Intensive Care Med (2017) 43:730–749

DOI 10.1007/s00134-017-4832-y

CONFERENCE REPORTS AND EXPERT PANEL

Prevention of acute kidney injury

and protection of renal function in the intensive
care unit: update 2017
Expert opinion of the Working Group on Prevention, AKI section, European Society of
Intensive Care Medicine
M. Joannidis1* , W. Druml2, L. G. Forni3, A. B. J. Groeneveld, P. M. Honore4, E. Hoste5, M. Ostermann6,
H. M. Oudemans‑van Straaten7 and M. Schetz8

© 2017 The Author(s). This article is an open access publication

Abstract
Background: Acute kidney injury (AKI) in the intensive care unit is associated with significant mortality and
morbidity.
Objectives: 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.
Method: 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.
Results: 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 dopa‑
mine, statins in cardiac surgery). Strong recommendations with lower-level evidence include controlled fluid resusci‑
tation 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.
Conclusion: The results of recent randomised controlled trials have allowed the formulation of new recommenda‑
tions 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.

*Correspondence: michael.joannidis@i‑med.ac.at
1
Division of Intensive Care and Emergency Medicine, Department
of Internal Medicine, Medical University Innsbruck,
Anichstasse 35, 6020 Innsbruck, Austria
Full author information is available at the end of the article

Professor Groeneveld succumbed to a long illness which he fought with

typical determination during the updating of this paper. He is sadly
missed by us all.
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Keywords: Acute kidney injury, Systematic review, Recommendations, Prevention, Volume expansion, Vasopressors

Introduction
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 [1–5]. The recent
AKI-EPI study demonstrates that the most frequent
causes of AKI in the critically ill are sepsis and hypovol-
aemia followed by nephrotoxic agents [6]. However, the
cause of AKI is often multifactorial with pre-existing co- Fig. 1 Grade system for grading recommendations (Modified from
morbidities further increasing the risk [3, 7–9]. Guyatt et al. [12])
The aim of this systematic review on the prevention
and avoidance of further progression of AKI, by core
members of the AKI section of the ESICM, is to provide: Table 1 Criteria for best practice statements (Modified
from Guyatt et al. [14])
••  A critical evaluation of the existing evidence Criteria for best practice statements
••  Give recommendations for clinical practice
1 Is the statement clear and actionable?
••  Update our previously published recommendations
2 Is the message necessary?
[10] and most recent guidelines [2, 11]
3 Is the net benefit (or harm) unequivocal?
4 Is the evidence difficult to collect and summarize?
Our recommendations principally concern critically
5 Is the rationale explicit?
ill patients on the ICU but can also be applied to those
6 Is this better to be formally GRADEd?
planned to be admitted to the ICU such as high-risk sur-
gical patients. By consensus, we primarily focussed on GRADE Gradings of Recommendations, Assessment, Development, and
Evaluation
the role of volume expansion, diuretics, inotropes, vaso-
pressors/vasodilators, hormones, nutrition, statins, seda-
tives and ischaemic preconditioning. discussions. The quality of the evidence was judged by
using the most recent GRADE (Gradings of Recommen-
Methodology dations, Assessment, Development and Evaluation) crite-
A systematic search of the literature was performed ria (Fig. 1) [12, 13]. The strength of the recommendations
using the following databases: MEDLINE (1966 was classified as either strong (Grade 1) or weak (Grade
through March 2017), EMBASE (1980 through March 2). The degree (i.e. quality) of evidence for the recom-
2017), CINAHL (1982 through March 2017), Web of mendations was classified from high (A) to very low (D)
Science (1955 through March 2017) and PubMed/ according to factors including study design consistency of
PubMed CENTRAL to identify key studies, prefer- the results and directness of the evidence (Fig. 1, ESM_1
ably randomised (placebo) controlled trials (RCT) and Table S1). Evidence was downgraded where there was a
meta-analyses, addressing strategies to prevent AKI in risk of bias, inconsistency and imprecision. Evidence was
adult critically ill patients. The following clinical con- upgraded for large effect size or significant dose–response
ditions were considered: major surgery, critical illness, gradient. If benefit or harm was unequivocal, but evidence
sepsis, shock and exposure to potentially nephrotoxic was difficult to categorize by the GRADE methodology,
drugs. Specifically, renal transplantation, primary we used best practice statements (BPSs), which represent
intrinsic renal disease (e.g. vasculitis) and hepatorenal ungraded strong recommendations [14] (Table 1).
syndrome were not considered. Search strategy and We acknowledge that there may be circumstances
endpoints are available as electronic supplementary whereby a recommendation cannot or should not be fol-
material (ESM_1). lowed for an individual patient. Furthermore, interven-
These recommendations are intended to provide clini- tions are generally investigated in isolation and not in
cal guidance and involved a modified Delphi process with combination, and as such recommendations relate to the
a consensus meeting during the annual congresses of the primary intervention. Local clinical guidelines will gov-
European Society of Intensive Care Medicine in 2014, ern the use of either a single intervention or a combina-
2015 and 2016 followed by electronic-based/telephone tion thereof.
732

