Safety of resuscitation with Ringers acetate

solution in severe burn (VolTRAB)An

observational trial
Jochen Gille
a,
*, Birgit Klezcewski
a
, Michael Malcharek
a
, Thomas Raff
b
,
Martin Mogk
c
, Armin Sablotzki
a
, Hischam Taha
d
a
Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, St. Georg Hospital GmbH Leipzig,
Germany
b
Department of Plastic and Handsurgery, St. Georg Hospital GmbH Leipzig, Germany
c
MoReData GmbH, Kerkrader Str. 11, 35394 Gieen, Germany
d
Department of Plastic & Reconstructive Surgery, Royal Devon & Exeter Hospital Foundation Trust, Exeter, Devon, UK
b ur ns x x x ( 2 0 1 3 ) x x x x x x
a r t i c l e i n f o
Article history:
Received 25 June 2013
Accepted 24 November 2013
Available online xxx
Keywords:
Burn resuscitation
Ringers acetate
Ringers lactate
SOFA score
a b s t r a c t
Background: A variety of crystalloids are available during uid resuscitation of the severely
burnt patient. There is a paucity of literature evidence on the comparative inuence of these
with regard to clinical outcomes. Signicant differences in crystalloids may be clinically
relevant given the large volumes employed during shock resuscitation.
Methods: The study compared two groups of severely burnt patients (TBSA 2070%). Pro-
spectively 40 consecutive patients treated with Ringers acetate (RA group) against a
retrospective control group of 40 patients treated with Ringers lactate (RL group). Outcome
parameters analysed includedSequential OrganFailure Assessment (SOFA)-scores at Days 3
and 7 after injury, mortality at 28 and 60 days, electrolyte and renal function, infection rates,
cumulative volume administration and duration of ventilator support.
Results: Groups RA and RL were comparable w.r.t. age, total body surface area burn size and
ABSI. SOFA-scores on Day 1 of admission also showed no signicant difference but were
signicantly lower inRAgroupbetweenthe 3rdand6thday. By Day 7 these differences could
be attributed as a group effect (P = 0.019). In particular low cardiovascular organ function
scores contributed to this. Total crystalloid use within the rst 28 days were equal in both
but differed within the RA group having lower observed volumes of colloid and incidence of
blood transfusion. Furthermore groupRAhad distinctly higher levels of platelets throughout
treatment. Elevated lactate levels were noted in RL group during the initial three days.
Survival rates at 28 days and 60 days showed no signicant difference.
Conclusion: Ringers acetate solutionis a suitable mediumfor the initial uidmanagement of
the acutely burnt patient. In comparison to Ringers lactate solution the study revealed
lower SOFA-scores for Ringers acetate solution (ClinicalTrials.gov number, NCT00609700).
# 2013 Elsevier Ltd and ISBI. All rights reserved.
* Corresponding author at: Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, St. Georg Hospital GmbH Leipzig,
Delitzscher Strasse 141, 04129 Leipzig, Germany. Tel.: +49 341 9092570; fax: +49 341 9092568.
E-mail address: Jochen.Gille@sanktgeorg.de (J. Gille).
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trial. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.11.021
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.elsevier.com/locate/burns
0305-4179/$36.00 # 2013 Elsevier Ltd and ISBI. All rights reserved.
http://dx.doi.org/10.1016/j.burns.2013.11.021
1. Introduction
Clinical outcome is inuenced greatly by appropriate initial
uid management during the shock phase of severe burns. The
aim of this intravenous uid treatment is to maintain adequate
intravascular volume for effective organ perfusion. There
continues to be no consensus on best uid type or volume to
achieve this with a variety of practices found in burns units [1].
The focus of debate has revolved around overall uid volume
used and the role of colloids [25]. The detailed reection of
crystalloid type used has been largely neglected.
Globally, Hartmanns 1932 modication of Ringers lactate
solution remains the most widely used [1,4,68]. The compo-
sitional properties have continued to sustain Ringers lactate
as the seemingly ideal resuscitation uid in severe burns.
Physiologic chloride levels with reduced sodium ions and
buffered with lactate that may be metabolised, ensures
minimised acidosis risk following large volume infusion [3].
Recent critical review has nevertheless brought Ringers
lactate use into question [4]. Potential negative effects are
listed in Table 1.
Acetate as an alternative anion has been proposed [9]. Its
advantages over standard lactate include its aqueous solubili-
ty, stability at high concentrations, inert bioactivity and
smaller molecular weight [7]. Unlike lactate, acetate is also
more rapidly metabolised with less oxygen demand and extra
hepatic [7]. The clinical application of this reduced metabolic
demand becomes relevant within the intermediate Zone of
Stasis in Jacksons burn wound model [10]. Comparisons of
electrolytic composition between Ringers acetate and lactate
shows no difference and is felt also not to play a role in
homeostasis.
There is a paucity of evidence in the literature on the
comparative inuence of crystalloid uid of choice with regard
to clinical outcomes in the severely burnt patient. Signicant
differences in composition of crystalloids may be clinically
relevant given the large volumes employed during shock
resuscitation. The aim of the current study was to evaluate the
safety of Ringers acetate compared to Ringers lactate solution
as the shock phase resuscitation uid by using organ function
scores as outcome measures.
