Management bundle (24 hours)

In our study, management tasks were analyzed, and some differences were found between SA-AKI and non-AKI septic patients (Table 1.2).

4.4.6.1. Steroids administration

In our study, steroids administration (32%) in those patients with septic shock was not

associated with a decrease (or an increase) in SA-AKI incidence. This finding of “no renal effect” despite the severity of those patients receiving steroids (most of them presented septic shock) is supported by the majority studies318 comparing the use or not of steroids in patients with septic shock. However, none of these studies have specifically studied the relationship between steroid administration and SA-AKI incidence.

CORTICUS study319 did not report renal outcomes. HYPRESS study320 reported no differences in RRT requirements (12.2% vs. 12.3%) or days free from RRT (7 vs. 6 days). More recently, the ADRENAL trial321 reported no significant between-group differences with respect to the number of days alive and free from RRT, and the use of RRT (steroid group 31% vs. placebo group 33%, p= 0.18). In contraposition, the group of Annane et al.322 _{recently reported a significantly higher number of organ-failure–free}

days (14 vs. 12 days, p=0.003) in the hydrocortisone-plus-fludrocortisone group than in the placebo group. No differences in the high RRT requirements were observed. Whether this benefitial effect could be related to fludrocortisone administration remains uncertain (in our study no fludrocortisone was administered) as very few studies have evaluated specifically fludrocortisone effect.323

4.4.6.2. Median blood glucose

In our study median blood glucose level goal (4 to 8.3 mmol/L with no hypoglycemia episodes) was achieved more frequently in the non-AKI septic group compared to the SA-AKI patients (49.7% vs. 36.2%; p=0.06). Although still non-significant from a statistical point of view, this could be concordant with first reports from Van den

Berghe et al.324who reported survival and renal benefits (less AKI and less RRT) in a surgical ICU with the use of an intensive insulin therapy (IIT) (maintenance of blood glucose at a level between 4.4 and 6.1 mmol/L). Same authors published 5 years later in the same journal a RCT325 this time in a medical ICU with a trend for a better renal outcome with the use of an IIT.

VISEP trial326 previously commented (HES vs. ringer lactate) was a two-by-two factorial trial, that randomly assigned patients with sepsis to receive either IIT to maintain euglycemia or conventional insulin therapy. The trial was stopped early for safety reasons as the rate of severe hypoglycemia (glucose level ≤2.2 mmol/L) was higher in the IIT group. There were no significant differences in the rate of SA-AKI and the need for RRT. Nice-sugar trial327 (intensive glucose control or conventional glucose control RCT) did not find differences in renal outcomes either. Finally, Azevedo et al.328 compared in a critically ill septic population IIT with a carbohydrate-restrictive strategy. Authors reported a significant correlation between blood glucose levels and the incidence of AKI (p=0.007) contrary to the results of our study were no correlation was observed between the median blood glucose levels during the first 24 h and the appearance of SA-AKI (7.4 mmol/L non-AKI septic group [IQR 5.7-9.6] vs. 7.9 mmol/L SA-AKI group [IQR 5.9-10.6], p=0.41), (Table 1.2).

4.4.6.3. Protective ventilation

In our study, in those patients whom required invasive MV (63%), a protective ventilation strategy (defined at that time by SSC as a median Ppl <30 cm H2O) seemed

to protect from developing SA-AKI. This finding gives support to the pulmonary- kidney crosstalk theory in critically ill patients (ventilator-induced AKI).329 Although differences between non-AKI septic patients and SA-AKI patients in terms of goal achievement (median Ppl <30 cm H2O) were not significant (73% in the non-AKI septic

group vs. 58% in the SA-AKI group) this was probably due to our small population size. Interestingly, median Ppl was significantly different between those ventilated patients who did not develop SA-AKI and those who did (24 cm H2O [IQR 20-30] in

the non-AKI group vs. 28 cm H2O [IQR 24-33] in the SA-AKI group, p=0.01).

The issue of AKI due to MV is an old but still virtually not understood phenomenon and is, however, of major concern.330 _{Traditionally, deteriorations in systemic and renal}

process.330 There is an emerging concept that MV exerts a broad spectrum of harmful biological responses with the capacity to affect functions of remote organs,331 including the kidney.332 An altered inflammatory net work, oxidative stress, and apoptosis have been considered the central hubs of this organ crosstalk in response to MV.333 Lung protective ventilation has become a cornerstone in the management of ARDS.334 This approach minimizes both the direct mechanical effects of ventilation and the inflammatory response arising from ARDS together with MV. The ARDS network in their RCT335 performed in patients with ARDS (60% of patients had sepsis) reported a significant increase in the number of days without failure of nonpulmonary organs or systems, with the lower tidal volume (VT) strategy (6 mL/Kg and Ppl≤30 cm H2O).

Despite these data, some studies report that lung-protective mechanical ventilation does not protect against AKI in patients without ARDS at onset of MV. In a secondary analysis336 of a RCT in 150 critically ill patients without ARDS at the beginning of MV, lung-protective mechanical ventilation (VT, 6 mL/kg) significantly reduced the development of ventilator associated ARDS, but not the development and/or worsening of AKI. The low incidence of sepsis in this trial (<10%) could explain these results as another study337 _{showed that injurious MV causes kidney apoptosis and dysfunction}

during sepsis but not after intra-tracheal acid instillation in an experimental model performed in rats which compared MV with two different VT strategies.