The erudite John Myburgh condenses fluid resuscitation data down to a palatable brew.

1. Resuscitation fluids:
which, when, how much?
UNSW
John Myburgh
MBBCh PhD FCICM FAICD
The George Institute for Global Health
St George Clinical School, University of New South Wales

2. Leith Infirmary 1831
Thomas Aitchinson Latta
c1790-1833

3. “The most wonderful and
satisfactory effect is the
immediate consequence
of the injection.”
“The quantity necessary
to be injected will
probably be found to
depend upon the quantity
of serum lost..”
Lewins: London Medical Gazette 1832

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

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

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

8. SAFE Study Investigators: NEJM 2004

10. “Professor Myburgh, I can’t find SAFE fluid
in MIMS.
Is it a crystalloid or a colloid?”
ICU Registrar: St George Hospital 2003

11. SAFE Study Investigators: NEJM 2004

12. Should you change practice?

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

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

16. Maitland: New Eng J Med 2011

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

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

19. Summary: albumin
Equivalence to saline in terms of safety and haemodynamic effect
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 unproven

20. What about synthetic colloids?

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

22. 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
Colloids vs crystalloids

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

24. Choice of Colloid: Severe sepsis
0
50
100
150
200
250
300
350
400
450
OCEANIA AMERICAS ASIA NORTHERN
EUROPE
SOUTHERN
EUROPE
WESTERN
EUROPE
All
mLperperson
Albumin Starch Gelatin Dextran
Choice of Colloid: Severe sepsis
SAFE TRIPS Investigators: Crit Care 2010

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

26. 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
HES: effects on renal function

27. Perner: New Engl J Med 2012

28. 6S 2012
P=0.48 P=0.09
SepNet (VISEP) 2008
P=0.07

29. ANZICS
Clinical Trials Group
Myburgh: New Engl J Med 2012

30. Myburgh: New Engl J Med 2012

32. Systematic reviews 2013
Systematic
review
HES
preparation
Comparator Patient
population
Mortality
RR (95% CI)
RRT
RR (95%CI)
Gattas 6% HES
(130/0.4-042)
Isotonic saline
Hypertonic saline
Lactated Ringer’s
Acetated Ringer’s
Albumin 4%, 5%,
20%
Gelatin 4%
Polygeline 3.4%
Dextran 70
HES (200/0.5)
HES (670/0.75)
Acutely ill patients in
intensive care,
perioperative and
operative setting
1.08 (1.00 to 1.17) 1.25 (1.08-1.44)
Haase 6% HES
(130/0.4-0.42)
Isotonic saline
Lactated Ringer’s
Acetated Ringer’s
Albumin 20%
Sepsis/septic shock 1.04 (0.89 to 1.22) 1.36 (1.08 to 1.72)
Zarychanski 6-10% HES
(130/0.4-0.42)
6-10% HES
(200/0.43-0.66)
Isotonic saline
Hypertonic saline
Lactated Ringer’s
Acetated Ringer’s
Albumin 4%, 5%,
20%
Gelatin 3%, 4%
Plasma
Critically ill patients
in emergency or
intensive care setting
1.06 (1.00 to 1.13) 1.32 (1.15 to 1.50)
Patel 6% HES
(130/0.4-0.42)
Isotonic saline
Acetated Ringer’s
Albumin 20%
Severe sepsis 1.13 (1.02 to 1.25) 1.42 (1.09 to 1.85)
Myburgh: Int Care Med (in press)

33. Study fluid volume and dose
Study HES Control Patient
population
HES Dose
Med (IQR)
RRT
RR (95%CI)
Mortality
RR (95%CI)
VISEP 10% HES
(200/0.5)
Lactated
Ringer’s
Severe sepsis 70 mL/kg
(33 to 144.2)
1.62
(1.19 to 2.21)
1.17
(0.94 to 1.47)
6S 6% HES
(130/0.4-0.42)
Acetated
Ringer’s
Severe sepsis 44 mL/kg
(24 to 75)
1.35
(1.01 to 1.80)
1.17
(1.01 to 1.36)
CHEST 6% HES
(130/0.4)
0.9%
saline
Adult ICU
patients
5 mL/kg
(3 to 9)
1.21
(1.00 to 1.45)
1.06
(0.96 to 1.18)

34. Summary: hydroxyethyl starch
Most commonly prescribed colloid globally.
Cost effectiveness not established
Evidence for dose-dependent nephrotoxcity with all HES preparations
Evidence for adverse effects related to accumulation in RES
No demonstrable clinical benefit and increased risk of harm over
crystalloids

35. Bayer: Critical Care Medicine 2011

36. Colloids vs crystalloids
Pere: Cochrane Library; Yesterday

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

38. Hartog Jacob Hamburger
1859-1924
Determination of osmotic pressure
very small amounts of liquid in a
volumetric way, using blood cells.
0.9% concentration of salt in human
blood = “Normal“ saline
Crystalloids: normal saline

39. Crystalloids: normal saline
The most commonly used resuscitation fluid globally.
Normal saline is the most extensively studied crystalloid in high-
quality 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

40. Yunos: JAMA 2012
Grade 2 or Grade 3 AKI Use of RRT in ICU
Log rank p=0.001
Log rank p=0.004

41. Crystalloids: balanced salt solutions
Physicochemical properties of balanced salt solutions render none as
“ideal”
Ringer’s lactate: hypotonicity
Ringers acetate: cardiotoxicity
Plasmalyte 148: alternative non-physiological anions
New, non-propietary solutions not established
No major emerging trials at present

42. 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
Consistent data on haemodynamic equivalence between colloids and
crystalloids
Net association of fluid retention with consequent adverse clinical effects
The place and rationale for “maintenance” fluids is questionable

43. Emerging issues in fluid resuscitation
Overall, there is little evidence to support the use of in acutely ill
patients.
In particular, semi-synthetic colloids are essentially non-biological
and non-physiological solutions
Restricted volumes of balanced salt solutions appear to be logical,
albeit unproven fluids of choice in the majority of patients

44. Emerging issues in fluid resuscitation
Paradigm shift to regard fluid resuscitation as same as a drug:
The type of fluid will affect patient outcome
Specific contraindications
The volume (dose) will affect patient outcome
Toxicity presents in the post resuscitation period.

45. “The dose makes the poison”
Paracelus
1495