RESEARCH ARTICLE
Mortality and associated risk factors in
patients with blood culture positive sepsis and
acute kidney injury requiring continuous renal
replacement therapy—A retrospective study
Mikko J. Ja¨rvisaloID1,2,3*, Tapio Hellman1, Panu UusaloID2,3
1 Kidney Center, Turku University Hospital and University of Turku, Turku, Finland, 2 Department of
Anaesthesiology and Intensive Care, University of Turku, Turku, Finland, 3 Perioperative Services, Intensive
Care and Pain Medicine, Turku University Hospital, Turku, Finland
* mikko.jarvisalo@tyks.fi
Abstract
Objectives
Septic acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT)
carries a mortality risk nearing 50%. Risk factors associated with mortality in AKI patients
undergoing CRRT with blood culture positive sepsis remain unclear as sepsis has been
defined according to consensus criteria in previous studies.
Methods
Risk factors associated with intensive care unit (ICU), 90-day and overall mortality were
studied in a retrospective cohort of 126 patients with blood culture positive sepsis and coinci-
dent severe AKI requiring CRRT. Comprehensive laboratory and clinical data were gathered
at ICU admission and CRRT initiation.
Results
38 different causative pathogens for sepsis and associated AKI were identified. ICU mortal-
ity was 30%, 90-day mortality 45% and one-year mortality 50%. Immunosuppression, his-
tory of heart failure, APACHE II and SAPS II scores, C-reactive protein and lactate at CRRT
initiation were independently associated with mortality in multivariable Cox proportional haz-
ards models. Blood lactate showed good predictive power for ICU mortality in receiver oper-
ating characteristic curve analyses with AUCs of 0.76 (95%CI 0.66–0.85) for lactate at ICU
admission and 0.84 (95%CI 0.72–0.95) at CRRT initiation.
Conclusions
Our study shows for the first time that lactate measured at CRRT initiation is predictive of ICU
mortality and independently associated with overall mortality in patients with blood culture posi-
tive sepsis and AKI requiring CRRT. Microbial etiology for septic AKI requiring CRRT is diverse.
PLOS ONE
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OPEN ACCESS
Citation: Ja¨rvisalo MJ, Hellman T, Uusalo P (2021)
Mortality and associated risk factors in patients
with blood culture positive sepsis and acute kidney
injury requiring continuous renal replacement
therapy—A retrospective study. PLoS ONE 16(4):
e0249561. https://doi.org/10.1371/journal.
pone.0249561
Editor: Aleksandar R. Zivkovic, Heidelberg
University Hospital, GERMANY
Received: January 7, 2021
Accepted: March 20, 2021
Published: April 5, 2021
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
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responses alongside final, published articles. The
editorial history of this article is available here:
https://doi.org/10.1371/journal.pone.0249561
Copyright: © 2021 Ja¨rvisalo et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: The data underlying
this study contain potentially identifying participant
information and cannot be shared publicly. Future
Background
Sepsis is the predominant etiology of severe acute kidney injury (AKI) requiring renal replace-
ment therapy (RRT) in critically ill patients [1]. The mechanisms underlying sepsis-associated
AKI still, remain to be fully characterized [2]. Despite improvements in intensive care, mortal-
ity in sepsis patients receiving continuous RRT (CRRT) for AKI remains close to 50% within
90 days following intensive care admission [3,4]. Although, differences in methodologies
employed for RRT at different intensive care units (ICUs) exist, CRRT is usually the modality
of choice to treat critically ill AKI patients with the highest comorbidity and presence of hemo-
dynamic instability.
Although a number of studies have explored risk factor associations with mortality in septic
AKI, a large proportion of patients included in these studies have had a clinical diagnosis of
sepsis defined according to the Sepsis-3 (suspected or confirmed infection with an increase�2
in Sequential organ failure assessment score (SOFA)) [5] or earlier consensus criteria, and
blood culture findings, whether positive or negative have not been described. Data on mortal-
ity and associated risk factors limited to patients with blood culture positive sepsis and AKI
requiring CRRT are virtually non-existent. Furthermore, very limited data are available for
blood stream infection pathogens leading to sepsis-associated AKI and the need for RRT.
It would be of great value to recognize risk factors associated with mortality in this patient
group and assess individual mortality risk more precisely early on and potentially target treat-
ments accordingly. Moreover, it would be important to characterize pathogens potentially
leading to septic AKI requiring intensive care and CRRT.
