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Renal effects of synthetic colloids and crystalloids in patients with

severe sepsis: A prospective sequential comparison*


Ole Bayer, MD; Konrad Reinhart, MD; Yasser Sakr, MD, PhD; Bjoern Kabisch, PhD; Matthias Kohl, PhD;
Niels C. Riedemann, MD; Michael Bauer, MD; Utz Settmacher, MD; Khosro Hekmat, MD; Christiane S. Hartog, MD

Objectives: Hydroxyethyl starch 200 is associated with renal hydroxyethyl starch group, 525 (237– 868) mL/kg in the gelatin
impairment in sepsis, but hydroxyethyl starch 130/0.4 and gelatin group, and 355 (173–911) mL/kg in the crystalloid group. The
are considered to be less harmful. We hypothesized that fluid difference was statistically significant for hydroxyethyl starch
therapy with only crystalloids would decrease the incidence of after adjustment for multiple testing. Mean daily fluid intake and
acute kidney injury. fluid balance were higher on days 0 and 1 in the crystalloid group.
Design: Prospective sequential comparison during intensive Acute kidney injury occurred in 70% of patients receiving hy-
care unit stay. droxyethyl starch (adjusted p ⴝ .002) and in 68% of patients
Setting: Surgical intensive care unit. receiving gelatin (adjusted p ⴝ .025) vs. 47% patients receiving
Patients: Patients with severe sepsis. crystalloids. Need for renal replacement therapy tended to be
Interventions: Changes in standard fluid therapy, with predom- higher in the hydroxyethyl starch group (34%; adjusted p ⴝ .086)
inantly 6% hydroxyethyl starch from January 2005 to June 2005, and in the gelatin group (34%; adjusted p ⴝ .162) in comparison
4% gelatin from January 2006 to June 2006, and only crystalloids to the crystalloid group (20%). Intensive care unit and hospital
from September 2008 to June 2009. mortality were similar in each group (hydroxyethyl starch: 35%
Measurements and Main Results: Acute kidney injury was and 43%; gelatin: 26% and 31%; crystalloids: 30% and 37%).
defined by the presence of at least one RIFLE class; 118 patients Conclusion: Fluid resuscitation with only crystalloids was
received hydroxyethyl starch, 87 patients received gelatin, 141 equally effective, resulted in a more positive fluid balance only on
patients received only crystalloids. Baseline serum creatinine the first 2 days, and was associated with a lesser incidence of
values were similar. Patients received median cumulative doses acute kidney injury. (Crit Care Med 2011; 39:1335–1342)
of 46 (interquartile range, 18 –92) mL/kg hydroxyethyl starch and KEY WORDS: plasma substitutes; severe sepsis; hydroxyethyl
43 (interquartile range, 18 –76) mL/kg gelatin. Total median fluid starch; gelatin; crystalloids; acute renal failure
amounts were 649 (interquartile range, 275–1098) mL/kg in the

I n recent years, meta-analyses and Although there is growing evidence Recent systematic reviews, however,
clinical trials have found that col- that the use of some starch solutions found that published evidence was insuf-
loid or crystalloid resuscitation may increase renal failure and mortal- ficient to uphold the claim that low-
lead to similar survival (1, 2). ity (7–10), “modern third-generation” molecular-weight starches have fewer
Fluid choice therefore is deemed to be of starches with low molecular weight side effects than older starches (9) and
secondary importance and sepsis man- (HES 130/0.4) are claimed to be safe for identified only one exploratory trial with
agement guidelines leave the choice of use in the intensive care unit (ICU) (11, HES 130/0.4 in the setting of ICU or
fluid to the user (3). Hydroxyethyl starch 12). In 2007, the Food and Drug Admin- sepsis patients (10).
(HES) is now the most commonly used istration approved use of 6% HES 130/ We therefore replaced 6% HES 130/
colloid, followed by gelatins, human al- 0.4 for the treatment and prophylaxis of 0.4 with 4% gelatin in the ICU, as well as
bumin, and dextrans (4 – 6). hypovolemia. in the emergency department and in the
operating rooms. To our surprise, the
need for renal replacement therapy (RRT)
remained unchanged at 36%. Further-
*See also p. 1565. sprogramm ProExzellenz; PE 108-2), the Foundation
From the Department of Anesthesiology and Inten- of Technology, Innovation, and Research Thuringia
more, both synthetic colloids were asso-
sive Care Medicine (OB, KR, YS, BK, MK, NCR, MB, (STIFT), and the German Sepsis Society (all ciated with a dose-related increase of re-
CSH), Jena University Hospital, Jena, Germany; De- to OB). nal failure (13).
partment of General, Visceral, and Vascular Surgery Dr. Reinhart received honoraria/speaking fees Gelatins are thought to be less neph-
(US), Jena University Hospital, Jena Germany; Depart- from B. Brann in the past. The remaining authors have
ment of Cardiothoracic Surgery (KH), Jena University not disclosed any potential conflicts of interest.
rotoxic, but this notion is derived from
Hospital, Jena, Germany. For information regarding this article, E-mail: trials in severe sepsis and kidney trans-
Supplemental digital content is available for this ar- konrad.reinhart@med.uni-jena.de plantation patients in whom gelatins
ticle. Direct URL citations appear in the printed text and Copyright © 2011 by the Society of Critical Care served as control to older HES solutions
are provided in the HTML and PDF versions of this article Medicine and Lippincott Williams & Wilkins
on the journal’s Web site (www.ccmjournal.com).
(8, 14). Randomized controlled trials that
DOI: 10.1097/CCM.0b013e318212096a address gelatin efficacy and safety are
Supported, in part, by an unrestricted grant of
the Thuringian Ministry of Cultural Affairs (Lande- scarce.

