Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 10  |  Issue : 1  |  Page : 46-53

Evaluation of the value of early use of norepinephrine infusion in the improvement of renal function in patients with severe sepsis with early renal impairment using cystatin C, a sensitive renal marker


Department of Anesthesiology, Intensive Care, and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo, Egypt

Date of Web Publication3-Aug-2018

Correspondence Address:
Amr Sobhy
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain-Shams University, 11566 Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.238464

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  Abstract 


Introduction Acute renal failure occurs in ∼23% of patients with severe sepsis. The combination of acute renal failure and severe sepsis may carry a mortality of up to 70%. Several studies have demonstrated that serum cystatin C level is a better marker of glomerular filtration rate (GFR) compared with serum creatinine, particularly for individuals with small-to-moderate decreases in GFR. To maintain organ perfusion in sepsis, a mean arterial pressure of 65 mmHg should be maintained with fluid therapy and vasopressors. Marked delays in initiation are associated with increase in mortality risk in patients with septic shock.
Patients and methods Sixty patients enrolled in the study proved to have severe sepsis with early renal impairment. Patients were randomly allocated into one of two groups (30 patients each): the norepinephrine infusion group (the N group) and the control group (the C group). The N group received norepinephrine infusion + conventional treatment for severe sepsis, whereas the C group was treated with conventional treatment for severe sepsis according to the latest Surviving Sepsis Campaign. For each patient, the following data were collected: age, body weight, hemodynamic changes, urine output, renal function as detected from levels of the sensitive renal marker cystatin C and from serum creatinine levels, blood urea nitrogen, and estimated GFR (eGFR).
Results There was a statistically significant increase in blood pressure and urine output in the N group at 10 min and 2 h, respectively, after norepinephrine infusion and on comparing subsequent measures with baseline values (T0) and also when compared with corresponding values in the C group. In addition, patients in the N group showed a statistically signifi cant decrease in serum cystatin C levels and an increase in eGFR based on cystatin C levels after 2 h of norepinephrine infusion, compared with baseline values and values in the C group, denoting marked improvement in GFR. Serum creatinine levels, blood urea nitrogen levels, and eGFR based on serum creatinine levels showed no significant difference in either group whether compared with baseline of the same group or when comparing both groups together.
Conclusion The results this study demonstrate that early continuous infusion of norepinephrine at 0.5–1 μg/ kg/min may have a renoprotective role in septic patients with early renal impairment detected by levels of the sensitive renal marker cystatin C.

Keywords: cystatin C, norepinephrine, renal impairment, sepsis


How to cite this article:
Sobhy A, Tharwat AI, Nabil A, Adel A. Evaluation of the value of early use of norepinephrine infusion in the improvement of renal function in patients with severe sepsis with early renal impairment using cystatin C, a sensitive renal marker. Ain-Shams J Anaesthesiol 2017;10:46-53

How to cite this URL:
Sobhy A, Tharwat AI, Nabil A, Adel A. Evaluation of the value of early use of norepinephrine infusion in the improvement of renal function in patients with severe sepsis with early renal impairment using cystatin C, a sensitive renal marker. Ain-Shams J Anaesthesiol [serial online] 2017 [cited 2018 Dec 11];10:46-53. Available from: http://www.asja.eg.net/text.asp?2017/10/1/46/238464




  Introduction Top


Acute renal failure (ARF) occurs in ∼19% of patients with moderate sepsis, in 23% with severe sepsis, and in 51% with septic shock when blood cultures are positive [1]. The combination of ARF and severe sepsis was reported to carry a mortality rate of up to 70%, whereas the mortality rate of ARF alone is 40–45% [2].

Glomerular filtration rate (GFR) is a representative index of renal function. Although measurement of insulin clearance is the gold standard for estimating GFR, it is cumbersome, and serum creatinine has been widely used as an endogenous filtration marker in clinical practice. However, when serum creatinine levels are used to estimate GFR, it should be borne in mind that they are influenced by age, sex, muscle mass, and protein intake and that they show low sensitivity for the detection of early renal dysfunction [3].

