Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017
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Acute kidney injury (AKI) in the intensive care unit is associated with significant mortality and morbidity.
To determine and update previous recommendations for the prevention of AKI, specifically the role of fluids, diuretics, inotropes, vasopressors/vasodilators, hormonal and nutritional interventions, sedatives, statins, remote ischaemic preconditioning and care bundles.
A systematic search of the literature was performed for studies published between 1966 and March 2017 using these potential protective strategies in adult patients at risk of AKI. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, exposure to potentially nephrotoxic drugs and radiocontrast. Clinical endpoints included incidence or grade of AKI, the need for renal replacement therapy and mortality. Studies were graded according to the international GRADE system.
We formulated 12 recommendations, 13 suggestions and seven best practice statements. The few strong recommendations with high-level evidence are mostly against the intervention in question (starches, low-dose dopamine, statins in cardiac surgery). Strong recommendations with lower-level evidence include controlled fluid resuscitation with crystalloids, avoiding fluid overload, titration of norepinephrine to a target MAP of 65–70 mmHg (unless chronic hypertension) and not using diuretics or levosimendan for kidney protection solely.
The results of recent randomised controlled trials have allowed the formulation of new recommendations and/or increase the strength of previous recommendations. On the other hand, in many domains the available evidence remains insufficient, resulting from the limited quality of the clinical trials and the poor reporting of kidney outcomes.
KeywordsAcute kidney injury Systematic review Recommendations Prevention Volume expansion Vasopressors
Acute kidney injury (AKI) affects up to 50% of critically ill patients and is independently associated with both short- and long-term morbidity and mortality [1, 2, 3, 4, 5]. The recent AKI-EPI study demonstrates that the most frequent causes of AKI in the critically ill are sepsis and hypovolaemia followed by nephrotoxic agents . However, the cause of AKI is often multifactorial with pre-existing co-morbidities further increasing the risk [3, 7, 8, 9].
Our recommendations principally concern critically ill patients on the ICU but can also be applied to those planned to be admitted to the ICU such as high-risk surgical patients. By consensus, we primarily focussed on the role of volume expansion, diuretics, inotropes, vasopressors/vasodilators, hormones, nutrition, statins, sedatives and ischaemic preconditioning.
A systematic search of the literature was performed using the following databases: MEDLINE (1966 through March 2017), EMBASE (1980 through March 2017), CINAHL (1982 through March 2017), Web of Science (1955 through March 2017) and PubMed/PubMed CENTRAL to identify key studies, preferably randomised (placebo) controlled trials (RCT) and meta-analyses, addressing strategies to prevent AKI in adult critically ill patients. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock and exposure to potentially nephrotoxic drugs. Specifically, renal transplantation, primary intrinsic renal disease (e.g. vasculitis) and hepatorenal syndrome were not considered. Search strategy and endpoints are available as electronic supplementary material (ESM_1).
Criteria for best practice statements
(Modified from Guyatt et al. )
Criteria for best practice statements
Is the statement clear and actionable?
Is the message necessary?
Is the net benefit (or harm) unequivocal?
Is the evidence difficult to collect and summarize?
Is the rationale explicit?
Is this better to be formally GRADEd?
We acknowledge that there may be circumstances whereby a recommendation cannot or should not be followed for an individual patient. Furthermore, interventions are generally investigated in isolation and not in combination, and as such recommendations relate to the primary intervention. Local clinical guidelines will govern the use of either a single intervention or a combination thereof.
We recommend controlled fluid resuscitation in volume depletion, while, however, avoiding volume overload (Grade 1C).
We recommend against the use of starches (Grade 1A) as harm has been shown and suggest not using gelatine or dextrans for fluid resuscitation (Grade 2C).
We recommend correction of hypovolaemia/dehydration using isotonic crystalloids in patients receiving intravascular contrast media (Grade 1B).
We recommend regular monitoring of chloride levels and acid–base status in situations where chloride-rich solutions are used (BPS).
We suggest the use of balanced crystalloids for large volume resuscitation (Grade 2C).
We suggest using human serum albumin if a colloid is deemed necessary for the treatment of patients with septic shock (Grade 2C).
We suggest prophylactic volume expansion with crystalloids to prevent AKI by certain drugs (specified below) (BPS).
We suggest not delaying urgent contrast-enhanced investigations or interventions for potential preventative measures (BPS).
Relative and overt hypovolaemia are significant risk factors for development of AKI [15, 16, 17, 18]. Timely fluid administration can restore circulating volume and renal perfusion, and may also reduce nephrotoxicity . Volume replacement should be performed in a controlled, monitored fashion  as injudicious use of fluids carries its own inherent risks and may even contribute to AKI by increasing renal interstitial oedema and renal parenchymal pressure [21, 22]. Moreover, goal-directed therapy including the use of central venous pressure (CVP) as a resuscitation target has not been shown to prevent AKI in sepsis . Volume replacement may be through crystalloids, colloids or their combination. Isotonic crystalloids represent the mainstay for correcting extracellular volume depletion with the caveat that hyperchloraemia is prevented to reduce potential renal vasoconstriction [24, 25]. Compared to crystalloids, colloids theoretically result in a greater plasma expansion. However, this effect depends on vascular barrier integrity which may be compromised in sepsis, particularly in the presence of vasoplegia [26, 27]. Consequently, the difference in required volumes for fluid resuscitation was minimal between crystalloids and colloids in large RCTs . Moreover, large volume replacement with colloids alone risks hyperoncotic impairment of glomerular filtration [29, 30] and osmotic tubular damage [31, 32].
Available artificial colloids include gelatines, dextrans and until recently, starches. Gelatines have a moderate volume effect. Although risk of osmotic nephrosis with gelatines exists , the lack of clear clinical data on deleterious effects on renal function [34, 35] is offset by the possible prion transmission, histamine release and coagulopathy [36, 37]. Dextrans have reasonably high volume effects although anaphylaxis, coagulation disorders, osmotic nephrosis and AKI may occur with doses above 1.5 g/kg/day [38, 39, 40, 41]. Human albumin (HA) is the only naturally occurring colloid and may appear attractive in hypooncotic hypovolaemia. It does increase the response to diuretics in patients with hypoalbuminaemia (e.g. nephrotic syndrome) [42, 43], has no negative effects on kidney function [44, 45], is safe  but can be costly.
Unsurprisingly, no studies have specifically addressed the effects of volume expansion compared to no volume resuscitation in overt hypovolaemia given the intuitive benefits of volume replacement. In severe sepsis, the beneficial effects of timely volume replacement on organ failure and mortality are well known, although the first RCT proving benefit of early volume resuscitation did not report kidney function . On the other hand, preoperative volume expansion failed to reduce the incidence of postoperative AKI ins 328 patients undergoing cardiac surgery , and a recent pilot RCT in sepsis could demonstrate that a volume-restrictive fluid protocol can reduced the incidence of AKI (RR 0.32; 95% CI 0.32–0.96) .
Crystalloids are considered the mainstay for volume expansion. Observational studies suggest an increased risk of AKI, renal replacement therapy (RRT) and mortality associated with the use of large volumes of normal saline (0.9% NaCl) as compared to so-called balanced solutions where chloride is partially replaced by another metabolizable anion [50, 51, 52]. An RCT comparing saline to a balanced solution (Plasmalyte®) in 2278 patients treated in four ICUs failed to show any superiority of balanced crystalloids regarding renal outcomes . The study has been criticized for the limited fluid doses, inclusion of patients with low disease severity and the absence of data on chloride levels . Similar results were observed in the pilot cluster-randomised, multiple-crossover SALT trial comparing saline to a balanced solution in 974 critically ill adults . Again, only modest volumes were used, but increased rates of AKI were found in the normal saline group if larger volumes were administered (ESM_2 Table S2). Studies on the effectiveness of sodium bicarbonate in preventing AKI, predominantly in patients undergoing cardiac surgery, have produced conflicting results [56, 57, 58, 59] as have consecutive meta-analyses [60, 61, 62, 63].
The effect of colloids on renal function has undergone extensive scrutiny over the last decade. Large RCTs have substantiated the increased risk of AKI and RRT with use of starches  particularly in sepsis [65, 66], where they also lead to increased mortality  (ESM_2 Table S3). This is verified by several meta-analyses [67, 68, 69, 70] which underpin the abandoning of starches in critically ill patients [20, 71, 72]. Clinical data on the effects of gelatine on renal function are scarce. A recent meta-analysis, including three trials in 212 patients comparing gelatins with crystalloids or albumin, indicated a 35% increased relative risk of developing AKI with gelatine .
In contrast to artificial colloids, the administration of albumin appears to be safe for the kidney. A large RCT comparing normal saline to 4% HA in various clinical settings failed to demonstrate any differences in renal function  (ESM_2 Table S3). In the ALBIOS trial the use of hyperoncotic (20%) albumin showed no effect on AKI or need for RRT in severe sepsis  but enabled a less positive fluid balance, confirming the results of another small trial . A post hoc analysis of the ALBIOS trial showed survival benefit in septic shock  confirmed by meta-analyses [76, 77]. Hypoalbuminaemia in cardiac surgery might be another indication with improved fluid balance as well as a reduced rate of AKI being observed in a single-centre RCT of 220 patients .
Hypovolaemia may also contribute significantly towards drug-induced renal injury, although the available evidence supporting preventative hydration is only observational with no consensus related to timing, optimal volume and type of solution [19, 237, 79]. Prophylactic volume expansion has been shown to prevent harm from amphotericin B, antivirals including foscarnet, cidofovir and adefovir [81, 82, 83] as well as drugs causing crystal nephropathy such as indinavir, acyclovir, and sulfadiazine .