Volume expansion Available artificial colloids include gelatines, dextrans

Recommendations and until recently, starches. Gelatines have a moderate
1. We recommend controlled fluid resuscitation in vol- volume effect. Although risk of osmotic nephrosis with
ume depletion, while, however, avoiding volume gelatines exists [33], the lack of clear clinical data on
overload (Grade 1C). deleterious effects on renal function [34, 35] is offset by
2. We recommend against the use of starches (Grade the possible prion transmission, histamine release and
1A) as harm has been shown and suggest not using coagulopathy [36, 37]. Dextrans have reasonably high
gelatine or dextrans for fluid resuscitation (Grade volume effects although anaphylaxis, coagulation disor-
2C). ders, osmotic nephrosis and AKI may occur with doses
3. We recommend correction of hypovolaemia/dehy- above 1.5 g/kg/day [38–41]. Human albumin (HA) is the
dration using isotonic crystalloids in patients receiv- only naturally occurring colloid and may appear attrac-
ing intravascular contrast media (Grade 1B). tive in hypooncotic hypovolaemia. It does increase the
4. We recommend regular monitoring of chloride levels response to diuretics in patients with hypoalbuminaemia
and acid–base status in situations where chloride- (e.g. nephrotic syndrome) [42, 43], has no negative effects
rich solutions are used (BPS). on kidney function [44, 45], is safe [46] but can be costly.
5. We suggest the use of balanced crystalloids for large
volume resuscitation (Grade 2C). Clinical studies
6. We suggest using human serum albumin if a colloid is Unsurprisingly, no studies have specifically addressed
deemed necessary for the treatment of patients with the effects of volume expansion compared to no volume
septic shock (Grade 2C). resuscitation in overt hypovolaemia given the intui-
7. We suggest prophylactic volume expansion with crys- tive benefits of volume replacement. In severe sepsis,
talloids to prevent AKI by certain drugs (specified the beneficial effects of timely volume replacement on
below) (BPS). organ failure and mortality are well known, although the
8. We suggest not delaying urgent contrast-enhanced first RCT proving benefit of early volume resuscitation
investigations or interventions for potential preven- did not report kidney function [47]. On the other hand,
tative measures (BPS). preoperative volume expansion failed to reduce the inci-
dence of postoperative AKI ins 328 patients undergoing
Rationale cardiac surgery [48], and a recent pilot RCT in sepsis
Relative and overt hypovolaemia are significant risk factors could demonstrate that a volume-restrictive fluid proto-
for development of AKI [15–18]. Timely fluid administra- col can reduced the incidence of AKI (RR 0.32; 95% CI
tion can restore circulating volume and renal perfusion, 0.32–0.96) [49].
and may also reduce nephrotoxicity [19]. Volume replace- Crystalloids are considered the mainstay for volume
ment should be performed in a controlled, monitored fash- expansion. Observational studies suggest an increased
ion [20] as injudicious use of fluids carries its own inherent risk of AKI, renal replacement therapy (RRT) and
risks and may even contribute to AKI by increasing renal mortality associated with the use of large volumes of
interstitial oedema and renal parenchymal pressure [21, normal saline (0.9% NaCl) as compared to so-called
22]. Moreover, goal-directed therapy including the use balanced solutions where chloride is partially replaced

comparing saline to a balanced solution ­(Plasmalyte®)