Cystatin C is a low-molecular-weight (13 kDa) protein with 120 amino acids that functions as a cysteine protease inhibitor. It is produced by all nucleated cells at a constant rate and is freely filtered and catabolized in proximal tubules without being secreted. For this reason, its serum concentration is determined by glomerular filtration and, thus, it is used as a marker of GFR [4].

Recently, several studies have demonstrated that serum cystatin C level is a better marker of GFR than serum creatinine, particularly for individuals with small-to- moderate decreases in GFR [5].

To maintain organ perfusion, current guidelines recommend maintaining a mean arterial pressure (MAP) of 65 mmHg with fluid therapy and vasopressors, even when hypovolemia has not been resolved [6].

Norepinephrine, the endogenous mediator of the sympathetic nervous system, is a potent α-adrenergic agonist with less pronounced β-adrenergic agonist effects. Norepinephrine increases MAP by vasoconstriction, with a small (10–15%) increase in cardiac output and stroke volume; it is more potent than dopamine and may be more effective at reversing hypotension in septic shock patients [7].

Marked delays in initiation of vasopressor/inotropic therapy are associated with a small increase in mortality risk in patients with septic shock [8].


  Aim of the work Top


The objective of this study was to assess the value of early use of norepinephrine infusion in the improvement of renal function in patients with severe sepsis with early renal impairment using cystatin C as a sensitive renal marker.

The primary endpoint was to assess the improvement in urine output and renal function, and the secondary endpoint of the study was to evaluate the effectiveness of early use of norepinephrine infusion in reducing the number of patients requiring hemodialysis.


  Methods Top


This is a prospective randomized controlled study performed on 60 patients arriving at the surgical intensive care unit of Ain Shams University Hospitals with severe sepsis and early renal impairment during the period from December 2013 to November 2014. After obtaining approval from the Ain Shams University Hospital ethical committee, informed consent was obtained from all patients or their legal guardians before enrollment in the study. The patients were randomly allocated into one of two groups (30 patients each) using the closed sealed envelope method of randomization.

The sample size was calculated using PS (version 3.0.43; Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA), with the following parameters: urine output used as the primary goal, where power of the study was 80%, SD was ± 2, mean was 20, and α-error was 0.05.

The control group (C group) received conventional treatment for severe sepsis according to the latest Surviving Sepsis Campaign [6]. Treatment consisted of fluid resuscitation (2000 ml crystalloid was given over 2 h) and broad-spectrum antibiotics. The cause was searched for by pan culture subsequently.

In the norepinephrine infusion group (N group), immediately after admission of patients, in addition to the standard therapy given to the C group a continuous infusion of norepinephrine (LEVOPHED, norepinephrine bitartrate injection, USP (United States Pharmacopeia), contains the equivalent of 4 mg base of LEVOPHED per 4 ml ampule (1 mg/ml); NOVAPLUS® manufactured by Hospira, Inc., Lake Forest, IL 60045, USA. CIBA Pharmaceuticals Company, USA diluted in 50 ml D5% (1 ml equivalent to 80 μg) was administered at 0.5–1 μg/kg/min through a central line using a syringe pump titrated to blood pressure (BP) [usual target: systolic blood pressure (SBP): 80–100 mmHg or MAP = 80 mmHg].

Patients

The patients enrolled in the study were aged between 25 and 70 years and had an American Society of Anesthesiology physical status of II or III, with proven severe sepsis and early renal impairment. Sepsis was defined as the presence (probable or documented) of infection, together with systemic manifestations of infection. Severe sepsis was defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion ([Table 1] and [Table 2]) [6]. In this study, we correlated general variables, such as fever and heart rate, inflammatory variables, such as leukocytosis, and oliguria to diagnosed severe sepsis.
Table 1 Diagnostic criteria for sepsis

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Table 2 Severe sepsis

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Early renal impairment was defined on the basis of the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal disease) classification as an increase in plasma creatinine level by 1.5-fold, a decrease in GFR by more than 25% of the normal range for age, or urine output less than 0.5 ml/kg/h over a period of 6 h [9]. In this study, we depended on the urine output criterion ([Table 3]).
Table 3 RIFLE classification of ARF

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Exclusion criteria

Patient refusal to consent (absolute), history of pre-existing cardiac or respiratory system failure, and coexisting renal or liver disease constituted the exclusion criteria.