Crit Care Med 2011 Vol. 39, No. 6 1335


Here, we report on the clinical out- many). Study phase III lasted from September kg/hr (or both) for ⱖ24 hrs, RIFLE “injury” by
comes of severe sepsis patients from 2008 until June 2009. All patients in phase III a two-fold increase in serum creatinine levels
three sequential treatment periods. Dur- were treated only with crystalloids (crystalloid or urine output ⬍0.3 mL/kg/hr (or both) for
ing the first two periods, patients were group). ⱖ24 hrs, and RIFLE “failure” was defined by a
sequentially treated with the synthetic Therapy for sepsis followed institutional three-fold increase in serum creatinine levels
colloids HES and gelatin and additional standard operating procedures based on the and new RRT or serum creatinine ⱖ354
crystalloids. In the third period, patients guidelines of the Surviving Sepsis Campaign ␮mol/L with an acute rise of at least 44
received only crystalloids. Apart from (3) and the German Sepsis Society (15). Dur- ␮mol/L or urine output ⬍0.3 mL/kg/hr ⱖ24
that, treatment protocols for severe sep- ing the HES and gelatin phase, the indication hrs (or both) or anuria ⱖ12 hrs for ⱖ24 hrs.
for colloid administration was left to the dis- AKI was defined by one or more RIFLE criteria
sis patients remained unchanged
cretion of the attending critical care physi- or new occurrence of RRT. Groups included
throughout.
cian. Standard hemodynamic management in- only patients for whom the entry criterion was
cluded vasopressors with noradrenaline to the most severe classification, i.e., patients in
MATERIALS AND METHODS maintain a mean arterial pressure ⬎65 mm the RIFLE risk group had no more severe
Hg, in addition to repeated fluid challenges injury than that defined by RIFLE risk.
Patients with crystalloids and synthetic colloids (gela- Secondary end points were cumulative
tin or hydroxyethyl starch) to allow the lowest fluid doses, total fluid balance, need for me-
The study population consisted of all pa- possible dose of vasopressors. If needed, do- chanical ventilation, maximum degree of or-
tients with severe sepsis or septic shock butamine (up to a dose of 10 ␮g/kg/min) or gan failure as assessed by Sequential Organ
treated in a 50-bed interdisciplinary surgical epinephrine (up to 0.15 ␮g/kg/min) was Failure Assessment (SOFA) score, vasopressor
ICU of a university hospital. Patients were added. Extended hemodynamic monitoring use, need for blood products, ICU length of
excluded from analysis if they had chronic with pulmonary artery catheter (Swan-Ganz stay, and ICU and hospital mortality. Total
renal failure requiring hemodialysis before CCOmbo; Edwards Life Sciences, Unter- fluids were defined as all intravenous fluids
ICU admission or had been enrolled in a ran- schleissheim, Germany) or PiCCO (Pulsiocath administered as maintenance or bolus fluids
domized HES trial (7). The local ethics board 5-Fr Thermodilution Catheter; Pulsion Medi- or for intravenous drug administrations, in-
waived the need for informed consent because cal Systems München, Germany) was consid- cluding blood products and human albumin,
of the observational nature of the study. ered if the required vasopressor dose increased parenteral and enteral feeding solutions, and
⬎0.4 ␮g/kg/min of noradrenaline. Central ve-
any oral intake. Creatinine clearance was de-
Procedures nous oxygen saturation was measured at least
termined from serum creatinine using the
two times per day from blood samples drawn
Cockcroft-Gault formula (17). Study period
Before July 2006, standard fluid treatment from the central venous catheter.
was length of stay in the ICU.
of hypovolemia in our ICU, emergency depart- Human albumin was not used for volume
Data recorded on admission included age,
ment, and the operating room consisted of a replacement. Its use was restricted to treat-
gender, body weight, referring facility, and