Prophylactic volume expansion is the mainstay of all recommendations to prevent contrast-associated AKI (CA-AKI) and is based on several randomised controlled studies performed in non-critically ill patients [85, 86, 87, 88, 89, 90]. However, studies comparing hydration to no hydration are scarce . Several pitfalls should be considered. First, CA-AKI is a diagnosis of exclusion and considerable variation exists with regard to the reported incidence rates, which are confounded by many factors such as transient fluctuations in measured serum creatinine in hospitalised patients and use of non-standardised diagnostic criteria . Secondly, CA-AKI does not occur in patients without other risk factors for AKI, whereas most critically ill patients receiving intravascular contrast have other risk factors. Moreover, individuals with high risk for CA-AKI may not be given contrast. For these reasons the role of CA-AKI is uncertain, particularly in an era where the use of low- or iso-osmotic agents and lower contrast volume administration have become standard practice. As indicated by an analysis of the Nationwide Inpatient Sample dataset comprising 5, 931,523 hospitalisations the OR for CA-AKI adjusted for age, sex, mechanical ventilation and combined co-morbidity score was 0.93 (0.88–0.97) . Whereas a retrospective single-centre cohort study in 747 critically ill patients showed a rate of CA-AKI of 16% , matched cohort studies could not demonstrate a relationship with IV contrast for computed tomography in the ICU [95, 96, 97] or emergency department . These findings are supported by a systematic review and Bayesian meta-analysis . In the most recent propensity-matched cohort study, IV contrast was not associated with an increased risk of AKI or dialysis, but a subgroup with pre-CT eGFR of at most 45 ml/min/1.73 m2 showed an increased risk of dialysis. The numbers in this subgroup were, however, small and subject to selection bias .
Although it seems prudent to correct hypovolaemia before contrast administration, prophylactic volume expansion in critically ll patients who are euvolaemic cannot be recommended on the basis of current data. No study demonstrates protection of pre-emptive volume expansion against CA-AKI in the critically ill. An RCT comparing hydration with isotonic bicarbonate versus normal saline failed to show superiority of either regimen but reported an excessively high rate of CA-AKI of 33% in both groups , which may be attributed to severity of illness in this critically ill cohort. Importantly, in patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI), hydration volumes above 11 ml/kg body weight (BW) were associated with continuously increased rates of AKI, requirement for RRT and mortality. The adjusted OR for developing AKI with hydration volumes greater than 25 ml/kg BW was 2.11 (CI 1.24–3.59) . We recommend that the clinical decision to perform a contrast study in ICU patients must weigh the potential benefits with the low but probably not zero risk of CA-AKI.
We recommend against loop diuretics given solely for the prevention of acute kidney injury (Grade 1B).
We suggest using diuretics to control or avoid fluid overload in patients that are diuretic-responsive (Grade 2D).
Oligoanuria is frequently the first indicator of acute renal dysfunction. Intensivists frequently use loop diuretics in a wide spectrum of AKI settings . The rationale for using diuretics to ameliorate AKI includes prevention of tubular obstruction, reduction in medullary oxygen consumption and increase in renal blood flow as well as reducing fluid overload and venous congestion [103, 104, 105]. Although there is no single parameter for fluid overload, increased CVP , peripheral oedema  and/or increased intra-abdominal pressure [108, 109] may be used as surrogates. A recent study demonstrated than a urinary output of at least 100 ml/h following a test dose of 1.0–1.5 mg furosemide/kg BW predicted reduced progression to a higher stage of AKI in oliguric patients .
Use of conservative fluid management including diuretics has been investigated in only one large RCT in patients with acute lung injury (FACTT trial) which showed a tendency to reduced requirement of RRT .
In cardiac surgery either no protection  or elevated postoperative serum creatinine levels were found in patients receiving furosemide . These findings were supported by a recent meta-analysis . In patients with acute heart failure, diuretic therapy with higher doses was more effective at reducing clinical symptoms, but at the cost of decreased renal function . To date four RCTs have examined the role of diuretics in established renal failure in the intensive care setting. No demonstrable improvements in clinically relevant outcomes, such as recovery of renal function or mortality, were observed [31, 116, 117, 118]. Other studies compared diuretics with dopamine or placebo, again with no perceived benefit [119, 120, 121]. Three meta-analyses confirmed that the use of diuretics in established AKI did not alter outcome but carried a significant risk of side effects such as hearing loss [122, 123, 124] (ESM_2 Table S4).
We recommend titrating vasopressors to a mean arterial pressure (MAP) of 65–70 mmHg (Grade 1B) rather than a higher MAP target (80–85 mmHg) in patients with septic shock. However, for patients with chronic hypertension we recommend aiming for a higher target (80–85 mmHg) for renal protection in septic shock (Grade 1C).
We recommend lowering systolic pressure to 140–190 mmHg rather than to 110–139 mmHg in patients with acute cerebral haemorrhage with severe admission hypertension (Grade 1C).
If vasopressors are needed for treatment of hypotension, we recommend norepinephrine (along with correction of hypovolaemia) as the first-choice vasopressor to protect kidney function (Grade 1B) and suggest vasopressin in patients with vasoplegic shock after cardiac surgery (Grade 2C).
We suggest individualizing target pressure when premorbid blood pressure is available (BPS).
Rationale for MAP target
Preservation or improvement of renal perfusion can theoretically be achieved through increasing cardiac output by fluid resuscitation or inotropic drugs, through renal vasodilators or systemic vasopressors. Optimal target mean arterial pressure (MAP) was studied in a large open-label multicentre RCT randomising 777 patients with septic shock to resuscitation with a MAP target of either 80–85 mmHg or 65–70 mmHg . In most of the patients the achieved MAP was above the set target. The study found no difference in mortality, incidence of AKI stage 2 (38.7% vs. 41.5%, p = 0.42) or need for RRT (33.5% vs. 35.8%, p = 0.5), but more atrial fibrillation in the high target group. However, in patients with known chronic hypertension a higher MAP resulted in a lower incidence of AKI stage 2 (38.9% vs. 52%, p = 0.02) and less RRT (31.7% vs 42.2%, p = 0.046); mortality was unchanged.
The safety of lowering systolic pressure was studied in a larger RCT in patients with acute cerebral haemorrhage with severe hypertension on admission . Patients were randomised to a systolic blood pressure target of 110–139 or 140–179 mmHg. The primary endpoint (death or disability) was not different between groups. However, the rate of serious renal adverse events was higher in the lower target group (9% vs. 4%, p = 0.002) (ESM_2 Table S5).
Rationale for choice of vasopressor
Norepinephrine is the most commonly used vasopressor in patients with vasodilatory shock. A large RCT comparing dopamine to norepinephrine as initial vasopressor in patients with shock found no difference in mortality between randomised groups. However, norepinephrine was associated with less tachycardia in the first hours and was superior regarding survival in cardiogenic shock patients. In addition, there was a trend towards more RRT-free days through day 28 in the norepinephrine group .
Vasopressin or the analogue terlipressin may have a role in the treatment of norepinephrine-refractory shock . Exogenous vasopressin has vasoconstrictive and antidiuretic properties and may increase glomerular filtration by preferential post-glomerular vasoconstriction . In the largest RCT in septic shock (VASST trial), vasopressin reduced mortality in the subgroup with less severe shock, but not in the entire population. There were no differences in RRT-free days . However, in a secondary analysis, a reduced progression to higher stages of AKI could be demonstrated in the subgroup of patients with AKI stage 1 at baseline . In a subsequent 2 × 2 RCT in 409 patients with early septic shock (VANISH trial) , the use of vasopressin compared to norepinephrine did not affect the proportion of patients who never developed AKI stage 3 (57% vs. 59.2%), the number of AKI stage 3-free days [difference −4 (−11 to 5)] or the incidence of AKI stage 3 [difference −5.1% (−15.2 to 5.0)]. The use of vasopressin reduced the need for RRT (difference −9.9% (−19.3 to −0.6), but only in non-survivors. A recent single-centre RCT in 300 patients with vasoplegic shock after cardiac surgery compared noradrenalin to vasopressin as first-choice vasopressor. The use of vasopressin was associated with less acute renal failure (10.3% vs. 35.8%, p < 0.0001) and less RRT (2.7% vs. 13.9%, p = 0.0016) . This trial, however, had some design issues (e.g. change in primary outcome during the study) and requires confirmation. The studies are summarized in ESM_2 Table S5.
Use of vasodilators
We recommend against low-dose dopamine for protection against AKI (Grade 1A).
We recommend not using levosimendan for renal protection in patients with sepsis (Grade 1B) and recommend against its use for renal protection in cardiac surgery patients with poor preoperative left ventricular function or needing postoperative haemodynamic support (Grade 1B).
We suggest not using fenoldopam or natriuretic peptides for renal protection in critically ill or cardiovascular surgery patients at risk of AKI (Grade 2B).
Early in the course of ischaemic AKI, renal blood flow (RBF) falls because of stimulation of the sympathetic nervous system and the release of vasoconstrictors such as endothelin, angiotensin II and vasoconstrictive prostaglandins [134, 135]. In contrast, during septic AKI global RBF seems to be well preserved [136, 137]. The main perfusion problem during sepsis seems to occur at the microvascular level and regionally in the outer medulla . When using vasodilators for kidney protection, several issues should be considered. First, vasodilators may cause hypotension by counteracting compensatory vasoconstriction, thus unmasking occult hypovolaemia. Hypotension may further compromise renal perfusion and correction of hypovolaemia is therefore crucial. Second, as a result of endothelial damage, nitric oxide (NO)-dependent vasodilators seem to be ineffective . Third, timing may be crucial, since delayed administration reduces effectiveness as a result of occlusion of the microcirculation .
