1. Hydroxyethyl Starch or Saline for
Fluid Resuscitation in Intensive Care
CHEST TRIAL - The Crystalloid
versus HydroxyEthyl Starch Trial
John A. Myburgh et al
NEJM – NOV 15, 2012

2. Background
• Intravenous fluid of choice in ICU to increase
intravascular volume is controversial.
• Globally, 0.9% sodium chloride is the most
commonly used fluid.
• But colloids are administered as often as
crystalloids.
• Hydroxyethyl starch (HES) is the most frequently
used colloid. – Finfer et al CRITICARE 2010

3. Investigators like-
• Schortgen F – LANCET - 2001
• Brunkhorst FM - NEJM – 2008
• Dart AB – Cochrane database- 2010
have proven that HES increases the risk of AKI in
critically ill patients.
But the HES used in all above studies was
• 10 %
• 200 kd mol. Wt.
• MRS- Molar Substitution Ratio (the number of
hydroxyethyl groups per glucose molecule) of
more than 0.5.

4. What we currently use is –
• 6%
• 130 kd
• MRS- 0.38-0.45
 It has not been compared with Normal saline as a
resuscitative fluid in critically ill.
 Additionally, the 6S trial - Scandinavian Starch for Severe
Sepsis/Septic Shock
comparing 6 %(130/0.42) HES vs Ringers lactate was
significantly associated with increased mortality in patients
with severe sepsis and septic shock.
Anders Perner et al – NEJM April 2012

5. CHEST TRIAL
Multicenteric , prospective, blinded, randomized controlled trial in
32 hospitals in Australia and New Zealand by the Australian and
New Zealand Intensive Care Society
Funding - National Health and MRC Australia
New South Wales Ministry of Health
Fresenius Kabi, the manufacturer of Voluven.
Funding agencies had no input into the design, conduct, data
collection, statistical analysis, writing of the manuscript.
Fresenius Kabi supplied the study fluids and distributed them to
participating sites

6. Inclusion criteria
The requirement for fluid resuscitation must be supported by
AT LEAST ONE of the following clinical signs:
a. Heart rate >90 beats per minute
b. Systolic blood pressure < 100 mmHg or
mean arterial pressure <75 mmHg or
at least 40 mmHg decrease in systolic or MAP from the
baseline recording
c. Central venous pressure <10 mmHg
d. Pulmonary artery wedge pressure <12 mmHg
e. Respiratory variation in systolic or mean arterial pressure of >5
mmHg
f. Capillary refill time >1 second
g. Urine output <0.5 ml/kg for 1 hour

7. Exclusion criteria
1)Age less than 18 years.
2) Previous allergic reaction to HES
3) Intracranial hemorrhage
4) Patients receiving renal replacement therapy or in
whom the ICU physician considers renal replacement
therapy is imminent (i.e. RRT will start in 6 hrs)
5) Serum creatinine value >350 μmol/L and urine output
averaging ≤10 ml/h over 12 hours
6) Severe hypernatremia (serum sodium >160 mmol/l)
7) Severe hyperchloremia (serum chloride >130 mmol/l)
8) Women of child-bearing age (18–49 years old)

8. 9) Breastfeeding women
10) Patients who have received >1000 mL HES
outside the ICU within the 24 hours before
randomization
11) Patients admitted to the ICU following cardiac
surgery burns or following liver transplant.
12) Life expectancy of less than 90 days
13) DNR patients
14) Transfer out from other ICU
15) Already received fluids same as planned in
study

9. Study randomisation and treatment
Sample size was planned to be 7000.
Patients were randomly assigned to receive either
6% HES (130/0.4) in 0.9% saline (Voluven, Fresenius
Kabi) or 0.9% saline in indistinguishable Freeflex
500-ml bags for all fluid resuscitation in the ICU
until discharge, death, or till 90 days post
randomization.
Max dose of resuscitation fluid- 50ml/kg/day
Fluid for maintenance- 0.9 % NS

10. Outcome Measures
Primary –
All cause mortality 90 days post randomization
The primary outcome was also examined in six
subgroup pairs on the basis of baseline features:
1) The presence or absence of diagnostic criteria for
AKI (RIFLE-R and RIFLE-I categories),
2) The presence or absence of sepsis at randomization
3) The presence or absence of trauma
4)With or without traumatic brain injury
5)The score (<25 vs. ≥25) on the Acute Physiology and
Chronic Health Evaluation (APACHE) II
6)Receipt or nonreceipt of HES before randomization

11. Secondary-
1) Incidence of AKI as defined by RIFLE criteria
2) Use of renal-replacement therapy
3) New organ failures not present at baseline
4) Duration of mechanical ventilation and RRT
5) Cause-specific mortality.
Tertiary outcomes
1)Duration of ICU f/b hospital stay
2) Rate of death in the ICU and hospital.

12. Statistical analysis
• Analyses were conducted on an intention-to
treat basis
• Binary outcomes were compared using relative
risks with 95% Ci & chi square tests
• Continuous outcomes were compared with the
use of mean differences and unpaired t-tests.

