SHOCK, Vol. 44, No. 5, pp.

431437, 2015

INCREASED FLUID ADMINISTRATION AFTER EARLY ACUTE KIDNEY

INJURY IS ASSOCIATED WITH LESS RENAL RECOVERY

Mario Raimundo, * Siobhan Crichton, John R. Martin, Yadullah Syed, *

Matt Varrier, * Duncan Wyncoll, * and Marlies Ostermann *
*Department of Critical Care, Guys & St Thomas Foundation Hospital, London, UK; Hospital de Santa
Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Division of Health and Social Care Research,
NIHR Biomedical Research Centre, Kings College London, London; John Farman Intensive Care Unit,
Addenbrookes Hospital, Cambridge; and Kings College London, London, UK

Received 9 May 2015; first review completed 4 Jun 2015; accepted in final form 27 Jul 2015

ABSTRACTIntroduction: In acute kidney injury (AKI), fluid accumulation is associated with poor outcome. We aimed to
determine whether fluid intake or output had the major role. Methods: Retrospective analysis of patients admitted to the
Intensive Care Unit between July 2007 and June 2009 who had AKI stage I. We collected fluid input, output, and
haemodynamic data on day of AKI I and on day of AKI III (if AKI III developed) or 72 h after AKI I (if patients did not
progress to AKI III). Univariable and multivariable logistic regression analyses were performed. Results: Among 210
patients with AKI I (median age 70 y; 138 males), 85 had a subsequent mean fluid gain >1 L/day. Their risk of AKI III or death
in intensive care unit was significantly higher compared with patients who gained 1 L/day (63.5% vs. 23.3%, P 0.001, and
43.5% vs. 24.8%, P 0.004, respectively). AKI I patients who gained >1 L/day had a significantly lower urine output (50 vs.
66 mL/h, P 0.02), lower mean arterial pressure (71 vs. 74 mmHg, P 0.01), higher arterial lactate level (2.7 vs. 2.0 mmol/L,
P < 0.001), and higher Sequential Organ Failure Assessment score (9.4 vs. 8.2, P 0.002) on day of AKI I compared with
those who gained 1 L/day. Multivariable analysis showed that only fluid intake was independently associated with
progression to AKI III (OR 1.8 per 1 L; 95% CI 1.1 8.8; P 0.02), but reduced urine output was not an independent
risk factor (OR 0.8; 95% CI 0.3 2.2; P 0.6). Conclusion: Increased fluid intake in early AKI was an independent risk
factor for AKI III.
KEYWORDSAcute kidney injury, fluid accumulation, fluid overload, progression, renal recovery

The results of this study were presented at the Annual
Conference of the European Society of Intensive Care Medi-
cine in Lisbon in 2012.
INTRODUCTION
Fluid resuscitation is a fundamental component of the acute
management of critically ill patients. Although correction of
hypovolaemia is essential, particularly in shock, there is grow-
ing concern regarding the adverse effects of fluid accumulation.
That a positive fluid balance is associated with longer duration
of mechanical ventilation, more postoperative complications, a
longer stay in the Intensive Care Unit (ICU), and increased
mortality has been well described (19). Indeed, data from the
Vasopressin in Septic Shock Trial demonstrated that the
quartile of patients with the highest positive fluid balance at
both 12 h and 4 days had the highest adjusted mortality (10).
How much of this is association and how much is causation
remains to be established.
Address reprint requests to Marlies Ostermann, PhD, MD, FRCP, Consultant in
Critical Care and Nephrology, Kings College London, Department of Critical Care
Medicine, Guys & St Thomas Foundation Hospital, London, SE1 7EH, UK. E-
mail: Marlies.Ostermann@gstt.nhs.uk
MO designed the protocol and led the research project. MR, YS, and JRM
collected the data from the computerized electronic medical records. SC performed
the statistical analyses. MR, MV, DW, and MO interpreted the results and formulated
the conclusions. MO wrote the first draft. All authors contributed to the manuscript
and approved the final manuscript.
The authors report no conflicts of interest.
DOI: 10.1097/SHK.0000000000000453
Copyright 2015 by the Shock Society
431
Copyright 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Optimal fluid management is particularly important in
patients with or at risk of acute kidney injury (AKI). Although
widely accepted that the correction of hypovolaemia is essen-
tial, there is a common (mis-)belief that it is also necessary to
maintain a positive fluid balance to limit renal injury and to
hasten recovery. Recent data suggest that a positive fluid
balance in patients with AKI is not only ineffective at prevent-
ing progression but also harmful and associated with reduced
chances of renal recovery and an increased risk of dying
(3,4,6,9,1113). Using data from the Fluid and Catheter Treat-
ment Trial, a multicenter, randomized controlled trial evaluat-
ing a conservative versus liberal fluid-management strategy in
1,000 patients with acute lung injury, Grams et al. (4) demon-
strated that a positive fluid balance after the onset of AKI was
strongly associated with increased mortality. A post hoc
analysis of the RENAL study that enrolled AKI patients
receiving renal replacement therapy (RRT) revealed that sur-
vivors had a significantly lower mean cumulative fluid balance
during stay in ICU compared with non-survivors (1,941 vs.
1,755 mL; P 0003) (12). Finally, the PICARD study dem-
onstrated that patients with fluid overload on the day of peak
creatinine were less likely to recover kidney function (13).
Given that fluid therapy and haemodynamic optimization are
key principles of the management of AKI, this has led experts,
including the Kidney Disease Improving Global Outcomes
AKI working group, to recommend that haemodynamic
monitoring should be considered in patients with AKI (14,15).
Clearly, fluid overload may result from excessive fluid input,
reduced urine production, or both. In clinical practice, an
important problem one often faces is whether fluid overload
432 SHOCK VOL. 44, No. 5
has resulted from overzealous fluid administration and is
iatrogenic in nature or whether it is because of oliguria and
therefore a marker of more severe kidney injury. Most studies
that demonstrated an association between fluid accumulation
and poor outcomes evaluated fluid balance in general without
differentiating between the two.
We recently reported that a higher oxygen delivery and mean
arterial pressure (MAP) in the first 12 h after diagnosis of AKI
stage I were independently associated with a lower risk of
progression to AKI stage III (16). We also showed that patients
with a cumulative fluid balance >1 L/day after the onset of AKI
had a six times greater risk of developing AKI stage III
compared with patients with less fluid gain. The aims of this
project were to determine whether oliguria or fluid adminis-
tration had the greatest impact on fluid gain and its association
with progression to AKI III.
MATERIALS AND METHODS
Setting
Guys & St Thomas NHS Foundation Hospital is a tertiary care centre with a
43-bed level 3 multidisciplinary adult ICU. The ICU has a fully computerized
electronic patient record system (ICIP, Philips) where all laboratory, haemody-
namic, and physiologic data are recorded at time of generation.
Patients and study design
As previously reported (16), we retrospectively reviewed an electronic
database containing data of all patients admitted to the ICU between July
2007 and June 2009 and identified those with AKI stage I as per serum
creatinine criteria of the AKI Network classification (17).
The electronic medical records of all patients with AKI I were screened.
Patients in whom advanced haemodynamic monitoring had been initiated for
clinical reasons within 12 h of the patient meeting the criteria for AKI I were
selected. We excluded renal transplant patients, re-admissions, and patients who
left the ICU within 24 h of diagnosis of AKI I or developed AKI stage III within
12 h of diagnosis of AKI I. AKI III was defined as per AKI Network
classification, i.e. increase of serum creatinine to >3-fold from baseline or
to 354 mmol/L with an acute rise of at least 44 mmol/L, or requirement for
RRT (17).
The outcomes of interest were progression to AKI III and mortality. Patients
were classified as progressors and non-progressors depending on whether they
developed AKI III or recovered renal function. Patients who progressed to AKI
II (but not AKI III) and recovered renal function were analyzed as non-
progressors.
Data collection
The data collection of the study was described elsewhere in detail (16). In
summary, we collected demographics, comorbidities, diagnosis, Acute Physi-
ology and Chronic Health Evaluation (APACHE) II score, and Sequential Organ
Failure Assessment (SOFA) score on admission to ICU, first available indexed
cardiac index and contemporaneous arterial oxygen saturation, hemoglobin,
arterial lactate, central venous pressure, MAP, and urine output during the first
12-h period after diagnosis of AKI I, SOFA score, 24-h urine output, type of
organ support and presence of sepsis on day of AKI I. Sepsis was defined as per
current consensus criteria (18). Oxygen delivery index (DO2I) was calculated as
DO2I 1.34  Hb  SaO2  cardiac index. Daily fluid balance was determined
from all recorded fluid input and output. We did not correct for insensible
losses. Cumulative fluid balance was computed by summation of the daily fluid
balances and calculated as total fluid gain and also as a percentage of body
weight. We recorded the type of intravenous fluids administered and the use of
diuretics from day of AKI I until 72 h later.
Statistical analysis
Categorical data were summarized using frequencies and percentages.
Continuous data were summarized using mean (SD) in which the data were
normally distributed, otherwise median [interquartile range (IQR)] was used.
The outcomes were progression to AKI III and hospital mortality. Demographic
Copyright 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
RAIMUNDO ET AL.
and clinical parameters were compared in patients with mean fluid gain 1 L/
day between day of AKI I and day of AKI III or resolution, to those with fluid
gain >1 L/day, using Chi-squared or Fishers exact test for categorical data and
unpaired tests or MannWhitney U tests as appropriate for continuous data.
Logistic regression models were used to examine the univariate associations
between net fluid gain, urine output and fluid administration, and outcomes (i.e.
progression to AKI III or death). Multivariable models were used to adjust for
possible confounders [age, sex, history of coronary artery disease (CAD), and /
or congestive cardiac failure (CCF), cardiac index (categorized as <2.5, 2.5
3.4, 5.5, or >5.5) and APACHE II and SOFA scores on admission to ICU]. Two
separate models were used, the first examining overall fluid balance, and the
second one analyzing fluid intake and output separately.
Patients with AKI I who died before they progressed to AKI III were
analyzed as non-progressors. Sensitivity analyses were carried out to explore
the impact of this approach. In the first sensitivity analysis, all patients who died
before progressing were excluded from the model. In the second sensitivity
analysis, we used a composite outcome for death or progression, representing a
worst case scenario in which all patients who died before progression would
have progressed if they had survived. The results of both sensitivity analyses
were consistent with the original analysis. Therefore, only the results of the
initial analysis were presented.
To determine whether the impact of fluid gain differed across subgroups of
patients, terms were included in the models to test for interactions between fluid
administration and CAD and / or CCF, cardiac index, diagnosis of sepsis on
admission to ICU, SOFA, and APACHE II scores. All tests were two sided and
P-values <0.05 were considered statistically significant. Analyses were con-
ducted using Stata12MP (Texas, USA).
Ethics
The study had institutional approval. Need for individual informed consent
was waived as this was a retrospective analysis of data collected prospectively
for routine care, and there was no breach of privacy or anonymity (UK National
Research Ethics Service).
RESULTS
Two thousand one hundred eighteen patients were admitted
to the ICU of whom 790 (37%) met the criteria for AKI I. Sixty-
nine patients were excluded (Fig. 1). Of the remaining 721
patients, 210 patients had complete haemodynamic data within
12 h of diagnosis of AKI I and were included in the analysis.
The median age of the cohort was 70 (IQR 5777), 68% were
males and 44% had underlying cardiac disease (CAD and / or
CCF) (Table 1). The median number of days between ICU
admission and AKI I was 1 (IQR 022).
Thirty patients (14.3%) received no intravenous fluids
between day of AKI I and 72 h later. In total, 49.5% were
administered only chloride-rich fluids (0.9% NaCl and / or
gelofusine), 15.7% received only balanced solutions, and
20.5% had a combination of chloride-rich and balanced fluids.
No patient received starch or dextran solutions.
Eighty-five patients (41%) developed AKI III of whom 78
(92%) received RRT. The mean time from diagnosis of AKI I to
AKI III was 2.6 days (SD 3.35). Five patients with AKI I died
before their renal function recovered or progressed. The
remaining 120 patients with AKI I did not progress to AKI
III. There was no difference in age, sex, or severity of illness on
admission to ICU between both the groups. Furthermore,
median cumulative fluid balance on day of AKI I was similar
in progressors and non-progressors (2,363 vs. 2,379,
respectively, P 0.995).
One hundred fifty three patients were given diuretics. Among
patients who progressed, 63.5% had received diuretics whereas
82.5% of those who did not progress were administered diu-
retics (P 0.002).
SHOCK NOVEMBER 2015 INCREASED FLUID ADMINISTRATION AND PROGRESSION OF AKI 433

