IV Fluid Choice - an ICU perspective

(With 2 Cautionary stories about Cochrane Meta-analysis)

Dr Vincent ChanSenior Registrar in Emergency and Intensive Care Medicine

17th April 2014

Introduction

• Iv fluids are a cornerstone treatment of emergency and intensive care medicine• There are numerous varieties of iv

fluids however their relative safety is under debate particularly with colloids• 2 Cochrane meta-analyses

demonstrated increased risk of harm with IV albumin and no increase in harm with IV Hydroxyethyl starches compared with crystalloids• 3 Large randomised Control trials in

Australian, New Zealand and Scandinavian intensive cares units have proved Cochrane wrong

Crystalloid, Colloid and Blood Products• Strictly speaking IV fluids include Crystalloid Colloid and Blood• This talk will be confined to Crystalloids and Colloids• Use of blood products and transfusion triggers deserve a separate

discussion in itself

Crystalloid and Colloids

• Crystalloids are predominately based on a solution of sterile water with added electrolytes to approximate the mineral content of human plasma. • Colloids are often based on crystalloid

solutions, thus containing water and electrolytes, but have the added component of a colloidal substance that does not freely diffuse across a semipermeable membrane• Colloids can raise the intravascular

volume quicker and using less volume than using crystalloids

Variations in Colloids and Crystalloids Formulations

Solution pH Na+ Cl- K+ Ca++ Lactate Glucose Osmolality Other0.9% normal saline 5.0 154 154 0 0 0 0 308 0Hartmann/CSL 5-7 131 112 5 2 28 0 255 0Plasma lyte 7.4 140 98 5 0 0 0 294 27mmol Acetate 23mmol Gluconate

5% dextrose in water (D5W) 4.0 0 0 0 0 0 50 g/L 252 0.45% normal saline withdextrose (D51/2 NS) 4.5 77 77 0 0 0 50 g/L 406 0Albumin (4%) 6.7-7.3 140 128 0 0 0 0 260 40 g/L albuminAlbumin (20%) 6.4-7.3 48-100 130-160 0 0 0 0 130 200 g/L albuminHetastarch 6% 5.5 154 154 0 0 0 0 310 60 g/L starchPentastarch 10% 5.0 154 154 0 0 0 0 326 100 g/L starchDextran-40(10% solution) 3.5-7.0 154 154 0 0 0 0 311 100 g/L dextranDextran-70(6% solution) 3.0-7.0 154 154 0 0 0 0 310 60 g/L dextranHaemaccel 3.5% 7.4 145 145 5 6.25 0 0 293 35 g/L gelatinGelofusine 7.4 154 125 0 0 0 0 308 40 g/L gelatin

Safety of Colloids

• It has been assumed over the past 60 years that both colloids and crystalloids are safe and effective means of intravenous fluid resuscitation

• The safety of colloids was first questioned by a rudimentary meta-analysis performed by Velanovich in 1989. (1)

• Subsequently in the BMJ in 1998 a systematic review questioned the safety of colloids in general[2] and a Cochrane Review in 1998, questioned specifically the safety of albumin.[3]

• This can only be resolved by a large randomised control trial

1. Velanovich V. Crystalloid versus colloid fluid resuscitation: a meta-analysis of mortality. Surgery. 1989;105:65-71

2. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomized trials. BMJ. 1998;316:961-964.

3. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317:235-240

The SAFE (Saline versus Albumin Fluid Evaluation) trial• Conducted by the Australia and New Zealand Intensive Care Society's

Clinical Trials Group (ANZICS-CTG) between 2001 and 2003• Published NEJM May 2004• Double blind prospective multi-centre randomised controlled trial• Determine the effect of fluid resuscitation with either 4% Albumin or

N/saline on mortality in a heterogeneous population of Intensive care Patients• Excluded patients – Burns, plasmapheresis, cardiac bypass surgery and

liver transplant• Randomized 6997 critically ill patients requiring fluid resuscitation to

receive 4% albumin or Normal Saline

The SAFE (Saline versus Albumin Fluid Evaluation) trial• There was no overall difference in outcome according to whether

patients received colloids or crystalloids (relative risk for death with colloid use = .99, 95% confidence interval .91-1.09, P = .87). • Prospective Subgroup Analysis• Trauma Patients appeared to be more likely to die if they received colloids

and this was statistically true for those patients with traumatic brain injury compared with trauma patients as a whole (relative risk for death = 1.62, 95% confidence interval 1.12-2.34, P = .009).• Severe Sepsis trends toward a reduction in death for who received colloids

(relative risk = .87, 95% confidence interval .74-1.02).• ARDS no statistically significant difference

Subgroups Identified in the Saline vs Albumin Fluid Evaluation Study

Outcome Albumin Saline RR (95% CI) P Value

Trauma 13.6% 10.0% 1.36 (.99-1.86) .06

(81 of 596) (59 of 590)

Severe sepsis 30.7% 35.3% .87 (.74-1.02) .09

(185 of 603) (217 of 615)