Low-dose or ‘renal’ dose dopamine has been advocated in the past to prevent selective renal vasoconstriction in a variety of conditions. This may not be the case in complex clinical conditions, where low-dose dopamine may even worsen renal perfusion . Several meta-analyses have concluded that ‘renal-dose’ dopamine has no benefit in either preventing or ameliorating AKI in the critically ill [141, 142, 143], the latest  being presented in ESM_2 Table S6.
Fenoldopam is a pure dopamine-A1 receptor agonist providing systemic and renal vasodilation and natriuresis, and it has been studied in cardiovascular surgery and critically ill patients. Two older meta-analyses, one including 1290 critically ill and surgical patients (mainly cardiovascular) from 16 RCTs and the other including 1059 cardiac surgery patients from 13 (partially overlapping) RCTs and case-matched studies, reported that the use of fenoldopam reduced the incidence of AKI, need for RRT and hospital mortality . Most studies were small with a moderate to high risk of bias and in the second meta-analysis 30% of the included studies were abstracts. The two most recent meta-analyses in cardiac surgery and major surgery used stricter inclusion criteria [145, 146] and only found a lower risk for AKI, but not for RRT or death. In addition, both showed an increased risk of hypotension and most included studies had a high risk of bias due to low sample size and fragility index, and use of different definitions for AKI. The most recent and largest RCT in post cardiac surgery patients with AKIN stage I  did not show any renal protection or clinical benefit from the use of fenoldopam, while fenoldopam conferred more hypotension. (Studies are summarized in ESM_2 Table S7).
Atrial natriuretic peptide (ANP) is produced by cardiac atria in response to an acute increase in stretch and/or pressure and induces afferent dilatation and efferent vasoconstriction, thereby increasing glomerular filtration and urinary sodium excretion with a dose-dependent hypotensive effect [148, 149]. B-type (brain) natriuretic peptide (BNP) is primarily produced in the cardiac ventricles and has similar effects [150, 151].
The two most recent meta-analyses including RCTs in the cardiac and cardiovascular surgery population found that the prophylactic infusion of low-dose ANP reduced postoperative peak creatinine  and the need for RRT [152, 153, 154]. However, the latter was based on only 24 cases of RRT in 563 patients. No effect was found in established AKI and high-dose ANP was associated with more frequent adverse effects (arrhythmias, hypotension) . Two later RCTs on the use of ANP in aortic arch (n = 42) and high-risk cardiac surgery (n = 367) confirmed a reduction in postoperative AKI and need for RRT (0/183 vs. 7/184, p = 0.015) [155, 156] (ESM_2 Table S8).
A recent meta-analysis including 15 RCTs in 9623 patients with acute decompensated heart failure showed that the use of BNP (nesiritide) was associated with worsening renal function: RR 1.08 (1.01–1.15), especially in the subgroup receiving a high dose (>0.01 μg/kg/min) and in patients without CKD .
In general, most BNP trials were small, not powered for the endpoints RRT or mortality, of poor quality with low fragility index; inclusion criteria varied and results were heterogeneous. Furthermore, hypotension and arrhythmia were frequently reported. A small subgroup meta-analysis on BNP in cardiovascular surgery also showed no benefit  (ESM_2 Table S8).
The calcium sensitizer levosimendan has inodilator, cardioprotective and anti-inflammatory effects [158, 159]. In a recent meta-analysis of RCTs in the cardiac surgery population (13 trials, 1345 patients), the use of levosimendan decreased the risk of AKI [OR 0.51 (0.24–0.79)], the need for RRT [OR 0.43 (0.25–0.76)] and mortality [OR 0.41 (0.27–0.62)] . The last meta-analysis of RCTs in the critically ill population with or at risk of AKI (33 RCTs, 3867 patients) found that, compared to placebo or another inotrope, levosimendan decreased the risk of AKI [RR 0.79 (0.63–0.99)] and the need for RRT [RR 0.52 (0.32–0.86)]. When limiting the analysis to high-quality studies, the difference in need for RRT between groups failed to reach significance [RR 0.41 (0.15–1.12)] . Studies in both meta-analyses were small, there was some heterogeneity, AKI was not always a predefined endpoint, different definitions of AKI were used and there might have been some outcome reporting bias.
Three large placebo-controlled RCTs have recently been published. In patients with sepsis the use of levosimendan was not beneficial in terms of a reduction of renal SOFA, need for RRT [OR 0.99 (0.66–1.49)] or mortality [OR 1.19 (0.82–1.72)], while its use was associated with more adverse events . In 882 patients with left ventricular dysfunction undergoing cardiac surgery, levosimendan had no effect on mortality or need for RRT . No effect on AKI and RRT was seen when levosimendan was given for haemodynamic support after cardiac surgery in 506 patients  (ESM_2 Table S9).
On the basis of current data no recommendation can be given, although it appears that shorter sedation using propofol or dexmedetomidine may have several advantages, possibly reducing the rate of AKI (BPS).
Sedation is necessary in many critically ill patients and this may affect cardiac function and/or vascular tone with renal consequences. In animal models propofol reduced markers of oxidative stress in the kidney [165, 166] and dexmedetomidine caused diuresis through reducing vasopressin secretion, enhancing renal blood flow and hence glomerular filtration  and showed renal protection [168, 169, 170, 171].
Propofol is commonly used as anaesthetic and for sedation in the intensive care unit . The “propofol infusion syndrome” comprises myopathy, rhabdomyolysis, hyperkalaemia and AKI [173, 174]. On the basis of the data from case reports/series, it is recommended to administer propofol for a maximum of 48 h and a maximum dose of 4 mg/kg/h . On the other hand, a recent propensity-matched cohort study in critically ill patients showed reduced risk of AKI and need for RRT in patients sedated with propofol as compared to midazolam . Furthermore a small RCT including 112 patients undergoing valvular heart surgery showed less AKI and significantly lower cystatin C levels in the group treated with propofol as compared to sevoflurane . However, the fact that remote ischaemic preconditioning showed less effect if patients were treated with propofol leaves uncertainty about the protective effect of propofol on the kidney .
α-2 Adrenergic agonists have multiple pharmacodynamic effects . In a placebo-controlled double-blind RCT dexmedetomidine demonstrated significant diuretic effects, with an almost 75% increase in diuresis after cardiac surgery, but did not affect renal function per se . Observational trials indicated protection of kidney function after cardiac surgery  but not when used for sedation during lung cancer resection . A placebo-controlled study in 90 patients undergoing coronary artery bypass graft (CABG) showed a dose-dependent reduction of NGAL levels with dexmedetomidine used for postoperative sedation . Another RCT in 200 patients showed that dexmedetomidine for 24 h at 0.4 μg/kg/h from start of anaesthesia resulted in reduced rate of AKI, morbidity and length of stay in the ICU  (ESM_2 Table S10).
Alltogether, the data for non-benzodiazepine sedatives, especially dexmedetomidine, are promising but currently not sufficiently convincing to give a clear recommendation.
We suggest targeting a blood glucose level at least below 180 mg/dL (10 mmol/l) for the prevention of hyperglycaemic kidney damage in the general ICU population (Grade 2B).
We suggest not using erythropoietin (Grade 2B) or steroids (Grade 2B) for prevention of acute kidney injury.
In critical illness hyperglycaemia has been associated with adverse outcomes [185, 186] attributed to oxidative stress, endothelial dysfunction, alterations in haemostasis, immune dysregulation and mitochondrial dysfunction. The anti-inflammatory effect of steroids may attenuate the inflammatory component of AKI pathogenesis. Erythropoietin (EPO), besides being a haematopoietic growth factor, also has tissue-protective properties by decreasing apoptosis and inflammation and by promoting neovascularization and tissue regeneration.
A large prospective RCT in 1548 surgical ICU patients compared tight glucose control (TGC) with insulin (target blood glucose 80–110 mg/dL) to standard care (insulin when blood glucose is greater than 200 mg/dL resulting in a mean blood glucose of 150–160 mg/dL) and showed not only an improved survival rate but also a 41% reduction in AKI requiring RRT . Additionally, TGC also reduced the number of patients with peak plasma creatinine greater than 2.5 mg/dL by 27%. A subsequent study in the medical ICU of the same hospital, including many patients that already had AKI on admission, did not confirm the effect on survival or need for RRT, but showed a 34% reduction in AKI, defined as a doubling of serum creatinine compared with the admission level . A combined analysis of both studies showed a more pronounced renal protection when normoglycaemia was achieved .
More recent RCTs in septic  and general [190, 191, 192, 193, 194] ICU patients (some of which had to be stopped early because of hypoglycaemia) including a large adequately powered multicentre trial in Australia and New Zealand (NICE-SUGAR)  did not confirm the renoprotective effect. The latter even found a higher mortality in patients treated with TGC compared to an intermediate level. Clinicians should, however, be aware of important differences between these landmark trials, such as the glycaemic target in the control group, the nutritional strategy and the methods used to measure blood glucose levels . The most recent meta-analysis on this issue did not find a mortality benefit [RR 1.06 (0.99–1.13)]  of TGC nor a renoprotective effect (evaluated by the need for RRT only) [RR 0.96 (0.83–1.11)]  (ESM_2 Table 11).
A major obstacle to the broad implementation of TGC is the increased risk of hypoglycaemia. Patients with AKI are at particular risk . On the other hand, a causal relationship between a short-lasting iatrogenic hypoglycaemia in the monitored setting of an ICU and outcome remains controversial [198, 199, 200]. If clinicians decide to adopt TGC strategies, fluctuations in glucose levels should be minimized and reliable tools should be employed to measure blood glucose . Because of the risk of hypoglycemia, current guidelines suggest more moderate blood glucose targets (less than 180 mg/dL , less than 150 mg/dl , 140–180 mg/dL ) in critically ill patients, although these targets have not been formally compared with tolerating hyperglycaemia  (ESM_2 Table S11).