of central venous pressure (CVP) as a resuscitation target by another metabolizable anion [50–52]. An RCT
has not been shown to prevent AKI in sepsis [23]. Volume
replacement may be through crystalloids, colloids or their in 2278 patients treated in four ICUs failed to show
combination. Isotonic crystalloids represent the main- any superiority of balanced crystalloids regarding
stay for correcting extracellular volume depletion with the renal outcomes [53]. The study has been criticized for
caveat that hyperchloraemia is prevented to reduce poten- the limited fluid doses, inclusion of patients with low
tial renal vasoconstriction [24, 25]. Compared to crys- disease severity and the absence of data on chloride
talloids, colloids theoretically result in a greater plasma levels [54]. Similar results were observed in the pilot
expansion. However, this effect depends on vascular barrier cluster-randomised, multiple-crossover SALT trial
integrity which may be compromised in sepsis, particularly comparing saline to a balanced solution in 974 criti-
in the presence of vasoplegia [26, 27]. Consequently, the cally ill adults [55]. Again, only modest volumes were
difference in required volumes for fluid resuscitation was used, but increased rates of AKI were found in the
minimal between crystalloids and colloids in large RCTs normal saline group if larger volumes were adminis-
[28]. Moreover, large volume replacement with colloids tered (ESM_2 Table S2). Studies on the effectiveness of
alone risks hyperoncotic impairment of glomerular filtra- sodium bicarbonate in preventing AKI, predominantly
tion [29, 30] and osmotic tubular damage [31, 32]. in patients undergoing cardiac surgery, have produced
 733

conflicting results [56–59] as have consecutive meta- the role of CA-AKI is uncertain, particularly in an era
analyses [60–63]. where the use of low- or iso-osmotic agents and lower
The effect of colloids on renal function has undergone contrast volume administration have become standard
extensive scrutiny over the last decade. Large RCTs have practice. As indicated by an analysis of the Nationwide
substantiated the increased risk of AKI and RRT with use Inpatient Sample dataset comprising 5, 931,523 hos-
of starches [64] particularly in sepsis [65, 66], where they pitalisations the OR for CA-AKI adjusted for age, sex,
also lead to increased mortality [66] (ESM_2 Table S3). mechanical ventilation and combined co-morbidity score
This is verified by several meta-analyses [67–70] which was 0.93 (0.88–0.97) [93]. Whereas a retrospective single-
underpin the abandoning of starches in critically ill centre cohort study in 747 critically ill patients showed
patients [20, 71, 72]. Clinical data on the effects of gela- a rate of CA-AKI of 16% [94], matched cohort studies
tine on renal function are scarce. A recent meta-analysis, could not demonstrate a relationship with IV contrast
including three trials in 212 patients comparing gelatins for computed tomography in the ICU [95–97] or emer-
with crystalloids or albumin, indicated a 35% increased gency department [98]. These findings are supported by
relative risk of developing AKI with gelatine [73]. a systematic review and Bayesian meta-analysis [99]. In
In contrast to artificial colloids, the administration of the most recent propensity-matched cohort study, IV
albumin appears to be safe for the kidney. A large RCT contrast was not associated with an increased risk of AKI
comparing normal saline to 4% HA in various clinical set- or dialysis, but a subgroup with pre-CT eGFR of at most