combination of crystalloids and synthetic col- ment of severe hypoalbuminemia ⬍15
surgical procedures preceding admission.
loids. In the first study phase from January 1, mmol/mL by 20% human albumin (Albunorm
Screening for the presence of severe sepsis was
2005 until June 30, 2005, patients were 20%; Octapharma, Langenfeld, Germany).
performed routinely by the senior physicians
treated with predominantly 6% HES (6% HES Continuous veno-venous hemodialysis was
in our ICU and documented by trained re-
130/0.4%; Voluven; Fresenius-Kabi Bad Hom- the single modality for RRT in our ICU during
burg) and crystalloids (HES group). Because search nurses. The main source of sepsis was
all study periods. Indications for RRT in our
of concerns about HES-related nephrotoxicity, also documented. The Simplified Acute Phys-
ICU included diuretic-resistant oliguria (urine
iology Score II and SOFA scores were calcu-
HES solutions were replaced by 4% gelatin. output ⬍0.5 mL/kg body weight) persistent
From January 1, 2006 to June 30, 2006, all for 6 hrs or anuria persistent for 3 hrs de- lated within 24 hrs of admission by the attend-
patients with severe sepsis or septic shock spite adequate volume therapy or associated ing physician who was in charge of the patient.
were treated with 4% modified gelatin (Gela- with volume overload with threatened or Data were collected prospectively from
fusal; Serumwerk Bernburg AG, Bernburg, established pulmonary edema, the presence vital sign monitors, ventilators, and infusion
Germany) and crystalloids (gelatin group). We of hyperkalemia, or severe metabolic acido- pumps and automatically recorded by a clin-
prospectively planned to compare the effects sis (pH ⬍7.1). ical information system. The clinical infor-
of the different fluid regimens in a before-and- mation system (Copra System GmbH,
after study with sequential treatment periods Sasbachwalden, Germany) provided staff
of 6 months that were separated by a washout Primary and Secondary with complete electronic documentation,
period of 6 months to allow for a complete Outcomes: Definitions and Data order entry (e.g., medication, fluid dose, and
implementation of the new standard fluid. The Collection Methods duration), and direct access to laboratory
analysis of the first two treatment periods was and microbiology results. We recorded the
published previously (13) and revealed that The primary end point for our analysis was use of nephrotoxic drugs, i.e., nonsteroidal
the need for RRT was not different between the development of acute kidney injury (AKI). anti-inflammatory drugs, diuretics, angio-
the two cohorts of ICU patients receiving HES New occurrence of RRT was a co-primary end tensin-converting enzyme inhibitors, anti-
or gelatin. We therefore extended our study. point. We defined AKI according to the stan- microbials and antimycotics, and iodinated
Gelatin was abolished and replaced by crystal- dardized and validated RIFLE criteria, includ- contrast media. Data on ICU and hospital
loids starting in July 2006. Until now, only ing separate criteria for creatinine and urine length of stay and ICU and hospital mortal-
balanced crystalloid solution (Jonosteril; Fre- output, and using the criteria that led to the ity were collected for all patients.
senius Kabi, Bad Homburg, Germany) has worst outcome. Urine output was measured Severe sepsis was defined as the presence
been used in the ICU, emergency department, over 24 hrs and calculated back to 6- or 12- of a defined focus on infection and at least two
and operating room, except in patients with hourly values (16). Accordingly, RIFLE “risk” of the four Systemic Inflammatory Response
hyperkalemia who receive normal saline (NaCl was fulfilled by a 1.5-fold increase in serum Syndrome criteria and infection-related or-
0.9%; Fresenius Kabi, Bad Homburg, Ger- creatinine levels or urine output ⬍0.5 mL/ gan dysfunction (18). A defined focus on

