British Journal of Anaesthesia 108 (1): 159170 (2012)

CORRESPONDENCE
Hydroxyethyl starch in patients with
trauma

Declaration of interest
S.F. was the principal investigator for the Saline vs Albumin
Fluid Evaluation (SAFE) study which was part funded by
CSL Ltd. (CSL manufactures albumin in Australia). CSL has
acted as a sponsor for scientific meetings of the Australian
and New Zealand Intensive Care Society and its clinical
trials group which S.F. previously chaired. CSL has paid
travel expenses for S.F. to present the results of the SAFE
study at scientific and industry-sponsored meetings. Fresenius Kabi paid travel and accommodation expenses for S.F.
to travel to Germany during the design of the Crystalloid vs
Hydroxy Ethyl Starch Trial (CHEST) (Fresenius Kabi manufactures Voluven in Germany).
S. Finfer*
Sydney, Australia
*
E-mail: sfinfer@georgeinstitute.org.au
1 James MFM, Michell WL, Joubert IA, Nicol AJ, Navsaria PH,
Gillespie RS. Resuscitation with hydroxyethyl starch improves
renal function and lactate clearance in penetrating trauma in a
randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma). Br J Anaesth 2011; 107: 693 702

& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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EditorJames and colleagues1 are to be congratulated on

their contribution to the literature on resuscitation fluids.
Their randomized trial comparing hydroxy ethyl starch with
saline for the resuscitation of severely injured trauma
patients was designed to examine two primary outcomes:
first, the volumes of fluid administered in the first 24 h
and, secondly, the number of patients achieving normal
gastrointestinal function by day 5. The volume of saline
administered was 1.5 times that of hydroxyethyl starch, a
ratio very similar to that seen when saline was compared
with albumin 4% in a broader population of patients in the
SAFE study.2 The authors state that similar proportions of
surviving patients recovered gastrointestinal function by
day 5, but the exact numbers of patients are not reported
and this seems an inappropriate way to report a primary
outcome measure. The CONSORT authors recommend that
for each primary and secondary outcome, the estimated
effect size and its precision, for example, 95% confidence
interval, are reported, for proportions both the numerator
and denominator should be given;3 James and colleagues
have not done this. Outcome-reporting bias is an increasingly
recognized problem which may distort the medical
literature;4 authors, journal reviewers, and editors should all
insist that the pre-stated primary outcome measures are
appropriately reported and emphasized. The title of the
paper and much of the manuscript focuses on safety and
secondary outcome measures without any allowance for
reporting multiple outcome measures. The authors conclude
that hydroxy ethyl starch improves renal function and lactate
clearance. While these are important considerations, additional information is required to assess these conclusions.
The authors assessed renal function using the RIFLE criteria
and report a significant increase in renal injury in the patients
with penetrating trauma assigned to receive saline. The
authors also state that no patients developed oliguria other
than those who were subsequently treated with dialysis. As
the RIFLE diagnosis of renal injury requires either a doubling
in baseline creatinine concentration or oliguria,5 I conclude
that the diagnosis of renal injury was made on the basis of
a doubling of creatinine concentration from baseline which
in the context of a randomized controlled trial means creatinine concentration measured before randomization.
Assessing both the statistical and clinical importance of
this finding is hampered as the authors have reported
neither the creatinine concentrations of the patients before
randomization nor their peak creatinine concentrations.
Reporting these data would assist readers to decide
whether the diagnosis of renal injury is clinically significant.
A further concern is that the diagnosis of renal injury is

subject to competing risk; that is to say, patients may have

died before they had the opportunity to develop renal
injury and this may have biased the results. The authors
state that mortality was 16.5% with no significant difference
between the groups; however, they have not reported the
number of patients who died in each group and this not
only makes interpretation of their report difficult but also
hampers the inclusion of these data in future meta-analyses.
It would have been helpful if the authors had been asked to
report the number of patients dying in each group and how
they handled the question of competing risk as part of the
review process for their paper. The significance of the rate
of change of the serum lactate concentrations is also
unclear. Epinephrine was the only vasopressor or inotropic
agent used during resuscitation and as administration of epinephrine can increase lactate production causing a transient
hyperlactataemia,6 it would be very useful if the authors also
reported the number of patients treated with epinephrine in
each group and the doses administered. James and colleagues have conducted an important trial and it may be that
their conclusions and interpretation are valid. Clinical trials
should be analysed and reported in the same systematic
and rigorous manner in which they should be conducted;
without the missing information highlighted above, a
proper evaluation of the clinical significance of James trial
is not possible.

