This study was approved by our local ethics committee (Ethics Committee for the Evaluation of Biomedical Research Projects of North Paris), and the need for informed consent was waived because of the noninterventional, retrospective design of the study. Figure 1 shows the flowchart of the study. All patients with a diagnosis of severe sepsis or septic shock 10 admitted to our surgical ICU between January 2006 and December 2010 were screened. Patients were excluded if they did not have central venous pressure (CVP) and/or cardiac output (CO) monitoring (for example, cervical cellulitis) or if they died within 24 hours of admission. The selected cohort was treated according to our local institution recommendations: antibiotics were administered within the 6 hours after admission and fluid resuscitation was initiated with crystalloids (NaCl 0.9% or Ringer’s lactate solution) or with gelatin solution for some others (Plasmion; Fresenius Kabi France, Sèvres, France). Norepinephrine was largely the most frequently used vasopressor, and some patients were given a combination of norepinephrine and either epinephrine or dobutamine in the presence of cardiac dysfunction, a decision made by the physician in charge. When mechanical ventilation was initiated, tidal volume was set to maintain an inspiratory plateau pressure less than 30 cmH₂O.

The patients’ characteristics are presented in Table 1. The physiological parameters are presented in Table 2. The following hemodynamic parameters were collected during the first 24 hours after admission: CVP, CO, systolic arterial pressure, diastolic arterial blood pressure (DAP), mean arterial blood pressure (MAP), central venous oxygenation saturation (ScvO₂) and mixed oxygen venous saturation (SvO₂). CO was measured with a pulmonary artery catheter and a Vigilance II monitor (Edwards Lifesciences, Irvine, CA, USA) or a transesophageal Doppler monitor (CardioQ-ODM; Deltex Medical, Chichester, UK). Because of hemodynamic variations during the unstable initial phase, the lower limits and the upper limits of the range (ULR) and the mean value over the first 24 hours were recorded. The association between the hemodynamic targets within 24 hours from admission (CVP = 8 to 12 mmHg; CO >5 L/min, MAP >65 mmHg, DAP >50 mmHg, ScvO₂ >70% and SvO₂ >60% 11 12 ) and progression or development of AKI was investigated. The ULR of each target was defined as the highest value achieved at any time within the first 24 hours after admission, and the lower limit range was defined as the lowest value of the hemodynamic parameter during the whole 24-hour period.

^aAKI−, no or transient acute kidney injury; AKI+, new or persistent acute kidney injury; CAD, Coronary artery disease; COPD, Chronic obstructive pulmonary disease; NSAID, Nonsteroidal anti-inflammatory drug; SAPS II, Simplified Acute Physiology Score II. ^bData are micrograms per kilogram per minute among patients receiving the drug. The data in the table are expressed as median (interquartile range) or number (%).

^aAKI−, no or transient acute kidney injury; AKI+, new or persistent acute kidney injury; CO, cardiac output; CVP, central venous pressure; DAP, diastolic arterial blood pressure; LLR, lower limit of the range; MAP, mean arterial blood pressure; SAP, systolic arterial blood pressure; ScvO₂, central venous oxygen saturation, ULR, upper limit of the range.

Daily fluid balance was calculated as the fluid input (volume of gelatins, crystalloids and feeding) minus fluid output (urine output, fluid from drains and gastric aspiration). Urine was collected upon admission for routine urinary laboratory workup.

The diagnosis of AKI was based on the Acute Kidney Injury Network (AKIN) classification. AKI upon admission was defined as an increase in serum creatinine level >50% from baseline or ≥26 μmol/L or oliguria (urinary output <0.5 ml/kg/h for 6 hours). Baseline serum creatinine levels were measured in blood samples taken before hospital admission when available (n = 37 (27%)). In cases where the baseline creatinine level or glomerular filtration rate (GFR) was not available, the lowest serum creatinine level measured during the patient’s hospital stay was used if the GFR was ≥75 ml/min/1.73 m² (n = 42 (31%)). In other cases, the baseline creatinine level was estimated by using the Modification of Diet in Renal Disease equation with a normal GFR value of 75 ml/min/1.73 m² (n = 58 (42%)) 13 . The primary endpoint was the development of a new AKI or persistent AKI during the 5 days following admission. New AKI was defined as (1) an increase in serum creatinine level ≥26 μmol/L or >50% compared to baseline value or (2) need for renal replacement therapy (RRT) after the first 24 hours from admission in patients who had no AKI upon admission. Persistent AKI was defined as a steady or increase in AKIN classification stage between the first 24 hours following admission and day 5 in patients with AKIN stage ≥1 at the time of inclusion in the study. Transient AKI was defined as downstaging of AKI between the first 24 hours following admission and day 5 (for example, from AKIN stage 1 to stage 0). Patients with no AKI or transient AKI are referred to throughout the article as the AKI − group, and patients with new or persistent AKI constitute the AKI + group.