Therefore, we aimed to study risk factors associated with ICU-, 90-day and overall mortality
in blood culture positive sepsis and associated severe AKI requiring CRRT and to identify the
responsible blood culture positive pathogens in this retrospective study.
Methods
Data sources, collection and study population
Patients admitted to the intensive care unit of Turku University Hospital, Turku, Finland, an aca-
demic tertiary medical center from January 1, 2010 through December 31, 2019, requiring CRRT
and with ascertained diagnosis of sepsis and positive blood culture(s) were included in this retro-
spective study. Patients without sepsis (n = 229) and patients with sepsis but negative blood cul-
tures (n = 115) were excluded, as were patients with maintenance dialysis dependency prior to
ICU admission (n = 22). Blood culture findings had been examined case by case and considered
to be relevant etiological agents for the sepsis present by an ICU infectious diseases senior consul-
tant. In one patient with a single blood culture positive for Staphylococcus capitis the culture find-
ing was considered a contamination, not a causative agent for sepsis by an infectious diseases
specialist and a microbiologist and the patient was excluded from the study. Therefore, 126
patients were included in the analyses (S1 Fig). Every patient included in the study fulfilled the
Sepsis-3 criteria for sepsis [5] in addition to presenting with blood culture positive bacteremia or
fungemia. The individual patient data were collected from the hospital’s medical documents with
the permission of the Turku University Clinical Research Center scientific review board and the
Hospital district of Southwest Finland. The data from the hospital software were combined and
the patient identity numbers removed before the statistical analyses. For this retrospective, regis-
try-based, non-interventional study the regulatory review board waived the need for informed
consent in terms of data collection and analysis and publication of results.
For the purpose of this study, blood pH, bicarbonate, lactate, base excess, electrolytes, and
other laboratory variables, blood pressure, need for invasive mechanical ventilation, PaO2/
PLOS ONE CRRT in blood culture positive sepsis
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data access requests should be sent to the Ethics
Committee of Southwest Finland Hospital District
(eettinen.toimikunta@tyks.fi) or the Department of
Anesthesiology and Intensive Care and the
Informatics Department of Turku University
Hospital via the corresponding author.
Funding: The author(s) received no specific
funding for this work.
Competing interests: The authors have declared
that no competing interests exist.
FiO2-ratio, diuresis and vasopressors were recorded at ICU admission and at CRRT initiation.
Other data extracted from patients’ medical records included demographics, chronic medical
conditions, fluid balance at CRRT initiation, CRRT dose and Acute Physiology and Chronic
Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II, and
SOFA score. Estimated glomerular filtration rate (eGFR) was assessed at baseline (within one-
year prior to ICU admission) and at 90 days and at one year after discharge in surviving
patients.
CRRT modality
Continuous Veno-Venous Hemodialysis for all patients was performed using Fresenius Multi-
filtrate CRRT monitors and 1.80 m2 polysulfone hemofilters Ultraflux AV1000 or Ultraflux
EMiC2 HCO membranes with CiCa dialysate to achieve regional citrate anticoagulation (Fre-
senius Medical Care, Bad Hamburg, Germany). Post-filter-ionized calcium levels were used
for anticoagulation monitoring. Blood and dialysate flow rates were prescribed according to
the weight of the patient and by the caring ICU physician to target a dialysis dose of> 25 ml/
kg/h. The methodology for CRRT remained unaltered for the entire study period.
Statistical analysis
Results are presented as mean ± standard deviation (SD) for the normally distributed continu-
ous variables and as median [inter-quartile range (IQR)] for skewed variables. Normality in
continuous covariates was tested with Kolmogorov-Smirnov and Shapiro-Wilk tests. Student’s
t-test was used to compare continuous normally distributed covariates and Chi-square test for
categorical covariates in the study subgroups. For skewed variables the comparisons between
groups were done using a non-parametric Kruskall-Wallis test. Comparisons between eGFR at
baseline and at 90 days and one year were done using paired t-tests. The relationship between
mortality and exposure variables of interest was examined using univariable and multivariable
Cox proportional hazard models. Variables that were significantly associated with mortality in
univariable Cox models were included as covariates in stepwise multivariable Cox propor-
tional hazards models. To avoid significant collinearity in the models in terms of laboratory
and clinical data at ICU admission and CRRT initiation, multivariable analyses were per-
formed by using two respective stepwise multivariable Cox models: one including significant
baseline characteristics and laboratory variables at ICU admission and one with baseline char-
acteristics and variables at CRRT initiation. Only variables with a significance P�0.15 were
included in the respective, final multivariable Cox models. Potential existence of multicolli-
nearity was assessed by examining variance inflation factors. For the Cox models, all variables
were further standardized to have a mean 0 and SD 1 in order to facilitate comparisons of the
magnitudes of hazard ratios between the exposure variables. Receiver operating characteristics
(ROC) curve analyses were conducted to estimate the area under the curve (AUC) as a mea-
sure of discriminative capacity of lactate at ICU admission and at CRRT initiation for mortal-
ity (ICU-mortality and 90-day mortality). Generally, we consider an AUC >0.90 outstanding,
an AUC 0.80–0.90 excellent, an AUC 0.70–0.80 acceptable and an AUC<0.70 poor
discrimination.
All statistical analyses were performed using statistical analysis system, SAS version 9.3
(SAS Institute Inc., Cary NC). P<0.05 was considered statistically significant.
Statement of ethics
The study protocol (reference number J26/19) was approved by the Turku University Clinical
Research Center scientific ethics review board and the Hospital district of Southwest Finland.
PLOS ONE CRRT in blood culture positive sepsis
PLOS ONE | https://doi.org/10.1371/journal.pone.0249561 April 5, 2021 3 / 13
For this retrospective, register-based, non-interventional study the regulatory review board
waived the need for informed consent in terms of data collection and analysis and publication
of results.
Results
Patient characteristics
The demographic, clinical and laboratory data of the whole study cohort and comparisons
between subgroups according to 90-day mortality are shown in Table 1 and the blood culture
findings in Table 2. We identified 38 different pathogens in the blood cultures. All of the blood
culture findings were examined case by case and considered to be relevant etiological agents
for the sepsis present by the ICU infectious diseases senior consultant. Fifteen patients had a
coinfection with at least two culture-positive pathogens in their blood samples. The most prev-
alent causative pathogens were: Staphylococcus aureus 25%, Escherichia coli 19%, Streptococcus
pneumoniae 12%, Streptococcus pyogenes (A) 11% and Candida albicans 6%. Only one patient
had septicemia caused by extended-spectrum beta-lactamase producing strain of Escherichia
coli. Methicillin or carbapenem resistant strains of bacteria were not observed. The median
time from ICU admission to diagnosis (positive blood culture(s)) was 0.3 (-0.6–1.3) days and
the median time from the positive blood culture(s) to CRRT initiation was 0.5 (-0.6–1.7) days.
The median number of blood culture samples per patient was 2 (2–4) and the median number
of positive blood cultures per patient was 2 (2–2). The source of infection was blood-born in
56 (44%), skin/soft tissues in 35 (28%), urinary in 14 (11%), abdominal in 11 (9%) and respira-
tory in 10 (8%) patients, respectively. The antimicrobial therapies employed are shown in S1
Table. The antimicrobial treatment remained unchanged in 49 (39%) patients, in 28 (22%)
patients an additional antimicrobial regimen was added to the treatment and in 49 (39%)
patients the treatment was changed entirely after positive blood culture findings. The median
time from the start of first empirical therapy to the initiation of specific antimicrobial therapy
based on blood culture findings was 1 (1–2.5) days.
Mean SOFA score was 14.6±3.3, mean Simplified acute physiology II (SAPS-II) score 58.8
±16.3 and mean Acute physiology and chronic health evaluation II (APACHE-II) score 26.5
±7.2. Almost all of the study patients (95%) needed vasopressor support and 76% were on inva-
sive mechanical ventilation during their ICU stay. A total of 90 patients (71%) were considered
to have septic shock according to the Sepsis 3-criteria [5]. The median time to CRRT initiation
was 9.9 (3.2–24.8) h.
At the start of CRRT 26 patients had an arterial blood pH<7.2, 14 a potassium >5mmol/l,
58 PaO2/FiO2 –ratio <26.6kPa indicative of at least moderate respiratory distress and 72 an
hourly diuresis <0.15ml/kg/h.
Determinants of mortality
Patients were followed up for a mean 836 days (range 1–3837 days). 81 patients (64%) died
during follow-up. ICU mortality was 30%, 28-day mortality 37%, 90-day mortality 45% and
one-year mortality 50%. When comparing subjects who deceased within 90 days following
ICU admission to those that survived, the non-survivors had higher SOFA, SAPS-II and APA-
CHE-II scores, were more often mechanically ventilated, had a higher norepinephrine and
total vasopressor requirement and had lower hemoglobin, C-reactive protein and pH and a
higher lactate level at ICU admission (Table 1). The non-surviving group also had a lower pH,
bicarbonate, hourly diuresis and mean arterial pressure and higher lactate and norepinephrine
requirement at CRRT initiation compared to those who were alive at 90 days (Table 3).
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Table 1. Patient characteristics and intensive care clinical and laboratory data in the whole study population and comparisons between subgroups according to
90-day mortality.
Variable Whole study cohort (n = 126) Survivors (n = 69) Non-survivors (n = 57) p-value
Demographics and baseline data
Female gender [n (%)] 38 (30) 21 (30) 16 (28) 0.77
Age (years) 64 (51–73) 63.1 (50.7–71.7) 67.1 (55.6–75.6) 0.10
Nosocomial infection [n (%)] 12 (10) 5 (7) 7 (12) 0.34
Immunosuppression [n (%)] 23 (18) 6 (9) 17 (30) 0.002
Diabetes [n (%)] 43 (34) 27 (39) 16 (28) 0.19
Hypertension [n (%)] 74 (59) 41 (59) 33 (58) 0.86
Pulmonary disease [n (%)] 18 (14) 10 (14) 8 (14) 0.94
Coronary artery disease [n (%)] 21 (17) 7 (10) 14 (25) 0.03
Peripheral arterial disease [n (%)] 15 (12) 6 (9) 9 (16) 0.22
Liver cirrhosis [n (%)] 5 (4) 2 (3) 3 (5) 0.50
Hematological disease [n (%)] 9 (7) 2 (3) 7 (12) 0.04
Solid malignancy [n (%)] 12 (10) 4 (6) 8 (14) 0.12
Baseline creatinine, n = 96 (μmol/l) 86 (64–122) 78 (63–138) 96 (72–129) 0.64
Baseline eGFR, n = 96 (ml/min/1.73m2) 84±29 85±23 81±35 0.49
Intensive care clinical data
Peak SOFA 14.6±3.3 13.7±2.9 15.6±3.5 0.0007
SAPS-II 58.8±16.3 53.6±14.6 65.3±16.2 <0.0001
APACHE-II 26.5±7.2 24.4±5.9 29.1±7.7 0.0003
ICU stay (days, ICU survivors, n = 88) 9.9 (5.0–19.7) 10.0 (5.9–21.9) 9.7 (4.5–15.0) 0.30
Medical patients [n (%)] 97 (77) 55 (80) 42 (74) 0.42
Mechanical ventilation [n (%)] 96 (76) 48 (70) 48 (84) 0.05
Days on mechanical ventilation (days) 6.9 (2.7–13.7) 8.6 (4.6–19.8) 4.2 (1.2–10.0) 0.001
Mean arterial pressure (mmHg) 70 (59–80) 71 (60–80) 67 (58–80) 0.65
Vasopressor use [n (%)] 120 (95) 64 (93) 56 (98) 0.15
Norepinephrine dose (μg/kg/min) 0.07 (0.02–0.20) 0.05 (0.02–0.15) 0.11 (0.05–0.21) 0.03
Maximum noradrenalin dose (μg/kg/min) 0.24 (0.16–0.44) 0.21 (0.13–0.40) 0.26 (0.18–0.51) 0.08
Number of vasopressors (n) 1 (1–2) 1 (1–2) 2 (1–2) 0.04
Laboratory data at intensive care admission
Hemoglobin (g/l) 106±18 110±17 101±19 0.007
Leukocytes (g/l) 12.3 (5.9–19.7) 13.4 (7.8–21.1) 9.8 (4.5–18.0) 0.10
Trombocytes (E9/l) 102 (53–173) 108 (69–172) 79 (50–173) 0.11
