This document discusses fluid resuscitation and intravenous fluids. It provides a brief history of intravenous fluids from early experiments in the 1800s to modern clinical trials. It notes emerging issues with ubiquitous fluid administration and inconsistent use. There is little evidence to support most colloids over crystalloids. Normal saline is commonly used but may cause harm, while balanced solutions are not clearly superior. Large clinical trials are needed to provide guidance on fluid type and use. The document calls for a paradigm shift toward treating fluid resuscitation more like a drug with specific indications and considerations of toxicity.

1. Fluid resuscitation: time for a new
paradigm
John A Myburgh
MBBCh PhD FCICM
UNSW
Professor of Critical Care Medicine
The George Institute for Global Health
University of New South Wales
St George Hospitals, Sydney

3. Leith Infirmary 1831
Thomas Aitchinson Latta
c1790-1833

4. “The most wonderful and
satisfactory effect is the
immediate consequence
of the injection.”
“The solution that was
used consisted of two
drachms of muriate, and
two scruples of carbonate
of soda to sixty ounces of
water. It was at the
temperature of 108 or
110o”
“The quantity necessary
to be injected will
probably be found to
Lewins: London Medical Gazette 1832
depend upon the quantity

5. “Verily sir, this is an
astonishing method of
medication, and I predict
will lead to wonderful
changes and
improvements in the
practice of medicine ”
Lewins: London Medical Gazette 1832

6. Sydney Ringer
1834-1910
Alexis Hartmann
1898-1964

7. Ernst Starling
1866-1927
“Das Blut ist ein ganz besonder Saft”
Faust (Goethe)
Edwin Cohn
1892-1953

10. “I don’t care if you use dog’s piss, as long as you use
it carefully.”
Malcolm Fisher AO

11. Hypovolaemia
24/30 studies
n=1104/1419
RRD 1.68 (1.25 – 2.23)
Burns
Overall excess mortality
of 6%
(95% C.I. 3 - 9%)
Hypoalbuminaemia
TOTAL
Favours
albumin
Favours
control
Roberts: BMJ 1998

12. “…I would attempt to sue anyone who gave me an
albumin infusion.
And, as for any attempt to secure my informed
consent to take part in a randomised trial . . . forget it !”
Chalmers BMJ:1998

14. SAFE Study Investigators: NEJM 2004

15. SAFE Study Investigators: NEJM 2004

16. Should you change practice?

17. Mortality at 28 days
Mortality at 2 years
SAFE Study Investigators: NEJM 2007

18. Sepsis
P=0.059
(Test for common relative risk)
MVLR adjusting for baseline covariates in patients with complete data:
919/1218 (75.5%)
0.71 (0.52 – 0.97) p=0.03.
SAFE Study Investigators: Int Care Med 2011

20. Lesson from SAFE
Do not change your practice on the basis of a meta-analysis
Large-scale trials are feasible and will answer a question
Randomised behaviour vs random behaviour
Challenge the dogma

21. Albumin in malaria
150 Children with severe malaria and metabolic acidosis
Assigned to 4.5% albumin or normal saline or control
No difference in resolution of base deficit
Reduced mortality: 2/56 (3.6%) vs. 11/61 (18.0%); p=0.013
Maitland: Clinical Inf Dis 2005

22. Albumin in malaria
Akech: PLoS Clinical Trials 2006

23. Maitland: New Eng J Med 2011

24. 2009-2011
Multicentred open-label RCT
Albumin vs saline bolus vs no bolus in febrile hypotensive
children
n=3141/3600
Primary outcome: Mortality at 48h
Mortality at 4 hours
Mortality at 4 weeks
Maitland: New Eng J Med 2011

25. T H Huxley
1825 - 1895
“That the great tragedy of
Science is the slaying of a
m
beautiful hypothesis with
an ugly fact”

26. What about synthetic colloids?

27. Capital cost
500mL
Cost
(AUD)
Normal Saline
Hartmann’s Solution
Plasmalyte®
Hypertonic Saline
0.61
0.61
1.54
2.54
Gelatins
Dextrans
Hetastarch
Albumin
Albumin (Australia)
14.99
38.34
53.00
42.75
0.00*