BJA

Correspondence

2 The SAFE Study Investigators. A comparison of albumin and saline

for fluid resuscitation in the intensive care unit. N Engl J Med 2004;
350: 224756
3 Moher D, Schulz KF, Altman DG. The CONSORT statement: revised
recommendations for improving the quality of reports of
parallel-group randomised trials. Lancet 2001; 357: 11914
4 Chan AW, Altman DG. Identifying outcome reporting bias in randomised trials on PubMed: review of publications and survey of
authors. Br Med J 2005; 330: 753
5 Bellomo R, Ronco C, Kellum J, Mehta R, Palevsky P. The Aw: Acute
renal failuredefinition, outcome measures, animal models, fluid
therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R20412
6 Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N,
Santamaria J. A comparison of epinephrine and norepinephrine in
critically ill patients. Intensive Care Med 2008; 34: 222634

Reply from the authors

EditorWe are grateful to Prof. Finfer for his interest in, and
comments on, our paper.1 We will attempt to answer his
queries as briefly as possible. The data he requested were
omitted from the final paper due to space limitations and
we are pleased to provide the information. The nature of the
submission format only allows two tables, so some of the
data have to be presented as text. The details of recovery of
gastrointestinal function on day 5 (the specified endpoint)
for surviving patients are as follows: P-HES 20/31 (64.5%),
P-SAL 17/30 (56.7%), B-HES 11/18 (61.1%), and B-SAL 12/20
(60%). The RIFLE criteria reported were based on a doubling
of the creatinine, since no patients met the criteria of oliguria
before they were classified as failure as stated in the paper.
Creatinine details are as follows:
P-HES

P-SAL

B-HES

B-SAL

Randomization
Mean

73.8

74.9

74.8

78.0

SD

15.2

22.1

24.6

28.4

Min.

38

44

41

35

Max.

118

153

323

166

Peak
Mean

81.9

141.0

161.8

155.7

SD

20.8

154.2

162.5

265.4

Min.

46

51

51

45

Max.

123

680

720

1215

Data are presented as mmol litre21. It is worth noting that

only one of the patients with the maximum values of creatinine at randomization went on to develop renal injury and all
others returned to baseline within days. The highest creatinine measured in the P-HES group was 123 mmol litre21 (classified as renal risk) and the lowest creatinine in the P-SAL
group classified as renal injury was 164 mmol litre21. All
patients classified as renal injury or failure had normal creatinines (,100 mmol litre21) at randomization except for one

160

P-HES

P-SAL

B-HES

B-SAL

30

28

14

19

Early deaths

ICU deaths

Post-ICU deaths

After exit

Survived
Total deaths

As is typical of trauma, the majority of deaths occurred

early either in the trauma unit or in the operating theatre
within the resuscitation period. The survival time after enrolment in those who died early ranged between 2 and 18 h
(the last being in theatre at the time of death). These
deaths were all the result of unsurvivable injuries as classified before unblinding. Three deaths in intensive care unit
(ICU) give an ICU mortality of 2.7%, which is similar to that
reported for trauma in the SAFE trial (2.5%).2 All of the ICU
patients who died suffered renal failure. The remaining four
deaths occurred after ICU discharge and there was only
one death before study exit in those leaving ICU (B-HES). In
terms of the survivor effect, analysis of renal injury in those
surviving the initial period shows a slightly increased proportion of renal injury (17%) in the P-SAL group from that
reported in the paper in which all patients were considered.
The difference between the penetrating trauma groups in
terms of renal injury remains significant (P0.024) after adjustment for the early deaths. Only one other patient died
within the study period (B-HES) and this could not have
affected the result in the penetrating category of the study.
Similar numbers of patients were exposed to epinephrine
at some point during the first 4 h of resuscitation and on
day 1 in each group in the two arms of the study. During
initial resuscitation, the following numbers received epinephrine: P-HES 3/36, P-SAL 3/31, B-HES 2/21, and B-SAL 1/22.
Those patients who only received inotropes in theatre did
not necessarily receive epinephrine as this was in the
control of the anaesthetist and not the resuscitation team.
In theatre: P-HES 5/33, P-SAL 3/30, B-HES 2/19, and B-SAL
1/21. We thus cannot be precisely sure which patients
received epinephrine in the 24 h resuscitation period. In
ICU, the inotrope was epinephrine, but the numbers were insignificant. Obviously, epinephrine could influence the
lactate level independently of tissue perfusion, but given
the relatively low incidence and similarity of usage
between the groups, it seems unlikely that this is a significant
confounder. We did not record the exact dose given in each
patient as this varied on a minute-to-minute basis in most
cases.

Declaration of interest
M.F.M.J. has received numerous travel grants and honoraria
from various fluid therapy companies including Baxter,

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doi:10.1093/bja/aer424

patient in B-HES whose initial creatinine was 323 mmol litre21

(as reported in the paper).
Mortality data are as follows: