Supplemental Digital Content
Supplemental Methods
Inclusion/exclusion criteria: Patients were included who presented with severe sepsis and/or
septic shock on the day of admission to the ICU, i.e. on day 0. Day 0 had a variable amount of
hours up to a maximum of 24 hours, depending on the time of admission. Day 1 started on
midnight following admission. Patients were excluded from analysis if they were < 18 years, had
received solid organ transplantation, had renal failure requiring hemodialysis before ICU,
received extracorporeal membrane oxygenation, if serum creatinine values were missing at
admission, or if they were admitted during the 1 month wash-out period between changes in
resuscitative fluid regimens.
Sepsis was defined according to consensus conference definitions, and severe sepsis was defined
by sepsis plus at least one organ failure (27). Screening for the presence of severe sepsis or septic
shock was performed routinely by the senior ICU physicians and documented by trained research
nurses.
Severe sepsis was defined as the presence of microbiologically proven, clinically proven, or
suspected infection; presence of Systemic Inflammatory Response Syndrome (SIRS); and
development of at least one organ dysfunction within the last 24 hours. Diagnosis of SIRS
required the fulfillment of at least two of the following criteria: hypo- (≤36°C) or hyperthermia
(≥38°C), tachycardia (≥90 bpm); tachypnea (≥20 breaths/min) and/or an arterial pCO2 ≤4.3 kPa
(32 mmHg) and/or mechanical ventilation; leukocytosis ≥12,000/μl or leukopenia ≤4,000/μl
and/or a left shift in the differential white blood cell count ≥10%. For the diagnosis of organ
dysfunction one of the following criteria had to be fulfilled: presence of acute encephalopathy
with reduced vigilance, agitation, disorientation, delirium not explained by psychotropic
medication; thrombocytopenia ≤100.000/μl or a drop in the thrombocyte count >30% within 24
hours not explained by hemorrhage; arterial hypoxemia with an arterial pO2 <10 kPa (75 mmHg)
when breathing room air or an oxygenation index (paO2/FiO2 ≤33kPa (250 mmHg) not
explained by presence of a pulmonary or cardiac disease; arterial hypotension with a systolic
blood pressure ≤90 mmHg or mean arterial blood pressure ≤70 mmHg for at least one hour
despite adequate fluid loading not explained by other causes of shock; renal dysfunction with an
urine output ≤0.5 ml/kg/h for at least one hour despite adequate fluid loading and/or increase of
serum creatinine more than twofold above the reference range of the local laboratory; metabolic
acidosis with a base deficit ≥5.0 mmol/l or a serum lactate ≥ 1.5fold above the reference range of
the local laboratory.
Septic shock was defined as the presence of infection and SIRS as defined in severe sepsis as
well as presence of arterial hypotension with a systolic blood pressure ≤90 mmHg or a mean
arterial blood pressure ≤70 mmHg for at least 2 hours or administration of a vasopressor
(dopamine ≥5 μg kg-1 min-1; noradrenaline, epinephrine, phenylephrine, or vasopressin in any
dosage) to maintain systolic blood pressure ≥90 mmHg or mean arterial blood pressure ≥70
mmHg despite adequate fluid loading.
Study groups:
HES period: From 1st January 2004 until 31st January 2006, patients were treated with
predominantly 6% HES (6% HES 130/0.4; Voluven; Fresenius-Kabi, Bad Homburg,
Germany) and crystalloids. 88 % of the administered HES was 6% HES 130/0.4, the rest 10%
HES 200/0.5. Gelatin period: Standard colloid therapy was switched from 6 % HES 130/0.4 to
4% gelatin as a result of increased renal failure in association with starch use (13). From 1st
March 2006 until 31st of March 2008, patients were volume resuscitated with 4% modified
gelatin (Gelafusal; Serumwerk Bernburg AG, Bernburg, Germany) and crystalloids.
Crystalloid period: Because a prospectively planned analysis showed that the change of standard
colloid from HES to gelatin had not decreased the incidence of acute kidney injury (26), we
abandoned the use of synthetic colloids altogether. Patients received only balanced crystalloid
solutions (Jonosteril; Fresenius Kabi, Bad Homburg, Germany) except for patients with
hyperkalemia who received normal saline (NaCl 0.9%; Fresenius Kabi, Bad Homburg,
Germany). All consecutive patients with severe sepsis from 1st May 2008 until 8th April 2010
were included in this group.
