g/l Resuscitated with normal saline or 4% albumin Finfer, S et al, BMJ 2006; 333: 1-6

33 What is the evidence for albumin and mobilization of interstitial titi fluid? ARDS Network, NEJM, 2006: 354; Boyd, JH, Critical Care Medicine, 2011: 39; 1-7

34 Hyperoncotic albumin and lasix combination: i systematic review Martin et al: 2 randomized controlled trials Patient populations: mechanical ventilation with acute lung injury N = 77 patients studied Results: Achievement negative fluid balance Greater weight loss Improved oxygenation Thiboutot et al, Am J Respir Crit Care Med 2009: 179, A3089

35 126 patients with cirrhosis and SBP Cefotaxime vs cefotaxime + 20% albumin Pi Primary Outcome: Renal impairment Renal impairment Death: Hospital 3 months Cefotaxime N = 63 Cefotaxime + albumin N = 63 P value 21(33) 6(10) (29) 26(41) 6(10) 14(22) Pao, S, NEJM, 1999

36 5% albumin versus normal saline for resuscitation in early septic shock (PRECISE) Design: Multi - center double blind randomized controlled trial Setting: 6 Canadian tertiary care centers Population: 50 patients with early suspected septic shock recruited from: emergency department (ED) and intensive care unit (ICU) Intervention: Blinded 500 ml boluses of 5% albumin or normal saline for fluid resuscitation ti first 7 days in ICU Primary outcome: Feasibility McIntyre, L et al, Journal of Critical Care, 2012; 27: 317

37 Additional albumin in sepsis evidence is also coming. ALBIOS Trial EARRS Trial RASP Trial Population Severe Sepsis/Septic Shock within 24 hours in ICU Septic shock within first 6 hours ICU admission Severe sepsis/septic shock within 6 hours of evolution Sample Size Intervention Primary Outcome Open label Up to 300 mls infused 20% albumin vs crystalloid fluid according to albumin levels in ICU 28 and 90 Day Mortality Open label 100 mls 20% albumin Q8H versus normal saline for first 3 days in ICU Blinded 500 ml boluses of 4% albumin versus ringers lactate until CVP is 8 mm Hg or recovery from hypotension 28 Day Mortality 28 Day Mortality

38 Feast Trial Maitland et al, NEJM, 2011 Although 3141 African FEAST children was with conducted febrile illness in and a impaired pediatric patient perfusion population, in Africa, with the majority of children having malaria.. Randomized boluses:5% albumin, 0.9% saline, or no bolus Bolus Bolus 5% albumin normal saline Control Results of FEAST should at least cause us to question some of the very basics of our fluid resuscitation ti practises. 48 hour death 10.6% 10.5% 7.3% 4 week death 12.2% 12.0% 8.7% Neurological sequlae Increased ICP/ pulmonary edema 2.2% 1.9% 2.0% 2.6% 2.2% 1.7%

39 A summary of the evidence for albumin in sepsis year 2012 With the present level of evidence 2012: Consider use for septic shock Avoid use in traumatic ti brain injury Mobilization fluid from interstitial space Acute lung Injury/Acute respiratory distress syndrome Paracentesis for cirrhosis More evidence is coming to understand the place of albumin in the critically ill

40 Thank you for your attention!