13. Results
• December 2009 - January 2012
• 7000 medical–surgical ICU patients
• 3500 patients assigned to receive 6% HES (130/0.4)
in 0.9% saline (HES group)
• 3500 to receive 0.9% saline (Saline group)
• The two groups of patients had similar
characteristics at baseline

17. Outcomes - First 4 days
HES group received
a) Significantly lower
1) Study fluid- p < 0.001
2) Non study fluid – p < 0.001
b) Significantly higher
1) Blood products – p <0.001
Though they had significantly lower positive fluid balance
(p= 0.03) , net CVP was significantly higher (p<0.001).
Variables like HR, MAP and lactate levels were not
significantly different

18. Outcomes
Primary –
All cause mortality 90 days post randomization
18% patients died in HES group within 90 days
after randomization vs 17.0% in the saline group
RR- 1.06; 95% CI- 0.96 to 1.18
P = 0.27
Not statistically significant

20. Subgroup anaylsis of primary outcome-
There was no significant heterogeneity in the
effect of treatment on 90-day mortality in any of
the predefined subgroups

22. Secondary outcomes
A ) Incidence of AKI as defined by RIFLE criteria

23. Post hoc analysis
Showed that
a) Serum creatinine levels were significantly
increased (P = 0.004) and
b) Urine output was significantly decreased
(p=0.003)
in the HES group, as compared with the saline
group, during the first 7 days

25. Other secondary outcomes
HES NS RR p

26. Tertiary outcomes

27. Adverse effects

28. Discussion
a) Primary outcome-
The similar mortality rates in either group may be d/t
a) exclusion of patients with intracranial hemorrhage
and those whom clinicians considered unlikely to
survive.
b) the inclusion of patients who had undergone
elective surgery.
c) recruitment after admission to the ICU, when the
requirements for fluid resuscitation are often
less than those for patients in the ER/OR

29. b) Secondary outcome –
Incidence of AKI as defined by RIFLE criteria
Use of HES was associated with significantly lesser no of
patients in the Risk and Injury group as per RIFLE criteria.
There was no statistically significant difference in patients in
Failure group.
This was contrary to the postulate on which the project was
conducted that HES may cause more incidence of AKI

30. But post hoc analysis showed significantly
higher creatinine levels and lower urine output in
initial 7 days suggesting a progressive reduction in
creatinine clearance and more severe acute kidney
injury.
HES was associated with increased urine output in
patients with less severe AKI , which may have
been due to
a) Increased intravascular volume or
b) Through a diuretic effect.

31. Initiation of RRT-
Though the criteria not been defined and decision
for initiation was of nephrologist unaware of
patient belongs to which group , significantly
higher no of patients in HES group required
initiation of RRT.
(21% relative increase)
This itself says about risk of AKI associated with
HES

32. New organ failure
Though HES group had less incidence of cardiovascular
failure, they had significantly high incidence of hepatic
failure.
The former can be explained due to the better
intravascular volume expansion by HES but this did not
reflect on the end organ perfusion parameters like HR,
MAP, Lactates.
HES group additionally required more blood products
Adverse effects were more with HES esp pruritus

33. Mechanism by which HES Causes
Pruritus- Deposition in Reticuloendothelial system
AKI- Osmotic nephrosis: AKI with accumulation of
proximal tubular lysosomes
( Dickenmann - Am J Kidney Dis 2008;51:491-503.)
Hepatic Failure- Lysosomal accumulation in
hepatocytes

34. Limitation of study
Was carried out in patients with lesser risk of
mortality, selected patients were from a
controlled scenario like ICU.
Previous studies (like 6S) which evaluated HES as
resucitative fluid had much sicker patients
(severe sepsis, EMS, Emergency surgery etc)

35. Conclusion- CHEST TRIAL
There is no evidence that resuscitation with 6% HES
as compared with saline, in the ICU provides any
clinical benefit to the patient.
Indeed, the use of HES resulted in an increased rate of
RRT.
Thus, the selection of resuscitation fluid in critically ill
patients requires careful consideration of its safety and
its cost.

36. Few eye openers- HES
First launched by Fresenius (Germany ) 1974, never
ever its safety has been assessed as per recent
standards.
Every time new composition is launched when
previous one noticed to have safety issues.
B.BRAUN (Tretraspan) and FRESENIUS KABI (Voluven)
are two major players, turnover worth billions USD.
Cost for 500 ml – 380- 400 INR

37. After the 6S trial, the principal author (Dr Perner) and NEJM
was threatened by FRESENIUS of legal suit for the losses it
might incur.
6S used Tetraspan and not Voluven, but both are exactly the
same.
Later the threat was withdrawn with authors specifying the
brand name Tetraspan in revised fresh online copy.
Funding of CHEST trial by FRESENIUS KABI may reflect
some conflict of interest.

38. Dr Joschiam Boltj (German researcher) whose field
of interest been HES , with over 90 publications
has been suspended as a faculty, his articles
withdrawn from the 16 journals and proceedings
of scientific misconduct are on.
He has been presenting favourable results for HES
in all his papers.
Multiple meta-analysis included his papers on HES

39. Eg- Meta- analysis of the use of HES in critically ill
(Zachyranski R et al.- JAMA 20 Feb- 2013)
Of 90 studies used , 7 were of BOLTJ
Only his papers favour HES.
Include them- no increase in mortality
Exclude them- significant increase.
Considered biggest medical fraud, amounting to 10
yrs rigorous imprisonement and fine.
Suspected to have favours from makers of HES