Management of sepsis patients
Therapy for sepsis followed institutional standard operating procedures (SOPs) based on the
guidelines of the Surviving Sepsis Campaign (16) and the German Sepsis Society (19). During
all three study periods, hemodynamic resuscitation was guided by Early Goal Directed Therapy
(EGDT) as has been described by Rivers et al. (2) with the modification that a preset goal of
MAP of ≥ 70 mm Hg was used instead of ≥ 70 mm Hg. Briefly, hemodynamic resuscitation had
to achieve the following primary endpoints: a central venous pressure (CVP) of at least 8 mmHg,
an arterial mean blood pressure (MAP) of at least 70 mmHg, and a central venous oxygen
saturation (ScvO2) of at least 70%. Standard hemodynamic management included vasopressors
with noradrenaline to achieve preset hemodynamic goals in addition to repeated fluid challenges
with crystalloids and/or synthetic colloids (gelatin or hydroxyethyl starch) to allow the lowest
possible dose of vasopressors. Human albumin 20% was not used for volume replacement. Its
use was restricted to the treatment of severe hypoalbuminemia < 15 g/L (Albunorm 20%,
Octapharma, Langenfeld, Germany).
ScvO2 and serum lactate levels were measured by blood gas measurement (Radiometer
Copenhagen, Radiometer GmbH, Willich-Schifbahn, Germany). Extended hemodynamic
monitoring with pulmonary artery catheter (Swan-Ganz CCOmbo; Edwards Life Sciences,
Unterschleissheim, Germany) or PiCCO (Pulsiocath 5-Fr Thermodilution Catheter; Pulsion
Medical Systems Munich, Germany) was considered if the required vasopressor dose increased >
0.3 µg/kg/min of noradrenaline.
Acute kidney injury (AKI)
RIFLE “risk” was fulfilled by a 1.5-fold increase in serum creatinine levels or urine output < 0.5
mL/kg/hr (or both) for > 24 hrs, RIFLE “injury” by a two-fold increase in serum creatinine levels
or urine output < 0.3 mL/kg/hr (or both) for >24 hrs, and RIFLE “failure” was defined by a
three-fold increase in serum creatinine levels and new RRT or serum creatinine > 354 µmol/L
with an acute rise of at least 44 µmol/L or urine output < 0.3 mL/kg/hr > 24 hrs (or both) or
anuria 12 hrs for 24 hrs (41). Urine output was measured over 24 hrs and calculated back to 6or 12- hourly values.
Continuous veno-venous hemodialysis was the single modality for RRT in our ICU during all
study periods. Indications for RRT included diuretic-resistant oliguria (urine output < 0.5 mL/kg
body weight) persistent for 6 hrs or anuria persistent for 3 hrs despite adequate volume therapy
or associated with volume overload with threatened or established pulmonary edema, the
presence of hyperkalemia, or severe metabolic acidosis (pH < 7.1).
Electronic patient data management system (PDMS)
The PDMS (Copra System GmbH, Sasbachwalden, Germany) automatically records data from
vital sign monitors, ventilators, and infusion pumps. The system also records order entries (e.g.,
medication, fluid dose and duration), laboratory and microbiology results.
Supplemental Table 1: Nephrotoxic drugs and adjunctive sepsis therapy
HES group p value Gelatin group p value Crystalloid group
(n = 360)
(n = 352)
(n = 334)
NSAID, n (%)a
Diuretics, n (%)b
ACE inhibitors, n (%)c
Vancomycin, n (%)
324 (90.0)
328 (91.1)
135 (37.5)
115 (31.9)
0.899
< 0.001
0.266
0.262
315 (89.5)
304 (86.4)
147 (41.8)
98 (27.8)
0.705
0.004
0.022
0.022
302 (90.4)
260 (77.8)
111 (33.2)
121 (36.2)
Aminoglycosides, n (%) d
43 (11.9)
0.635
32 (9.1)
0.523
36 (10.8)
Antimycotics, n (%) e
62 (17.2)
0.537
35 (9.9)
0.038
51 (15.3)
Iodinated contrast media,
n (%)
Insulin, n (%)a
80 (22.2)
0.401
70 (19.9)
0.924
65 (19.5)
331 (91.9)
0.046
321 (91.2)
0.109
291 (87.1)
Hydrocortisone, n (%)
169 (46.9) <0.001
208 (59.1)
<0.001
79 (23.7)
HES hydroxyethyl starch. P values were calculated with Fisher’s exact test. For p value
adjustment the Bonferroni-Holm method was used.