Patients with AKI I

n=790

Exclusions:
discharge from ICU within 24h of AKI (n=23)
AKI III within 12h of AKI I (n=28)
re-admission to ICU (n=18)

Patients with AKI I

n=790

Patients with AKI I

and haemodynamic
monitoring within
12h of AKI I
n=210

Mean fluid gain 1L/day Mean fluid gain >1L/day

n=125 n=85

Progression Death in ICU Progression Death in ICU

to AKI III n=31 (24.8%) to AKI III n=37 (43.5%)
n=28 (23%) n=54 (63.5%)

Abbreviations: AKI = acute kidney injury; ICU = intensive care unit;

FIG. 1. Patient flow. AKI, acute kidney injury; ICU, intensive care unit.

Ninety-one patients (43%) died in hospital. Hospital survi-
vors were younger (69 years vs. 72 years, P 0.007). On day
of AKI I, they had a significantly lower SOFA score (8.1 vs. 9.5,
P < 0.001), higher urine output (66 mL/h vs. 54 mL/h,
P < 0.001), and lower total cumulative fluid balance
(1,844 mL vs. 2,536 mL, P 0.011) compared with hospi-
tal non-survivors.
Characteristics of patients with fluid accumulation
following AKI
Eighty-five patients (40%) had a mean fluid gain >1 L/day
following the day of AKI I (Fig. 1, Table 2). Daily fluid intake,
output, and fluid balance are displayed in Figure 2. In this
cohort, the risk of AKI III or dying in ICU was significantly
higher compared with patients who gained 1 L/day although
no significant difference in severity of illness on admission to
ICU was observed. They had a significantly lower urine output,
lower MAP, higher lactate level, higher SOFA score, and a
higher incidence of hypotension (i.e. MAP < 65 mmHg for
>1 h) on the day of AKI I compared with those who gained 1
L/day, but there was no difference in cumulative fluid balance,
cardiac index, or systemic DO2I (Table 2).
On the day of AKI III or 72 h after AKI I, patients who had
gained >1L/day following the diagnosis of AKI I had a
significantly lower urine output and a lower MAP despite
the increased need for vasopressor treatment, compared with
patients who had gained less fluid (Table 3).
There was no evidence that higher fluid gains resulted from
prolonged illness. Among patients with AKI I who progressed
to AKI III, there was a negative correlation between time, AKI
I, and AKI III (r 0.23, P 0.036). In patients who
progressed within 3 days of AKI I, the mean fluid gain was
1.9 L/day (SD 1.7, maximal gain 9.7 L). In patients who
took longer to progress to AKI III, the average fluid gain was
0.8 L/day (SD 0.6, maximal gain 1.8 L). For comparison,
the mean fluid gain of AKI I patients who did not progress was
0.5 L/day (SD 0.9, maximal gain 3.2 L).
Differentiation between fluid intake and output
In a univariable analysis, both increased fluid intake and
reduced urine output were risk factors for progression to AKI
III and hospital mortality (Table 4). Multivariable analysis
adjusting for age, sex, presence of cardiac disease (CAD or
CCF), DO2I, MAP, type of fluid, diuretic use, SOFA score, and
APACHE II score confirmed that fluid gain was an independent
risk factor for progression to AKI III and mortality (Table 4).
Use of diuretics and fluid type were not independently associ-
ated with progression or mortality.

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434 SHOCK VOL. 44, No. 5 RAIMUNDO ET AL.