tings failed to demonstrate any differences in renal func- 45 ml/min/1.73 m2 showed an increased risk of dialysis.
tion [46] (ESM_2 Table S3). In the ALBIOS trial the use The numbers in this subgroup were, however, small and
of hyperoncotic (20%) albumin showed no effect on AKI subject to selection bias [97].
or need for RRT in severe sepsis [74] but enabled a less Although it seems prudent to correct hypovolaemia
positive fluid balance, confirming the results of another before contrast administration, prophylactic volume
small trial [75]. A post hoc analysis of the ALBIOS trial expansion in critically ll patients who are euvolaemic
showed survival benefit in septic shock [74] confirmed cannot be recommended on the basis of current data. No
by meta-analyses [76, 77]. Hypoalbuminaemia in cardiac study demonstrates protection of pre-emptive volume
surgery might be another indication with improved fluid expansion against CA-AKI in the critically ill. An RCT
balance as well as a reduced rate of AKI being observed comparing hydration with isotonic bicarbonate versus
in a single-centre RCT of 220 patients [78]. normal saline failed to show superiority of either regimen
Hypovolaemia may also contribute significantly towards but reported an excessively high rate of CA-AKI of 33%
drug-induced renal injury, although the available evidence in both groups [100], which may be attributed to sever-
supporting preventative hydration is only observational ity of illness in this critically ill cohort. Importantly, in
with no consensus related to timing, optimal volume patients with chronic kidney disease (CKD) undergoing
and type of solution [19, 79, 80]. Prophylactic volume percutaneous coronary intervention (PCI), hydration vol-
expansion has been shown to prevent harm from ampho- umes above 11 ml/kg body weight (BW) were associated
tericin B, antivirals including foscarnet, cidofovir and ade- with continuously increased rates of AKI, requirement
fovir [81–83] as well as drugs causing crystal nephropathy for RRT and mortality. The adjusted OR for develop-
such as indinavir, acyclovir, and sulfadiazine [84]. ing AKI with hydration volumes greater than 25 ml/kg
Prophylactic volume expansion is the mainstay of all BW was 2.11 (CI 1.24–3.59) [101]. We recommend that
recommendations to prevent contrast-associated AKI the clinical decision to perform a contrast study in ICU
(CA-AKI) and is based on several randomised controlled patients must weigh the potential benefits with the low
studies performed in non-critically ill patients [85–90]. but probably not zero risk of CA-AKI.
However, studies comparing hydration to no hydration
are scarce [91]. Several pitfalls should be considered. Diuretics
First, CA-AKI is a diagnosis of exclusion and consider- Recommendations
able variation exists with regard to the reported inci- 1. We recommend against loop diuretics given solely for
dence rates, which are confounded by many factors such the prevention of acute kidney injury (Grade 1B).
as transient fluctuations in measured serum creatinine in 2. We suggest using diuretics to control or avoid fluid
hospitalised patients and use of non-standardised diag- overload in patients that are diuretic-responsive
nostic criteria [92]. Secondly, CA-AKI does not occur in (Grade 2D).
patients without other risk factors for AKI, whereas most
critically ill patients receiving intravascular contrast have Rationale
other risk factors. Moreover, individuals with high risk Oligoanuria is frequently the first indicator of acute renal
for CA-AKI may not be given contrast. For these reasons dysfunction. Intensivists frequently use loop diuretics in
734