a
Nonsteroidal anti-inflammatory drugs, including ibuprofen and diclofenac
b
including mannitol and furosemide
c
angiotensin-converting enzyme (ACE) inhibitors, including ramipril, perindopril, lisinopril and
enalapril
d
including tobramycin and gentamicin
e
including amphotericin B and fluconazole
Supplemental Table 2: Parameters at onset of renal replacement therapy
HES group p value Gelatin group p value Crystalloid group
(n = 120)
(n = 111)
(n = 74)
277
< 0.001
162
0.209
191
[213-363]
[121-244]
[137-248]
Serum creatinine (µmol/l) at
onset renal replacement
therapy, median [IQR]
Mean urine output at onset
0.19
0.602
0.25
0.237
0.22
renal replacement therapy, [0.06-0.49]
[0.12-0.58]
[0.06-0.53]
(ml/kgBW/h), median
[IQR]
Serum potassium levels at
5.0
0.591
4.9
0.648
4.8
onset renal replacement
[4.6-5.4]
[4.6-5.4]
[4.6-5.3]
therapy, (mmol/L), median
[IQR]
Serum bicarbonate levels at
20.1
0.911
20.8
0.331
20.1
onset renal replacement
[17.6-22.2]
[17.2-23.2]
[17.7-22.2]
therapy, (mmol/L), median
[IQR]
paO2/FiO2-ratios at onset
218
0.789
203
0.344
218
renal replacement therapy,
[170-283]
[157-270]
[153-289]
(%), median [IQR]
HES hydroxyethyl starch, IQR interquartile range. P values were calculated with the Mann–
Whitney test.
Supplemental Table 3: Multiple logistic regression analysis with RRT as dependent binary
variable.
Baseline creatinine: (per µmol/l)
Baseline SAPS-II: (per point)
Cardiac / thoracic surgery: yes vs. no
Liver cirrhosis: yes vs. no
Antimycotics: yes vs. no
Vancomycin: yes vs. no
Ionidated contrast media: yes vs. no
Human albumin 20%: yes vs. no
n
1024
1024
1024
1024
1024
1024
1024
1024
Adjusted OR (95%CI)
1.006 (1.004,1.008)
1.02 (1.01,1.03)
2.96 (2.14,4.11)
2.30 (1.31,4.03)
1.50 (0.99,2.29)
2.58 (1.86,3.58)
2.32 (1.61,3.35)
2.06 (1.51,2.83)
p value
< 0.001
< 0.001
< 0.001
0.004
0.057
< 0.001
< 0.001
< 0.001
Added after model selection:
Period effects:
Period: ref.=Crystalloids
Gelatin 4%
1024
1.92 (1.32,2.82)
< 0.001
HES 6% (130/0.4)
1024
2.01 (1.34,3.02)
< 0.001
HES hydroxyethyl starch
Variables considered in the analysis: age, liver cirrhosis, diabetes, baseline creatinine, baseline
SAPS-II, cardiac / thoracic surgery, non-steroidal anti-inflammatory drugs, ACE inhibitors,
aminoglycosides, antimycotics, vancomycin, ionidated contrast media, diuretics, human albumin
20%, study period using dummy coding. Forward and backward stepwise multiple logistic
regression analysis based on AIC (Akaike Information Criterion) was used to derive a
multivariable model where the Hosmer-Lemeshow goodness of fit test (C-test: p = 0.108, H-test:
p = 0.281) and ROC curve analysis (AUC = 0.67) indicate an acceptable fit and discrimination,
respectively. P values were obtained by Wald's test. After model selection the period effect was
studied.
Supplemental Figure 1: Patient flow
All surgical ICU patients (1st Jan 2004 – 30th Apr 2010), n = 24326
Excluded:
< 18 years n = 428
Prior renal replacement therapy n = 718
Solid organ transplantation1 n = 575
Extracorporal membrane oxygenation (ECMO) n = 155
No baseline creatinine n = 51
1 month wash-out period between fluid changes n = 642
HES period
n = 7069
Gelatin period
n = 7783
Crystalloid period
n = 6905
Excluded:
No criteria for severe sepsis / septic shock n = 20711
HES period
n = 360
1
Gelatin period
n = 352
Crystalloid period
n = 334
Mainly patients receiving heart, lung or liver transplants. Patients undergoing renal
transplantation were treated by urologists at a different location and are therefore not included.
Supplemental Figure 2: Heart rate, MAP, CVP, ScvO2, hemoglobin and noradrenaline
dose during the ICU stay. Daily means of heart rate, mean arterial pressure (MAP), central
venous pressure (CVP), central venous saturation concentrations (ScvO2), hemoglobin values,
and cumulative daily dose of noradrenaline, presented as median and interquartile ranges.
***/+++ p < .001, **/++p < .01, */+p < .05 (*comparisons between HES and crystalloid groups;
+comparisons between gelatin and crystalloid groups); n denotes patients with available data.
Supplemental Figure 3: Daily procalcitonin serum levels. Presented as median and
interquartile ranges, +p < .05 (+comparisons between gelatin and HES groups); n denotes
patients with available data.
Procalcitonin