Methodology

On arrival at the intensive care unit, all patients were continuously monitored by electrocardiography, using a noninvasive blood pressure monitor, and by pulse oximetry. A urinary catheter was inserted if not already present. A central line was inserted and 500 ml of Ringer's solution was administered as a loading dose over 15–20 min, followed by 1500 ml Ringer's solution over the next 2 h.

Baseline investigations were conducted, which included complete blood picture analysis; estimation of bleeding time, clotting time, prothrombin time, and the international normalized ratio; and liver function tests.

Renal assessment was conducted by evaluating blood urea nitrogen (BUN), serum creatinine, and serum cystatin C levels by ELISA, and by estimating GFR for each patient using the simplified MDRD equation:

eGFR[ml/min/1.37m2] = 186.3 × [serum creatine (mg/dl)]−1.154 × [age(years)]−0.203 × 0.742,

on the basis of cystatin C levels:

GFR = 76.6 × cystatin C(mg/l)−1.16.

The C group received conventional treatment for severe sepsis according to the latest Surviving Sepsis Campaign [6]. Treatment consisted of fluid resuscitation (2000 ml crystalloid was administered over 2 h) and broad-spectrum antibiotics. The cause was searched for by pan culture subsequently.

In the N group, immediately after admission of patients, in addition to the standard therapy given to the C group a continuous infusion of norepinephrine [LEVOPHED, norepinephrine bitartrate injection, USP, containing the equivalent of 4 mg base of LEVOPHED per 4 ml ampule (1 mg/ml); CIBA Pharmaceuticals Company] diluted in 50 ml D5% (1 ml equal 80 μg) was administered at 0.5–1 μg/kg/min through a central line using a syringe pump titrated to BP (usual target: SBP: 80–100 mmHg or MAP = 80 mmHg).

For 2 h after the start of the treatment in the two groups the following data were collected: hemodynamic data were obtained continually for clinical assessment; however,recording for the study purpose was performed at designated time intervals; noninvasive blood pressure was measured and recorded every 5 min; heart rate was recorded every 5 min; and urine output was recorded every 30 min.

At the end of the 2 h, blood samples were obtained for assessment of renal function, with BUN, serum creatinine, and serum cystatin C levels estimated by ELISA and GFR estimated for each patient using the abovementioned equations, as the primary endpoint, and the number of patients who required hemodialysis as the secondary endpoint.

Statistical methods

Statistical analysis was carried out using SPSS, version 22.0 (SPSS Inc., Chicago, Illinois, USA).

Quantitative (numerical) variables were presented as mean ± SD and qualitative (categorical) data as number of cases and percentage. Error bars represent 95% confidence interval (95% CI).

Analysis of unpaired numerical variables was carried out using the unpaired Student t-test, whereas analysis of paired numerical variables was carried out using the repeated-measures general linear model analysis of variance.

Analysis of categorical data was carried out using Fisher's exact test or the χ2-test, when appropriate.

The significance level was set at P-values of 0.05 or less, and a P-value of 0.01 or less was considered highly significant.


  Results Top


Demographic data

With respect to age and body weight of the patients, there were no statistically significant differences between the two groups (P > 0.05). The average age was 47 ± 10 years, with a male predominance (57.0%).

The most common existing comorbidities were diabetes, including patients requiring oral hypoglycemic agents or insulin (26.6%), and hypertension (23.6%). The most common causes of sepsis were intra-abdominal sepsis (40%), chest infection (22%), polytrauma (11%), and head trauma (7%).