ARDS 39.3% 42.4% .93 (.61-1.41) .72

(24 of 61) (28 of 66)

Hydroxyethyl Starch

• Derived from Maize Starch• Hydrolysed amylopectin in the C2 C3 and

C6 units of the macromolecules• Eliminated only through the kidneys as

the products of endogenous hydrolysis• C2 units impairs hydrolysis more

effectively than one in position C6• Charactered by

• mean molecular weight in Daltons• C2/C6 ratio

• Voluven and Volulyte • New generation low molecular weight and

low C2/C6 Ratio HES 130/0.42• Most commonly used colloid in intensive

care units globally

The Boldt Affair• Joachim Boldt MD PHD• Chief Anaesthetist at Ludwigshafen Hospital in Rhineland Germany• Leading Advocate of Hyroxyethyl starch (HES)• Prolific submitting on average 1 paper a month • 11 papers demonstrated a relative reduction in mortality with HES• Some have been cited in manufacturers product information sheets, submissions to

regulatory authorities, clinical trial protocols and Meta-analysis.• Cochrane review in 2007 with regards to Colloids versus crystalloids for fluid

resuscitation in critically ill patients analysed 55 studies concluded that there was no significant difference

• Discovered in 2011 to have published 101 articles of which 89 papers did not have institutional review board approval

• Lead to dismissal from post, multiple article retractions and ongoing criminal investigations

THE 6S Trial: Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis• Published NEJM July 2012• 6S trial Group Scandinavian Critical Care Trials Group• Multicentre parallel group blinded clinical trial• Conducted between 2009 and 2011 in Denmark, Norway, Finland and

Iceland• To assess the effect of HES 130/0.4 compared with a balanced crystalloid

solution on mortality and end stage kidney failure in patients with severe sepsis.• 798 patients with Severe Sepsis

• 398 randomised to HES 130/0.42 for fluid resuscitation• 400 randomised to Ringers Acetate group

The 6S Trial: Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis• HES 130/0.42 significantly increased the risk of death or dependence

on dialysis at day 90, as compared with Ringer's acetate. • HES 130/0.42 increased the absolute risk of death at 90 days by 8

percentage points, corresponding to a number needed to harm of 13.• Similar results were observed in analyses adjusted for risk factors and

in the subgroups of patients with shock or acute kidney injury at the time of randomization.

CHEST Trial: Hydroxyethyl starch or saline for fluid resuscitation in intensive care.• Crystalloid versus Hydroxyethyl Starch Trial (CHEST)• Australian And New Zealand Intensive Care Society Clinical Trial Groups• Published NEJM Nov 2012• Multicentre, prospective, blinded, parallel-group, randomized, controlled

trial conducted in 32 hospitals in Australia and New Zealand conducted between 2009 and • 7000 patients intensive care patients who required fluid resuscitation over

and that required for maintenance or replacement fluids• 3500 assigned to receive 6% HES (130/0.4) max dose of 50ml/kg day then open label

0.9% Saline• 3500 patients assigned to receive 0.9% N/Saline

CHEST Trial: Hydroxyethyl starch or saline for fluid resuscitation in intensive care - Conclusion• There was no significant difference in mortality at 90 days in ICU

patients who received 6% HES (130/0.4) in 0.9% saline and those who received 0.9% saline alone for fluid resuscitation. • The effect on mortality did not differ significantly in six predefined

subgroup pairs: Acute Kidney Injury, Sepsis, Trauma, Traumatic Brian injury, APACHE Score and receiving HES before Randomisation• However more patients who received resuscitation with HES were

treated with renal-replacement therapy• 6% HES does not have any clinical benefit compared with Saline in

ICU patients

Which Colloid?

• 4% albumin is generally safe • Small advantage in Sepsis• Except in trauma and head injuries

• Hydroxyethyl Starch• No benefit over Normal Saline• Increased mortality with Severe Sepsis• More likely to require Renal Replacement

Therapy• Gelofusin

• Modified Gelatine of bovine origin – Succinylated

• Gelatine derivatives are mainly eliminated unchanged through the kidney

• Produced in BSE-free countries• No large RCTS

Which Crystalloid?

• Normal Saline is the default fluid for most situations• Exceptions:• Hartmann's for Burns• Hypertonic Saline in Intracranial Hypertension• Blood products in severe blood loss

• There is a move in intensive care to use of more physiological crystalloids such as Hartmann's, lactated ringers and Plasma lyte• Particularly in reducing hyperchloraemia and metabolic acidosis• Diabetic Ketoacidosis – high risk

• However there is a distinct lack of high-level evidence with regards to crystalloid choice

SPLIT Study: 0.9% saline vs. Plasma Lyte® 148 for fluid therapy in intensive care trial• Australian and New Zealand Intensive Care Society Clinical Trials

Group• The study hypothesis is that routinely using Plasma Lyte® 148 for fluid

therapy instead of 0.9% saline will reduce the risk of developing acute kidney failure• Pilot Randomised multicentre trial recruiting 2000 Patients• In Progress

QUESTIONS?