a wide spectrum of AKI settings [102]. The rationale for sor to protect kidney function (Grade 1B) and suggest
using diuretics to ameliorate AKI includes prevention vasopressin in patients with vasoplegic shock after
of tubular obstruction, reduction in medullary oxygen cardiac surgery (Grade 2C).
consumption and increase in renal blood flow as well as 4. We suggest individualizing target pressure when pre-
reducing fluid overload and venous congestion [103– morbid blood pressure is available (BPS).
105]. Although there is no single parameter for fluid
overload, increased CVP [106], peripheral oedema [107] Rationale for MAP target
and/or increased intra-abdominal pressure [108, 109] Preservation or improvement of renal perfusion can
may be used as surrogates. A recent study demonstrated theoretically be achieved through increasing cardiac
than a urinary output of at least 100 ml/h following a test output by fluid resuscitation or inotropic drugs, through
dose of 1.0–1.5 mg furosemide/kg BW predicted reduced renal vasodilators or systemic vasopressors. Optimal tar-
progression to a higher stage of AKI in oliguric patients get mean arterial pressure (MAP) was studied in a large
[110]. open-label multicentre RCT randomising 777 patients
with septic shock to resuscitation with a MAP target of
Clinical studies either 80–85 mmHg or 65–70 mmHg [125]. In most of
Use of conservative fluid management including diuretics the patients the achieved MAP was above the set target.
has been investigated in only one large RCT in patients The study found no difference in mortality, incidence of
with acute lung injury (FACTT trial) which showed a AKI stage 2 (38.7% vs. 41.5%, p = 0.42) or need for RRT
tendency to reduced requirement of RRT [111]. (33.5% vs. 35.8%, p = 0.5), but more atrial fibrillation in
In cardiac surgery either no protection [112] or ele- the high target group. However, in patients with known
vated postoperative serum creatinine levels were found in chronic hypertension a higher MAP resulted in a lower
patients receiving furosemide [113]. These findings were incidence of AKI stage 2 (38.9% vs. 52%, p = 0.02) and
supported by a recent meta-analysis [114]. In patients less RRT (31.7% vs 42.2%, p = 0.046); mortality was
with acute heart failure, diuretic therapy with higher unchanged.
doses was more effective at reducing clinical symp- The safety of lowering systolic pressure was studied in
toms, but at the cost of decreased renal function [115]. a larger RCT in patients with acute cerebral haemorrhage
To date four RCTs have examined the role of diuretics in with severe hypertension on admission [126]. Patients
established renal failure in the intensive care setting. No were randomised to a systolic blood pressure target of
demonstrable improvements in clinically relevant out- 110–139 or 140–179 mmHg. The primary endpoint
comes, such as recovery of renal function or mortality, (death or disability) was not different between groups.
were observed [31, 116–118]. Other studies compared However, the rate of serious renal adverse events was
diuretics with dopamine or placebo, again with no per- higher in the lower target group (9% vs. 4%, p = 0.002)
ceived benefit [119–121]. Three meta-analyses confirmed (ESM_2 Table S5).
that the use of diuretics in established AKI did not alter
outcome but carried a significant risk of side effects such Rationale for choice of vasopressor
as hearing loss [122–124] (ESM_2 Table S4). Norepinephrine is the most commonly used vasopressor
in patients with vasodilatory shock. A large RCT com-
Vasopressors paring dopamine to norepinephrine as initial vasopressor
Recommendations in patients with shock found no difference in mortality
1. We recommend titrating vasopressors to a mean arte- between randomised groups. However, norepinephrine
rial pressure (MAP) of 65–70 mmHg (Grade 1B) was associated with less tachycardia in the first hours
rather than a higher MAP target (80–85 mmHg) in and was superior regarding survival in cardiogenic shock
patients with septic shock. However, for patients patients. In addition, there was a trend towards more
with chronic hypertension we recommend aiming for RRT-free days through day 28 in the norepinephrine
a higher target (80–85 mmHg) for renal protection in group [127].
septic shock (Grade 1C). Vasopressin or the analogue terlipressin may have a
2. We recommend lowering systolic pressure to role in the treatment of norepinephrine-refractory shock
140–190 mmHg rather than to 110–139 mmHg in [128]. Exogenous vasopressin has vasoconstrictive and
patients with acute cerebral haemorrhage with severe antidiuretic properties and may increase glomerular fil-
admission hypertension (Grade 1C). tration by preferential post-glomerular vasoconstriction
3. If vasopressors are needed for treatment of hypoten- [129]. In the largest RCT in septic shock (VASST trial),
sion, we recommend norepinephrine (along with cor- vasopressin reduced mortality in the subgroup with less
rection of hypovolaemia) as the first-choice vasopres- severe shock, but not in the entire population. There were
 735