C-reactive protein (mg/l) 190 (94–290) 222 (135–333) 150 (58–228) 0.004
Creatinine (μmol/l) n = 114 237 (176–339) 254 (178–353) 228 (176–325) 0.28
Urea (mmol/l) n = 97 16.8 (12.4–23.7) 16.7 (12.9–23.7) 17.3 (10.9–24.7) 0.83
Troponin T (ng/l) n = 95 79 (33–318) 62 (34–190) 96 (33–511) 0.28
International normalized ratio n = 113 1.3 (1.1–2.0) 1.2 (1.1–1.5) 1.6 (1.3–2.5) 0.0003
Alanine aminotransferase (IU/l) n = 103 62 (29–196) 60 (28–141) 76 (29–362) 0.37
Bilirubin (μmol/l) n = 105 21 (13–42) 19 (11–38) 25 (13–53) 0.30
pH 7.27 (7.20–7.34) 7.29 (7.24–7.37) 7.23 (7.15–7.32) 0.005
Base excess -9.3±6.2 -8.6±5.9 -10.2±6.4 0.16
Bicarbonate (mmol/l) 17.2±4.4 17.8±4.4 16.6±4.5 0.15
Lactate (mmol/l) 2.8 (1.6–5.9) 2.3 (1.3–5.2) 4.1 (2.0–8.2) 0.004
Sodium (mmol/l) 135 (132–138) 134 (131–138) 136 (132–138) 0.38
Potassium (mmol/l) 4.2 (3.8–4.8) 4.2 (3.9–4.8) 4.2 (3.8–4.8) 0.55
Chloride (mmol/l) 106 (102–109) 105 (102–108) 107 (102–110) 0.34
(Continued)
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Table 1. (Continued)
Variable Whole study cohort (n = 126) Survivors (n = 69) Non-survivors (n = 57) p-value
Ionized calcium (mmol/l) 1.04±0.11 1.05±0.12 1.03±0.10 0.40
SOFA = Sequential organ failure assessment; SAPS-II = simplified acute physiology II score; APACHE-II = acute physiology and chronic health Evaluation II score.
https://doi.org/10.1371/journal.pone.0249561.t001
Table 2. Blood culture findings.
Pathogen Number of patients with positive cultures (%)
Staphylococcus aureus 31 (25)
Escherichia coli 24 (19)
Streptococcus pneumoniae 15 (12)
Streptococcus pyogenes (A) 14 (11)
Candida albicans 8 (6)
Enterococcus faecalis 5 (4)
Pseudomonas aeruginosa 5 (4)
Staphylococcus epidermidis 4 (3)
Streptococcus mitis 4 (3)
Klebsiella pneumoniaea 4 (3)
Streptococcus betahemolyticus (not A) 3 (2)
Enterococcus faecium 3 (2)
Klebsiella oxytoca 3 (2)
Bacteroides fragilis 3 (2)
Streptococcus dysgalactiae 2 (2)
Neisseria meningitidis 2 (2)
Proteus vulgaris 2 (2)
Serratia marcescens 2 (2)
Clostridium septicum 2 (2)
Staphylococcus haemolyticus 2 (2)
Candida glabrata 2 (2)
Strepticoccus anginosus 1 (1)
Streptococcus salivarius 1 (1)
Enterococcus gallinarum 1 (1)
Aerococcus viridans 1 (1)
Haemophilus influenzae 1 (1)
Moraxella nonliquefaciens 1 (1)
Corynebacterium minutissimum 1 (1)
Pseudomonas mendocina 1 (1)
Citrobacter brakii 1 (1)
Citrobacter freundii 1 (1)
Raoultella planticola 1 (1)
Proteus mirabilis 1 (1)
Fusobacterium nucleatum 1 (1)
Bacteroides ovatus 1 (1)
Clostridium bifermentas 1 (1)
Clostridium clostriforme 1 (1)
Candida dubliensis 1 (1)
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Risk factors for mortality were assessed using univariable and multivariable Cox propor-
tional hazards models. Age, history of heart failure, immunosuppression, peak SOFA,
APACHE II and SAPS II scores, CRP, international normalized ratio, lactate, pH and bicar-
bonate at ICU admission and lactate, pH, bicarbonate and base excess at CRRT initiation were
associated with mortality in the univariable models (S2 Table).