Hemodynamic parameters

The baseline SBP, diastolic blood pressure (DBP), and MAP readings showed no statistically significant difference between the two groups (P > 0.05). The N group showed increases in SBP, DBP, and MAP values starting 10 min after norepinephrine infusion, when compared with baseline readings, with highly significant differences (P < 0.001). In contrast, there were no statistically significant changes in SBP, DBP, or MAP in the C group ([Table 4]).
Table 4 Changes in MAP (mmHg)

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Urine output

Although the baseline urine volume in both groups was oliguric, as required by the admission criteria of the study, there were no statistically significant differences between the two groups (P > 0.05).

The N group showed an increase in urine output 1 h after norepinephrine infusion, and this increase was statistically significant in comparison with the C group and in comparison with baseline values (P < 0.05; [Table 5]).
Table 5 Changes in UOP (ml)

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Renal function

Patients in the N group showed a statistically significant decrease in serum cystatin C levels and an increase in the estimated GFR (eGFR) based on cystatin C levels 2 h safter norepinephrine infusion in comparison with baseline values and when compared with the C group, denoting marked improvement in GFR, whereas measurement of serum creatinine, BUN, and eGFR based on serum creatinine levels showed no significant difference in either group whether comparing with baseline or comparing both groups together. This reflects a delayed response for these parameters to the early phase of renal injury, and hence a late diagnostic value. Further, there was a reduction in the number of patients who needed hemodialysis in the N group compared with the C group (3.3 versus 6.7%), but the difference was statistically nonsignificant ([Table 6],[Table 7],[Table 8]).
Table 6 Number of patients need hemodialysis

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Table 7 Changes in Cystatine C (mg/l)

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Table 8 Changes in eGFR based on Cystatine C (ml/min/1.73 m2)

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  Discussion Top


Early initiation of fluid resuscitation and rapid administration of appropriate antimicrobials are critical determinants of outcome and the central tenets of management [10]. On the basis of these factors, we hypothesized that early hemodynamic support using vasopressor infusion may result in decreased incidence of renal failure in septic patients.

Although there has been a lot of study on the comparison of vasopressors/inotropes individually and in combination, there has been a relative paucity in the literature on the timing of their initiation in septic shock. The 2012 Surviving Sepsis Guidelines recommend that vasopressor support be started for fluid-refractory shock as part of the 6-h bundle based solely on expert opinion [6].

A rat model of endotoxic shock has suggested potential benefit with higher proportionate splanchnic blood flow, lower lactate levels, and less overall fluid support requirement for early compared with delayed norepinephrine administration [11]. A porcine model of fecal peritonitis/shock has demonstrated that delayed resuscitation (inclusive of antibiotics, fluids, and pressors) was associated with increased physiologic instability and higher pressor requirements [12]. Conversely, in a small (n = 95) retrospective human study, no difference in organ dysfunction or intensive care unit (ICU) length of stay was observed with early (<1.37 h) versus late (>1.37 h) administration of vasopressors [13]. As in this study, serum creatinine was used as a renal marker, rather than serum cystatin C.

This is also in agreement with the results of vance Beck et al. [8], who conducted a cohort study comprising over 8670 patients from 28 ICUs in Canada, the USA, and Saudi Arabia. The primary endpoint was survival to hospital discharge. Secondary endpoints were length of ICU and hospital stay, as well as duration of ventilator support and vasopressor dependence. Analyses involved multivariate linear and logistic regression analyses. In total, 8640 patients met the definition for septic shock with time of vasopressor/ inotropic initiation documented. Of them, 6514 were suitable for analysis. The overall unadjusted hospital mortality rate was 53%. Independent mortality correlates included liver failure [odds ratio (OR) 3.46, 95% confidence interval (CI) 2.67–4.48], metastatic cancer (OR 1.63, CI 1.32–2.01), AIDS (OR 1.91, CI 1.29–2.49), hematologic malignancy (OR 1.88, CI 1.46–2.41), neutropenia (OR 1.78, CI 1.27–2.49), and chronic hypertension (OR 0.62, CI 0.52–0.73). Delay of initiation of appropriate antimicrobial therapy (OR 1.07/h, CI 1.06–1.08), age (OR 1.03/year, CI 1.02–1.03), and Acute Physiology and Chronic Health Evaluation II score (OR 1.11/point, CI 1.10– 1.12) were also found to be significant independent correlates of mortality. After adjustment, only a weak correlation between vasopressor delay and hospital mortality was found (adjusted OR 1.02/h, 95% CI 1.01–1.03, P < 0.001). This weak effect was entirely driven by the group of patients with the longest delays (>14.1 h). There was no significant relationship between vasopressor initiation delay and duration of vasopressor therapy (P = 0.313), and there was only a trend toward longer duration of ventilator support (P = 0.055) among survivors. They concluded that marked delays in initiation of vasopressor/inotropic therapy are associated with a small increase in mortality risk in patients with septic shock.