no differences in RRT-free days [130]. However, in a sec- Third, timing may be crucial, since delayed administra-
ondary analysis, a reduced progression to higher stages of tion reduces effectiveness as a result of occlusion of the
AKI could be demonstrated in the subgroup of patients microcirculation [139].
with AKI stage 1 at baseline [131]. In a subsequent 2 × 2
RCT in 409 patients with early septic shock (VANISH Clinical studies
trial) [132], the use of vasopressin compared to norepi- Low-dose or ‘renal’ dose dopamine has been advocated
nephrine did not affect the proportion of patients who in the past to prevent selective renal vasoconstriction in
never developed AKI stage 3 (57% vs. 59.2%), the num- a variety of conditions. This may not be the case in com-
ber of AKI stage 3-free days [difference −4 (−11 to 5)] plex clinical conditions, where low-dose dopamine may
or the incidence of AKI stage 3 [difference −5.1% (−15.2 even worsen renal perfusion [140]. Several meta-analyses
to 5.0)]. The use of vasopressin reduced the need for have concluded that ‘renal-dose’ dopamine has no benefit
RRT (difference −9.9% (−19.3 to −0.6), but only in non- in either preventing or ameliorating AKI in the critically
survivors. A recent single-centre RCT in 300 patients ill [141–143], the latest [141] being presented in ESM_2
with vasoplegic shock after cardiac surgery compared Table S6.
noradrenalin to vasopressin as first-choice vasopressor. Fenoldopam is a pure dopamine-A1 receptor agonist
The use of vasopressin was associated with less acute providing systemic and renal vasodilation and natriu-
renal failure (10.3% vs. 35.8%, p < 0.0001) and less RRT resis, and it has been studied in cardiovascular surgery
(2.7% vs. 13.9%, p = 0.0016) [133]. This trial, however, and critically ill patients. Two older meta-analyses, one
had some design issues (e.g. change in primary outcome including 1290 critically ill and surgical patients (mainly
during the study) and requires confirmation. The studies cardiovascular) from 16 RCTs and the other including
are summarized in ESM_2 Table S5. 1059 cardiac surgery patients from 13 (partially overlap-
ping) RCTs and case-matched studies, reported that the
Use of vasodilators use of fenoldopam reduced the incidence of AKI, need
Recommendations for RRT and hospital mortality [144]. Most studies were
1. We recommend against low-dose dopamine for pro- small with a moderate to high risk of bias and in the
tection against AKI (Grade 1A). second meta-analysis 30% of the included studies were
2. We recommend not using levosimendan for renal abstracts. The two most recent meta-analyses in cardiac
protection in patients with sepsis (Grade 1B) and surgery and major surgery used stricter inclusion criteria
recommend against its use for renal protection in car- [145, 146] and only found a lower risk for AKI, but not
diac surgery patients with poor preoperative left ven- for RRT or death. In addition, both showed an increased
tricular function or needing postoperative haemody- risk of hypotension and most included studies had a high
namic support (Grade 1B). risk of bias due to low sample size and fragility index, and
3. We suggest not using fenoldopam or natriuretic pep- use of different definitions for AKI. The most recent and
tides for renal protection in critically ill or cardiovas- largest RCT in post cardiac surgery patients with AKIN
cular surgery patients at risk of AKI (Grade 2B). stage I [147] did not show any renal protection or clinical
benefit from the use of fenoldopam, while fenoldopam
Rationale conferred more hypotension. (Studies are summarized in
Early in the course of ischaemic AKI, renal blood flow ESM_2 Table S7).
(RBF) falls because of stimulation of the sympathetic Atrial natriuretic peptide (ANP) is produced by car-
nervous system and the release of vasoconstrictors such diac atria in response to an acute increase in stretch and/
as endothelin, angiotensin II and vasoconstrictive prosta- or pressure and induces afferent dilatation and efferent
glandins [134, 135]. In contrast, during septic AKI global vasoconstriction, thereby increasing glomerular filtration
RBF seems to be well preserved [136, 137]. The main and urinary sodium excretion with a dose-dependent
perfusion problem during sepsis seems to occur at the hypotensive effect [148, 149]. B-type (brain) natriuretic
microvascular level and regionally in the outer medulla peptide (BNP) is primarily produced in the cardiac ven-
[138]. When using vasodilators for kidney protection, tricles and has similar effects [150, 151].
several issues should be considered. First, vasodilators The two most recent meta-analyses including RCTs in
may cause hypotension by counteracting compensatory the cardiac and cardiovascular surgery population found
vasoconstriction, thus unmasking occult hypovolaemia. that the prophylactic infusion of low-dose ANP reduced
Hypotension may further compromise renal perfusion postoperative peak creatinine [152] and the need for RRT
and correction of hypovolaemia is therefore crucial. Sec- [152–154]. However, the latter was based on only 24 cases
ond, as a result of endothelial damage, nitric oxide (NO)- of RRT in 563 patients. No effect was found in estab-
dependent vasodilators seem to be ineffective [135]. lished AKI and high-dose ANP was associated with more
736