2. Materials and methods
2.1. Study population
Ethical approval was obtained from the Saxonian Chamber of
Physicians. Study inclusion and exclusion criteria are shown
in Table 2 and were applied to the initial 40 consecutive
patients admitted and treated for severe burns after 1st
January 2007 within a 12 bed intensive care burns unit.
Ringers acetate was used as the exclusive resuscitation uid
in these patients (RA group).
Data for control group RL was collated as the rst 40
patients retrospectively from 1st January 2007 having all been
treated with Ringers lactate and if indicated colloid uids. The
study period was from 27.05.2004. to 02.03.2009.
2.2. Fluid therapy
Ringers acetate and lacate similar constituents (Table 3) differ
in the presence of lactate as a metabolisable anion.
The initial infusion rate was calculated according to
Parklands Formula at 4 mL/kg/%TBSA burn. This was titrated
to maintain a urine output of 0.51.0 mL/kg/h. After 12 h 20%
human albumin was infused to maintain serum albumin
concentration above 20.0 g/L. Administration of synthetic
hydrocolloid was accepted in the treatment of acute hypo-
tension. In the event of unstable cardiovascular function,
patients received vasopressor support suchas noradrenaline.
In case of severe derangement of coagulation fresh frozen
plasma was administered. Enteral nutrition was normally
initiated within6 h of admissionor at the earliest opportunity
thereafter.
Table 1 Potential limitations of Ringers lactate solution.
Hepatic mediated metabolism [8,9]
Increased aerobic demand [8,9,28]
Rebound-alkalosis [28]
Lactate level not reliable in tissue hypoxia [8,28]
Neutrophil activation through oxygen free radical release
(D-lactate) [32]
Increased apoptosis gene expressing (D-lactate) [35,36]
Table 2 Inclusion and exclusion criteria.
Inclusion criteria Exclusion criteria
Age 18 years and <80 years Age 80 years
Burned surface
area 20% and 70%
Presentation lag with burn 24 h
Burn <24 h >70% TBSA
Consent to study treatments Expected survival time <24 h
Acute or chronic heart failure
NYHA III or IV
Acute respiratory distress
syndrome
Chronic renal failure
Hepatic failure
Hypertension
Pre- and eclampsia
Table 3 Composition of used crystalloids.
Ringers
acetate
Ringers lactate
(Hartmann)
Na
+
130 mmol/l 131 mmol/l
K
+
5.4 mmol/l 5.4 mmol/l
Ca
2+
0.9 mmol/l 1.8 mmol/l
Mg
2+
1 mmol/l
Cl

112 mmol/l 112 mmol/l

Metabol.
anion
Acetate 27 mmol/l L-Lactate 28 mmol/l
pH 68 57
Theor. osmo 276 mOsm/l 277 mOsm/l
Company Serumwerke Bernburg B. Braun Melsungen AG
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2.3. Outcome parameters
Sequential Organ Failure Assessment (SOFA) scores (Table 4)
from Days 1 to 7 were used as the primary measure of outcome
for comparison [11,12]. Further, the number of patients
suffering organ failure (SOFA > 2) within 28 days of treatment
were recorded. The Day 1 SOFA score was dened as the
measure at 0600 h the next day. All subsequent scores were
recorded at 0600 h in 24 h intervals. Sedated patient scores
were based on available data pre-sedation.
Cumulative intravenous uid administration (crystalloid,
colloid or packed red cells) and acid alkaline balance (lactate,
pH, base excess and bicarbonate) at Days 1, 3 and 7 after injury,
was used as the secondary outcome measure. Here too, Day 1
was dened as the day of hospital admission. Readings
recorded were those with the greatest difference from the
normal distribution.
Other recorded parameters include frequency and duration
of dialysis in the event of renal failure and total number of
ventilated days on ICU, total number of days on ICU, complica-
tions of infection and mortality rates at Day 28 and Day 77.
2.4. Statistical analysis
The tabulated results display the median and interquartile
range (IQR). The data was analysed by Normal QQ plot and
ShapiroWilk tests to test for normal distribution, the outcome
of which was increased likelihood of null hypothesis rejection.
Non-parametric MannWhitney-U-testing was applied to
single univariate comparisons between Groups A and B.
Fisher exact testing was used where relationships were noted
between group variable (type of Ringers solution) and
categorical parameters. Brunners test was applied for
dynamic longitudinal non-parametric data analysis [13].
Nonparametric correlation was expressed with the Spearman
correlation coefcient. A correlation coefcient r > 0.4 was
considered clinical relevant. The alpha level of the study was
P = 0.05 with applied Holm correction of signicance levels of
individual parameter changes (using R for Windows, Version
2.80).
A post hoc power analysis revealed a power of 72% to
detect a difference of 2 in the primary outcome parameter
SOFA score.
Table 4 The Sequential Organ Failure Assessment (SOFA)-score.
