1. Current Controversies in Perioperative Fluid Therapy Dr Rob Stephens Consultant in Anesthesia UCLH Honorary Senior Lecturer UCL

2. Contents Introduction Difficulties Crystalloids Colloids – the new ones Colloids – Starches Crystalloids vs Colloids Dose and end-points

3. Owning up / Disclaimer Study ‘Hextend®’- ‘balanced’ large MW starch My Anaesthesia department fan of ODM In my department using saline is a crime Sometimes I give drug reps a hard time when they come to our dept….. then eat their food My girlfriend is a vet

4. Introduction Human Most studies in ICU Pure perioperative studies- few But sepsis big reason for surgery – so relevant Is there a clinical problem? Conflicting evidence – apparently We rarely practice EBM in real life

5. Introduction: Difficulties in thinking about fluids Fluid studies – Different fluids – Different colloid carrier solutions – Different outcomes – Different assessments of ‘how full’ – Different patient groups – Plus adding inotropes – ‘perioperative optimisation’ – Many fluid studies in critical care

7. Introduction: Difficulties in thinking about fluids Fluid studies – Different fluids – Different colloid carrier solutions – Different outcomes – Different assessments of ‘how full’ – Different patient groups – Plus adding inotropes – ‘perioperative optimisation’ – Many fluid studies in critical care

8. Introduction: what I’ll do Human stuff Use Clinical trials Use Meta-analysis Break subject down to components

9. Contents Introduction Difficulties Crystalloids Colloids – the new ones Colloids – Starches Crystalloids vs Colloids Dose and end-points

10. Crystalloids Why 0.9%? Hartog Hamburger's studied red cell lysis in 1882 “0.9% was the concentration of salt in human blood” actual concentration is 0.7- 0.6% Cholera Epidemic 1830s ‘Thomas Latta solution’ reconstituted was Na 134 mmol/l, CL 118 mmol/l and HC0 3 16 mmol/l ‘Balanced’ vs not- ‘normal’ saline vs new anions Hartmann’s Saline 0.9%Plasmalyte Na + 131 Na + 150 Na + 140 K + 5K + 5 Ca ++ 2 Mg ++ 1.5 Cl - 111 Cl - 150 Cl - 98 Lactate - 29Acetate - 27 Gluconate - 23

11. Crystalloids Basic idea of ‘balanced’? – Ions more similar to plasma – Saline – High Chloride lack other ions – Saline - no buffer/precursor present in plasma Animal + Volunteer + Lab studies – – saline- less coagulation – saline – less survival – saline – less GI blood flow – saline - ?renal dysfunction Yunos 2010

12. Crystalloids: balanced vs not Comparative balanced vs not Animal studies + case reports- acidosis Scheingraber et al (1999) only 24 patients! – Major Gynaecology surgery – Randomised to 30ml/kg/hr Saline or Hartmann’s

13. Crystalloids balanced vs not Scheingraber 1999

14. Crystalloids balanced vs not Does it really matter?? Admission to ICU Bex  outcome Trauma - BEx  outcome Does this BEx matter?? Other effects noted – – Renal – less urine in volunteers – mis-diagnosis –wrong treatment – Nausia

15. Crystalloids balanced vs not Comparative balanced vs not Burdett 2012 meta-analysis – 13 trials, 706 patients – Metablolic – acidosis / hyperventiulation / chloride – No mortality / renal / clinical bleeding differences

16. Observational study using Healthcare database Non randomised, unblinded Adults - major open abdominal surgery… Received either …….on the day of surgery 0.9% saline - 30,994 patients or a balanced crystalloid solution -926 patients Shaw 2012

17. Saline‘Balanced’p= Mortality in hospital5.6%2.9%<0.001 1+ Complications33.723%<0.001 Transfusion11.5%1.8%<0.001 Renal failure requiring dialysis4.8%1%<0.001 Shaw 2012

18. Contents Introduction Difficulties Crystalloids Colloids – the new ones Colloids – Starches Crystalloids vs Colloids Dose and end-points

19. Colloids New: Background? Colloids have 2 parts Colloid – Starches (potato/maize) & Gelatins & Dextrans – trend to lower MW starches Carrier solution – – Saline vs ‘balanced’ – Last 10 years – attention paid to carrier – ‘New’ anions - acetate – New propriatory colloids – geloplasma®, Volulyte® PlasmaVolume® Colloid Carrier

20. The Jury is out on alternative Anions and ideal SID J Cardiothorac Vasc Anesth. 2010 Jun;24(3):389-93. The new-generation hydroxyethyl starch solutions: the Holy Grail of fluid therapy or just another starch? Murphy GS, Greenberg SB Murphy 2010