frequent adverse effects (arrhythmias, hypotension) [154]. tion using propofol or dexmedetomidine may have
Two later RCTs on the use of ANP in aortic arch (n = 42) several advantages, possibly reducing the rate of AKI
and high-risk cardiac surgery (n = 367) confirmed a (BPS).
reduction in postoperative AKI and need for RRT (0/183
vs. 7/184, p = 0.015) [155, 156] (ESM_2 Table S8). Rationale
A recent meta-analysis including 15 RCTs in 9623 Sedation is necessary in many critically ill patients and
patients with acute decompensated heart failure showed this may affect cardiac function and/or vascular tone with
that the use of BNP (nesiritide) was associated with wors- renal consequences. In animal models propofol reduced
ening renal function: RR 1.08 (1.01–1.15), especially in markers of oxidative stress in the kidney [165, 166] and
the subgroup receiving a high dose (>0.01 μg/kg/min) dexmedetomidine caused diuresis through reducing vas-
and in patients without CKD [157]. opressin secretion, enhancing renal blood flow and hence
In general, most BNP trials were small, not powered for glomerular filtration [167] and showed renal protection
the endpoints RRT or mortality, of poor quality with low [168–171].
fragility index; inclusion criteria varied and results were
heterogeneous. Furthermore, hypotension and arrhyth- Clinical studies
mia were frequently reported. A small subgroup meta- Propofol is commonly used as anaesthetic and for seda-
analysis on BNP in cardiovascular surgery also showed tion in the intensive care unit [172]. The “propofol infu-
no benefit [152] (ESM_2 Table S8). sion syndrome” comprises myopathy, rhabdomyolysis,
The calcium sensitizer levosimendan has inodilator, hyperkalaemia and AKI [173, 174]. On the basis of the
cardioprotective and anti-inflammatory effects [158, data from case reports/series, it is recommended to
159]. In a recent meta-analysis of RCTs in the cardiac administer propofol for a maximum of 48 h and a maxi-
surgery population (13 trials, 1345 patients), the use of mum dose of 4 mg/kg/h [175]. On the other hand, a
levosimendan decreased the risk of AKI [OR 0.51 (0.24– recent propensity-matched cohort study in critically ill
0.79)], the need for RRT [OR 0.43 (0.25–0.76)] and mor- patients showed reduced risk of AKI and need for RRT
tality [OR 0.41 (0.27–0.62)] [160]. The last meta-analysis in patients sedated with propofol as compared to mida-
of RCTs in the critically ill population with or at risk of zolam [176]. Furthermore a small RCT including 112
AKI (33 RCTs, 3867 patients) found that, compared to patients undergoing valvular heart surgery showed less
placebo or another inotrope, levosimendan decreased AKI and significantly lower cystatin C levels in the group
the risk of AKI [RR 0.79 (0.63–0.99)] and the need for treated with propofol as compared to sevoflurane [177].
RRT [RR 0.52 (0.32–0.86)]. When limiting the analysis However, the fact that remote ischaemic preconditioning
to high-quality studies, the difference in need for RRT showed less effect if patients were treated with propofol
between groups failed to reach significance [RR 0.41 leaves uncertainty about the protective effect of propofol
(0.15–1.12)] [161]. Studies in both meta-analyses were on the kidney [178].
small, there was some heterogeneity, AKI was not always α-2 Adrenergic agonists have multiple pharmacody-
a predefined endpoint, different definitions of AKI were namic effects [179]. In a placebo-controlled double-blind
used and there might have been some outcome report- RCT dexmedetomidine demonstrated significant diu-
ing bias. retic effects, with an almost 75% increase in diuresis after
Three large placebo-controlled RCTs have recently cardiac surgery, but did not affect renal function per se
been published. In patients with sepsis the use of levo- [180]. Observational trials indicated protection of kid-
simendan was not beneficial in terms of a reduction of ney function after cardiac surgery [181] but not when
renal SOFA, need for RRT [OR 0.99 (0.66–1.49)] or mor- used for sedation during lung cancer resection [182]. A
tality [OR 1.19 (0.82–1.72)], while its use was associated placebo-controlled study in 90 patients undergoing coro-
with more adverse events [162]. In 882 patients with left nary artery bypass graft (CABG) showed a dose-depend-
ventricular dysfunction undergoing cardiac surgery, lev- ent reduction of NGAL levels with dexmedetomidine
osimendan had no effect on mortality or need for RRT used for postoperative sedation [183]. Another RCT in
[163]. No effect on AKI and RRT was seen when levosi- 200 patients showed that dexmedetomidine for 24 h at
mendan was given for haemodynamic support after car- 0.4 μg/kg/h from start of anaesthesia resulted in reduced
diac surgery in 506 patients [164] (ESM_2 Table S9). rate of AKI, morbidity and length of stay in the ICU [184]
(ESM_2 Table S10).
Sedation Alltogether, the data for non-benzodiazepine seda-
Recommendations tives, especially dexmedetomidine, are promising but
1. On the basis of current data no recommendation currently not sufficiently convincing to give a clear
can be given, although it appears that shorter seda- recommendation.
 737