A recent large RCT (n = 4494) demonstrated no significant effect of the intraoperative administration of dexamethasone on a composite endpoint of major complications after cardiac surgery. The RR for RIFLE-Failure was 0.7 (0.44–1.14) . A post hoc analysis of this trial showed a beneficial effect on the need for RRT (RR 0.44 (0.19–0.96)), an effect that was mainly seen in patients with eGFR less than 15 ml/min/1.73 m2 and remains to be confirmed . Another placebo-controlled RCT in 7507 patients found no effect of methylprednisolone on the incidence of AKI stage 3 after cardiac surgery .
Prospective randomised placebo-controlled trials on the renoprotective effect of erythropoietin have mainly been performed in the setting of cardiac surgery [206, 207, 208, 209, 210]. A recent meta-analysis (5 studies, 423 patients) found no effect of erythropoietin on the incidence of AKI: RR 0.64 (0.35–1.16). Surprisingly, a preplanned subgroup analysis found a significant reduction of AKI in patients without high risk for AKI: RR 0.37 (0.24–0.61; p < 0.0001) . Similar results were obtained in the most recent meta-analysis, which in addition showed more protection with pre-anaesthetic administration . Another RCT in cardiac surgery including 75 patients with pre-existing renal impairment found no differences in postoperative levels of serum creatinine, cystatin C or NGAL . A second meta-analysis (on a total of 2759 patients) that also included studies in ICU patients [214, 215] likewise did not establish a renoprotective effect of erythropoietin: incidence of AKI RR 0.72 (0.79–1.19); dialysis requirement RR 0.72 (0.31–1.70), mortality RR 0.96 (0.78–1.18), all without significant heterogeneity amongst studies . It should, however, be emphasized that in the largest study in ICU patients  AKI was only reported as an adverse effect and not clearly defined. Two more recent RCTs in the setting of thoracic aortic surgery  and contrast administration in diabetics  confirmed the absence of beneficial effect of EPO on the incidence of AKI or need for RRT in critically ill patients (ESM_2 Table S12).
We recommend not using high-dose IV selenium for renal protection in critically ill patients (1B).
We suggest not using N-acetylcysteine to prevent contrast-associated AKI in critically ill patients because of conflicting results and possible adverse effects (Grade 2B).
We suggest that all patients with or at risk of acute kidney injury have adequate nutritional support preferably through the enteral route (BPS).
Starvation accelerates protein breakdown and impairs protein synthesis in the kidney, whereas feeding might exert the opposite effects and promote renal regeneration. In animal experiments increased protein intake has been shown to reduce tubular injury [219, 220], and enteral versus parenteral nutrition improved the resolution of AKI . On the other hand, amino acids infused before or during ischaemia may also enhance tubular damage and accelerate loss of renal function . This may also extend to high-dose glutamine when given to patients during the injury phase of AKI . Furthermore, brief periods of reduced food intake appear to increase resistance against ischaemia–reperfusion injury in rodents . This “amino acid paradox” may be related to the increase in metabolic work for transport processes which may aggravate ischaemic injury. Enhanced autophagy, induced by nutrient deprivation and promoting the repair of cellular damage, may be an alternative explanation. In this context permissive underfeeding during the acute phase of critical illness may be protective against AKI.
One aspect of nutrition is the adequate supply of nutritional co-factors and antioxidants such as the glutathione precursor N-acetylcysteine (NAC), antioxidant vitamins (vitamin E (α-tocopherol) and vitamin C (ascorbic acid)) as well as selenium. However, these antioxidants have also been investigated in pharmacological doses with the intention to provide protection against damage by oxygen radicals.
Protein(s) and amino acids augment renal perfusion and improve renal function, representing recruitment of “renal reserve capacity” . An RCT investigating the effects of daily intravenous amino acid supplementation up to 100 g/day in 424 critically ill patients could not find a significant effect on the duration of AKI despite an increase in eGFR in the treatment group . Furthermore, there was a trend towards increased need for RRT which corresponds to findings from the EPaNIC trial where early parenteral nutrition increased the duration of RRT probably driven by higher urea levels . Correspondingly, lower caloric intake (defined as receiving less than 60% of requirements, also called permissive underfeeding) has been found to be associated with a lower risk for RRT (RR 0.711, 95% CI 0.545–0.928) .
A host of RCTs have been performed comparing NAC to placebo or other interventions with or without hydration in non-critically ill patients receiving radiocontrast media [229, 80]. Results are controversial as alluded to earlier but the latest meta-analysis assessing the efficacy of intravenous NAC only showed no reduction of AKI or RRT . The ACT trial, currently the largest RCT including 2308 patients undergoing coronary and peripheral vascular angiography, failed to demonstrate any beneficial effect of NAC . RCTs in the critically ill population are not available.
RCTs examining the role of NAC in the prevention of renal dysfunction in high-risk contexts like cardiac surgery showed controversial results [240, 241, 242, 243, 244, 245, 246] (ESM_2 Table S13). In addition IV NAC may be harmful leading to allergic reactions  and decreased cardiac output or survival in patients with septic shock [248, 249].
A small RCT in 42 patients showed that selenium supplementation decreased the requirement for RRT from 43% to 14% in patients with SIRS . These finding could, however, not be reproduced in consecutive trials  including two larger RCTs involving 249 and 1089 patients with sepsis [252, 253].
We recommend against the perioperative use of high-dose statins to prevent postoperative AKI in cardiac surgery (Grade 1A).
We suggest the short-term use of atorvastatin or rosuvastatin to prevent contrast-associated AKI in high-risk patients undergoing coronary contrast angiography (Grade 2B).
The pleiotropic effect of statins, including antioxidant, anti-inflammatory and antithrombotic effects, may contribute to nephroprotection .
Statins may have a beneficial role in high-risk patients exposed to contrast administration for angiography, as suggested by three recent RCTs [255, 256, 257]. In a multicentre trial in China, 2998 patients with type 2 diabetes or mild to moderate CKD undergoing coronary or peripheral arterial angiography were randomised to a 5-day course of rosuvastatin versus no statin . The incidence of CA-AKI was significantly lower in those receiving rosuvastatin (2.3% vs. 3.9%, respectively, p = 0.01). In a single-centre study , 504 statin-naïve patients with acute coronary syndrome (ACS) scheduled to undergo an early invasive strategy were randomised to high-dose rosuvastatin at the time of admission versus treatment with atorvastatin commenced at hospital discharge; 6.7% of patients in the early high-dose statin group developed CA-AKI compared to 15.1% in the control group. The 30-day rate of adverse cardiovascular and renal events was also significantly reduced in the rosuvastatin group (3.6% vs. 7.9%, respectively, p = 0.036). An RCT in 410 CKD patients showed less CA-AKI in patients randomised to a single dose of atorvastatin within 24 h before contrast exposure compared to the control group (4.5% vs. 17.8%, p = 0.005) . Two more recent RCTs found similar effects of statins in diabetics with CKD [258, 259]. These positive findings were confirmed by several meta-analyses combining studies in patients undergoing coronary angiography [260, 261, 262, 263] (ESM_2 Table S14). One of these meta-analyses concluded that short-term, pre-procedural, intensive statin treatment only reduced CA-AKI in ACS patients and recommended further studies in non-ACS patients . This meta-analysis, however, did not include the largest RCT . Although, these results lend support to the short-term use of statins before procedures involving intra-arterial contrast exposure in patients with coronary artery disease with or without diabetes and/or CKD, it must be considered that most of the studies were performed outside the ICU, thereby warranting downgrading of the level of evidence.
In patients undergoing cardiac surgery, two large meta-analyses including data from observational studies found conflicting evidence regarding the role of preoperatve statin in preventing postoperative AKI [265, 266], and a Cochrane analysis of small RCTs found no effect . Two recent placebo-controlled RCTs investigated the effects of perioperative high-dose atorvastatin (i.e. 80 mg, followed by 40 mg daily) in elective cardiac surgery  and valvular heart surgery  and showed no renal benefit. Furthermore, in the largest trial, statin-naïve patients with CKD had a higher incidence of AKI when treated with statin  (ESM_2 Table S15). Finally, an even larger placebo-controlled RCT in 1922 cardiac surgery patients that included AKI as a secondary outcome demonstrated renal harm in those receiving rosuvastatin 20 mg/day in the perioperative period .
Remote ischaemic preconditioning
We suggest not using remote ischaemic preconditioning for prevention of AKI in critically ill patients (Grade 2A).
Remote ischaemic preconditioning (RIPC) or several short cycles of limb ischaemia is achieved through inflation of a blood pressure cuff. The mechanism by which RIPC prevents AKI is incompletely understood.
In cardiac surgery several single-centre RCTs demonstrated reduced incidence of AKI and need for RRT [271, 272, 273]. However, several others, including four larger and multicentric RCTs [274, 275, 276, 277] did not confirm these beneficial effects, nor was a change in creatinine or mortality demonstrated. The conflicting results in cardiac surgery may be explained by inclusion of low-risk patients in trials that showed no benefit, and the use of propofol and opioids, treatments that may blunt the beneficial effects of RIPC.
In 13 recent meta-analyses the effect of RIPC was evaluated in different cohorts and definitions of AKI [178, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289]. Though several meta-analyses found a reduction of AKI [278, 279, 281, 282, 283, 284, 286, 287, 289, 290] this was restricted to stage 1 AKI , or subgroups such as percutaneous coronary interventions [278, 279], or cardiac surgery with propofol-free anaesthesia . The meta-analyses are limited by risk of bias, heterogeneity in definitions of AKI, low event rates and underestimation of influence of co-morbidities [283, 289]. Finally, a Cochrane review including studies on patients undergoing surgery could not show a benefit on renal outcomes  (ESM_2 Table S16).