1336 Crit Care Med 2011 Vol. 39, No. 6


Table 1. Patient baseline characteristics. RESULTS
Hydroxyethyl Gelatin Crystalloid
Starch Group Group Group Participants
(n ⫽ 118) (n ⫽ 87) (n ⫽ 141)
A total number of 400 patients were
Age (yr) mean ⫾ SD 65.0 ⫾ 16.2 63.0 ⫾ 14.2 66.4 ⫾ 13.9 treated for severe sepsis in our ICU dur-
Male, n (%) 79 (56) 57 (66) 91 (65) ing the three sequential study periods.
Comorbidities, n (%)
Hypertension 59 (42) 44 (51) 69 (49) Fifty-four patients fulfilled exclusion
Diabetes mellitus 32 (23) 19 (22) 36 (26) criteria (chronic renal failure requiring
Cancer 16 (11)a 19 (22) 34 (24) hemodialysis before ICU admission, n ⫽
Chronic renal failure 19 (13) 10 (11) 16 (11) 45; participation in a randomized con-
Liver cirrhosis 8 (6) 8 (9) 4 (3)
Surgical procedures, n (%)
trolled HES trial described previously,
Abdominal 48 (41) 25 (29)b 68 (48) n ⫽ 9) (7).
Cardiac/thoracic surgery 36 (31) 36 (41)a 38 (27) One hundred eighteen patients re-
Trauma 6 (5) 5 (6) 9 (6) ceived HES 6%, 87 received gelatin 4%,
Othersd 22 (19) 13 (15) 16 (11) and 141 patients received crystalloids.
No surgery 6 (5) 8 (9) 10 (7)
Source of sepsis, n (%) The baseline characteristics of patients
Respiratory 52 (44) 44 (51) 52 (37) were similar except for fewer patients
Abdominal 29 (25)c 25 (29)b 66 (47) with cancer in the HES group and fewer
Urogential 7 (6) 3 (3) 5 (4) patients with an abdominal source of sep-
Othere 30 (25)a 15 (17) 18 (13)
Hemodynamic and laboratory values,
sis in the HES and gelatin groups, and
median (interquartile range) fewer patients with abdominal surgery
Mean blood pressure, mm Hg 75 (68–83) 74 (68–81) 74 (68–80) and more patients with cardiac/thoracic
Heart rate, beats/min 96 (81–106) 95 (85–111) 92 (81–109) surgery in the gelatin group. SOFA score
Central venous pressure, mm Hg 8 (5–11)a 10 (7–12) 9 (7–13) was lower in the HES group, but creati-
Vasopressor use, n (%) 103 (87) 77 (89) 129 (91)
C-reactive protein, mg/dL 183 (88–268) 179 (91–241) 182 (100–251)
nine, creatinine clearance, and Simplified
Platelet count, ⫻103/mL 158 (99–217) 160 (104–246) 156 (93–235) Acute Physiology Score II scores did not
Serum creatinine, ␮mol/L 99 (83–159) 103 (71–150) 98 (74–142) differ between groups (Table 1).
Creatinine clearance, mL/min 54 (41–79) 68 (44–98) 59 (40–89)
Simplified Acute Physiology Score II 53 (41–63) 51 (41–64) 57 (41–70)
score Hemodynamics and Fluid
Sequential Organ Failure Assessment 9 (7–11)a 9 (7–13) 10 (7–12)
Balance
score