TABLE 1. Baseline characteristics and outcome of patients with AKI I however, were characterized by a significantly lower MAP,
Parameter Total (n 210) higher lactate level, and more hypotensive episodes in the first
Age, median (IQR) 70 (57 77) 12 h of AKI I compared with those who gained less fluid.
Male sex (%) 142 (68) Multivariable analysis showed that fluid intake but not oliguria
Comorbidities was independently associated with AKI progression. Impor-
CAD/CCF, n (%) 92 (44) tantly, on the day of AKI I, there was no difference in
Chronic hypertension, n (%) 81 (39)
cumulative fluid balance up to that point between the groups.
Diabetes mellitus, n (%) 40 (19)
Malignancy, n (%) 28 (13) Furthermore, on the day of AKI III, patients who had gained
COPD, n (%) 27 (13) more fluid also had a significantly lower MAP than patients
CKD, n (%) 25 (12) who had gained less than 1 L/day suggesting that fluid therapy
Neurological disease, n (%) 23 (11) had been used to overcome haemodynamic instability.
Chronic liver disease, n (%) 12 (6)
Our results add to the growing evidence that fluid accumu-
Admission diagnosis
Post surgery, n (%) 72 (34) lation is harmful for patients with AKI and is associated with an
Cardiac, n (%) 54 (26) increased risk of progression to severe AKI and an increased
Sepsis, n (%) 38 (18) risk of dying. Importantly, there are no benefits from fluid
Respiratory, n (%) 34 (16) accumulation. It is well known that fluid overload results in
Other, n (%) 12 (6)
tissue edema, obstruction of capillary blood flow and lymphatic
Severity of illness on admission to ICU
APACHE II score, median (IQR) 18 (1422) drainage, impairment of oxygen transport, and progressive
SOFA score, mean (SD) 7.1 (2.8) organ dysfunction (19). These effects are pronounced in encap-
Severity of illness on day of AKI I sulated organs such as the liver and kidneys that lack the
SOFA score, mean (SD) 8.7 (2.7) capacity to accommodate extra volume without an increase in
Arterial lactate (mmol/L), median (IQR) 1.8 (1.32.6)
interstitial pressure. Studies in patients with advanced chronic
Presence of sepsis, n (%) 125 (60)
Treatment with vasopressors, n (%) 187 (89) cardiac failure have shown that a raised CVP (but not low MAP
Treatment with mechanical ventilation, n (%) 191 (91) or low cardiac index) was an independent predictor of AKI
Outcome (20). This may explain why historically, renal decapsulation
Progression to AKI III, n (%) 85 (41) was shown to be protective against AKI avoiding renal
Days spent in ICU, median (IQR) 12 (623)
compartment syndrome (21).
ICU mortality 32.4%
Hospital mortality 43.3% Our analysis reveals that increased fluid intake rather than a
reduced urine output was the main contributor to harm from
APACHE, Acute Physiology and Chronic Health Evaluation; CAD,
coronary artery disease; CCF, congestive cardiac failure; CKD, chronic fluid accumulation. This is an important and relevant finding in
kidney disease; COPD, chronic obstructive pulmonary disease; ICU, line with the results of a systematic review of studies that
intensive care unit; IQR, interquartile range; SD, standard deviation; examined the role of goal-directed therapy (GDT) during the
SOFA, sequential organ failure assessment.
peri-operative period (22). Analysis of 24 trials with renal
outcome and fluid balance data showed that GDT use was
When analyzing fluid intake and urine output separately, associated with a significantly lower incidence of AKI. This
fluid intake remained independently associated with pro- benefit was, however, only apparent in those studies in which
gression to AKI III, but reduced urine output was no longer GDT resulted in no greater overall quantity of fluid adminis-
an independent risk factor (Table 4). tration in the GDT group compared with the control group. In
The risk of progression to AKI III or death in patients with addition, a statistically significant reduction in postoperative
fluid accumulation was not associated with DO2I (P 0.57 and AKI was only seen in studies that incorporated inotropic drugs
P 0.24, respectively), MAP in the 12-h period after diagnosis in GDT. This suggests that resuscitation of cardiac index is
of AKI I (P 0.82 and 0.80, respectively), presence of cardiac important in avoiding or attenuating AKI at a time of physio-
disease (P 0.54 and 0.27, respectively), admission APACHE logical demand but simultaneous avoidance of fluid loading
II scores (P 0.20 and 0.45, respectively), or admission SOFA might be of equal importance.
score (P 0.84 and 0.15, respectively). AKI I patients with Fluids remain one of the mostly widely used and abused
sepsis on admission to ICU were less likely to progress to AKI medical therapies with fluid management often delegated to the
III (35.3% vs. 51.2%; P 0.02) but sepsis on admission was not junior members of the clinical team. Optimal fluid management
associated with increased mortality (P 0.87). This suggests of early AKI is challenging, especially in the context of critical
that the increased risk of progression or death associated illness. This is because of several problems: first, critical illness
with fluid administration was similar across various high- is often associated with reduced systemic vascular resistance,
risk subgroups. altered regional blood flow distribution, and increased capillary
permeability (17). As a result, fluid status and adequacy of fluid
replacement may be difficult to assess. Second, during acute
DISCUSSION
illness, factors such as hypotension, pain, and nausea can
This study shows that patients with AKI I who subsequently activate the sympathetic and reninangiotensin systems and
gained 1 L/day had a significantly higher risk of progression stimulate secretion of antidiuretic hormone which may trigger
to AKI III or dying compared with patients who gained less sodium and water retention potentially leading to oliguria. In
fluid. The cohort of AKI I patients who gained >1 L/day, this context, administration of fluid may lead to further salt and