In summary, the effects by which RIPC prevents AKI are incompletely understood. RIPC for prevention of AKI has mainly been evaluated in cardiovascular surgery and after contrast administration. Larger studies and meta-analyses are not consistent in demonstrating a preventive effect of RIPC for AKI.
AKI care bundles
We suggest using the KDIGO recommendations to reduce the incidence of AKI after cardiac surgery (Grade 2C).
The use of AKI care bundles outside the intensive care unit has some benefits, including the potential to improve the outcome of AKI (BPS).
Care bundles have been proposed as tools to improve the quality of care and outcome of patients with AKI. Ideally, they should contain a small set of practices, processes or treatments that are evidence-based, endorsed and/or recommended by guidelines and broadly accepted as appropriate and/or standard care by local stakeholders. They are designed such that if one element is not implemented, the remaining elements are not impacted.
Outside the critical care setting, different AKI care bundles have been implemented with variable improvement in clinical care, more efficient resource use and potentially improved outcomes, especially if combined with educational measures and electronic alerting [291, 292, 293]. To date, care bundles comprising the KDIGO recommendations have only been investigated in one study including 274 cardiac surgery patients at high risk for AKI as determined by AKI biomarkers. The study showed less postoperative AKI (although mainly by the urine output criteria) without, however, influencing any major patient-centred outcome like RRT or renal recovery at day 30 . The treatment strategy included avoidance of nephrotoxins and hyperglycaemia as well as applying goal-directed haemodynamic optimisation. It is unclear which element was effective because goal-directed therapy (GDT) neither prevented AKI nor reduced the need for RRT in septic shock, as shown by a secondary analysis  and a meta-analysis of three recent large RCTs , but avoiding nephrotoxins, hyperglycaemia and hypovolaemia seems to be reasonable.
Conclusions and summary
Prompt resuscitation of the circulation with fluids, vasopressors and inotropes remains the cornerstone in the prevention of AKI. Volume expansion with isotonic crystalloids is only recommended in states of true and suspected hypovolaemia. Uncontrolled volume expansion and the use of starches and dextrans should be avoided. Following or together with fluid resuscitation hypotensive patients should be given a vasoconstrictor, preferably norepinephrine, and titrated individually with a target MAP of 65–70 mmHg being adequate in most individuals without pre-existing chronic hypertension. The potential role of vasopressin requires further investigation. Together with these measures a review of all medications with the cessation of those known to be nephrotoxic is mandatory. Diuretics should not be used for prevention of AKI alone but may benefit the kidney by relieving renal congestion. Frank hyperglycaemia should be avoided. The effect of statins appears to depend on the setting, with promising results in contrast administration but no effect or even harm in cardiac surgery. There is low-level evidence that the choice of the sedative may impact kidney function. The conflicting results on ischaemic preconditioning preclude a firm recommendation.
Heterogeneous definitions of AKI still hamper comparison of different studies, despite the commendable efforts by the ADQI, AKIN and KDIGO working groups [2, 296, 297]. In addition, AKI is frequently reported as a secondary outcome. Although several RCTs have fuelled the literature on prevention of AKI over the past 4–5 years, the available evidence remains insufficient. Many recommendations are therefore formulated as weak with low grade quality of evidence. More high-quality studies with consensus AKI definitions will be required to fill the knowledge gaps.
Open access funding provided by University of Innsbruck and Medical University of Innsbruck.
Compliance with ethical standards
Conflicts of interest
MJ has received honoraria or research support from Baxter Healthcare Corp, AM-Pharma, CLS Behring, Fresenius and Astute Medical. WD declares no conflicts of interest. LF has received honoraria and research support from Astute Medical, Fresenius, Baxter Gambro Renal and Orthoclinical Diagnostics. PH had received research grants from Baxter, AM Pharma, Bellco, and Pfizer EH received speaker’s fees from Alexion and Astute Medical, and a research grant from Bellco. MO has received honoraria and research funding from Fresenius Medical Care and Baxter Gambro. HO has financial congress support from Dirinco (Netherlands) and speaker’s honoraria from Fresenius and Gambro/Baxter. MS declares no conflicts of interest.
- 6.Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, Edipidis K, Forni LG, Gomersall CD, Govil D, Honore PM, Joannes-Boyau O, Joannidis M, Korhonen AM, Lavrentieva A, Mehta RL, Palevsky P, Roessler E, Ronco C, Uchino S, Vazquez JA, Vidal Andrade E, Webb S, Kellum JA (2015) Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 41:1411–1423PubMedCrossRefGoogle Scholar
- 7.Piccinni P, Cruz DN, Gramaticopolo S, Garzotto F, Dal Santo M, Aneloni G, Rocco M, Alessandri E, Giunta F, Michetti V, Iannuzzi M, Belluomo Anello C, Brienza N, Carlini M, Pelaia P, Gabbanelli V, Ronco C, Investigators N (2011) Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT). Minerva Anestesiol 77:1072–1083PubMedGoogle Scholar
- 8.Srisawat N, Sileanu FE, Murugan R, Bellomod R, Calzavacca P, Cartin-Ceba R, Cruz D, Finn J, Hoste EE, Kashani K, Ronco C, Webb S, Kellum JA, Acute Kidney Injury-6 Study Group (2015) Variation in risk and mortality of acute kidney injury in critically ill patients: a multicenter study. Am J Nephrol 41:81–88PubMedCrossRefGoogle Scholar
- 9.Bell S, Dekker FW, Vadiveloo T, Marwick C, Deshmukh H, Donnan PT, Van Diepen M (2015) Risk of postoperative acute kidney injury in patients undergoing orthopaedic surgery–development and validation of a risk score and effect of acute kidney injury on survival: observational cohort study. BMJ 351:h5639PubMedPubMedCentralCrossRefGoogle Scholar
- 10.Joannidis M, Druml W, Forni LG, Groeneveld AB, Honore P, Oudemans-van Straaten HM, Ronco C, Schetz MR, Woittiez AJ, Critical Care Nephrology Working Group of the European Society of Intensive Care Medicine (2010) Prevention of acute kidney injury and protection of renal function in the intensive care unit. Expert opinion of the Working Group for Nephrology, ESICM. Intensive Care Med 36:392–411PubMedCrossRefGoogle Scholar
- 11.Ichai C, Vinsonneau C, Souweine B, Armando F, Canet E, Clec’h C, Constantin JM, Darmon M, Duranteau J, Gaillot T, Garnier A, Jacob L, Joannes-Boyau O, Juillard L, Journois D, Lautrette A, Muller L, Legrand M, Lerolle N, Rimmele T, Rondeau E, Tamion F, Walrave Y, Velly L, Société française d’anesthésie et de réanimation (Sfar), Société de réanimation de langue française (SRLF), Groupe francophone de réanimation et urgences pédiatriques (GFRUP), Société française de néphrologie (SFN) (2016) Acute kidney injury in the perioperative period and in intensive care units (excluding renal replacement therapies). Ann Intensive Care 6:48PubMedPubMedCentralCrossRefGoogle Scholar
- 18.Himmelfarb J, Joannidis M, Molitoris B, Schietz M, Okusa MD, Warnock D, Laghi F, Goldstein SL, Prielipp R, Parikh CR, Pannu N, Lobo SM, Shah S, D’Intini V, Kellum JA (2008) Evaluation and initial management of acute kidney injury. Clin J Am Soc Nephrol 3:962–967PubMedPubMedCentralCrossRefGoogle Scholar
- 20.Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43:304–377PubMedCrossRefGoogle Scholar
- 23.Kellum JA, Chawla LS, Keener C, Singbartl K, Palevsky PM, Pike FL, Yealy DM, Huang DT, Angus DC, ProCESS and ProGReSS-AKI Investigators (2016) The effects of alternative resuscitation strategies on acute kidney injury in patients with septic shock. Am J Respir Crit Care Med 193:281–287PubMedPubMedCentralCrossRefGoogle Scholar
- 24.Chowdhury AH, Cox EF, Francis ST, Lobo DN (2012) A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and Plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 256:18–24PubMedCrossRefGoogle Scholar
- 25.Wilkes NJ, Woolf R, Mutch M, Mallett SV, Peachey T, Stephens R, Mythen MG (2001) The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesth Analg 93:811–816PubMedCrossRefGoogle Scholar
- 28.Perner A, Prowle JR, Joannidis M, Young P, Hjortrup PB, Pettilä V (2017) Fluid management in acute kidney injury. Intensive Care Med. doi: 10.1007/s00134-017-4817-x
- 33.Skinsnes OK (1947) Gelatin nephrosis; renal tissue changes in man resulting from the intravenous administration of gelatin. Surg Gynecol Obstetri 85:563–571Google Scholar