The p values were calculated with the Student’s t test or the Mann-Whitney test and Fisher’s exact
Hemodynamics and fluid balances
test, as appropriate. were analyzed during the first 14 days of
a
.01 ⬍ p ⬍ .05; b.001 ⬍ p ⬍ .01; cp ⬍ .001; dincludes neurosurgical, metabolic, renal urinary tract, the treatment period in the ICU. Mean
and gynecologic procedures; eincludes catheter-related, wound, central nervous system, and blood- arterial pressures were significantly
stream infections and endocarditis. Hydroxyethyl starch and gelatin groups were compared with the higher in the HES group after day 2 (Fig.
crystalloid group. 1). Although mean heart rates did not
differ, mean values for central venous
pressure and central venous oxygen sat-
infection was defined by either an organism variables, respectively. In case of primary uration were higher in the crystalloid
cultured from blood or a sterile site or an and secondary outcomes, resulting p values group on single study days (Fig. 1). Nor-
abscess or volume of infected tissue (e.g., were adjusted by the Bonferroni-Holm adrenaline use was similar in the first 3
pneumonia, peritonitis, skin or soft tissue method. Otherwise, the unadjusted p values days and significantly higher in the crys-
infection). Infection-related organ dysfunc- are reported. talloid group on days 4 – 8 and days 10
tion was considered to be present if at least In addition, forward and backward stepwise and 11 (Fig. 1). Daily fluid intake and
one of the following applied: respiratory, multiple logistic regression analysis based on mean daily fluid balance were signifi-
hematologic, or hepatic SOFA score ⬎1 and Akaike information criterion was performed to cantly higher in the crystalloid group at
cardiovascular SOFA score of 1, 3, or 4 or identify risk factors for AKI and RRT. The baseline (day 0) and on day 1 (Fig. 1).
renal SOFA score ⬎2. Organ dysfunction resulting model was checked by the Hosmer- Fluid volumes are given in Table 2. The
was defined previously (7). cumulative fluid volumes administered
Lemeshow goodness-of-fit test as well as the
area under the receiver-operating character- were significantly higher in both the HES
Statistical Analysis istic curve. In a second step, we added period and the gelatin groups than in the crys-
All analyses were performed in SPSS ver- effects of HES and gelatin as categorical talloid group on day 0 and 1 (Fig. 1). The
sion 17.0 and R version 2.11.1 (R Development variables with crystalloids as reference cat- total amount of fluids was significantly
Core Team 2010; R Foundation for Statistical egory. Thereafter, we added variables for the high in the HES group (Table 2). The
Computing, Vienna, Austria). All reported p total fluid amount when the three periods ratios of total fluid amounts were 1.47:1
values are two-sided. were analyzed separately. For the dose– (crystalloid compared to HES group) and
For univariate analyses, we applied the t response relationship between total fluid 1.44:1 (crystalloid compared to gelatin
test or the Mann-Whitney test and Fisher amount and AKI and RRT, we computed group) on days 0 –1 and 1.17:1 and 1.21:1
exact test for continuous and categorical linear and quadratic fits. for the first 4 days, respectively.

Crit Care Med 2011 Vol. 39, No. 6 1337


Figure 1. Means of daily heart rate, daily arterial pressure, daily central venous pressure, daily central venous saturation concentrations, daily Sequential
Organ Failure Assessment scores, cumulative daily dose of noradrenaline, daily fluid intake, and daily fluid balance for days 0 –14. Median and interquartile
range are presented. ***/ⴙⴙⴙp ⬍ .001, **/ ⫹⫹ p ⬍ .01, */⫹ p ⬍ .05 (*comparisons between hydroxyethyl starch [HES] and crystalloids groups; ⫹
comparisons between gelatin and crystalloid groups). ScvO2, central venous oxygen saturation.