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SHOCK NOVEMBER 2015 INCREASED FLUID ADMINISTRATION AND PROGRESSION OF AKI 435
TABLE 2. Characteristics of AKI I patients stratified by mean fluid gain
Mean daily fluid balance Mean daily fluid balance
1,000 mL (n 125) >1,000 mL (n 85) P value
Age, median (IQR) 70 (56.577) 70.5 (57.577) 0.83
Male sex, n (%) 82 (68) 54 (66) 0.71
Comorbidities:
CAD/CCF, n (%) 55 (44) 37 (44) 0.95
Chronic hypertension, n (%) 52 (42) 29 (34) 0.27
Diabetes mellitus, n (%) 27 (22) 13 (15) 0.25
Malignancy, n (%) 16 (13) 12 (14) 0.84
COPD, n (%) 17 (14) 9 (11) 0.52
CKD, n (%) 17 (14) 10 (12) 0.70
Neurological disease, n (%) 12 (10) 11 (13) 0.45
Chronic liver disease, n (%) 7 (6) 5 (6) 0.93
APACHE II score on admission to ICU, median (IQR) 17 (1421) 18 (1422) 0.58
SOFA score on admission to ICU, mean (SD) 6.91 (2.70) 7.42 (2.85) 0.19
Progression to AKI III, n (%) 28 (23.3) 54 (63.5) <0.001
ICU length of stay (days), median (IQR) 11 (622) 12 (724) 0.48
ICU mortality, n (%) 31 (24.8) 37 (43.5) 0.004
Parameters within 12h of AKI I
SOFA score, mean (SD) 8.2 (0.2) 9.4 (0.3) 0.002
Arterial lactate (mmol/L), median {IQR) 2.0 (1.8) 2.7 (2.3) <0.001
Hb (g/dL), median (IQR) 9.6 (8.810.5) 9.6 (8.910.5) 0.92
Cardiac index (L/min/m2), median (IQR) 3.0 (2.44.0) 3.0 (2.13.7) 0.30
DO2I (mL/min/m2), median (IQR) 359 (280.9483) 362 (270.5479.5) 0.45
CVP (cm H2O), median (IQR) 13 (1018) 16 (1119) 0.08
MAP (mmHg), median (IQR) 74 (7079) 71 (6877) 0.010
MAP <65 mmHg for 1 h, n (%) 51 (40.8) 58 (68.2) <0.001
Cumulative fluid balance (mL), median (IQR) 1,844 (8293,812) 2,520 (1,4643,762) 0.12
Fluid balance (% of BW), median (IQR) 2.60 (1.085.21) 3.50 (1.935.72) 0.15
Hourly urine output (mL), median (IQR) 66 (44101) 50 (3281) 0.02
Treatment with vasopressors, n (%) 108 (86.4) 79 (92.9) 0.18
Parameters on day of AKI III or day of recovery
Arterial lactate (mmol/L), median (IQR) 1.7 (1.3) 2.1 (1.7) 0.02
Hb (g/dL), median (IQR) 9.5 (910.1) 9.4 (8.810) 0.64
Cardiac index (L/min/m2), median (IQR) 3.4 (2.74.1) 3.2 (2.73.9) 0.77
DO2I (mL/min/m2), median (IQR) 392 (327492) 392 (335475) 0.92
CVP (cm H2O), median (IQR) 14 (1017) 15 (1219) 0.06
MAP (mmHg), median (IQR) 77 (7283) 70 (6679) <0.001
MAP <65 mmHg for 1 h, n (%) 26 (20.8) 41 (48.2) <0.001
Cumulative fluid balance (mL), median (IQR) 2,858 (1,1224,856) 6,562 (4,6838,174) <0.001
Daily fluid balance (% of BW), median (IQR) 3.84 (1.666.28) 8.90 (5.4812.07) <0.001
Hourly urine output (mL), median (IQR) 95 (64129) 39 (1773) <0.001
Treatment with vasopressors, n (%) 70 (56) 66 (78) 0.001
AKI, acute kidney injury; APACHE, Acute Physiology and Chronic Health Evaluation; BW, body weight; CAD, coronary artery disease; CCF, congestive
cardiac failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVP, central venous pressure; DO2I, indexed systemic
oxygen delivery; H2O, water; Hb, haemoglobin in g/dL; ICU, intensive care unit; IQR, interquartile range; MAP, mean arterial pressure; SD, standard
deviation; SOFA, sequential organ failure assessment.