- 37.Tabuchi N, deHaan J, Huet RCGG, Boonstra PW, vanOeveren W (1995) Gelatin use impairs platelet adhesion during cardiac surgery. Thromb Haemostasis 74:1447–1451Google Scholar
- 49.Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettila V, Aaen A, Lodahl D, Berthelsen RE, Christensen H, Madsen MB, Winkel P, Wetterslev J, Perner A, CLASSIC Trial Group; Scandinavian Critical Care Trials Group (2016) Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med 42:1695–1705PubMedCrossRefGoogle Scholar
- 53.Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R (2015) Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial. JAMA 314:1701–1710PubMedCrossRefGoogle Scholar
- 55.Semler MW, Wanderer JP, Ehrenfeld JM, Stollings JL, Self WH, Siew ED, Wang L, Byrne DW, Shaw AD, Bernard GR, Rice TW, SALT Investigators and the Pragmatic Critical Care Research Group (2017) Balanced crystalloids versus saline in the intensive care unit: the SALT randomized trial. Am J Respir Crit Care Med. doi: 10.1164/rccm.201607-1345OC
- 56.Haase M, Haase-Fielitz A, Bellomo R, Devarajan P, Story D, Matalanis G, Reade MC, Bagshaw SM, Seevanayagam N, Seevanayagam S, Doolan L, Buxton B, Dragun D (2009) Sodium bicarbonate to prevent increases in serum creatinine after cardiac surgery: a pilot double-blind, randomized controlled trial. Crit Care Med 37:39–47PubMedCrossRefGoogle Scholar
- 59.Haase M, Haase-Fielitz A, Plass M, Kuppe H, Hetzer R, Hannon C, Murray PT, Bailey MJ, Bellomo R, Bagshaw SM (2013) Prophylactic perioperative sodium bicarbonate to prevent acute kidney injury following open heart surgery: a multicenter double-blinded randomized controlled trial. PLoS Med 10:e1001426PubMedPubMedCentralCrossRefGoogle Scholar
- 64.Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA, CHEST Investigators, Australian and New Zealand Intensive Care Society Clinical Trials Group (2012) Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 367:1901–1911PubMedCrossRefGoogle Scholar
- 65.Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K, German Competence Network Sepsis (SepNet) (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125–139PubMedCrossRefGoogle Scholar
- 66.Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, Madsen KR, Moller MH, Elkjaer JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Soe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjaeldgaard AL, Fabritius ML, Mondrup F, Pott FC, Moller TP, Winkel P, Wetterslev J, 6S Trial Group, Scandinavian Critical Care Trials Group (2012) Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 367:124–134PubMedCrossRefGoogle Scholar
- 67.Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer S, CHEST Management Committee (2013) Fluid resuscitation with 6% hydroxyethyl starch (130/0.4 and 130/0.42) in acutely ill patients: systematic review of effects on mortality and treatment with renal replacement therapy. Intensive Care Med 39:558–568PubMedCrossRefGoogle Scholar
- 68.Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, Fergusson DA (2013) Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA 309:678–688PubMedCrossRefGoogle Scholar
- 69.Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, Mbuagbaw L, Szczeklik W, Alshamsi F, Altayyar S, Ip W, Li G, Wang M, Wludarczyk A, Zhou Q, Annane D, Cook DJ, Jaeschke R, Guyatt GH (2015) Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med 41:1561–1571PubMedCrossRefGoogle Scholar
- 70.Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, Wetterslev J (2013) Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ 346:f839PubMedPubMedCentralCrossRefGoogle Scholar
- 71.Mutter TC, Ruth CA, Dart AB (2013) Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev 7:CD007594. doi: 10.1002/14651858.CD007594.pub3.
- 72.Reinhart K, Perner A, Sprung CL, Jaeschke R, Schortgen F, Johan Groeneveld AB, Beale R, Hartog CS, European Society of Intensive Care Medicine (2012) Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med 38:368–383PubMedCrossRefGoogle Scholar
- 74.Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L, ALBIOS Study Investigators (2014) Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 370:1412–1421PubMedCrossRefGoogle Scholar
- 75.Dubois MJ, Orellana-Jimenez C, Melot C, De Backer D, Berre J, Leeman M, Brimioulle S, Appoloni O, Creteur J, Vincent JL (2006) Albumin administration improves organ function in critically ill hypoalbuminemic patients: a prospective, randomized, controlled, pilot study. Crit Care Med 34:2536–2540PubMedCrossRefGoogle Scholar
- 78.Lee EH, Kim WJ, Kim JY, Chin JH, Choi DK, Sim JY, Choo SJ, Chung CH, Lee JW, Choi IC (2016) Effect of exogenous albumin on the incidence of postoperative acute kidney injury in patients undergoing off-pump coronary artery bypass surgery with a preoperative albumin level of less than 4.0 g/dl. Anesthesiology 124:1001–1011PubMedCrossRefGoogle Scholar
- 86.Mueller C, Buerkle G, Buettner HJ, Petersen J, Perruchoud AP, Eriksson U, Marsch S, Roskamm H (2002) Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 162:329–336PubMedCrossRefGoogle Scholar
- 88.Ozcan EE, Guneri S, Akdeniz B, Akyildiz IZ, Senaslan O, Baris N, Aslan O, Badak O (2007) Sodium bicarbonate, N-acetylcysteine, and saline for prevention of radiocontrast-induced nephropathy. A comparison of 3 regimens for protecting contrast-induced nephropathy in patients undergoing coronary procedures. A single-center prospective controlled trial. Am Heart J 154:539–544PubMedCrossRefGoogle Scholar
- 89.Masuda M, Yamada T, Mine T, Morita T, Tamaki S, Tsukamoto Y, Okuda K, Iwasaki Y, Hori M, Fukunami M (2007) Comparison of usefulness of sodium bicarbonate versus sodium chloride to prevent contrast-induced nephropathy in patients undergoing an emergent coronary procedure. Am J Cardiol 100:781–786PubMedCrossRefGoogle Scholar
- 90.Briguori C, Airoldi F, D’Andrea D, Bonizzoni E, Morici N, Focaccio A, Michev I, Montorfano M, Carlino M, Cosgrave J, Ricciardelli B, Colombo A (2007) Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation 115:1211–1217PubMedGoogle Scholar
- 91.Nijssen EC, Rennenberg RJ, Nelemans PJ, Essers BA, Janssen MM, Vermeeren MA, Ommen VV, Wildberger JE (2017) Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet 389:1312–1322PubMedCrossRefGoogle Scholar
- 97.McDonald JS, McDonald RJ, Williamson EE, Kallmes DF, Kashani K (2017) Post-contrast acute kidney injury in intensive care unit patients: a propensity score-adjusted study. Intensive Care Med. doi: 10.1007/s00134-017-4699-y
- 98.Hinson JS, Ehmann MR, Fine DM, Fishman EK, Toerper MF, Rothman RE, Klein EY (2017) Risk of acute kidney injury after intravenous contrast media administration. Ann Emerg Med 69:577–586.e4Google Scholar
- 99.Ehrmann S, Quartin A, Hobbs BP, Robert-Edan V, Cely C, Bell C, Lyons G, Pham T, Schein R, Geng Y, Lakhal K, Ng CS (2017) Contrast-associated acute kidney injury in the critically ill: systematic review and Bayesian meta-analysis. Intensive Care Med. doi: 10.1007/s00134-017-4700-9
- 100.Valette X, Desmeulles I, Savary B, Masson R, Seguin A, Sauneuf B, Brunet J, Verrier P, Pottier V, Orabona M, Samba D, Viquesnel G, Lermuzeaux M, Hazera P, Dutheil JJ, Hanouz JL, Parienti JJ, du Cheyron D (2017) Sodium bicarbonate versus sodium chloride for preventing contrast-associated acute kidney injury in critically ill patients: a randomized controlled trial. Crit Care Med 45:637–644PubMedCrossRefGoogle Scholar
- 101.Liu Y, Li H, Chen S, Chen J, Tan N, Zhou Y, Liu Y, Ye P, Ran P, Duan C, Chen P (2016) Excessively high hydration volume may not be associated with decreased risk of contrast-induced acute kidney injury after percutaneous coronary intervention in patients with renal insufficiency. J Am Heart Assoc. doi: 10.1161/JAHA.115.003171
- 109.Cordemans C, De Laet I, Van Regenmortel N, Schoonheydt K, Dits H, Huber W, Malbrain ML (2012) Fluid management in critically ill patients: the role of extravascular lung water, abdominal hypertension, capillary leak, and fluid balance. Ann Intensive Care 2:S1PubMedPubMedCentralCrossRefGoogle Scholar
- 111.National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL (2006) Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354:2564–2575CrossRefGoogle Scholar
- 115.Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O’Connor CM, NHLBI Heart Failure Clinical Research Network (2011) Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 364:797–805PubMedPubMedCentralCrossRefGoogle Scholar
- 118.van der Voort PHJ, Boerma EC, Koopmans M, Zandberg M, de Ruiter J, Gerritsen RT, Egbers PH, Kingma WP, Kuiper MA (2009) Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: a double blind randomized controlled trial. Crit Care Med 37:533–538PubMedCrossRefGoogle Scholar