Organ system SOFA score
1 2 3 4
Cardiovascular
Blood pressure, mmHg
Catecholamines
MAP < 70 Dobutamine Adrenaline 0.1 mg/kg/min
or noradrenaline 0.1 mg/kg/min
Adrenalin >0.1 mg/kg/min
or noradrenaline >0.1 mg/kg/min
Respiratory
PaO
2
/FiO
2
, mmHg <400 <300 <200
a
<100
a
CNS
Glasgow Coma Scale 1314 1012 69 <6
Coagulation
Platelets, Gpt/l <150 <100 <50 <20
Hepatic
Bilirubin, mmol/l 2032 33101 102204 >204
Renal
Ceatinin, mmol/l
Urine output (UO), mL/d
100170 171299 300440 or <500 (UO) >440 or <200 (UO); dialysis
a
Values are with respiratory support.
Table 5 Baseline patient and injury characteristics.
Ringers acetate, n = 40 Ringers lactate, n = 40 P-value
Age, median (IQR), y 52 (31.75) 47.5 (17.25) 0.596
Gender, male 29 (72.5%) 35 (87.5%) 0.094
Body weight, median (IQR), kg 84 (28.75) 80 (30.5) 0.75
No. of inhalation injury
a
7 (18%) 12 (30%) 0.293
TBSA,
b
median (IQR), % 32 (18.75) 30 (18.5) 0.914
Full thickness burn, median (IQR), % 27.5 (13.25) 26.5 (9.75) 0.713
ABSI, median (IQR) 9 (3) 8 (3) 0.523
SOFA at admission, median (IQR) 4 (5) 4 (5.25) 0.588
a
Determined using results of bronchoscopy.
b
TBSA indicates percentage of total body surface area.
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3. Results
3.1. Patient characteristics
Group RA and RL were comparable on day of admission with
respect to demographics, severity of burn, SOFA-score and
previous medical history (Tables 5 and 6).
3.2. Primary outcome parameter: SOFA-score
Group SOFA scores on day of admission were comparable as an
expression of severity of injury [4 (4) v. 4 (5.25), P = 0.588]. On Day
2 values differed with lower scores in the RA group without
getting signicance [3.5 (6) v. 6 (6.25), P = 0.085]. By Day 3
signicant divergence had manifested between group RA and
RL at individual points [Day 3: 5 (5.25) v. 8 (6.25), P = 0.013; Day 4:
5.5 (5.5) v. 9 (5.5), P = 0.008; Day 5: 4 (6) v. 8 (5.25), P = 0.006; Day 6: 3
(5) v. 7 (7), P = 0.044] (Fig. 1), as well as a general trend (P = 0.019)
with Ringers acetate showing lower values. Although lower
also on Day 7 after admission, this could not be shown as
statistically signicant [3 (6) v. 8 (6.25), P = 0.063].
On looking at single organ system failure SOFA gures,
there were signicantly lower cardiovascular scores for
Ringers acetate between the fourth and sixth day (Table 7).
This trend was reected across the group during the study
period (P = 0.026).
Although the remaining parameter SOFA scores demon-
strated isolated differences this did not translate as a
demonstrable signicant group effect over the study period.
The initial 28 days were characterised by a high proportion
of patients with organ failure (SOFA score > 2), within both the
RA and RL groups (Table 8). A marked signicantly lower score
over this period was shown by the clotting SOFA-score for RA
[20 (51.3% v. 30 (75%), P = 0.029]. This trend was reected by the
renal SOFA values [16 (41.0%) v. 25 (62.5%), P = 0.056].
3.3. Total uid infusion
3.3.1. Crystalloids
First day total infusion uid volumes for RA and RL groups
were 5625 (8450) mL v. 4900 (5550) mL (P = 0.456) respectively.
Throughout their admission the cumulative volumes of
crystalloid remained similar in both groups [Day 3: 19,150
(13,025) mL v. 16,150 (10,225), P = 0.506; Day 7: 27,100
(17,825) mL v. 22,850 (12,412) mL, P = 0.246; Day 28: 42,850
(35,462) mL v. 34,070 (41,500), P = 0.757] (Fig. 2).
3.3.2. Synthetic colloids
Application of synthetic colloids included hydroxyl-ethyl
starch (HES) and gelatine. Standard medication consisted in
HES whilst gelatine was only given exceptionally. In both
groups the quantity of supplementary infused synthetic
Table 6 Co-morbidities in previous medical history.
Ringers acetate, n = 40 Ringers lactate, n = 40 P-value
Hypertension 14 (35%) 12 (30%) 0.633
Myocardial infarction 0 2 (5%) 0.152
Cerebrovascular event (stroke) 2 (5%) 2 (5%) 1
Chronic heart disease 3 (7.5%) 2 (5%) 0.644
Pancreatitis 3 (7.5%) 0 0.077
Diabetes mellitus 7 (17.5%) 3 (7.5%) 0.176
Chronic liver disease 1 (2.5%) 1 (2.5%) 1
COPD 2 (5%) 3 (7.5%) 0.644
Known malignancy 1 (2.5%) 0 0.314
Chronic renal disease 3 (7.5%) 0 0.077
Fig. 1 Variation of SOFA score during the first 7 days of
admission.
Table 7 Cardiovascular SOFA-score during first 7 days
of treatment.