water accumulation. Finally, critical illness is a dynamic proc-
ess in which fluid requirements can change rapidly and
unpredictably.
There is no evidence that fluid accumulation is beneficial or
necessary in AKI or during acute illness. Van Biesen et al. (23)
previously showed that additional fluid loading not only failed
to improve renal function but was also associated with worsen-
ing respiratory function. The data available so far favor more-
restrictive fluid management strategies than have been
employed historically. It is, however, important to note that
the existing studies only demonstrate associations between
fluid overload and harm but do not prove a causal relationship.
Further clinical trials are required to study fluid therapy in more
detail and to identify an optimal fluid regime during critical
illness, especially in patients with AKI. In addition, better tools
are necessary to guide clinicians when to initiate and when to
cease fluid administration. Until then, clinicians should focus
on both daily fluid balance and cumulative fluid balance, as
duration of fluid accumulation might also influence outcomes.
To our best knowledge, this is the first study that analyzed the
different components of fluid overload in more detail and
showed that fluid administration had a greater impact on fluid
accumulation than oliguria. We acknowledge some important
limitations in our study. First, our results are based on a
retrospective analysis of a heterogeneous patient population
with different acute and chronic comorbidities admitted to a
single centre. This may reduce the generalizability of the data.
Second, we defined AKI by serum creatinine criteria and use of
RRT only. Third, we performed a retrospective observational
study and consequently it cannot prove a causal relationship
between fluid intake, fluid output, and outcome. Fourth, we
focused on patients with AKI I in whom hemodynamic

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436 SHOCK VOL. 44, No. 5 RAIMUNDO ET AL.

FIG. 2. Daily fluid intake and output and fluid balance. AKI, acute kidney injury.