- 125.Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, Legay F, Le Tulzo Y, Conrad M, Robert R, Gonzalez F, Guitton C, Tamion F, Tonnelier JM, Guezennec P, Van Der Linden T, Vieillard-Baron A, Mariotte E, Pradel G, Lesieur O, Ricard JD, Herve F, du Cheyron D, Guerin C, Mercat A, Teboul JL, Radermacher P, Investigators S (2014) High versus low blood-pressure target in patients with septic shock. N Engl J Med 370:1583–1593PubMedCrossRefGoogle Scholar
- 132.Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ, VANISH Investigators (2016) Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA 316:509–518PubMedCrossRefGoogle Scholar
- 133.Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, Rhodes A, Landoni G, Osawa EA, Melo RR, Sundin MR, Grande SM, Gaiotto FA, Pomerantzeff PM, Dallan LO, Franco RA, Nakamura RE, Lisboa LA, de Almeida JP, Gerent AM, Souza DH, Gaiane MA, Fukushima JT, Park CL, Zambolim C, Rocha Ferreira GS, Strabelli TM, Fernandes FL, Camara L, Zeferino S, Santos VG, Piccioni MA, Jatene FB, Costa Auler JO Jr, Filho RK (2017) Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: the VANCS randomized controlled trial. Anesthesiology 126:85–93PubMedCrossRefGoogle Scholar
- 144.Landoni G, Biondi-Zoccai GG, Tumlin JA, Bove T, De Luca M, Calabro MG, Ranucci M, Zangrillo A (2007) Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Am J Kidney Dis 49:56–68PubMedCrossRefGoogle Scholar
- 145.Zangrillo A, Biondi-Zoccai GG, Frati E, Covello RD, Cabrini L, Guarracino F, Ruggeri L, Bove T, Bignami E, Landoni G (2012) Fenoldopam and acute renal failure in cardiac surgery: a meta-analysis of randomized placebo-controlled trials. J Cardiothorac Vasc Anesth 26:407–413PubMedCrossRefGoogle Scholar
- 147.Bove T, Zangrillo A, Guarracino F, Alvaro G, Persi B, Maglioni E, Galdieri N, Comis M, Caramelli F, Pasero DC, Pala G, Renzini M, Conte M, Paternoster G, Martinez B, Pinelli F, Frontini M, Zucchetti MC, Pappalardo F, Amantea B, Camata A, Pisano A, Verdecchia C, Dal CE, Cariello C, Faita L, Baldassarri R, Scandroglio AM, Saleh O, Lembo R, Calabro MG, Bellomo R, Landoni G (2014) Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial. JAMA 312:2244–2253PubMedCrossRefGoogle Scholar
- 154.Nigwekar SU, Navaneethan SD, Parikh CR, Hix JK (2009) Atrial natriuretic peptide for preventing and treating acute kidney injury. Cochrane Database Syst Rev CD006028. doi: 10.1002/14651858.CD006028.pub2
- 157.Xiong B, Wang C, Yao Y, Huang Y, Tan J, Cao Y, Zou Y, Huang J (2015) The dose-dependent effect of nesiritide on renal function in patients with acute decompensated heart failure: a systematic review and meta-analysis of randomized controlled trials. PLoS One 10:e0131326PubMedPubMedCentralCrossRefGoogle Scholar
- 158.Papp Z, Edes I, Fruhwald S, De Hert SG, Salmenpera M, Leppikangas H, Mebazaa A, Landoni G, Grossini E, Caimmi P, Morelli A, Guarracino F, Schwinger RH, Meyer S, Algotsson L, Wikstrom BG, Jorgensen K, Filippatos G, Parissis JT, Gonzalez MJ, Parkhomenko A, Yilmaz MB, Kivikko M, Pollesello P, Follath F (2012) Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol 159:82–87PubMedCrossRefGoogle Scholar
- 159.Hasslacher J, Bijuklic K, Bertocchi C, Kountchev J, Bellmann R, Dunzendorfer S, Joannidis M (2011) Levosimendan inhibits release of reactive oxygen species in polymorphonuclear leukocytes in vitro and in patients with acute heart failure and septic shock: a prospective observational study. Crit Care 15:R166PubMedPubMedCentralCrossRefGoogle Scholar
- 160.Bove T, Matteazzi A, Belletti A, Paternoster G, Saleh O, Taddeo D, Dossi R, Greco T, Bradic N, Husedzinovic I, Nigro Neto C, Lomivorotov VV, Calabro MG (2015) Beneficial impact of levosimendan in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Heart Lung Vessel 7:35–46PubMedPubMedCentralGoogle Scholar
- 162.Gordon AC, Perkins GD, Singer M, McAuley DF, Orme RM, Santhakumaran S, Mason AJ, Cross M, Al-Beidh F, Best-Lane J, Brealey D, Nutt CL, McNamee JJ, Reschreiter H, Breen A, Liu KD, Ashby D (2016) Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med 375:1638–1648PubMedCrossRefGoogle Scholar
- 163.Mehta RH, Leimberger JD, van Diepen S, Meza J, Wang A, Jankowich R, Harrison RW, Hay D, Fremes S, Duncan A, Soltesz EG, Luber J, Park S, Argenziano M, Murphy E, Marcel R, Kalavrouziotis D, Nagpal D, Bozinovski J, Toller W, Heringlake M, Goodman SG, Levy JH, Harrington RA, Anstrom KJ, Alexander JH, LEVO-CTS Investigators (2017) Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. N Engl J Med. doi: 10.1056/NEJMoa1616218
- 164.Landoni G, Lomivorotov VV, Alvaro G, Lobreglio R, Pisano A, Guarracino F, Calabro MG, Grigoryev EV, Likhvantsev VV, Salgado-Filho MF, Bianchi A, Pasyuga VV, Baiocchi M, Pappalardo F, Monaco F, Boboshko VA, Abubakirov MN, Amantea B, Lembo R, Brazzi L, Verniero L, Bertini P, Scandroglio AM, Bove T, Belletti A, Michienzi MG, Shukevich DL, Zabelina TS, Bellomo R, Zangrillo A, CHEETAH Study Group (2017) Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. doi: 10.1056/NEJMoa1616325
- 183.Balkanay OO, Goksedef D, Omeroglu SN, Ipek G (2015) The dose-related effects of dexmedetomidine on renal functions and serum neutrophil gelatinase-associated lipocalin values after coronary artery bypass grafting: a randomized, triple-blind, placebo-controlled study. Interact Cardiovasc Thorac Surg 20:209–214PubMedCrossRefGoogle Scholar
- 189.Schetz M, Vanhorebeek I, Wouters PJ, Wilmer A, van den Berghe G (2008) Tight blood glucose control is renoprotective in critically ill patients. J Am Soc Nephrol 19: 571–578Google Scholar
- 190.Arabi YM, Dabbagh OC, Tamim HM, Al-Shimemeri AA, Memish ZA, Haddad SH, Syed SJ, Giridhar HR, Rishu AH, Al-Daker MO, Kahoul SH, Britts RJ, Sakkijha MH (2008) Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med 36:3190–3197PubMedCrossRefGoogle Scholar
- 191.Investigators N-SS, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hebert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ (2009) Intensive versus conventional glucose control in critically ill patients. N Engl J Med 360:1283–1297CrossRefGoogle Scholar
- 192.Preiser JC, Devos P, Ruiz-Santana S, Melot C, Annane D, Groeneveld J, Iapichino G, Leverve X, Nitenberg G, Singer P, Wernerman J, Joannidis M, Stecher A, Chiolero R (2009) A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med 35:1738–1748PubMedCrossRefGoogle Scholar
- 194.De La Rosa GC, Donado JH, Restrepo AH, Quintero AM, Gonzalez LG, Saldarriaga NE, Bedoya M, Toro JM, Velasquez JB, Valencia JC, Arango CM, Aleman PH, Vasquez EM, Chavarriaga JC, Yepes A, Pulido W, Cadavid CA (2008) Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial. Crit Care 12:R120CrossRefGoogle Scholar
- 200.NICE-SUGAR Study Investigators, Finfer S, Liu B, Chittock DR, Norton R, Myburgh JA, McArthur C, Mitchell I, Foster D, Dhingra V, Henderson WR, Ronco JJ, Bellomo R, Cook D, McDonald E, Dodek P, Hebert PC, Heyland DK, Robinson BG (2012) Hypoglycemia and risk of death in critically ill patients. N Engl J Med 367:1108–1118CrossRefGoogle Scholar
- 201.Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, Inzucchi SE, Ismail-Beigi F, Kirkman MS, Umpierrez GE (2009) American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. EndocrPract 15:353–369Google Scholar
- 202.van den Berghe G (2013) What’s new in glucose control in the ICU? Intensive Care Med 39:823–825Google Scholar
- 203.Dieleman JM, Nierich AP, Rosseel PM, van der Maaten JM, Hofland J, Diephuis JC, Schepp RM, Boer C, Moons KG, van Herwerden LA, Tijssen JG, Numan SC, Kalkman CJ, van Dijk D, Dexamethasone for Cardiac Surgery Study Group (2012) Intraoperative high-dose dexamethasone for cardiac surgery: a randomized controlled trial. JAMA 308:1761–1767PubMedCrossRefGoogle Scholar
- 204.Jacob KA, Leaf DE, Dieleman JM, van Dijk D, Nierich AP, Rosseel PM, van der Maaten JM, Hofland J, Diephuis JC, de Lange F, Boer C, Kluin J, Waikar SS, Dexamethasone for Cardiac Surgery Study Group (2015) Intraoperative high-dose dexamethasone and severe AKI after cardiac surgery. J Am Soc Nephrol 26:2947–2951PubMedPubMedCentralCrossRefGoogle Scholar
- 205.Whitlock RP, Devereaux PJ, Teoh KH, Lamy A, Vincent J, Pogue J, Paparella D, Sessler DI, Karthikeyan G, Villar JC, Zuo Y, Avezum A, Quantz M, Tagarakis GI, Shah PJ, Abbasi SH, Zheng H, Pettit S, Chrolavicius S, Yusuf S (2015) Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): a randomised, double-blind, placebo-controlled trial. Lancet 386:1243–1253PubMedCrossRefGoogle Scholar
- 210.Tasanarong A, Duangchana S, Sumransurp S, Homvises B, Satdhabudha O (2013) Prophylaxis with erythropoietin versus placebo reduces acute kidney injury and neutrophil gelatinase-associated lipocalin in patients undergoing cardiac surgery: a randomized, double-blind controlled trial. BMC Nephrol 14:136PubMedPubMedCentralCrossRefGoogle Scholar