Treatment
day
Ringers
acetate
Ringers
lactate
P-value
Median IQR Median IQR
1 0.5 3 1 3 0.339
2 1 2.5 3 3 0.346
3 1 3 3 3 0.117
4 1 3.25 3 2 0.015
5 1 3.25 3 2.5 0.005
6 1 3 3 4 0.035
7 1 3.25 3 3.5 0.065
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colloids (HES and gelatine) on Day 1 was comparable [0
(625) mL v. 500 (1000) mL, P = 0.225]. Thereafter however,
signicant lower volumes were used in the RA group
compared to those of RL patients Day 3 [1250 (2125) mL v.
2500 (1500) mL, P = 0.004), Day 7 [2250 (2500) mL v. 4250
(2375) mL, P = 0.005), and Day 28 [3250 (4250) mL v. 7250
(6500) mL, P < 0.001). These differences were also seen as
group effect (P = 0.002) (Fig. 3).
3.3.3. Human albumin 20%
On the rst day human albumin 20% was given in 9 patients of
the RA group and 7 patients in the RL group resulting in
median 0 (0) mL v. 0 (0) mL, P = 0.65. Albumin use throughout
the study were similar in both groups [Day 3: 250 (500) mL v.
100 (625) mL, P = 0.963; Day 7: 600 (912) mL v. 325 (900) mL,
P = 0.757; Day 28: 2050 (1600) mL v. 1900 (1450) mL; P = 0.483].
3.3.4. Fresh frozen plasma (FFP)
Despite group RA and RL similarities of FFP use on Day 1 with
application in only 9 patients in RA group and 14 patients in
the RL group [0 (0) mL v. 0 (880) mL, P = 0.09], the further course
was characterised by a signicant lower demand in RA
patients [Day 3: 1100 (2792) mL v. 3080 (5060) mL, P < 0.001;
Day 7: 1980 (4070) mL v. 5060 (9548) mL, P < 0.001; Day 28: 3300
(3520) mL v. 12,329 (17,886) mL, P < 0.001]. This translated also
as a group effect (Fig. 4a).
3.3.5. Red packed cells (RPC)
Transfusion of RPC was rare on the rst day of treatment (2
patients in RA group and 1 patient in the RL group)
corresponding with a median 0 (0) mL v. 0 (0), P = 0.564. In
the following periods erythrocyte substitution was signi-
cantly lower for RA patients (Day 3: 300 (1950) mL v. 1200
(3000) mL, P = 0.027; Day 7: 2100 (3750) mL v. 3600 (6000) mL,
P = 0.029; Day 28: 4800 (3150) mL v. 8400 (10,740) mL, P = 0.044]
(Fig. 4b). Serum haemoglobin concentration (mmol L
1
) was
similar at all measure intervals, thus excluding differences in
transfusion reaction (Fig. 4c).
In both groups a correlation between platelet count and
transfusion could be seen (RA group r = 0.62, P = <0.01; RL
group r = 0.5, P = 0.001). This was also the issue for all patients
(n = 80, r = 0.47, P < 0.01).
At the midpoint of treatment an increase in platelet
concentration was noted within both group RA and RL that
normalised towards the end of the study period. This increase
was most notable in the Ringer acetate group and was
statistically signicant as a group effect over the 28 days
(Fig. 4d).
Analysis of other clotting parameters such as prothrombin
time (PT), activated partial thromboplastin time (aPTT), time of
thrombin, brinogen and antithrombin III revealed no
differences.
Table 8 Organ failure (SOFA > 2) within first 28 days of treatment.
Ringers acetate, n = 40 Ringers lactate, n = 40 P-value
Cardiovascular 34 (85%) 35 (87.5%) 0.966
Respiratory 32 (80%) 37 (92.5%) 0.163
Coagulation 20 (50%) 30 (75%) 0.029
Hepatic 11 (27.5%) 16 (40%) 0.201
Renal 16 (40%) 25 (62.5%) 0.056
Neurological 4 (10%) 9 (22.5%) 0.21
Fig. 2 Cumulative crystalloid infusion fluid.
Fig. 3 Cumulative synthetic colloid (HES and gelatine)
infusion volumes.
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3.4. Acidbase balance
3.4.1. Lactate
Over the initial ve days of treatment lactate concentrations
were signicantly lower in the RA group [Day 1: 1.45
(1.33) mmol L
1
v. 3.3 (2.65) mmol L
1
, P < 0.001; Day 2: 1.2
(1.1) mmol L
1
v. 2.3 (3.05) mmol L
1
, P = 0.003; Day 3: 0.9
(0.55) mmol L
1
v. 2 (1.15) mmol L
1
, P < 0.001; Day 4: 0.9
(0.9) mmol L
1
v. 1.25 (0.87) mmol L
1
, P = 0.014; Day 5: 0.9
(0.85) mmol L
1
v. 1.6 (1.1) mmol L
1
, P = 0.006). Thereafter,
although levels became comparable in both groups it could be
noted that lactate concentrations remained within normal
limits throughout the study period whilst the Ringers lactate
group only normalised after Day 4 (Fig. 5).
3.4.2. pH-value, base excess and hydrogen carbonate
Mean pH-values remained consistently within normal limits
for both groups throughout the study. Base excess (BE) values
were initially deranged at admission but thereafter were
within normal limits for both groups. The Ringer acetate group
had lower BE levels but these were not statistically signicant.