In the multivariable Cox proportional hazards model the significant explanatory variables
at ICU admission for death were: SAPS II score (HR 1.85, 95%CI 1.35–2.52, p = 0.0001), his-
tory of heart failure (HR 2.21, 95%CI 1.29–3.81, p = 0.004), immunosuppression (HR 2.85,
95%CI 1.46–5.57, p = 0.002), pH (HR 0.78, 95%CI 0.61–0.99, p = 0.04) and C-reactive protein
at ICU admission (HR 0.70, 95%CI 0.54–0.91, p = 0.007) (Fig 1). In the multivariable model
for CRRT initiation the significant explanatory variables for death were: APACHE II score
(HR 1.71, 95%CI 1.31–2.23, p<0.0001), history of heart failure (HR 2.78, 95%CI 1.65–4.68,
p = 0.0001), immunosuppression (HR 2.42 95%CI 1.40–4.20, p = 0.002) and lactate at CRRT
initiation (HR 1.57, 95%CI 1.33–1.86, p<0.0001) (Fig 1).
Table 3. Variables at initiation of CRRT according to 90-day mortality.
Variable Survivors (n = 69) Nonsurvivors (n = 57) p-value
CRRT initiation after ICU admission (h) 11.6 (3.9–27.9) 8.7 (3.1–23.3) 0.42
Dialysis dose (ml/kg/h) 33.7 (27.8–36.0) 34.4 (29.9–36.1) 0.58
Creatinine (μmol/l) n = 117 325 (247–460) 300 (200–391) 0.20
Urea (mmol/l) n = 100 20.0 (14.5–26.1) 21.2 (15.7–33.9) 0.38
Potassium (mmol/l) 4.1 (3.8–4.6) 4.2 (3.9–4.7) 0.87
pH 7.29 (7.23–7.37) 7.27 (7.15–7.33) 0.009
Bicarbonate (mmol/l) 18.4±3.8 16.3±4.2 0.004
Lactate (mmol/l) 1.7 (1.1–3.6) 5.0 (2.0–7.6) <0.0001
Diuresis (ml/kg/h) 0.15 (0.06–0.29) 0.05 (0.02–0.24) 0.006
Fluid Balance (ml) 2855 (470–5748) 2395 (326–5689) 0.52
Mean arterial pressure (mmHg) 70 (65–80) 67 (60–75) 0.03
Norepinephrine dose (μg/kg/min) 0.10 (0.05–0.23) 0.17 (0.11–0.29) 0.02
PaO2/FiO2-ratio (kPa) 28.0 (19.3–39.4) 24.4 (16.0–38.1) 0.19
CRRT = Continuous renal replacement therapy; ICU = intensive care unit.
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Fig 1. Variables independently associated with mortality in respective multivariable Cox proportional hazards models for ICU admission (Panel A) and CRRT
initiation (Panel B).
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When only patients with septic shock (n = 90) were included in the multivariable model the
results remained similar. Variables independently associated with mortality in patients with
septic shock were: APACHE II score (HR 1.759, 95%CI 1.303–2.376, p = 0.0002), history of
heart failure (HR 2.211, 95%CI 1.178–4.152, p = 0.01), immunosuppression (HR 2.173, 95%CI
1.177–4.011, p = 0.01) and lactate at CRRT initiation (HR 1.449, 95%CI 1.206–1.742,
p<0.0001).
ICU mortality was 65% and 90-day mortality 74% in patients with lactate exceeding 4
mmol/l at CRRT initiation compared to 9% and 26% in patients with lactate�2 mmol/l
(p<0.0001, for both comparisons) (Fig 2). A lactate exceeding 4 mmol/l at CRRT initiation
was chosen as a lower limit for the high lactate subgroup based on the ROC curve analysis data
as a lactate of 4.3 mmol/l had a similar Youden’s J index as a lactate of 5mmol/l and the best
sensitivity and specificity combination (sensitivity 0.74 and corresponding specificity 0.84) for
discriminating patients deceased in the ICU from ICU survivors. Lactate showed good univar-
iate predictive power for ICU mortality in the ROC curve analyses with AUCs of 0.76 (95%CI
0.66–0.85) for lactate measured at ICU admission and 0.84 (95%CI 0.72–0.95) at CRRT initia-
tion (Fig 3). However, for 90-day mortality only lactate at CRRT initiation showed fair predic-
tive value with an AUC of 0.75 (95%CI 0.66–0.84), whereas, the AUC for lactate at ICU
admission was rather poor 0.66 (95%CI 0.56–0.75).