28. Colloids vs crystalloids
Colloid
Trials
n
RR
95%CI
Albumin
23
7754
1.01
0.92 to 1.10
HES
16
637
1.05
0.63 to 1.75
Gelatin
11
506
0.91
0.49 to 1.72
Dextran
9
834
1.24
0.94 to 1.65
Perel: Cochrane Collaboration 2007

29. Colloids for fluid resuscitation
Colloid
Trials
n
RR
95%CI
Albumin v HES
25
1234
1.14
0.91 to 1.43
Albumin v gelatin
7
636
0.97
0.68 to 1.39
Albumin v dextran
4
360
3.75
0.42 to 33.09
Gelatin v HES
18
1337
1.00
0.80 to 1.25
Bunn: Cochrane Collaboration 2009

30. Fluid volumes delivered
SAFE TRIPS Investigators: Crit Care 2010

31. Colloid use in severe sepsis
Choice Choice of Colloid: Severe sepsis sepsis
of Colloid: Severe
Albumin
Starch
Gelatin
Dextran
450
400
350
mL per person
300
250
200
150
100
50
0
OCEANIA
AMERICAS
ASIA
NORTHERN
EUROPE
SOUTHERN
EUROPE
WESTERN
EUROPE
All
SAFE TRIPS Investigators: Crit Care 2010

32. Renal replacement therapy: 31.0 v 18.8% p=0.001
Brunkhorst: New Engl J Med 2008

33. HES: effects on renal function
Outcome
Trials
n
RR
95%CI
Renal replacement therapy
34
1236
1.38
0.89 to 2.16
RRT : sepsis
3
702
1.59
1.2 to 2.1
Author-defined ARF
34
1199
1.50
1.12 to 1.87
Author-defined ARF: sepsis
4
832
1.55
1.22 to 1.96
Dart: Cochrane Collaboration 2010

34. Starch use in Australia….
6% hydroxyethyl starch 130/0.4 is the first starch approved by the
Therapeutic Goods Administration in November 2006.
2008 marketing of HES started
December 2008 over >40 hospitals in Australia used HES: >200,000
units distributed
30% of semi-synthetic colloid market
Australia was in a unique position to conduct a large-scale
randomised controlled trial.

35. ANZICS
Clinical Trials Group

36. Design and outcomes
Power
N=7000
To detection ARR 3.5% from baseline mortality of 21%
(α=0.05; β0.9)
To detect RRI in renal failure by 1.3 from baseline of 6%.
Outcomes
All-cause mortality at 90 days
Incidence of acute renal injury/acute renal failure
Interval mortality rates
Organ failures (respiratory, cardiovascular, coagulation and hepatic)
Incidence of pruritis (D90)
Quality of life and functional outcome assessments (6 months)
Cost-effectiveness analysis

37. Joachim Boldt

38. Gattas: Anes Analg 2012

39. n=7000
ANZICS
Clinical Trials Group

41. Scandinavian Starch for Severe
Sepsis/Septic Shock Trial
MC DB RCT
6% HES (130/0.42) in Ringers acetate vs Ringers acetate (33mL/kg/d)
Severe sepsis + fluid resuscitation
Primary outcome: Death or RRT at day 90
10% ARR from incidence of 50% (α 0.05, β=0.8)
n=800
Perner A: with permission

42. Scandinavian Starch for Severe
Sepsis/Septic Shock Trial
Inclusion criteria fulfilled 1211
Exclusions
6 Age < 18 years
0 Allergy towards IMP
138 Dialysis
1 Organ transplant
5 Burn injury >10%
9 Intracraniel bleeding
21 S-K+ >6 mM
25 Other trial
15 No active therapy
152
>1000 ml synthetic colloid
51 No informed consent
804 randomised patients
Post-randomisation exclusions
4 deleted from database during the trial
(Violation of in-/exclusion criteria
AND no trial fluid given)
798 patients analysed
2 consent withdrawn after end of trial both in
the HES group
100% follow-up
Perner A: with permission

43. Scandinavian Starch for Severe
Sepsis/Septic Shock Trial
Perner A: with permission

44. Scandinavian Starch for Severe
Sepsis/Septic Shock Trial
Kaplan Meier curves of survival censored at 90 days
Survival Distribution Function
Day 90 composite endpoint
1.0
0.8
0.6
0.4
0.2
0.0
0
20
40
60
80
Days
Perner A: with permission

