3. Rudyard Kipling
1865-1936
I keep six honest serving-men:
(They taught me all I knew)
Their names are What and Where
and When
And How and Why and Who
6. “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
depend upon the quantity of
serum lost..”
Lewins: London Medical Gazette 1832
7. “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
10. Thomas Graham
1805-1869
Crystalloids
“substances such as salt, sugar and
urea that could be crystallised with
ease”
Colloids (from Κθλλη, glue)
“these included substances such as
gelatin or glue, gum, egg-albumin,
starch and dextrin”
Colloid properties
“non- crystallisable, form gummy
masses when evaporated to dryness,
diffuse with extreme slowness and
would not pass through animal
membranes”
18. “I don’t care if you use dog’s piss, as long as you
use it carefully.”
Malcolm Fisher AO
What?
19. 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
20.
21. SAFE Study Investigators: NEJM 2004
2001-2003
Multicentred blinded RCT
Albumin vs saline
ICU patients
n=6997
Primary outcome: Mortality at 28d
22. Fluid volumes
Ratio of albumin to saline for first four days = 1:1.4
1 2 3 4
0
500
1000
1500
2000
Albumin
Saline
p<0.001
p<0.001
p=0.026
Day
Volumeadministered(mL)
SAFE Study Investigators: NEJM 2004
27. 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.
28. Caironi: New Eng J Med 2014
Multicentred open-label RCT
20% albumin (>30g/L) vs crystalloid: severe sepsis
n=1818
Primary outcome: Mortality at 28d
2008-2012
30. 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
32. Renal replacement therapy: 31.0 v 18.8% p=0.001
Brunkhorst: New Engl J Med 2008
P=0.48 P=0.09
Multicentred 2x2; open label RCT
10% HES 200/0.5 vs in Ringer’s lactate
n=537/600 (adaptive); severe sepsis
Primary outcome: Mortality at 28 days
2003-2005
34. Perner: New Engl J Med 2012
Multicentred blind RCT
6% HES 130/0.42 in Ringer’s acetate vs Ringer’s acetate
n=798; severe sepsis
Primary outcome: Mortality or RRT at 90d
2009-2011
35. Myburgh: New Engl J Med 2012
Multicentred blind RCT
6% HES 130/0.4 in saline vs 0.9% saline
n=7000; ICU patients
Primary outcome: Mortality at 90d
2009-2012
37. Regulatory responses
14 June 2013 (Revised 11 October 2013).
Restriction of HES in high-risk patients
24 June 2013.
“Boxed” warning against use of HES in high-risk patients
27 June 2013.
Withdrawal of registration of HES and recall of unused stock
8 April 2014
Restriction of HES in high-risk patients.
38. EU
EMA’s PRAC
recommend that
marketing
authorisations for
HES products be
suspended
UK
MHRA suspends use
of HES infusions,
recommends
crystalloids for fluid
resuscitation; supports
with position
statement by Faculty
of Intensive Care
Medicine, Intensive
Care Society, and
Royal College of
Anesthetists
USA
FDA issues Safety
Letter recommending
boxed warning for
HES solutions on
increased mortality,
severe renal injury,
and risk of bleeding
Germany
BfArM recommends
to stop using HES
products
Italy
HES products
suspended and
recalled
Ireland
Irish Board of
Medicine
recommends stop
use and distribution
of HES
Poland
Polish competent
Authorities decide to
stop use and
distribution of HES
immediately
Switzerland, France,
Spain, Czech
Republic
Recommend not to
use HES in specific
indications
Canada
Health Canada issues
advisory with
contraindications and
warnings for the use
of HES in patients with
sepsis, renal
impairment or severe
liver disease.