Lactate clearance during the first 24 hours of CRRT (difference between lactate at CRRT
initiation and 24 hours later) was not significantly associated with mortality (HR 0.96, 95%CI
0.89–1.05, p = 0.36) although lactate measured at every time point during CRRT (6h, 12h, 18h,
24h and 48h) were positively associated with mortality (HRs ranging between 1.12–1.67 and
p<0.0001 for all respective univariate Cox models). Fig 4 shows the development of lactate
during CRRT according to 90-day mortality. Lactate values were significantly higher at every
Fig 2. Survival probability according to lactate at CRRT initiation adjusted for acute physiology and chronic health
evaluation II score.
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time point during the first 48h of CRRT in the patients who deceased by day 90 compared to
others.
Only five (8%) of the surviving patients remained dialysis-dependent at 6 months. Esti-
mated GFR remained attenuated in survivors at 90 days (n = 52, baseline: 86±21 vs. 90-days 78
±28 ml/min/1.72m2, p = 0.01) and at one-year (n = 30, baseline: 84±19 vs. 90-days 70±24 ml/
min/1.72m2, p = 0.0007) compared to baseline values.
Discussion
The present study shows for the first time that blood lactate at CRRT initiation is indepen-
dently associated with overall mortality in patients with blood culture positive sepsis and coin-
cident severe AKI requiring CRRT. Furthermore, lactate measured at ICU admission and at
CRRT initiation were both higher in patients who died within 90 days of ICU admission and
Fig 3. Area under the curve (AUC) of receiver operating characteristics curve (ROC) analyses for lactate at ICU
admission (panel A) and lactate at CRRT initiation (panel B) in relation to ICU mortality.
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Fig 4. Lactate clearance during CRRT according to 90-day mortality.
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lactate at CRRT initiation showed good predictive power for discriminating those who died in
the ICU.
Several previous studies have explored risk factors associated with mortality in RRT depen-
dent sepsis-associated AKI but most studies have defined sepsis according to the Sepsis-3 (sus-
pected or shown infection with an increase in SOFA score�2) [5] or earlier consensus
criteria, whereas, blood culture findings have seldom been described. One former study
reported blood culture findings in ICU patients with RRT, but the number of patients was very
limited, and the patient group was not restricted to sepsis-associated AKI [6]. The ICU mortal-
ity of 30% in our current study was similar to that reported in larger series of patients with cul-
ture-positive or culture-negative septic shock in Europe [7]. Some [8,9], but not all [10] former
studies have observed a difference in outcomes between culture-positive and culture-negative
septic shock. In a previous study, patients with a clinical diagnosis of sepsis based on the for-
mer 2001 International Sepsis Definitions Conference criteria (without blood culture data)
[11] and coincident CRRT-dependent AKI had similar mortality compared to non-septic AKI
patients on CRRT [12]. The rate of positive blood culture findings in patients considered septic
has varied between 40–70% in previous studies [8,13–15]. To our best knowledge only a single
previous South Korean study has reported blood culture data in a cohort of 210 CRRT patients
with sepsis but even in that cohort microbial etiology was not documented in 29% of included
patients and 53.8% had a malignancy [16].
Sepsis-associated hyperlactatemia is the result of stress-induced accelerated anaerobic
metabolism, impaired tissue oxygen delivery and extraction, peripheral shunting, increased
adrenergic stimulation and to a lesser degree impaired lactate clearance [17]. Hyperlactatemia
is indisputably associated with increased mortality in broad patient populations with sepsis
and septic shock [18], but data on patients with blood culture positive septic AKI requiring
CRRT are scarce [19]. Passos and coworkers examined the association between lactate, lactate
clearance and mortality in 186 patients with sepsis according to the formerly used systemic
inflammatory response syndrome (SIRS) based criteria and coincident AKI requiring CRRT
[20]. In their study lactate clearance during the first 24 hours of CRRT treatment and lactate at
24 hours were independently associated with 48-hour and 28-day mortality, but lactate at
CRRT initiation was not. Only 24% of the study patients had a blood stream infection as
opposed to the present study. Our current findings show that in blood culture positive sepsis
patients both lactate at ICU admission and CRRT initiation are predictive of ICU mortality
and lactate at CRRT initiation is also predictive of long-term mortality at least up to 90 days.
