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

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

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

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

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

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

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

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

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 % Cholera Epidemic 1830s ‘Thomas Latta solution’ reconstituted was Na 134 mmol/l, CL 118 mmol/l and HC mmol/l ‘Balanced’ vs not- ‘normal’ saline vs new anions Hartmann’s Saline 0.9%Plasmalyte Na Na Na K + 5K + 5 Ca ++ 2 Mg Cl Cl Cl - 98 Lactate - 29Acetate - 27 Gluconate - 23

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

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

Crystalloids balanced vs not Scheingraber 1999

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

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

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

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

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

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

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

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

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

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

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

Colloids – Starches Perioperative studies Sepsis studies Fraud in research

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

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

Colloids – Starches Perioperative n=StarchComparitorORp Death %2.24% Transfusion % CoagulationNo difference in any test Renal Replacement Therapy %3% Renal FnNo change in creatinine or creatinine clearance Van Der Linden 2012

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)

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

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% 90 days Guidet / Myburgh / Perner 2012

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

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

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

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 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

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

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

‘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 ) Gelatins RR 0.91 (95% CI Perel 2013

‘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

Crystalloids vs Colloids Scandinavian Starch for Severe Sepsis/Septic Shock (6S) – 130/0.4 Starch balanced vs balanced crystalloid798 – more 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 90 days – more RRT RR: 1.21; p=0.04

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% 90 days more Renal injury with HES ~ 1: 1.3 HES: NaCl volumes

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

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 ’

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

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

No mortality difference: 10 % control vs 8.9% treatment GDT reduced complications overall RR of 0.68 (95%CI , 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

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

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

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

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

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

Thanks and extra resources Prof Monty Mythen, Dr Ellie Walker, Dr Gautam Kumar, Prof Mike James