Hydrogen carbonate concentration in both groups was not
signicantly different over the rst seven days remaining
within normal physiological limits, although RL group showed
Fig. 4 (a) Cumulative fresh frozen plasma infusion fluid volumes; (b) cumulative red packed cells infusion fluid volumes; (c)
haemoglobin concentration; and (d) platelet count.
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a tendency of higher increases in hydrogen carbonate levels
over time to Day 7 having had an initial lower start point.
3.5. Other secondary outcome parameters
Mortality rates at 28 and 60 days showed no signicant
difference between the two groups. Nevertheless, a trend to
fewer days of intensive care treatment (23.5 v. 34.5 days,
P = 0.07) and a signicant shorter hospital admission time
could be observed in the Ringers acetate group (38 v. 50.5 days,
P = 0.025).
Renal dialysis and ltration measures were comparable
w.r.t. frequency and duration. Ventilatory support was
signicantly shorter in the Ringers acetate group (303 v.
1070 h, P = 0.015) (Table 9).
Rates of infection were similar in both groups as shown in
Table 10 with the exception of tendency of lower intra-
abdominal infection rates in the Ringers acetate group (0 v. 4,
P = 0.051) (Table 10).
4. Discussion
The current study compared the use of Ringers acetate with
Ringers lactate solution in the uid resuscitation of severe
burns. The two randomised groups had similar burns and
SOFA-scores on day of admission. The main ndings of this
study are the demonstration that Ringers acetate is safe as a
resuscitation medium, and further, that it might have some
clinical advantages when compared to Ringers lactate as a
control group.
4.1. Organ function
Patients randomised to the Ringers acetate group, demon-
strated signicantly lower SOFA scores than those of the
Ringers lactate group by Day 3 of treatment (Fig. 1). This was
largely due to lower cardiovascular SOFA scores, this
demonstrated rstly at the distinct level from the third to
sixth day and secondly also at the group effect level
throughout the observation period (Table 7). This result can
be understood as meaning a greater haemodynamic stability
in the RA group. Similar lower RA SOFA scores were noted for
hepatic, clotting and neurological function, but their clinical
relevance is considered to be minimal.
The impact of acetate on the cardiovascular system has
been well reported, yet found to be inconsistent and
contradictory. Cardiac depressive effects [14] contrast with
Fig. 5 Variation of serum lactate concentration during first
7 days of treatment.
Table 9 Other secondary outcome parameters.
Ringers acetate, n = 40 Ringers lactate, n = 40 P-value
No. of CRRT 7 (18%) 10 (25%) 0.446
Ventilator days 303 1070 0.015
Outcome d 28 (death) 2 (5%) 2 (5%) 1
Outcome d 60 (death) 3 (7.5%) 6 (15%) 0.288
Days ICU, median (IQR) 23.5 (27.25) 34.5 (40.75) 0.07
Days hospital stay, median (IQR) 38 (31.5) 50.5 (46.75) 0.025
Table 10 Infectious complications.
Ringers acetate, n = 40 Ringers lactate, n = 40 Signicance P-value
Pulmonary 17 (42.5%) 12 (30%) 0.245
Bloodstream 23 (57.5%) 26 (65%) 0.491
Urogenital 12 (30%) 11 (27.5%) 0.805
Gynaecological 1 (2.5%) 0 0.314
Intra-abdominal 0 4 (10%) 0.051
Central venous catheter 7 (17.5%) 2 (5%) 0.077
Skin/wound 32 (80%) 34 (85%) 0.556
Others 0 1 (2.5%) 0.314
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vasodilatory and inotropic ndings associated with an
increase in cardiac index [15,16]. Kashimoto et al. found no
haemodynamic differences of Ringers lactate (RL) and acetate
(RA) [17]. Animal studies of haemodynamic inuences in
burns comparing RA with RL exist. Conahan et al. demon-
strated RA resuscitation resulted in improved cardiac output
and contractility. They postulated a relation to their ndings
that myocardial ATP levels in Ringer acetate patients was
similar to those of non-burn injured hearts, whilst in Ringers
lactate hearts these myocardial ATP levels were signicantly
lower [18]. Based on these ndings these authors have
recommended acetate substitution of lactate during burns
shock resuscitation. This has not translated into clinical
management of such patients, with 91.9% of questioned
clinicians continuing to prefer Ringers lactate resuscitation in
the context of burns care [1].
The current study supports Conahan et al. [18] with respect
to burn resuscitation, but should be interpreted with caution.
It may cautiously be extrapolated that the use of Ringers
acetate is benecial when used during burns shock phase. The
positive haemodynamic stability effect of RA may also be
superior to Ringers lactate as with other parameters.
Mechanical ventilation time was signicantly reduced in the
RA group (Table 9). The utilisation of catecholamines may be
entirely due to the sedation of the ventilated patient.
Furthermore, haemodynamic stability can independently lead
to early weaning from ventilatory support back to spontane-
ous breathing. The impact of rigid ventilatory regimes on the
initial treatment phase of burns care presents in itself an
interesting avenue for further investigation.