TABLE 3. Changes between day of AKI I and day of AKI III or 72 h later stratified by mean fluid gain
Change in parameters between day of AKI I Mean daily fluid balance Mean daily fluid balance
and day of AKI III or 72 h later 1000 mL (n 125) >1000 mL (n 85) P value
Hb (g/dL), median (IQR) 0.3 (0.9 to 0.5) 0.2 (1.1 to 0.8) 0.98
Cardiac index (L/min/m2), median (IQR) 0.26 (1.27) 0.43 (1.00) 0.30
DO2I (mL/min/m2), median (IQR) 18.2 (16.2) 35.9 (12.6) 0.41
CVP (cm H2O), median (IQR) 0 (4 to 4) 0 (5 to 5) 0.68
MAP (mmHg), median (IQR) 2.8 (2.3 to 9.3) 0.4 (6 to 5.9) 0.03
Mean fluid gain (mL), median (IQR) 324 (72 to 629) 1,899 (1,3462,746) <0.001
Mean fluid gain (% of BW), median (IQR) 0.40 (0.15 to 0.86) 2.66 (1.943.69) <0.001
Mean fluid intake (mL), median (IQR) 2,565 (1,9823,080) 3,370 (2,7403,909) <0.001
Mean fluid intake (% of BW), median (IQR) 3.37 (2.664.24) 4.26 (3.435.58) <0.001
Mean urine output, median (IQR) 97.1 (69.9116.3) 45.2 (22.675.2) <0.001
AKI, acute kidney injury; BW, body weight; CVP, central venous pressure; DO2I, indexed systemic oxygen delivery; H2O, water; Hb, haemoglobin in g/dL;
IQR, interquartile range; MAP, mean arterial pressure.

TABLE 4. Association between mean fluid balance, urinary output, and fluid intake between AKI and progression to AKI III or recovery and
hospital mortality
Univariable analysis
Progression to AKI III Death in hospital
OR (95% CI) P value OR (95% CI) P value
Fluid gain (per liter/day) 2.7 (1.93.7) <0.001 1.7 (1.32.1) <0.001
Urine output (per liter/day) 0.2 (0.10.3) <0.001 0.5 (0.40.7) <0.001
Fluid intake (per liter/day) 2.3 (1.82.8) <0.001 1.5 (1.31.7) <0.001

Patients with high fluid gain (>1 liter/day)

Urine output (per liter/day) 0.2 (0.10.4) <0.001 0.5 (0.30.9) 0.02
Fluid intake (per liter/day) 2.9 (1.84.9) <0.001 1.5 (1.12.1) 0.005

Patients with less fluid gain (1 liter/day)

Urine output (per liter/day) 0.4 (0.20.6) <0.001 0.6 (0.40.8) 0.005
Fluid intake (per liter/day) 2.2 (0.53.3) <0.001 1.4 (0.63.0) 0.02
Multivariable analysis
Progression to AKI III Death in hospital
OR (95% CI) P value OR (95% CI) P value
Model 1*
Fluid gain (per liter/day) 2.7 (1.84.1) <0.001 1.6 (1.22.1) 0.001
Model 2*
Urine output (per liter/day) 0.8 (0.32.2) 0.6 0.8 (0.41.4) 0.66
Fluid intake (per liter/day) 1.8 (1.18.8) 0.02 1.3 (1.01.8) 0.09
AKI, acute kidney injury; APACHE, Acute Physiology and Chronic Health Evaluation; CAD, coronary artery disease; CCF, congestive cardiac failure; CI,
confidence interval; MAP, mean arterial pressure; OR, odds ratio; SOFA, sequential organ failure assessment.
*All models adjusted for age, sex, CAD and/or CCF, DO I, MAP, diuretic use, type of fluids administered, SOFA, and APACHE scores on admission.
2

Copyright 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
SHOCK NOVEMBER 2015
monitoring was undertaken for clinical reasons within 12 h of
AKI I. We acknowledge that our findings may not be general-
izable to all AKI I patients. Finally, we were unable to
determine the exact etiology of AKI and the causes of death.
Despite these limitations there still appears to be a strong
suggestion that fluid administration above and beyond that
necessary carries significant risks.
In conclusion, our study showed that increased fluid gain in
patients with AKI stage I was independently associated with an
increased risk of progression to AKI III. Fluid intake rather than
a reduction in urine output was independently associated with
progression to AKI III.
Given the high mortality associated with AKI in ICU, the
human and financial impact of delayed or failed renal recovery,
and the cost and complexity of RRT, it is important not to cause
any additional iatrogenic harm. Correcting hypovolaemia and
hypotension without causing fluid overload may be an import-
ant first step in the right direction.
ACKNOWLEDGMENT
The authors would like to dedicate this article to Professor
David Bennett who sadly died on 21st February 2012. He was a
great mentor and friend who inspired us to embark on
this project.
The authors thank Dr N Chernykh and Dr S Slanova for
helping with the data collection and Professor L Forni for
revising the manuscript.
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