45. Round Table 2012:
Types of intravenous fluids
John A Myburgh
Monty Mythen
MBBCh PhD FCICM
MBBS FRCA MD FFICM
Professor of Critical Care Medicine
The George Institute for Global Health
University of New South Wales
St George Hospitals, Sydney
Professor of Anaesthesia and Critical Care
University College, London

46. Emerging issues in fluid resuscitation
Ubiquitous intervention in acute medicine
Selection and use is entirely dependent on geography
Administered by relatively junior medical staff in random fashion
Inconsistent haemodynamic and physiological endpoints
Net association of fluid retention with consequent adverse clinical
effects
The place and rationale for “maintenance” fluids is questionable

47. Emerging issues in fluid resuscitation
Consistent data on ratios of crystalloid:colloid ratio of 1:1.4
Overall, there is little evidence to support the use of colloids
Paradigm shift to regard fluid resuscitation as same as a drug:
Context specific in various patient populations
Specific indications and contraindications
Toxicity relating to the volume, rate of administration and type
of fluid

48. What about crystalloids?
“Abnormal” saline vs “Balanced” salt solutions

49. Crystalloids: normal saline
The most commonly used resuscitation fluid globally.
Normal saline is the most extensively studied crystalloid in highquality randomised-controlled trials.
Established, although unproven, role in trauma resuscitation,
particularly traumatic brain injury
There is increasing evidence of potential iatrogenic harm:
Hyperchloraemic acidosis
Oedema
Microcirculatory effects

50. Crystalloids: normal saline
Increased mortality in febrile children with compensated shock in
low-income countries when administered as bolus
Emerging trials: association with acute kidney injury
Observational data in peri-operative patients –comparisons with
Ringers Lactate
Observational data in critically ill patients – chloride restrictive
vs chloride liberal fluid resuscitation
An increasing imperative to conduct a large-scale high quality
randomised-controlled trial to determine safety and efficacy
comparing saline to a physiological solution

51. Crystalloids: balanced salt solutions
Physicochemical properties of balanced salt solutions render none as
“ideal”
Relates to requirement of a solution with a SID of 24, using
endogenous anions.
Ringer’s lactate: hypotonicity
Ringers acetate: cardiotoxicity
Plasmalyte 148: alternative non-physiological anions
New, non-propietary solutions not established
Questions emerge in relation to developmental and regulatory
requirements
No major emerging trials at present

52. Colloids: albumin
Equivalence to saline in terms of safety
Cost effectiveness not established
Increased mortality in traumatic brain injury
Related to the development of intracranial hypertension
Potential hypotonicity
Potential beneficial effects for fluid resuscitation in sepsis
Increased mortality in febrile children with compensated shock in
low-income countries when administered as bolus
Emerging trials
Albumin as an infusion to maintain normoalbuminaemia post
resuscitation
Potential non-colligative properties

53. Colloids: hydroxyethyl starch
Most commonly prescribed colloid globally.
Cost effectiveness not established
Evidence for nephrotoxcity with hyperoncotic, high MW
preparations
Evidence for adverse effects related to accumulation in RES
Uncertainty about the purported increased safety profile associated
with formulary changes
No substantive evidence of safety or effectiveness over crystalloids
SSSSSS and CHEST will change the landscape

54. Colloids: gelatins
Second most commonly used synthetic colloid after hydroxyethyl starch
Cost effectiveness not established
Emerging evidence of potential nephrotoxcity
No current or emerging trials at present

55. Publications from Round Table (i)
The current status of fluid therapy in the ICU:
Recognition of importance
Emerging evidence that selection and use can have a direct impact
on outcome
We need a paradigm shift
Recommendations for education, practice improvement , quality
assurance and audit

56. Publications from Round Table (ii)
Future directions for fluid therapy in ICU:
Unmet needs (better fluids?)
Research questions and priorities
Evaluation for use (research methods: observation, RCT),
meaningful outcomes

57. “A suitable clinical
investigation is required
to resolve between such
conflicting authorities the
mass of the profession is
unable to decide; and
thus, instead of any
uniform mode of
treatment, every town
and village has its
different system or
systems, while the daily
lists of mortality proclaim
the general inefficiency of
the whole.”
Lancet 1832