The limited literature available suggests a positive respira-
tory effect of RA. Animal models have shown a reduction in
alveolar ventilation and mechanical respiratory effort. How-
ever, acetate was shown to induce a large thermogenic effect,
and the 10% decrease in respiratory exchange ratio was offset
by an equivalent increase in oxygen consumption, therefore
resulting in no change in net respiratory carbon dioxide
elimination [19]. The clinical relevance of these observations
remains unclear.
4.2. Cumulative uid balance
Initial burns uid management within our institution is
crystalloid and based on the Parkland Formula. Synthetic
colloids are only used in the event of unstable circulation.
Within this study both groups had comparable volumes of
uid, hence increased colloid use seen in the Ringers lactate
group may correspond to haemodynamic instability in this
group (Fig. 3).
The elevated use of FFP and RPC of the RL group was
unexpectedly high (Fig. 4a and b). Surgical management of
burns did not change during the study period. Perioperative
conditions were optimised likewise (management of coagula-
tion, thermoregulation). Although no discernible differences
were noted in plasma clotting function, a possible theoretical
inuence of the increased synthetic colloid exists. The
signicantly higher platelet levels in excess of the physiologi-
cal norms is conspicuous in the RA group (Fig. 4d) and is to our
knowledge the rst description of this in the literature. It is at
present not possible to discern if the observed differences led
to decreased volumes of RPC transfusion. However, a statisti-
cal correlation between platelet count and transfusion could
be seen as well in both groups as in all patients. In principle,
more favourable effects and outcomes could be expected by
those patients with decreased blood transfusion needs. In a
multi-centre study the number of transfusions received was
associated with mortality and infectious episodes in patients
with major burns even after factoring for indices of burn
severity [20].
4.3. Metabolic response
Lactate and base excess (BE), together with diuresis are
excellent indicators for adequate resuscitation during burn
shock [21,22]. In the current study there were signicantly
higher lactate levels with RL group up to Day 5 of treatment
(Fig. 5). Mean pH-values remained within normal limits for
both RL and RA groups. Collectively with the normalised
base excess levels at Day 2 the resuscitation could be
considered a success. The continued elevated lactate levels
meant that one could not exclude tissue hypoxia. An
increase in serum lactate concentration in the absence of
base-excess change is more highly suggestive of uid
infusion particle excess [23,24]. An iatrogenically elevated
lactate level may mislead physicians to a more liberal uid
management resulting in an unnecessary uid burden with
potential harm.
The negative effect of infused lactate on clinical outcome
has as yet not been investigated. The hypoxic conditions
during shock, may lead to exacerbated negative effects [25].
1.0 mol of lactate is degraded aerobically within the liver
requiring 3.0 mol of oxygen, creating 2 mol of carbon dioxide.
In contrast, acetate is degraded by 2.0 mol oxygen, indepen-
dent of the liver; producing only 1.0 mol of carbon monoxide
[7,9].
Animal studies have shown distinct lactate concentration
increases, leading to increased oxygen demand [26]. Aoki et al.
showed a study of 20 burns patients monitored by gastro-
mucosal tonometry, comparing resuscitation with Ringers
acetate and lactate. They looked at the pCO
2
and pH-values
and then their differences within 72 h of burns injury [27]. The
Ringers acetate group was signicantly faster at reaching
normal values. The authors conclude that Ringers acetate
resuscitation is more effective at correcting the dysoxia in the
splanchnicus region. Of interest, contrary to our own ndings,
the two groups showed no statistically signicant differences
in serum lactate concentrations.
Ringers lactate is a rebound alkali in response to
metabolisation of lactate to hydrogen carbonate, following
the survival of the shock phase and normalisation of hepatic
function [28]. Acetate in a similar setting with impaired
hepatic perfusion showed signicantly higher base-excess
[29]. Supporting historical animal studies had already
illustrated how extrahepatic metabolism of acetate was
superior to that of lactate due to improved puffer function
during shock[30]. In our study pH, BE andhydrogen carbonate
were not signicantly different in the two groups. Tentative-
ly, one may suggest that the Ringers acetate mediated
metabolism was less changeable suggesting more stable
metabolic activity.
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4.4. Outcome parameters
Choice of resuscitation uid alone could not be shown to
inuence mortality rates in our limited study albeit of
insufcient power. Nevertheless, it could be demonstrated
that hospital admission periods were signicantly less for the
Ringers acetate group (38 v. 50.5 days). Similar differences
were reected in length of intensive care unit (ICU) treatment
but could not be conrmed as statistically signicant (Table 9).
As ICU admission is also inuenced by clinical and logistical
factors, it remains questionable to singularly isolate resusci-
tation uid choice. No differences in infection rates were
found between the two uid groups (Table 10) with infection as
a major factor of prolonged ICU and overall hospital admis-
sion.
Immunological compromise through Ringers lactate solu-
tion, especially on leucocyte function is well described [3133].
In an experimental shock study Rhee et al. demonstrated
activation of neutrophils through Ringers lactate infusion
rather than to reperfusion injury [31]. Further analyses suggest
these negative effects are due to the D-lactate isomer [32,34
36]. Koustova et al. found detrimentally increased oxygen free
radical liberation by neutrophils after application of Ringers
lactate solution [32].