With regard to serum creatinine and BUN levels, and eGFR based on serum creatinine levels, we found in this study that there was no statistically significant difference in serum creatinine and BUN levels, and eGFR based on serum creatinine levels in either group, whether comparing with baseline or comparing both groups together. This reflects a delayed response for these parameters to early phase ofrenalinjury, andhencealatediagnosticvalue([Figure 1]). With regard to serum cystatin C levels, results of this study showed no statistically significant difference between the two groups at baseline (1.56 ± 0.32 and 1.42 ± 0.342 for the N group and C group, respectively). However, both groups showed a higher than normal range in values (0.7 ± 0.2), denoting early renal injury despite normal serum creatinine levels in both groups (0.920 ± 0.3334 and 1.083 ± 0.308, respectively; [Table 6]).
Figure 1 Changes in eGFR based on MDRD (ml/min/1.73 m2): T0: on admission, T1: 2 hours Norepinephrine infusion, N-group: Norepinephrine infusion, C- group: control group, n: number, ml: milliter, mg: milligram, dl: deciliter, eGFR cr: estimated glomular filtration rate based on MDRD, min: minute, m2: meter square, MDRD: Modification of Diet in Renal Disease

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Later, patients of the N group showed a statistically significant decrease in serum cystatin C levels (0.94 ± 0.15) and an increase in eGFR based on cystatin C levels (91.6 ± 16.4) after 2 h of norepinephrine infusion in comparison with baseline values (1.56 ± 0.32 and 45.8 ± 11.31, respectively) and in comparison with the C group (1.5 ± 0.47 and 49.56 ± 15.73, respectively), denoting marked improvement in GFR.

Many studies found that cystatin C is more specific and sensitive than creatinine. For example, in the study by Herget et al. [14] over 85 patients who were at high risk of developing ARF underwent daily evaluation of serum creatinine and cystatin C levels. ARF was defined according to the Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal disease classification as an increase in the creatinine level by at least 50% (R criteria), by at least 100% (I criteria), or by at least 200% (F criteria). In analogy, ARF was detected when cystatin C levels increased by at least 50%, at least 100%, or at least 200%. Results showed that 44 patients developed ARF and 41 served as controls. In ARF determination by the R, I, and F criteria, the increase in the cystatin C level significantly preceded that of creatinine. Specifically, serum cystatin C levels increased by at least 50% 1.5 ± 0.6 days earlier compared with creatinine levels. Serum cystatin C demonstrated a high diagnostic value in detecting ARF, as indicated by the area under the receiver operating characteristic curve values of 0.82 and on the 2 days before the R criteria were fulfilled by creatinine. Cystatin C detected ARF according to the R criteria with a sensitivity of 55 and 82% on these days, respectively. Cystatin C also performed excellently, detecting ARF defined by the I and F criteria 2 days before creatinine, and it performed moderately well in predicting renal replacement therapy in the further course of ARF. They concluded that serum cystatin C is a useful detection marker of ARF, and may detect ARF 1 or 2 days earlier than creatinine.

