What is the right fluid to use?

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1 What is the right fluid to use? L McIntyre Associate Professor, University of Ottawa Senior Scientist, Ottawa Hospital Research Institute Centre for Transfusion Research CCCF, November 2, 2016

2 Disclosures CIHR funding for FLUID Trial Member: Surviving Sepsis Campaign Committee

3 Phases of fluid resuscitation Early Fluid Resuscitation Phase What fluid to give? Who to give it to? Stabilization Phase How to give it? When to give it? De-resuscitation Phase

4 Early resuscitation phase. Plasma 3 L ISS 10 L IC 30 L Blood Cells 2 L Load with usual care resuscitation crystalloid fluids Courtesy of Sheldon Magder

5 Compositions of resuscitation crystalloid fluids Plasma Normal Ringers Plasma-Lyte saline lactate Osmolarity PH Sodium Potassium Calcium Magnesium Chloride Acetate 27 Lactate Gluconate 23 Reddy et al, Crit Care, 2016

6 What is the mechanism for NS induced hyperchloremic metabolic acidosis (HCMA)? Chloride is part of SID equation SID = (Na + K) (Cl + Lactate) Normal SID = +40 Excess saline administration excess chloride in plasma Reduces SID Kaplan et al, Critical Care, 2005 Li et al, Biomed and Biotechnol, 2016

7 Effects of NS/high chloride on the kidney High chloride causes: Afferent renal artery vasoconstriction Reduced GFR Bullivan et al, Am J Physiol, 1989 Imig et al, J Lab Clin Med, 1993 Chowdhury, Annals of Surgery, 2012

8 Chloride and association with acute kidney injury Neyra, JA, Crit Care Med, 2015 Zhang, Z, BMC Nephrol, 2013 Kimura, S, J Inten Care, 2014 Van Regenmortel et al, Ann Intens Care, 2016

9 Author Year Clinical evidence for AKI and other adverse effects with NS Population Sample Size (matched) Death at 30 Days or Hospital Mortality Matched (%) P Value or OR and 95% CIs Dialysis or RIFLE Failure* Matched (%) P Value or OR and 95% CIs Infections Matched (%) C T C T C T P Value or OR and 95% CI Shaw 2015 SIRS and >= 500 mls Crystalloid N = OR (95% CI) 0.38 ( ) OR (95% CI) 0.57 ( ) McCluske y 2013* Non-cardiac surgery N = P < P = Raghunat han 2013 Sepsis N = OR (95% CI) 0.86( )** OR (95% CI) 0.95( )** Shaw 2012 Abdominal Surgery N = OR (95% CI) 0.77( ) P< OR (95% CI) 0.61( ) Shaw et al, Crit Care, 2015; McCluskey et a, Anesth Anal, 2013; Raghunathan et al, CMM, 2014; Shaw, Ann Surg, 2012

10 SPLIT Trial Design: Double blind cluster double crossover randomized controlled feasibility trial Setting: 4 ICUs in New Zealand Interventions: Normal Saline (NS) versus Plasma-Lyte (PL) Primary outcome: proportion of patients AKI Results: 2278 patients 99.1% and 99.5% received Pl/NS ~ APACHE II score: 14 ~ 70% surgical patients Young et al, JAMA, 2015 Outcomes PL NS AD and 95% CIs Primary AKI 9.6% 9.2% 0.4 (-2.1 to 2.9) Secondary Low fluid dose received in SPLIT RRT (-1.6 to 1.4) Hospital Death (-3.3 to 1.17)

11 Salt Trial: Balanced crystalloids versus saline in ICU (n = 974) Single centre pilot cluster multiple cross over RCT comparing Saline to balanced crystalloids (ringers lactate and plasma-lyte) Primary Outcome: difference in proportion of NS use between groups Secondary Outcome: Major adverse kidney events first 30 day Semler, M et al, AJRCCM, 2016 published on line Saline Group Balanced Group P value Quantity to 30 days (L) 1.4 ( ) 1.6 ( ) 0.40 Median (IQR) Proportion of Saline (%) 91% 21% < MAKE 30 days (%) Death 30 days Death 60 days Dialysis Dialysis post hospital

12 Annals of Internal Medicine, 2014 Indirect Comparison Saline vs Balanced Crystalloids Odds Ratio and 95% Confidence Interval 0.78 ( )

13 Where may colloids fit into resuscitation?

14 Why may we use colloid as compared to crystalloid fluid for resuscitation? Plasma 3 L ISS 10 L IC 30 L Blood Cells 2 L Iso-oncotic colloid (4 5% albumin) Hyper-oncotic colloid (20-25% albumin) Courtesy of Sheldon Magder

15 Are colloids better maintained in the intravascular space compared to crystalloids? RCT/Yr Population Fluid Comparators SAFE/2004 VISEP/2008 McIntyre/2008 McIntyre/2012 Perner/2012 Annane/2013 Critically ill N = 6997 Severe Sepsis/Septic Shock N = 537 Septic Shock N = 40 Septic Shock N = 50 Severe Sepsis and shock N = 800 Critically ill N = % albumin vs normal saline 10% HES vs ringers lactate 10% HES vs 0.9% saline 5% albumin vs 0.9% saline 6% HES (130/0.42) vs ringers acetate Any colloid vs Any crystalloid Ratio Colloid/Crystalloid 1:1.4 1:1.4 1:1.1 1:1.4 1:1.1 1:1.5

16 What are albumin s functions? Maintenance of colloid oncotic pressure Transport protein Binds drugs Binds inflammatory mediators Anti-oxidant effects Vascular permeability Biological plausibility...yes!! Clinically relevant improvements in outcome? Vincent, JL Best Practise and Research Clinical Anesthesiology 2009; 23:

17 Albumin Saline RR of Death 95% CI Overall 726/ / ( ) Trauma 81/596 59/ ( ) ARDS 24/61 28/ ( ) Severe sepsis 185/ / ( ) Finfer et al, NEJM 2004

18 SAFE Severe Sepsis: 28 day mortality Finfer et al, Intensive Care Medicine, 2010

19 ? Gattinoni et al, NEJM, 2014

20 Survival 28 Days Survival 24 Months 20.4% 33.2% Myburgh J et al, NEJM 2008

21 Possible reasons for increase death with albumin in TBI Aken et al, Anesthesiology 2012 Cooper et al J Neurotrauma, 2013

22

23

24 In summary Early resuscitation phase start with crystalloid fluids Attention to specific physiological abnormalities and clinical populations Avoid HES fluids in resuscitation of the critically ill For albumin post initial resuscitation phase Consider 5% (?20-25%) in septic shock Avoid TBI After initial resuscitation completed, judicious use of all fluids

25 Disclaimer: content and suggestions will change as new evidence is generated!! Thank-you for your attention

26 Balanced crystalloids and metabolic alkalosis Seizures Dysrhythmias (mostly supraventricular) Cardio pulmonary arrest Leftward shift of oxyhemoglobin dissociation curve Fitzgibbons et al, J of Emerg Med, 1999; Lawson et al, Anaesth and Anal, 1973 Yunos, NM et al, CCM, 2011, 39(11):

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