IV Fluid Choice - An ICU Perspective

1. IV Fluid Choice - an ICU
perspective
(With 2 Cautionary stories about Cochrane
Meta-analysis)
Dr Vincent Chan
Senior Registrar in Emergency and Intensive Care Medicine
17th
April 2014

2. 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

3. 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

4. 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

5. Variations in Colloids and Crystalloids
Formulations
Solution pH Na+ Cl- K+ Ca++ Lactate Glucose Osmolality Other
0.9% normal saline 5.0 154 154 0 0 0 0 308 0
Hartmann/CSL 5-7 131 112 5 2 28 0 255 0
Plasma 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 with
dextrose (D51/2 NS) 4.5 77 77 0 0 0 50 g/L 406 0
Albumin (4%) 6.7-7.3 140 128 0 0 0 0 260 40 g/L albumin
Albumin (20%) 6.4-7.3 48-100 130-160 0 0 0 0 130 200 g/L albumin
Hetastarch 6% 5.5 154 154 0 0 0 0 310 60 g/L starch
Pentastarch 10% 5.0 154 154 0 0 0 0 326 100 g/L starch
Dextran-40
(10% solution) 3.5-7.0 154 154 0 0 0 0 311 100 g/L dextran
Dextran-70
(6% solution) 3.0-7.0 154 154 0 0 0 0 310 60 g/L dextran
Haemaccel 3.5% 7.4 145 145 5 6.25 0 0 293 35 g/L gelatin
Gelofusine 7.4 154 125 0 0 0 0 308 40 g/L gelatin

6. 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

7. 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

8. 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

9. 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)

10. 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

11. 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

12. 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

13. 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.

14. 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

15. 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

16. 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

17. 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

18. 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

19. QUESTIONS?