Further, Redl-Wenzl et al. [15] conducted a prospective study of 56 patients with extremely low resistance states due to abdominal sepsis, who remained hypertensive (MAP < 60 mmHg) despite optimal fluid therapy and greater than 20 μg/kg/min dopamine and cumulative doses of dopamine and dobutamine of greater than 30 μg/ kg/min. During norepinephrine infusion (dosage ranging between 0.1 and 2 μg/kg/min; mean dose rate: 0.4 μg/kg/min) MAP and systemic vascular resistance index increased significantly (P < 0.001). After 8 h a significant increase in stroke volume (P < 0.05) and decrease in heart rate (P < 0.05) could be observed. There was no significant change in cardiac index, oxygen delivery, and oxygen consumption. Creatinine clearance increased significantly (P < 0.005) from a control value of 75 ± 37 to 102 ± 43 ml/min after 48-h norepinephrine treatment. They concluded that norepinephrine can be used safely in the treatment of severe septic shock states. MAP and GFR improved markedly without deleterious effects on cardiac index, oxygen delivery, and oxygen consumption.


  Conclusion Top


The results of this study demonstrated that early continuous infusion of 0.5–1 μg/kg/min norepinephrine may have a renoprotective role in septic patients with early renal impairment detected by the sensitive renal marker serum cystatin C.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Riedemann NC, Guo RF, Ward PA. The enigma of sepsis. J Clin Invest 2003; 112:460–467.  Back to cited text no. 1
    
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Ympa YP, Sakr Y, Reinhart K, Vincent JL. Has mortality from acute renal failure decreased? A systematic review of the literature. Am J Med 2005; 118:827–832.  Back to cited text no. 2
    
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Laterza OF, Price CP, Scott MG. Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 2002; 48:699–707.  Back to cited text no. 3
    
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Filler G, Bökenkamp A, Hofmann W, Le Bricon T, Martínez-Brú C, Grubb A. Cystatin C as a marker of GFR – history, indications, and future research. Clin Biochem 2005; 38:1–8.  Back to cited text no. 4
    
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Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002; 40:221–226.  Back to cited text no. 5
    
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Póvoa PR, Carneiro AH, Ribeiro OS, Pereira AC, Portuguese Community-Acquired Sepsis Study Group Influence of vasopressor agent in septic shock mortality. Results from the Portuguese Community-Acquired Sepsis Study (SACiUCI study). Crit Care Med 2009; 37:410–416.  Back to cited text no. 7
    
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Beck V, Chateau D, Bryson GL, Pisipati A, Zanotti S, Parrillo JE, Kumar A, Cooperative Antimicrobial Therapy of Septic Shock (CATSS) Database Research Group. Timing of vasopressor initiation and mortality in septic shock: a cohort study. Crit Care 2014; 18:R97.  Back to cited text no. 8
    
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Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8:R204-R212.  Back to cited text no. 9
    
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Gaieski DF, Pines JM, Band RA, Mikkelson ME, Massone R, Furia FF, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38: 1045–1053.  Back to cited text no. 10
    
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Sennoun N, Montemont C, Gibot S, Lacolley P, Levy B. Comparative effects of early versus delayed use of norepinephrine in resuscitated endotoxic shock. Crit Care Med 2007; 35:1736–1740.  Back to cited text no. 11
    
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Corrêa TD, Vuda M, Blaser AR, Takala J, Djafarzadeh S, Dünser MW, et al. Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis. Crit Care Med 2012; 40:2841–2849.  Back to cited text no. 12
    
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Subramanian S, Yilmaz M, Rehman A, Hubmayr RD, Afessa B, Gajic O. Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock: an observational study. Intensive Care Med 2008; 34:157–162.  Back to cited text no. 13
    
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Herget-Rosenthal S, Marggraf G, Hüsing J, Göring F, Pietruck F, Janssen O, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004; 66:1115–1122.  Back to cited text no. 14
    
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Redl-Wenzl EM, Armbruster C, Edelmann G, Fischl E, Kolacny M, Wechsler-Fördös A, Sporn P The effects of norepinephrine on hemodynamics and renal function in severe septic shock states. Intensive Care Med 1993; 19:151–154.  Back to cited text no. 15
    


    Figures

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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