Quantitative parameters are reported as median and interquartile range (IQR; 25th to 75th percentile), and qualitative parameters are expressed as number and percentage. Categorical variables were compared using the χ² test or Fisher’s exact test as appropriate. Continuous variables were compared using the Mann–Whitney U test.

The study patients’ characteristics are presented in Table 1. After screening and application of selection criteria, 137 patients were included (Figure 1). AKI was diagnosed in 105 patients (77%) upon ICU admission. From among those patients, 69 were found to have new or persistent AKI after admission. Respectively, 5 (16%) of 32 patients with AKIN stage 1 AKI upon admission, 14 (46%) of 30 patients with AKIN stage 2 AKI upon admission and 35 (47%) of 47 of patients with AKIN stage 3 AKI were subsequently classified as AKI + (that is, persistent AKI).

Thirty-two patients required RRT, which was initiated early (1 day (1 to 2) after ICU admission). The AKI + group scored higher on the Simplified Acute Physiology Score II, as well as higher base deficit and bilirubin levels upon admission. AKI + patients had a higher positive fluid balance during the first 24 hours after admission (3,591.5 ml/kg/h (2,597.5 to 5,714) vs. 2,905 ml/kg/h (1350 to 4717.5); P = 0.008) and lower urinary output (0.6 ml/kg/h (0.4 to 1.2) vs. 0.9 ml/kg/h (0.7 to 1.4); P = 0.0045). Need for mechanical ventilation, use of vasopressors and/or use of inotropes did not differ between groups. The origin of infection and causative pathogens did not differ between groups either (Table 1).

The tested hemodynamic variables are presented in Table 2. Only CVP level and DAP (mean and ULR) were statistically different between patients with AKI + and AKI−. CVP values were higher in the AKI + group (4 mmHg (2 to 6) vs. 6 mmHg values in brackets are Interquartile range, as specified in the Methods (statistical analysis) section (3 to 8), respectively; P < 0.0001). In addition, CVP was associated with new or persistent AKI (odds ratio (OR) = 1.23 (1.10 to 1.38); P = 0.0003). In the full adjusted model, the ORs were 1.05 (0.93 to 1.19; (P = 0.3988) for PEEP (for 1 cmH₂O) and 1.05 (1.01 to 1.09; P = 0.0154) for positive fluid balance (for each 250 ml). The association between CVP and new or persistent AKI remained (OR = 1.22 (1.08 to 1.39) for an increase of 1 mmHg; P = 0.002) after adjustment for fluid balance and PEEP level), together with a quasi-linear relationship between CVP level and the risk of developing new or persistent AKI (Figure 2). The excretion fraction of sodium was higher (1% (0.3 to 2.9) vs. 0.5% (0.2 to 0.9); P = 0.031), and the urine/plasma creatinine ratio (38.3 (23.7 to 62.5) vs. 65.5 (44.1 to 115.3); P = 0.001) was lower, in the AKI + group than in the AKI − group. The excretion fraction of urea (26.2% (13.8 to 62.5) vs. 30.1% (18 to 46.5); P = 0.21), urinary sodium/potassium ratio (0.6 (0.4 to 1.3) vs. 0.7 (0.4 to 1.3); P = 0.77) and plasma urea/creatinine ratio (96.8 (60.9 to 119.6) vs. 100.6 (74.2 to 132.5); P = 0.19) did not differ between groups.

The cohort ICU length of stay was 9 days (5 to 17). The mortality rates were 23% (32 patients) and 26% (37 patients) in the ICU and at 28 days, respectively. The AKI + group had a higher mortality rate in the ICU (39% vs. 6%; P = 0.0003), in the hospital (45% vs. 16%; P = 0.0004) and at day 28 (38% vs. 15%; P = 0.003) than AKI − patients (Figure 3). Among the 14 survivors requiring RRT, 1 was continued on it after ICU discharge.