- 214.Endre ZH, Walker RJ, Pickering JW, Shaw GM, Frampton CM, Henderson SJ, Hutchison R, Mehrtens JE, Robinson JM, Schollum JB, Westhuyzen J, Celi LA, McGinley RJ, Campbell IJ, George PM (2010) Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). Kidney Int 77:1020–1030PubMedCrossRefGoogle Scholar
- 216.Zhao C, Lin Z, Luo Q, Xia X, Yu X, Huang F (2015) Efficacy and safety of erythropoietin to prevent acute kidney injury in patients with critical illness or perioperative care: a systematic review and meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol 65:593–600PubMedPubMedCentralCrossRefGoogle Scholar
- 224.Mitchell JR, Verweij M, Brand K, van de Ven M, Goemaere N, van den Engel S, Chu T, Forrer F, Muller C, de Jong M, van IJcken W, IJzermans JN, Hoeijmakers JH, de Bruin RW (2010) Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice. Aging Cell 9:40–53Google Scholar
- 235.Zhao SJ, Zhong ZS, Qi GX, Tian W (2016) The efficacy of N-acetylcysteine plus sodium bicarbonate in the prevention of contrast-induced nephropathy after cardiac catheterization and percutaneous coronary intervention: a meta-analysis of randomized controlled trials. Int J Cardiol 221:251–259PubMedCrossRefGoogle Scholar
- 238.Sun Z, Fu Q, Cao L, Jin W, Cheng L, Li Z (2013) Intravenous N-acetylcysteine for prevention of contrast-induced nephropathy: a meta-analysis of randomized, controlled trials. PLoS One 8:e55124Google Scholar
- 243.Sisillo E, Ceriani R, Bortone F, Juliano G, Salvi L, Veglia F, Fiorentini C, Marenzi G (2008) N-acetylcysteine for prevention of acute renal failure in patients with chronic renal insufficiency undergoing cardiac surgery: a prospective, randomized, clinical trial. Crit Care Med 36:81–86PubMedCrossRefGoogle Scholar
- 252.Angstwurm MW, Engelmann L, Zimmermann T, Lehmann C, Spes CH, Abel P, Strauss R, Meier-Hellmann A, Insel R, Radke J, Schuttler J, Gartner R (2007) Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med 35:118–126PubMedCrossRefGoogle Scholar
- 253.Bloos F, Trips E, Nierhaus A, Briegel J, Heyland DK, Jaschinski U, Moerer O, Weyland A, Marx G, Grundling M, Kluge S, Kaufmann I, Ott K, Quintel M, Jelschen F, Meybohm P, Rademacher S, Meier-Hellmann A, Utzolino S, Kaisers UX, Putensen C, Elke G, Ragaller M, Gerlach H, Ludewig K, Kiehntopf M, Bogatsch H, Engel C, Brunkhorst FM, Loeffler M, Reinhart K, for SepNet Critical Care Trials G (2016) Effect of sodium selenite administration and procalcitonin-guided therapy on mortality in patients with severe sepsis or septic shock: a randomized clinical trial. JAMA intern med 176: 1266-1276Google Scholar
- 255.Han Y, Zhu G, Han L, Hou F, Huang W, Liu H, Gan J, Jiang T, Li X, Wang W, Ding S, Jia S, Shen W, Wang D, Sun L, Qiu J, Wang X, Li Y, Deng J, Li J, Xu K, Xu B, Mehran R, Huo Y (2014) Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. J Am Coll Cardiol 63:62–70PubMedCrossRefGoogle Scholar
- 256.Leoncini M, Toso A, Maioli M, Tropeano F, Villani S, Bellandi F (2014) Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: results from the PRATO-ACS Study (Protective EFFECT of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome). J Am Coll Cardiol 63:71–79PubMedCrossRefGoogle Scholar
- 257.Quintavalle C, Fiore D, De Micco F, Visconti G, Focaccio A, Golia B, Ricciardelli B, Donnarumma E, Bianco A, Zabatta MA, Troncone G, Colombo A, Briguori C, Condorelli G (2012) Impact of a high loading dose of atorvastatin on contrast-induced acute kidney injury. Circulation 126:3008–3016PubMedCrossRefGoogle Scholar
- 259.Li J, Li Y, Xu B, Jia G, Guo T, Wang D, Xu K, Deng J, Han Y (2016) Short-term rosuvastatin therapy prevents contrast-induced acute kidney injury in female patients with diabetes and chronic kidney disease: a subgroup analysis of the TRACK-D study. J Thorac Dis 8:1000–1006PubMedPubMedCentralCrossRefGoogle Scholar
- 261.Lee JM, Park J, Jeon KH, Jung JH, Lee SE, Han JK, Kim HL, Yang HM, Park KW, Kang HJ, Koo BK, Jo SH, Kim HS (2014) Efficacy of short-term high-dose statin pretreatment in prevention of contrast-induced acute kidney injury: updated study-level meta-analysis of 13 randomized controlled trials. PLoS One 9:e111397PubMedPubMedCentralCrossRefGoogle Scholar
- 264.Marenzi G, Cosentino N, Werba JP, Tedesco CC, Veglia F, Bartorelli AL (2015) A meta-analysis of randomized controlled trials on statins for the prevention of contrast-induced acute kidney injury in patients with and without acute coronary syndromes. Int J Cardiol 183:47–53PubMedCrossRefGoogle Scholar
- 265.Liakopoulos OJ, Choi YH, Haldenwang PL, Strauch J, Wittwer T, Dorge H, Stamm C, Wassmer G, Wahlers T (2008) Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30,000 patients. Eur Heart J 29:1548–1559PubMedCrossRefGoogle Scholar
- 267.Lewicki M, Ng I, Schneider AG (2015) HMG CoA reductase inhibitors (statins) for preventing acute kidney injury after surgical procedures requiring cardiac bypass. Cochrane Database Syst Rev 3:CD010480Google Scholar
- 271.Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Gorlich D, Kellum JA, Meersch M, Renal RI (2015) Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA 313:2133–2141PubMedCrossRefGoogle Scholar
- 274.Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, Coburn M, Schaelte G, Boning A, Niemann B, Roesner J, Kletzin F, Strouhal U, Reyher C, Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A, Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M, Schon J, Sander M, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G, Hasenclever D, Zacharowski K (2015) A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med 373:1397–1407PubMedCrossRefGoogle Scholar
- 275.Hong DM, Lee EH, Kim HJ, Min JJ, Chin JH, Choi DK, Bahk JH, Sim JY, Choi IC, Jeon Y (2014) Does remote ischaemic preconditioning with postconditioning improve clinical outcomes of patients undergoing cardiac surgery? Remote Ischaemic Preconditioning with Postconditioning Outcome Trial. Eur Heart J 35:176–183PubMedCrossRefGoogle Scholar
- 276.Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, Knight R, Kunst G, Laing C, Nicholas J, Pepper J, Robertson S, Xenou M, Clayton T, Yellon DM, ERICCA Trial Investigators (2015) Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 373:1408–1417PubMedCrossRefGoogle Scholar
- 277.Walsh M, Whitlock R, Garg AX, Legare JF, Duncan AE, Zimmerman R, Miller S, Fremes S, Kieser T, Karthikeyan G, Chan M, Ho A, Nasr V, Vincent J, Ali I, Lavi R, Sessler DI, Kramer R, Gardner J, Syed S, VanHelder T, Guyatt G, Rao-Melacini P, Thabane L, Devereaux PJ, Remote IMPACT Investigators (2016) Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): a randomized controlled trial. CMAJ 188:329–336PubMedCrossRefGoogle Scholar
- 283.Pierce B, Bole I, Patel V, Brown DL (2017) Clinical outcomes of remote ischemic preconditioning prior to cardiac surgery: a meta-analysis of randomized controlled trials. J Am Heart Assoc. doi: 10.1161/JAHA.116.004666
- 284.Yi B, Chen X, Shi H, Lin T, Lin H, Xu Y, Rong J (2017) Remote ischaemic preconditioning reduces acute kidney injury in adult patients undergoing cardiac surgery with cardiopulmonary bypass: a meta-analysis. Eur J Cardiothorac Surg 51:616–623Google Scholar
- 289.Sukkar L, Hong D, Wong MG, Badve SV, Rogers K, Perkovic V, Walsh M, Yu X, Hillis GS, Gallagher M, Jardine M (2016) Effects of ischaemic conditioning on major clinical outcomes in people undergoing invasive procedures: systematic review and meta-analysis. BMJ 355:i5599PubMedPubMedCentralCrossRefGoogle Scholar
- 290.Zhou CC, Ge YZ, Yao WT, Wu R, Xin H, Lu TZ, Li MH, Song KW, Wang M, Zhu YP, Zhu M, Geng LG, Gao XF, Zhou LH, Zhang SL, Zhu JG, Jia RP (2017) Limited clinical utility of remote ischemic conditioning in renal transplantation: a meta-analysis of randomized controlled trials. PLoS One 12:e0170729PubMedPubMedCentralCrossRefGoogle Scholar
- 293.Bhagwanani A, Carpenter R, Yusuf A (2014) Improving the management of acute kidney injury in a district general hospital: introduction of the DONUT bundle. BMJ Qual Improv Rep. doi: 10.1136/bmjquality.u202650.w1235
- 294.Meersch M, Schmidt C, Hoffmeier A, Van Aken H, Wempe C, Gerss J, Zarbock A (2017) Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial. Intensive Care Med. doi: 10.1007/s00134-016-4670-3
- 295.Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ, Davies A, Delaney A, Harrison DA, Holdgate A, Howe B, Huang DT, Iwashyna T, Kellum JA, Peake SL, Pike F, Reade MC, Rowan KM, Singer M, Webb SA, Weissfeld LA, Yealy DM, Young JD (2015) A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe investigators. Intensive Care Med 41:1549–1560PubMedCrossRefGoogle Scholar
- 296.Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup (2004) 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 8:R204–R212PubMedPubMedCentralCrossRefGoogle Scholar
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