Australia
Australian TGA initiated risk/benefit
review, added contraindications for sepsis
and liver disease, strengthened warning
on risk of severe renal impairment and
bleeding disorders
Regulatory responses
40. Brit J Anaes / Acta Anes Scan: 2013
D Angus USA
M Antonelli ITA
A Artigas ESP
M Bauer GER
R Bellomo AUS
G Bernard USA
J Bion UK
L Brochard FRA
C Brun BuissonFRA
F Brunkhorst GER
V BumbasirevicSER
H Burchardi GER
P Caironi ITA
J Carlet FRA
J Chalmers AUS
J Chastre FRA
G Citerio ITA
D Cook CAN
J Cooper AUS
P Dellinger USA
T Evans UK
S Finfer AUS
H Flaaten NOR
R Freebairn NZ
C French AUS
D Gattas AUS
L Gattinoni ITA
H Gerlach GER
E G-BourboullisGRE
C Hartog GER
C Hinds UK
U Kaisers GER
M Levy USA
J Lipman AUS
S MacMahon AUS
D McAuley UK
S McGuiness NZ
L McIntyre CAN
M Maggorini SUI
J Mancebo ESP
J Marshall CAN
R Moreno POR
J Morgan AUS
J Myburgh AUS
C Natanson USA
R Norton AUS
D Payen FRA
A Perner DEN
V Perkovic AUS
A Pesenti ITA
V Pettilla FIN
C Putensen GER
M Quintel GER
M Ranieri ITA
K Reinhardt GER
A Rhodes UK
C Richard FRA
N RiedermannGER
I Roberts UK
G Rubenfeld CAN
F Schortgen FRA
G Sigurdsson ICE
C Sprung ISR
N Stochetti ITA
P Suter SUI
J Takala SUI
T Thompson USA
A Turner AUS
T Walsh UK
S Webb AUS
N Webster UK
T Welte GER
M White AUS
C WiedermannGER
D Young UK
R Zarychanski CAN
Brit J Anaes: On line 12 December 2013
41. Is the PRAC decision in the best interest of patients?
Increased relative risk of death ~ 6%
Increased relative risk of RRT ~ 27%
Could there be a place for HES in the future?
Only through robust, unbiased clinical trial network
Is there new evidence of safety for HES?
CRISTAL
RAFTING
BaSES
Bion: Int Care Med 2013
42. Annane: JAMA 2013
Multicentred open-label RCT
Colloids vs crystalloids
Hypotensive, hypovolaemic patients
No pre-randomisation fluids
n=2857/3010
Primary outcome: Mortality at 28d
2003-2012
43. Study or Subgroup
1.1.1 Low Risk of Bias
Yates 2014
Perner 2012
Myburgh 2012
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 2.07, df = 2 (P = 0.35); I² = 4%
Test for overall effect: Z = 2.12 (P = 0.03)
1.1.2 Intemediate Risk of Bias
Alavi 2012
Skhirtladze 2014
Nagpal 2012
Feldheiser 2013
Hamaji 2013
James 2011
Gondos 2010
Siegemund 2012
Guidet 2012
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 3.43, df = 7 (P = 0.84); I² = 0%
Test for overall effect: Z = 1.18 (P = 0.24)
1.1.3 High Risk of Bias
Du 2011
Dubin 2010
Yang 2011
Hung 2012
Lu 2012
Zhao 2013
Zhu 2011
Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Not applicable
Total (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 5.59, df = 10 (P = 0.85); I² = 0%
Test for overall effect: Z = 2.45 (P = 0.01)
Test for subgroup differences: Chi² = 0.13, df = 1 (P = 0.72), I² = 0%
Events
5
201
597
803
0
1
1
1
1
12
15
33
40
104
2
1
0
0
7
5
2
0
907
Total
104
398
3315
3817
32
81
35
26
24
56
50
117
100
521
21
9
26
41
22
80
45
0
4338
Events
2
172
566
740
0
0
0
0
0
6
14
36
32
88
2
5
0
0
12
5
4
0
828
Total
98
400
3336
3834
28
79
35
28
24
53
50
124
96
517
22
11
25
39
20
40
45
0
4351
Weight
0.2%
29.1%
59.2%
88.5%
0.1%
0.1%
0.1%
0.1%
0.8%
1.7%
4.1%
4.7%
11.5%
100.0%
M-H, Random, 95% CI
2.36 [0.47, 11.86]
1.17 [1.01, 1.36]
1.06 [0.96, 1.18]
1.10 [1.01, 1.20]
Not estimable
2.93 [0.12, 70.79]
3.00 [0.13, 71.22]
3.22 [0.14, 75.75]
3.00 [0.13, 70.16]
1.89 [0.77, 4.68]
1.07 [0.58, 1.98]
0.97 [0.65, 1.45]
1.20 [0.83, 1.74]
1.15 [0.91, 1.46]
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
1.11 [1.02, 1.20]
HES 130/0.38-0.45 Crystalloid Risk Ratio Risk Ratio
M-H, Random, 95% CI
0.01 0.1 1 10 100
Favours HES130/0.38-0.45 Favours crystalloid
HES and mortality
Increased mortality:
RR 1.11 (1.02-1.20)
NNH 53
French: unpublished (with permission)
44. HES and RRT
Study or Subgroup
1.2.1 Low RIsk of Bias
Yates 2014
Perner 2012
Myburgh 2012
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 2.05, df = 2 (P = 0.36); I² = 3%