21. Colloids – Which? Meta-analysis 2012 Bunn – Gelatins, HES, Albumin, analyzed all ways – 86 trials, 5,484 patients, Small studies – Voluven® – Gelofusine® – Gelatins vs Starches…… Bunn 2012

23. Contents Introduction Difficulties Crystalloids Colloids – the new ones Colloids – Starches Crystalloids vs Colloids Dose and end-points

24. Colloids – Starches? Starches – classification – Average MW – % Carbons substituted with HE groups – C2/6 ratio Starches – history

26. Colloids – Starches Complex as mixed studies, most in sepsis Concern about side effects early on Less Mw, less persistence – 130kDa, 6%, substitution ratios c0.40 – ‘tetrastarch’ Renal issues Itch + bleeding

27. Colloids – Starches Perioperative studies Sepsis studies Fraud in research

28. Colloids – Starches Perioperative Perioperative + Lab studies – MW > 200kDa – Substitution > 0.4 – More concentrated > 6% In healthy volunteers (Waitzinger) – 6% and 10% solutions of HES 130/0.4 – no clinically relevant accumulation in plasma – either after 1 dose or after repetitive infusion  side effects

29. Colloids – Starches Perioperative Perioperative Meta-analysis 59 small studies including 4529 patients Looked at ‘modern starches’ ie 130/0.4 – Average 77 patients per trial Van Der Linden 2012

30. Colloids – Starches Perioperative n=StarchComparitorORp Death19181.15%2.24%0.50.079 Transfusion215136.9%46.60.730.0004 CoagulationNo difference in any test Renal Replacement Therapy 7401.8%3%0.60.35 Renal FnNo change in creatinine or creatinine clearance Van Der Linden 2012

31. Colloids – Starches Sepsis Different in Sepsis – disruption of Endothelium/ glycocalyx – leakage out + ? damage Studies 2012 – Scandinavian Starch for Severe Sepsis/Septic Shock (6S) – CHEST (Crystalloid versus Hydroxy-Ethyl Starch Trial) – CRYSTMAS (Crystalloids Morbidity Associated with Severe Sepsis)

32. Colloids – Starches Sepsis Scandinavian Starch for Severe Sepsis/Septic Shock (6S) – 130/0.4 Starch balanced vs balanced crystalloid798 – more death @ 90 days, 51 vs 43% – more RRT and bleeding Guidet / Myburgh / Perner 2012

33. Colloids – Starches Sepsis CRYSTMAS (Crystalloids Morbidity Assoc’ with Severe Sepsis) – 130/0.4 Starch in 0.9% NaCl vs NaCl 196 – no difference in death or renal function (trends) – Mortality 40% HES vs 34% saline @ 90 days Guidet / Myburgh / Perner 2012

34. Colloids – Starches Sepsis CHEST (Crystalloid versus Hydroxy-Ethyl Starch Trial) – 130/0.4 Starch in 0.9% NaCl vs NaCl 6500 – no difference in death @ 90 days – Mortality 17% HES vs 18% saline @ 90 days – more RRT RR: 1.21; p=0.04 Guidet / Myburgh / Perner 2012

35. European Society of Intensive Care Medicine – Large Starches – 6% HES 130/0.4 Do not use with severe sepsis or risk of renal injury “We recommend crystalloids be used as the initial fluid of choice…” Colloids – Starches Sepsis

36. Colloids – Starches Fraud Fraud in research – Joachim Boldt – 88 out of 102 articles retracted in 2011

37. Colloids – Starches Fraud Fraud in research – Joachim Boldt- Starch studies – 7 trials, 590 patients Meta-analysis after removing his studies – Total of 38 studies with 10 880 patients, most ICU HES associated with – higher mortality (RR, 1.09; 95% CI, 1.02 to 1.17) – more renal failure (RR, 1.27; 95% CI, 1.09 to 1.47) – more RRT (RR, 1.32; 95% CI, 1.15 to 1.50). Zarychanski 2013

38. Contents Introduction Difficulties Crystalloids Colloids – the new ones Colloids – Starches Crystalloids vs Colloids Dose and end-points

39. Crystalloids vs Colloids Debate going on since colloids invented Theory - but less leak with colloids? ‘need to use 3x crystalloid as colloid’ ‘Crystalloid vs Colloid ’ meta-analysis update 2013 Perel 2013