Lactate clearance during the first 24 hours of CRRT was not associated with mortality despite
lactate levels were measured at several time points during the first 48 hours of CRRT. This may
partly be a result from the fact that many of the patients without lactate clearance in the begin-
ning of CRRT died shortly after or even within 24 hours from CRRT initiation. CRRT potently
extracts lactate when its production is not ongoing and massive. In the absence of lactate clear-
ance and coincident clinical deterioration during the first 24 hours of CRRT the benefit of con-
tinuing CRRT becomes questionable. Our current finding that lactate measured at CRRT
initiation is highly predictive of mortality in spite of lactate clearance during the first 24 hours
of CRRT shifts risk prediction to an earlier stage. Furthermore, our current findings show that
only 26% of blood culture positive sepsis patients with lactate exceeding 4 mmol/l at CRRT ini-
tiation are alive at 90 days follow-up. This emphasizes the importance of considering lactate
levels for risk-stratification purposes when making decisions on initiating CRRT in critically
ill sepsis patients with AKI.
We identified 38 different causative pathogens for sepsis and associated AKI in the present
study. The bacteria with the highest incidence were Staphylococcus aureus, Escherichia coli,
Streptococcus pneumoniae and Streptococcus pyogenes. Only one patient had septicemia caused
PLOS ONE CRRT in blood culture positive sepsis
PLOS ONE | https://doi.org/10.1371/journal.pone.0249561 April 5, 2021 10 / 13
by an extended-spectrum beta-lactamase producing strain of Escherichia coli. Methicillin or
carbapenem resistant strains of bacteria were not observed. The blood culture findings were
similar to those previously reported in septic emergency department patients in Finland [21].
C-reactive protein at ICU admission was surprisingly independently and inversely associated
with mortality in this selected and comorbid patient population which is in contrast with pre-
vious studies in broad sepsis patients [22]. Immunosuppression, history of heart failure and
APACHE II and SAPS II scores were also independently associated with mortality in the Cox
models.
At 6 months ca. 8% of the surviving patients were on maintenance dialysis and eGFR
remained attenuated in survivors at 90-days and at one-year following sepsis-associated AKI
and CRRT. These findings are in line with previous reports showing a high incidence of
chronic kidney disease in primary survivors of septic AKI [23].
The limitations of this study pertain to its retrospective design and limited sample size.
However, the study population was limited to patients with true blood culture positive sepsis,
AKI and CRRT treatment compared to former studies in septic AKI and RRT with more het-
erogenous patient populations due to the definition of sepsis. Since data of the current study
were collected at a single tertiary medical center in a developed country, the results concerning
blood culture data may not apply to other institutions in other geographical areas. The preva-
lence of extended spectrum antibiotic resistance is extremely low in Finland, which, was also
observed in the blood culture positive pathogens of this study. Nevertheless, the findings were
quite distinct, and a limited sample size is not likely to detract from the validity of the main
findings of this study concerning the associations between lactate and early and late mortality
and its predictive value for ICU mortality.
Conclusions
Our study shows for the first time that lactate measured at CRRT initiation is predictive of
ICU mortality and independently associated with overall mortality in patients with blood cul-
ture positive sepsis and AKI requiring CRRT. Microbial etiology for septic AKI requiring
CRRT is diverse.
Supporting information
S1 Fig. Flow-chart of the study.
(PPTX)
S1 Table. Antimicrobial regimens used: 1st empiric treatment; specific treatment; and all
antimicrobial regimes used during intensive care unit (ICU) stay.
(DOCX)
S2 Table. Factors associated with mortality in univariate models. For comparability, the
hazard ratios are for standardized variables with mean 0 and SD 1.
(DOCX)
Acknowledgments
The authors are grateful to Mrs Eveliina Loikas, RN, for help with the data collection and to
Mrs Noora Kartiosuo, MSc, for statistical consultation.
Author Contributions
Conceptualization: Mikko J. Ja¨rvisalo, Tapio Hellman, Panu Uusalo.
PLOS ONE CRRT in blood culture positive sepsis
PLOS ONE | https://doi.org/10.1371/journal.pone.0249561 April 5, 2021 11 / 13
Data curation: Mikko J. Ja¨rvisalo, Tapio Hellman, Panu Uusalo.
Formal analysis: Mikko J. Ja¨rvisalo.
Investigation: Mikko J. Ja¨rvisalo, Panu Uusalo.
Methodology: Mikko J. Ja¨rvisalo, Tapio Hellman.
Project administration: Mikko J. Ja¨rvisalo.
Visualization: Tapio Hellman, Panu Uusalo.
Writing – original draft: Mikko J. Ja¨rvisalo.
Writing – review & editing: Tapio Hellman, Panu Uusalo.
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