Ayuste et al. used an animal model to show that during
haemorrhagic shock, hepatic and pulmonary apoptosis
increased with conventional racemic RL uid resuscitation,
but decreased upon elimination of the D-lactate isomer [35].
Ringers acetate has also been shown to inuence
immunological function. In healthy and cancer affected
adults, RA led to increased allogeneic mixed lymphocyte
reaction and natural killer cell (NK-cell) activity. On the basis
of these ndings RA might have the advantage of stimulating
antibody production and cell-mediated immunity [37]. What
the clinical signicance of these ndings is for the severely
burnt patient remains unclear. Our study was unable to
measure a notable signicant difference in infusion uid effect
upon immunological function. The Ringers lactate used
contained L-lactate, therefore negative effects with regard to
gene expression and white cell activity may not be expected.
4.5. Limitations
The current study has several recognisable limitations. It
utilised a retrospective analysis of the RL group which was
over an extended study period of about 5 years during which
time practices may have changed. Nevertheless, the prospec-
tive arm of the study demonstrates that Ringers acetate
solution is a suitable alternative for burn resuscitation. The
advantages of Ringers acetate over Ringers lactate infusion
regime found in this study should, given the limitations of the
study design, be interpreted with caution.
Small patient numbers prevent current study prediction of
effects on mortality rates. With regard to the primary outcome
parameter SOFA score the post hoc power analysis revealed a
Power of 72% which can still be considered convincing.
However, only a randomised study stratifying patients upon
admission would be able to compare effects of both uids. To
realise this in a reasonable time period a multicenter RCT
would be favourable.
5. Summary
Fluid resuscitation with Ringers acetate solution in patients
with severe burns injury appears safe. The current study
indicated better organ function of patients treated with
Ringers acetate solution when compared retrospectively to
those treated with Ringers lactate. Improved haemodynamics
represented by a lower cardiovascular SOFA score is central to
this difference. Due to the limitations of the study design this
difference remains questionable.
Higher platelet concentrations noted in the RA group may
have accounted for an improved clotting status and decreased
blood product transfusion. The use of blood lactate levels as a
hypoxic marker becomes unreliable with Ringers lactate (RL)
resuscitation. Ringers acetate use, at best in trend whilst not
statistically signicant, appears to maintain a more stable
metabolic status.
r e f e r e n c e s
[1] Greenhalgh D. Burn resuscitation: the results of the ISBI/
ABA survey. Burns 2010;36:17682.
[2] Cochran A, Morris SE, Edelman LS, Safe JR. Burn patient
characteristics and outcomes following resuscitation with
albumin. Burns 2007;33:2530.
[3] Tricklebank S. Modern trends in uid therapy for burns.
Burns 2009;35:75767.
[4] Alvarado R, Chung K, Cancio L, Wolf S. Burn resuscitation.
Burns 2009;35:414.
[5] Lawrence A, Faraklas I, Watkins H, Allen A, Cochran A,
Morris S, et al. Colloid administration normalizes
resuscitation ratio and ameliorates uid creep. J Burn
Care Res 2010;31:407.
[6] Lee JA. Sydney Ringer (18341910) and Alexis Hartmann
(18981964). Anaesthesia 1981;36:111521.
[7] Nakatani T. Overview of the effects of Ringers acetate
solution and a new concept: renal ketogenesis during
hepatic inow occlusion. Methods Find Exp Clin Pharmacol
2001;23(November (9)):51928.
[8] Raum M, Rixen D, Linker R, Gregor S, Holzgraefe B,
Neugebauer E, et al. Beeinussung der Plasma-Laktat-
konzentration durch laktathaltige Infusionslo sungen. AINS
2002;37:3568.
[9] Zander R. Flu ssigkeitstherapie. Melsungen: Bibliomed
Medizinische Verlagsgesellschaft mbH; 2006.
[10] Jackson DM. The diagnosis of the depth of burning. Br J Surg
1953;40:588.
[11] Vincent JL, Moreno R, Takala J, Willatts S, Mendonc a A,
Bruining H, et al. The SOFA (Sepsis-related Organ Failure
Assessment) score to describe organ dysfunction/failure.
Intensive Care Med 1996;22:70710.
[12] Moreno R, Vincent JL, Matos R, Mendonc a A, Cantraine F,
Thijs L, et al. The use of maximum SOFA score to quantify
organ dysfunction/failure in intensive care. Results of a
prospective, multicentre study. Intensive Care Med
1999;25:68696.
[13] Brunner E, Langer F. Nichtparametrische Analyse
longitudinaler Daten. Mu nchen Wien: R.Oldenbourg-
Verlag; 1999.
[14] Aizawa Y, Ohmori T, Imai K, Nara Y, Matsuoka M, Hirasawa
Y. Depressant action of acetate upon the human
cardiovascular system. Clin Nephrol 1977;8(November (5)):
47780.
b ur ns x x x ( 2 0 1 3 ) x x x x x x 9
JBUR-4228; No. of Pages 10
Please cite this article in press as: Gille J, et al. Safety of resuscitation with Ringers acetate solution in severe burn (VolTRAB)An observational
trial. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.11.021
[15] Nitenberg A, Huyghebaert MF, Blanchet F, Amiel C.