1338 Crit Care Med 2011 Vol. 39, No. 6


Table 2. Total fluids and blood products administered during intensive care unit stay regarding age, hemodynamics, and se-
rum creatinine. However, patients receiv-
Hydroxyethyl Gelatin Crystalloid
ing synthetic colloids less often had an
Starch Group Group Group
abdominal source of sepsis.
(n ⫽ 118) (n ⫽ 87) (n ⫽ 141)
Colloids were associated with higher
Total fluid amount, median (mL/kg) 649 (275–1098)b 525 (237–868) 355 (173–911) mean arterial pressure on most study
BWa (IQR) days, whereas on some days central ve-
Total amount of study fluids, median 46 (18–92)c 43 (18–76)d 105 (41–270) nous oxygen saturation and central ve-
(mL/kg) BW (IQR) nous pressure were higher in the crystal-
Total amount of crystalloids, median 359 (206–619) 345 (216–649) 325 (180–636) loid group and mean SOFA scores were
(mL/kg) BW (IQR)
Blood products, median units (IQR)
lower in the colloid groups.
Fresh-frozen plasma 8 (4–16) 6 (4–12) 6 (4–12) The use of nephrotoxic drugs was not
Platelet concentrates 3 (2–5)b 2 (1–3) 2 (1–3) different between study groups except
Red blood cells 2 (2–4) 2 (2–2) 2 (1–4) that patients receiving HES also received
Human albumin 20%, median (mL/kg) 12 (5–24) 8 (5–27) 10 (4–19) more antifungals (amphotericin B and
BW IQR
fluconazole) and patients receiving gela-
BW, body weight; IQR, interquartile range. tin also received more angiotensin-
a
Total fluid amount includes oral and parenteral fluids, including nutrition, drug administration, blood converting enzyme inhibitors. Multivari-
products, albumin, and intravenous volume replacement; b.01 ⬍ p ⬍ .05; c.001 ⬍ p ⬍ .01; dp ⬍ .001. The ate analysis suggests that besides
p values were calculated with the Mann-Whitney test. Hydroxyethyl starch and gelatin groups were administration of HES and gelatin, anti-
compared with the crystalloid group. fungal medication as well as 20% human
albumin, cardiothoracic surgery, and io-
Morbidity and Mortality: AKI Multiple logistic regression analysis dinated contrast media are independent
and RRT with AKI as a dependent binary variable risk factors for AKI.
showed that baseline creatinine, cardio-
Patient exposure to a range of nephrotoxic thoracic surgery, antimycotics, human Meaning of the Study in
drugs did not differ between groups except for albumin 20%, iodinated contrast media, Relation to Other Studies
a higher use of antimycotics in the HES HES 6%, and gelatin 4% were indepen-
group and angiotensin-converting enzyme dent risk factors. A dose-dependency of Adverse effects of starch solutions on
inhibitors in the gelatin group (Supplemen- adverse effects (per mL/kg body weight) renal outcomes have been demonstrated
tary Table I [Supplemental Digital Content 1, was only apparent for crystalloids with a repeatedly in sepsis and other critically ill
http://links.lww.com/CCM/A232]). There was linear or maybe even quadratic risk in- patients (7–10, 14, 19, 20). Our findings
also no difference in serum creatinine at on- crease (Table 4). HES and gelatin were do not support the hypothesis that mod-
set of renal replacement therapy (Supple- also independent risk factors after mul- ern third-generation starches are devoid
mentary Table II [Supplemental Digital Con- tiple logistic regression with RRT as of negative effects on kidney function (11,
tent 1, http://links.lww.com/CCM/A232]). dependent variable without an apparent 12) because 6% HES 130/0.4 comprised
AKI occurred in 47% of patients in the dose– effect relationship for any colloid ⬎90% of the starches in this study (13).
crystalloid group, in 70% of patients in or crystalloid (Supplementary Table III Experimental data also suggest that im-
the HES group (adjusted p ⫽ .002), and [Supplemental Digital Content 1, pairment of kidney function after 6%
in 68% of patients in the gelatin group http://links.lww.com/CCM/A232]). HES 130/0.4 and 10% HES 200/0.5 only
(adjusted p ⫽ .025; Table 3). Patients differs by degree (21), and a recent exper-
were allocated to RIFLE classes according imental study suggests that both 6% HES
to their highest risk. The RIFLE risk and DISCUSSION 130/0.4 and gelatin may induce signifi-
RIFLE injury classes contained few pa- cantly more impairment of renal function
tients who were evenly distributed. The Principal Findings and damage to kidney morphology than
majority of patients were allocated to the crystalloid (22).
RIFLE failure class, 47% of patients after In severe sepsis patients, a change of Other investigators also have found
administration of HES (adjusted p ⫽ fluid replacement regimen from HES and that adverse effects of starches or gelatins
.002), 40% after gelatin (adjusted p ⫽ gelatin to only crystalloids was associated were related to the cumulative dose (7,
.162), and 25% of patients after crystal- with a significantly lower incidence of 20, 23, 24). In retrospective observational
loids. RRT tended to occur more fre- AKI and RRT. ICU and hospital mortality studies, HES administration in low cu-
quently in patients who received HES were similar between the groups. Inter- mulative doses in the range of 15–20 mL/
(34%) compared to crystalloids (20%; ad- estingly, patients in the crystalloid group kg, which is less than half of the recom-
justed p ⫽ .086). In the gelatin group, the received more fluid volume and had a mended maximum daily dose, was not
differences were only significant before p more positive fluid balance only on the associated with an increased incidence of
value adjustment (Table 3). first two days of treatment in the ICU. AKI or acute renal failure (6, 25).
Severity scores, ICU and hospital mor- The total amount of fluid administered The need of RRT that was observed in
tality, and ICU length of stay did not was significantly higher in the HES than our study after synthetic colloids was
differ significantly between groups after in the crystalloid group during the whole 34% after both HES and gelatin. This rate
adjustment of p values, but there was a ICU stay. is considerably higher than the rates ob-
trend toward shorter ICU length of stay in The sequential study cohorts of severe served elsewhere after the use of crystal-
the crystalloid group (Table 3). sepsis patients were similar at baseline loids or albumin. In a recent multicenter