40. ‘Crystalloid vs Colloid ’ meta-analysis update 2013 Theatre + ICU No difference overall Starches may increase risk of death, renal failure RR 1.10 (95% CI 1.02 - 1.19) Gelatins RR 0.91 (95% CI 0.49 - 1.72 Perel 2013

41. ‘SAFE’ – Australian/NZ study – Blind RCT in 6997 general ICU patients – Albumin vs Saline – No difference in any outcome at 28 days – some subgroup differences – 1: 1.4 fluid volume ratio SAFE Study Investigators 2004

42. Crystalloids vs Colloids Scandinavian Starch for Severe Sepsis/Septic Shock (6S) – 130/0.4 Starch balanced vs balanced crystalloid798 – more death @ 90 days, 51 vs 43% – more RRT and bleeding CRYSTMAS (Crystalloids Morbidity Assoc’ with Severe Sepsis) – 130/0.4 Starch in 0.9% NaCl vs NaCl 196 – no difference in death or renal function (trends) CHEST (Crystalloid versus Hydroxy-Ethyl Starch Trial) – 130/0.4 Starch in 0.9% NaCl vs NaCl 6500 – no difference in death @ 90 days – more RRT RR: 1.21; p=0.04

43. CHEST (Crystalloid versus Hydroxy-Ethyl Starch Trial) Australian/NZ study 6500 patient RCT 130/0.4 Starch in 0.9% NaCl vs NaCl Mortality 17% HES vs 18% saline @ 90 days more Renal injury with HES ~ 1: 1.3 HES: NaCl volumes

44. Contents Introduction Difficulties Crystalloids Colloids – the new ones Colloids – Starches Crystalloids vs Colloids Dose and end-points

45. Overlap with next talk Complex as studies – often add inotropes / vasopressors – often have different endpoints – varying methodology Laparoscopy /type of surgery may alter balance.. ‘Guessing’ ‘Liberal’ ‘Restrictive/Zero balance’ ‘Goal Directed Therapy ’

46. Dose and end-points Studies Zero Balance Brandstrup Meta-analysis 2012 x 2 Brandstrup 2012

47. 31 studies of 5292 pts Studies where investigators….. “Targeted to increase global blood flow” 24 before surgery to 6 hours after Grocott Cochrane review

48. No mortality difference: 10 % control vs 8.9% treatment GDT reduced complications overall RR of 0.68 (95%CI 0.58 - 0.80, P < 0.001) and 3/12 specific complication rates renal failure, respiratory failure wound infections Reduced length of stay in the treatment group by 1 day

49. Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance? 150 pts elective colorectal surgery Randomized to fluid therapy during surgery Near maximal Stroke Volume guided by Doppler Zero balance and normal weight Postoperative care same Directed towards zero weight gain Brandstrup 2012

50. Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance? Brandstrup 2012 No significant differences between the groups for any complications in 30 days the length of hospital stay [Z 5 (1–61) vs D: 5 (2–41) 1 patient died in each group

51. Perioperative Fluid Management Strategies in Major Surgery: A Stratified Meta-Analysis Meta-analysis of RCT including trials – Restrictive/Zero balance vs Liberal – Goal Directed Therapy vs Liberal Goal Directed Therapy – 24 studies including 3861 patients – Average study size 90 patients – from 10 countries Restrictive/Zero balance – 12 studies including 1169 patients – Average study size 80 patients – From 9 countries ‘Guessing’ ‘Liberal’ ‘Restrictive/Zero balance’ ‘Goal Directed Therapy ’ Corcoran 2012

52. Perioperative Fluid Management Strategies in Major Surgery: A Stratified Meta-Analysis Goal Directed Therapy vs Liberal GDT – lower risk of pneumonia (RR 0.7, 95% CI 0.6 to 0.9) – renal complications (0.7, 95% CI 0.5 to 0.9) – shorter length of hospital stay (mean 2 days, 95% CI 1 to 3) Restrictive/Zero balance vs Liberal Liberal more – pneumonia (RR 2.2, 95% [CI] 1.0 to 4.5) – pulmonary edema (RR 3.8, 95% CI 1.1 to 13), – longer hospital stay (mean 2 days, 95% CI 0.5 to 3.4) Corcoran 2012

53. Summary Difficulties Crystalloids Colloids – the new ones Colloids – Starches Crystalloids vs Colloids Dose and end-points Thank you

54. Thanks and extra resources Prof Monty Mythen, Dr Ellie Walker, Dr Gautam Kumar, Prof Mike James www.ucl.ac.uk/anaesthesia/people/stephens http://www.acid-base.com