Analysis of increased myocardial contractility during
sodium acetate infusion in humans. Kidney Int
1984;26(November (5)):74451.
[16] Saragoc a MA, Mulinari RA, Bessa AM, Draibe SA, Ferreira
Filho SR, Ribeiro AB, et al. Comparison of the hemodynamic
effects of sodium acetate in euvolemic dogs and in dogs
submitted to hemorrhagic shock. Braz J Med Biol Res
1986;19(3):4558.
[17] Kashimoto S, Narumi Y, Matsukawa T, Oguchi T,
Kumazawa T. Comparative effects of Ringers acetate and
lactate solutions on intraoperative central and peripheral
temperatures. J Clin Anesth 1998;10(February (1)):237.
[18] Conahan ST, Dupre A, Giaimo ME, Fowler CA, Torres CS,
Miller HI. Resuscitation uid composition and myocardial
performance during burn shock. Circ Shock 1987;23(1):
3749.
[19] Burnier P, Tappy L, Je quier E, Schneeberger D, Chiole ro R.
Metabolic and respiratory effects of infused sodiumacetate
in healthy human subjects. Am J Physiol
1992;263(December (6 Pt. 2)):12716.
[20] Palmieri TL, Caruso DM, Foster KN, Cairns BA, Peck MD,
Gamelli RL, et al. Effect of blood transfusion on outcome
after major burn injury: a multicenter study. Crit Care Med
2006;34(June (6)):16027.
[21] Huang Y, Yan B, Yang Z. Clinical study of a formula for
delayed rapid uid resuscitation for patients with burn
shock. Burns 2005;31:61722.
[22] Cochran A, Edelman L, Safe J, Morris S. The relationship of
serumlactate and base decit in burn patients to mortality.
J Burn Care Res 2007;28:23140.
[23] Knichwitz G. Kann die Laktatkonzentration immer als
Hypoxiemarker interpretiert werden? AINS 2002;37:3526.
[24] Schaffarztik W. Base excess. Anaesthesist 2007;56:47881.
[25] Holtzman S, Balderman SC. Comparison of lactate and
pyruvate during endotoxic shock. Surg Gynecol Obstet
1977;145(November (5)):67781.
[26] Raum M, Rixen D, Linker R, Gregor S, Holzgraefe B,
Neugebauer E. Beeinussung der Plasma-Laktat-
konzentration durch laktathaltige Infusionslo sungen. AINS
2002;37:3568.
[27] Aoki K, Yoshino A, Yoh K, Sekine K, Yamazaki M, Aikawa N.
A comparison of Ringers lactate and acetate solutions and
resuscitative effects on splanchnic dysoxia in patients with
extensive burns. Burns 2010;36:10805.
[28] Zander R. Base Excess und Laktatkonzentration von
Infusionslo sungen und Blutprodukten. AINS 2002;37:359
63.
[29] Hartseld SM, Thurmon JC, Corbin JE, Benson GJ, Aiken T.
Effects of sodium acetate, bicarbonate and lactate on acid
base status in anaesthetized dogs. J Vet Pharmacol Ther
1981;4(March (1)):5161.
[30] Schumer W, Moss GS, Nyhus LM. Metabolism of lactic acid
in the Macacus rhesus monkey in profound shock. AmJ Surg
1969;118(August (2)):2005.
[31] Rhee P, Burris D, Kaufmann C, Pikoulis M, Austin B, Ling G,
et al. Lactated Ringers solution resuscitation causes
neutrophil activation after hemorrhagic shock. J Trauma
1998;44:3139.
[32] Koustova E, Stanton K, Gushchin V, Alam HB, Stegalkina S,
Rhee PM. Effects of lactated Ringers solutions on human
leukocytes. J Trauma 2002;52:8728.
[33] Valeri CR, Ragno G, Veech RL. Effects of the resuscitation
uid and the hemoglobin based oxygen carrier (HBOC)
excipient on the toxicity of the HBOC: Ringers D,L-lactate,
Ringers L-lactate, and Ringers ketone solutions. Artif Cells
Blood Substit Immobil Biotechnol 2006;34(6):6016.
[34] Chan L, Slater J, Hasbargen J, Herndon DN, Veech RL, Wolf
S. Neurocardiac toxicity of racemic D,L-lactate uids. Integr
Physiol Behav Sci 1994;29:38394.
[35] Ayuste EC, Chen H, Koustova E, Rhee P, Ahuja N, Chen Z,
et al. Hepatic and pulmonary apoptosis after hemorrhagic
shock in swine can be reduced through modications of
conventional Ringers solution. J Trauma 2006;60(1):5263.
[36] Jaskille A, Koustova E, Rhee P, Britten-Webb J, Chen H,
Valeri CR, et al. Hepatic apoptosis after hemorrhagic shock
in rats can be reduced through modications of
conventional Ringers solution. J Am Coll Surg
2006;202(January (1)):2535.
[37] Ishizaka S, Kikuchi E, Tsujii T. Effects of acetate on human
immune system. Immunopharmacol Immunotoxicol
1993;15(MarchJune (2/3)):15162.
b ur ns x x x ( 2 0 1 3 ) x x x x x x 10
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