Crit Care Med 2011 Vol. 39, No. 6 1339


Table 3. Primary and secondary outcomes

Hydroxyethyl Gelatin Crystalloid


Starch Group Group Group
(n ⫽ 118) p Adjusted p ((n ⫽ 87) p Adjusted p ((n ⫽ 141)

RIFLE risk, n (%)a 15 (13) .698 1.000 10 (11) .831 1.000 15 (11)
RIFLE injury, n (%)b 12 (10) .842 1.000 14 (16) .319 1.000 16 (11)
RIFLE failure, n (%)c 56 (47) ⬍.001 0.002 35 (40) .018 .162 35 (25)
AKI, n (%)d 83 (70) ⬍.001 0.002 59 (68) .003 .025 66 (47)
Renal replacement therapy, n (%) 40 (34) .011 0.086 30 (34) .019 .162 28 (20)
Sequential Organ Failure score maximum, 11 (9–14) .355 1.000 13 (10–15) .332 1.000 12 (9–14)
median (IQR)e
Sequential Organ Failure score mean, 7 (6–10) .032 .227 8 (6–10) .122 .853 8 (6–11)
median (IQR)e
Intensive care unit mortality, n (%) 41 (35) .506 1.000 23 (26) .550 1.000 43 (30)
Hospital mortality, n (%) 51 (43) .311 1.000 27 (31) .393 1.000 52 (37)
Intensive care unit length of stay, days, 14 (6–28) .070 .421 13 (6–26) .167 1.000 10 (5–20)
median (IQR)

IQR, interquartile range.


a
Five-fold increase in serum creatinine levels and/or urine output ⬍0.5 mL/kg/hr for ⱖ24 hrs; btwo-fold increase in serum creatinine levels and/or urine
output ⬍0.3 mL/kg/hr for ⱖ24 hrs; cthree-fold increase in serum creatinine levels and/or renal replacement therapy, serum creatinine ⱖ354 ␮mol/L with
an acute increase of at least 44 ␮mol/L, and/or urine output ⬍0.3 mL/kg/hr ⱖ24 hrs or anuria ⱖ12 hrs for ⱖ24 hrs; ddefined by any RIFLE category; ewithin
28 days of admission to the intensive care unit. The p values were calculated with the Mann-Whitney test and Fisher’s exact test, as appropriate. For p value
adjustment, the Bonferroni-Holm method was used.