Test for overall effect: Z = 2.77 (P = 0.006)
1.2.2 Intermediate Risk of Bias
Skhirtladze 2014
Lee 2011
Nagpal 2012
James 2011
Guidet 2012
Siegemund 2012
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 2.15, df = 5 (P = 0.83); I² = 0%
Test for overall effect: Z = 1.90 (P = 0.06)
Total (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 4.66, df = 8 (P = 0.79); I² = 0%
Test for overall effect: Z = 3.35 (P = 0.0008)
Test for subgroup differences: Chi² = 0.45, df = 1 (P = 0.50), I² = 0%
Events
4
87
235
326
1
1
1
2
21
28
54
380
Total
104
398
3352
3854
81
53
35
56
100
117
442
4296
Events
0
65
196
261
0
0
0
3
11
23
37
298
Total
98
400
3375
3873
79
53
35
53
96
124
440
4313
Weight
0.2%
24.4%
61.0%
85.7%
0.2%
0.2%
0.2%
0.7%
4.5%
8.5%
14.3%
100.0%
M-H, Random, 95% CI
8.49 [0.46, 155.59]
1.35 [1.01, 1.80]
1.21 [1.00, 1.45]
1.25 [1.07, 1.47]
2.93 [0.12, 70.79]
3.00 [0.12, 72.02]
3.00 [0.13, 71.22]
0.63 [0.11, 3.63]
1.83 [0.93, 3.59]
1.29 [0.79, 2.11]
1.44 [0.99, 2.11]
1.28 [1.11, 1.47]
HES 130/0.38-0.45 Crystalloid Risk Ratio Risk Ratio
M-H, Random, 95% CI
0.01 0.1 1 10 100
Favours [experimental] Favours [control]
Increased use of RRT
RR 1.28 (1.11-1.47)
NNH 52
French: unpublished (with permission)
45. HES- Sales Analysis- EU5
Note: Total HES Sales
irrespective of bottle size and %
Source: IMS Colloids Q2 2014 Data
6S trial
CHEST
1Reg Action- Jun’13
46. HES- Sales Analysis- China
Source: IMS Colloids Q2 2014 Data
Note: Total HES Sales irrespective of bottle size and
%
47. David Suzuki
1936-
The whole sector of public
dialogue has been badly
contaminated, deliberately, by
the corporate sector.
The whole purpose is to sow
confusion and doubt.
And it has worked.
53. Hartog Jacob Hamburger
1859-1924
‘Normal’ saline
0.9% saline is the most commonly used resuscitation fluid worldwide.
Titrational volumetric determination of osmotic
pressure in red blood cells
0.9% concentration of salt in human blood:
“Normal“ saline
Actual normality = 0.6% saine
54. Morgan: Crit Care 2008
Why does saline cause an acidosis?
n=851Cl-
154
Na+
154
Na+
154
Cl-
130
24 mEq/l
A “balanced” crystalloid will reduce extracellular SID at a rate that
precisely counteracts a dilutional alkalosis induced by weak acids.
55. Venkatesh: Anaes Int Care 2006
Why does saline cause an acidosis?
n=851
-10
-8
-6
-4
-2
0
2
4
6
8
10
0 50 100 150 200
[Hb] (g/L
SBE(mEq/L)
Need to give lots of saline
Need to give it fast
56. Model Result
Rat endotoxin infusion
+ fluid resuscitation
with NS, CSL, HES
Saline: ↓survival + worse SID
and BE than HES and CSL
Kellum: CCMed 2002
Rat CLP + HCl infusion ↑[Cl-]: hypotension Kellum: Chest 2004
Rat CLP + HCl infusion ↓BE: ↑TNF, IL-6 and IL-10 Kellum: Chest 2006
Cell culture LPS
stimulation with HCl or
lactic acid
HCl: pro-inflammatory
LA: anti-inflammatory (NO,
IL-6:IL-10 and NFKB binding)
Kellum: AJPRICP
2004
Animal data: saline / sepsis
57. Model Result
Greyhound
denervated kidney +
renal arterial hypertonic
infusion
NH4Cl > NaCl: ↓RBF + GFR Wilcox: JCI 1983
Rat isolated kidney ↑[Cl-]: ↑ pressor response to
A-II
Quilley: BJP 1983
Rat HCl infusion ↑markers of intestinal injury Pedoto: JLCM 2001
Animal data: kidney and gut
58. Model Result
Volunteers: 50ml/kg
CSL or NS over 1hr
CSL: ↓ osmolality,↑ diuresis
NS: ↑ time to micturition
Wiliams: A&A 1999
Reid Clin Sci 2003
Renal TP recipients:
CSL v NS
NS: ↑ Acidosis ↑K+ with
markers of intestinal injury
O’Malley: A&A 2005
Elderly surgical
patients: CSL v NS
NS: ↑acidosis and CO2 gap Wilkes: A&A 2001
Humans: kidney and gut
62. Yunos: JAMA 2012
Grade 2 or Grade 3 AKI Use of RRT in ICU
Log rank p=0.001
Log rank p=0.004
Single centre, sequential pilot observational trial
6m saline, gelatin, 4% albumin / 6m RL, PL-148, 20% albumin
n=760
OR 0.52
68. Shaw: Ann Surg 2012
Favours Plasmaltye
n=926
Favours Saline
n=30994
Registry, propensity-score based observational trial
Saline vs buffered salt solutions
69.
70. Saline and acid-base over time
Nested, cohort study within the SAFE study
n=691, 3 general ICUs
Bellomo: Crit Care Med 2006
Volume of fluid is predictor of acid base change
Changes are minor – alkalosis predominates
Influenced by disease severity and time
71. Plasma-‐Lyte
148®
vs
saline
n=2281
pa6ents
Primary
outcome
AKI
Secondary
outcome:
RRT,
Hospital
mortality
73. John Maynard Keynes
1883-1946
The difficulty lies, not in new
ideas, but in escaping old ones,
which ramify, for those brought up
with them, as most of us have been,
into every corner of our minds.
How?
74. The physiological fallacy
Fluid bolus therapy is self-evidently beneficial
Based on a common phenotype and surrogate variables
An inference, that cannot be measured, is made that the patient
has inadequate organ blood flow.
The second inference, that also cannot be measured, is that a fluid
bolus will restore the complexity of altered haemodynamics in a
predictable and safe fashion for the duration of the illness.
80. 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
81. 4.6 v 2.6%: HR:1.79 (1.17 to 2.74); p=0.008
Maitland: BMC Med 2013
83. Multicentred open-label RCT
Protocolised liberal v conservative fluid strategy x 7d: ALI
n=1001
Primary outcome: Mortality at 60d
2000-2005
NHLBI ARDSnet: New Engl J Med 2006
84. Fluid volumes and outcomes
Boyd: Crit Care Med 2011
VASST study: fluid balance / CVP at 12h and 4d
n=778
85. Fluid volumes and outcomes
Bouchard: Kidney Int 2009
Dialysed Non-dialysed
Program to Improve Outcome in Acute Kidney Disease
n=618
5 US centres
86.
87. Restrictive fluid strategies
Brandstrup: Ann Surg 2003
Multicentre, single blinded RCT
Restrictive vs standard fluids, surgical patients
n=172
Perioperative complications
88. Permissive hypovolaemia in burns
Parkland
Permissive
Arlati: Resuscitation 2007
Multicentre, retrospective 2-cohort study
n=24
90. Mikkelsen: Am J RespCrit Care Med 2012
OR 4.03 (1.53–10.59), p= 0.004
FACCT follow-up: 122 of 213/406 survivors
Neuropsychological assessment at 12 months
91. Fluids are unvalidated, lethal drugs
Drug: A term of varied usage. In medicine, it refers to any
substance with the potential to prevent or cure disease or
enhance physical or mental welfare. (www.WHO.int)
92. How and why?
Myburgh: New Engl J Med 2013
Fluids should be administered with the same caution that is used
with any intravenous drug
Consider the type, dose, indications, contraindications, potential for
toxicity and cost.
Resuscitation fluids should only be used in patients with
symptomatic hypovolaemia.
93. How?
Myburgh: New Engl J Med 2013
Fluid resuscitation is a component of a complex physiological
process
Identify the fluid that is most likely to be lost and replace the fluid
lost in equivalent volumes
Consider serum osmolality and the acid-base status when
selecting a resuscitation fluid
Consider cumulative fluid balance and actual body weight when
selecting the dose of resuscitation fluid
Consider the early use of catecholamines as concomitant
treatment of shock
94. When, how and why?
Myburgh: New Engl J Med 2013
Fluid requirements change over time in critically ill patients.
The cumulative dose of resuscitation and maintenance fluids is
associated with pathological oedema that is associated with
adverse outcomes
Oliguria is a normal response to hypovolaemia and should not be
used solely as a trigger or end-point for fluid resuscitation,
particularly in the post-resuscitation period.
95. When and how?
Myburgh: New Engl J Med 2013
Fluid requirements change over time in critically ill patients.
The use of a fluid challenge in the post-resuscitation period (>24
hours) is questionable
The use of hypotonic maintenance fluids is questionable once
dehydration has been corrected.
96. Who and what?
Myburgh: New Engl J Med 2013
Specific considerations apply to different categories of patients.
Bleeding patients require control of haemorrhage and transfusion
Isotonic, buffered salt solutions are pragmatic initial resuscitation
fluids for the majority of acutely ill patients.
Consider saline in patients with hypovolaemia and alkalosis
Consider albumin during early resuscitation of patients with sepsis
97. Who and what?
Myburgh: New Engl J Med 2013
Specific considerations apply to different categories of patients.
Saline or isotonic crystalloids are indicated in traumatic brain injury
Albumin is contraindicated in traumatic brain injury
Hydroxyethyl starch should not be used in any patient population
The safety of other semi-synthetic colloids has not been established
The safety of hypertonic saline has not been established