Table 4. Multiple logistic regression analysis with acute kidney injury as dependent binary variable
trial with 537 severe sepsis patients, need
Adjusted Odds Ratio for RRT was 18.6% in the Ringer’s lactate
n (95% Confidence Interval) p group and 31% in the HES group; 28-day
mortality rates were 24.1% and 26.7%,
Age (per yr) 333 1.02 (1.00–1.03) .101 respectively (7). In the severe sepsis sub-
Simplified Acute Physiology Score II 333 1.02 (1.00–1.03) .064
(per point)
group of the SAFE trial (n ⫽ 1218),
Baseline creatinine (per ␮mol/L) 333 1.01 (1.01–1.02) ⬍.001 which compared 4% albumin to 0.9%
Cardiac/thoracic surgery, yes vs. no 333 1.94 (1.09–3.46) .024 saline, RRT occurred in 18.7% of patients
Antimycotics, yes vs. no 333 2.54 (1.15–5.61) .021 assigned to albumin compared to 18.2%
Vancomycin, yes vs. no 333 1.85 (0.99–3.45) .053
Ionidated contrast media, yes vs. no 333 2.02 (1.16–3.53) .013 of patients assigned normal saline. The
Human albumin 20%, yes vs. no 333 2.19 (1.24–3.87) .007 28-day mortality rates were 30.7% and
Added after model selection 35.3%, respectively (26).
Period effects A high need for RRT may coincide
Period, reference ⫽ crystalloids
Gelatin 4% 333 3.65 (1.81–7.35) ⬍.001 with a widespread use of synthetic col-
HES 6% 130/0.4 333 4.52 (2.27–8.99) ⬍.001 loids. Synthetic colloids and especially
Dose–effect relationship HES solutions are preferred volume ex-
Crystalloids (per mL/kg BW) 136 1.005 (1.002–1.008) .002
Crystalloids, quadratic (per mL/kg BW 136 1.00001 (1.00000–1.00001) .009
panders in Germany (4, 27). A represen-
squared) tative survey conducted in German ICUs
HES 6% 130/0.4 (per mL/kg BW) 112 1.010 (0.998–1.022) .115 in 2003–2004 found an incidence of acute
HES 6% 130/0.4, quadratic (per mL/kg BW 112 1.0001 (1.0000–1.0001) .116 renal failure in these patients of 42.4%
squared) (28). The survey also documented that
Gelatin 4% (per mL/kg BW) 85 1.001 (0.990–1.012) .865
Gelatin 4%, quadratic (per mL/kg BW 85 1.00000 (0.99997–1.00002) .785 35.2% of patients with severe sepsis and
squared) septic shock received synthetic colloids
mostly in form of HES 6%, HES 10%, or
BW, body weight; HES, hydroxyethyl starch. gelatin (29).
Variables considered in the analysis: age, liver cirrhosis, diabetes, baseline creatinine, baseline
An international sepsis register docu-
Simplified Acute Physiology Score II, cardiac/thoracic surgery, nonsteroidal anti-inflammatory drugs,
angiotensin-converting enzyme inhibitors, aminoglycosides, antimycotics, vancomycin, ionidated
mented an overall need for RRT of 21.3%
contrast media, diuretics, human albumin 20%, period effects of HES 6% 130/0.4 and gelatin 4% as in ⬎12,000 patients from eight countries.
categorical variables with crystalloids as reference category, crystalloids (linear and quadratic, per The only European country was Ger-
mL/kg BW), HES 6% (130/0.4; linear and quadratic, per mL/kg BW), and gelatin 4% (linear and many, where HES is widely used. Need
quadratic, per mL/kg BW). Forward and backward stepwise multiple logistic regression analysis based for RRT in German patients was 33.4%,
on Akaike information criterion) was used to derive a multivariable model in which the Hosmer- whereas the RRT rates in non-European
Lemeshow goodness of fit test (C-test: p ⫽ .712, H-test: p ⫽ .464) and receiver-operator curve analysis
countries ranged between 11.7% and
(area under the curve ⫽ 0.62) indicate an acceptable fit and discrimination, respectively. The p values
were obtained by Wald’s test. After model selection, a period effect was studied, then the model was 25.9%. Hospital mortality rates for severe
applied to the subcohorts, and the variables for synthetic colloids and crystalloids were added sepsis patients were 43.4% in Germany
correspondingly to investigate the dose– effect relationship. and 49.6% overall (30).

1340 Crit Care Med 2011 Vol. 39, No. 6


AKI occurred in 47% of patients in the Limitations of This Study and patients. Study designs can be found on
crystalloid group, and significantly more Future Research the respective Web sites.
frequently after gelatin 4% (68%) and
HES 6% (70%). The need for RRT was This study has several limitations, CONCLUSIONS
also higher in both the HES and the namely that it was a single-center un-
gelatin groups, but the difference was blinded study with small sample sizes in The results of this study question the
nonsignificant after adjustment for mul- all groups, with changes of fluid regimen superiority of synthetic colloids over
tiple testing. There may be several rea- with possibly extended inception period, crystalloids with respect to their volume-
post hoc adjusted analyses, and multivar- saving potential in severe sepsis. Syn-
sons for the failure to achieve signifi-
iate modeling. Conclusions therefore thetic colloid use did not lead to a less
cance. The Bonferroni-Holm adjustment
should be drawn with circumspection. positive total fluid balance. This chal-
for multiple testing may have been too
The lack of baseline differences does not lenges a common rationale for their use
conservative or the sample size may have
preclude the presence of unidentified in patients with severe sepsis. The results
been too small, particularly in the gelatin from our study place serious doubt on the
group differences because of the nonran-
group. Gelatin has a lower molecular assumption that third-generation HES
domized nature of the study. It remains
weight (30 kDa) than HES (130 kDa) and 130/0.4 and low-molecular-weight gelatin
unclear whether the observed differences
was used as 4% solution compared to the are innocuous regarding renal function. To
in mean arterial pressures are attribut-
6% HES solution. Little is known about date, there is a lack of evidence from well-
able to different patient management.
the mechanisms of colloid-associated The crystalloid group included more pa- designed studies in intensive care to sup-
renal impairment (31). Previous studies tients with an abdominal source of sepsis. port the widespread use of synthetic col-
(8, 14) suggest that gelatin may have a We do not believe this constitutes a con- loids. Fortunately, such trials are now
lesser effect on renal function com- founder, because the multivariate analy- underway for 6% HES 130/0.4.
pared to HES. The lower incidence of sis identified no association between
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