Hormonal manipulation [196] of TGC nor a renoprotective effect (evaluated

Recommendations by the need for RRT only) [RR 0.96 (0.83–1.11)] [196]
1. We suggest targeting a blood glucose level at least (ESM_2 Table S11).
below 180 mg/dL (10 mmol/l) for the prevention of A major obstacle to the broad implementation of TGC
hyperglycaemic kidney damage in the general ICU is the increased risk of hypoglycaemia. Patients with AKI
population (Grade 2B). are at particular risk [197]. On the other hand, a causal
2. We suggest not using erythropoietin (Grade 2B) or relationship between a short-lasting iatrogenic hypo-
steroids (Grade 2B) for prevention of acute kidney glycaemia in the monitored setting of an ICU and out-
injury. come remains controversial [198–200]. If clinicians
decide to adopt TGC strategies, fluctuations in glucose
Rationale levels should be minimized and reliable tools should be
In critical illness hyperglycaemia has been associated employed to measure blood glucose [195]. Because of the
with adverse outcomes [185, 186] attributed to oxida- risk of hypoglycemia, current guidelines suggest more
tive stress, endothelial dysfunction, alterations in hae- moderate blood glucose targets (less than 180 mg/dL
mostasis, immune dysregulation and mitochondrial [20], less than 150 mg/dl [52], 140–180 mg/dL [201]) in
dysfunction. The anti-inflammatory effect of steroids may critically ill patients, although these targets have not been
attenuate the inflammatory component of AKI pathogen- formally compared with tolerating hyperglycaemia [202]
esis. Erythropoietin (EPO), besides being a haematopoi- (ESM_2 Table S11).
etic growth factor, also has tissue-protective properties A recent large RCT (n = 4494) demonstrated no sig-
by decreasing apoptosis and inflammation and by pro- nificant effect of the intraoperative administration of
moting neovascularization and tissue regeneration. dexamethasone on a composite endpoint of major com-
plications after cardiac surgery. The RR for RIFLE-Failure
Clinical studies was 0.7 (0.44–1.14) [203]. A post hoc analysis of this trial
A large prospective RCT in 1548 surgical ICU patients showed a beneficial effect on the need for RRT (RR 0.44
compared tight glucose control (TGC) with insulin (target (0.19–0.96)), an effect that was mainly seen in patients
blood glucose 80–110 mg/dL) to standard care (insulin with eGFR less than 15 ml/min/1.73 m2 and remains to
when blood glucose is greater than 200 mg/dL resulting be confirmed [204]. Another placebo-controlled RCT in
in a mean blood glucose of 150–160 mg/dL) and showed 7507 patients found no effect of methylprednisolone on
not only an improved survival rate but also a 41% reduc- the incidence of AKI stage 3 after cardiac surgery [205].
tion in AKI requiring RRT [187]. Additionally, TGC also Prospective randomised placebo-controlled trials on
reduced the number of patients with peak plasma creati- the renoprotective effect of erythropoietin have mainly
nine greater than 2.5 mg/dL by 27%. A subsequent study been performed in the setting of cardiac surgery [206–
in the medical ICU of the same hospital, including many 210]. A recent meta-analysis (5 studies, 423 patients)
patients that already had AKI on admission, did not con- found no effect of erythropoietin on the incidence of
firm the effect on survival or need for RRT, but showed AKI: RR 0.64 (0.35–1.16). Surprisingly, a preplanned sub-
a 34% reduction in AKI, defined as a doubling of serum group analysis found a significant reduction of AKI in
creatinine compared with the admission level [188]. A patients without high risk for AKI: RR 0.37 (0.24–0.61;
combined analysis of both studies showed a more pro- p < 0.0001) [211]. Similar results were obtained in the
nounced renal protection when normoglycaemia was most recent meta-analysis, which in addition showed
achieved [189]. more protection with pre-anaesthetic administration
More recent RCTs in septic [65] and general [190–194] [212]. Another RCT in cardiac surgery including 75
ICU patients (some of which had to be stopped early patients with pre-existing renal impairment found no
because of hypoglycaemia) including a large adequately differences in postoperative levels of serum creatinine,
powered multicentre trial in Australia and New Zealand cystatin C or NGAL [213]. A second meta-analysis (on a
(NICE-SUGAR) [191] did not confirm the renoprotec- total of 2759 patients) that also included studies in ICU
tive effect. The latter even found a higher mortality in patients [214, 215] likewise did not establish a renopro-
patients treated with TGC compared to an intermediate tective effect of erythropoietin: incidence of AKI RR 0.72
level. Clinicians should, however, be aware of important (0.79–1.19); dialysis requirement RR 0.72 (0.31–1.70),
differences between these landmark trials, such as the mortality RR 0.96 (0.78–1.18), all without significant
glycaemic target in the control group, the nutritional heterogeneity amongst studies [216]. It should, however,
strategy and the methods used to measure blood glucose be emphasized that in the largest study in ICU patients
levels [195]. The most recent meta-analysis on this issue [215] AKI was only reported as an adverse effect and not
did not find a mortality benefit [RR 1.06 (0.99–1.13)] clearly defined. Two more recent RCTs in the setting of
738

thoracic aortic surgery [217] and contrast administration effects of daily intravenous amino acid supplementation
in diabetics [218] confirmed the absence of beneficial up to 100 g/day in 424 critically ill patients could not
effect of EPO on the incidence of AKI or need for RRT in find a significant effect on the duration of AKI despite
critically ill patients (ESM_2 Table S12). an increase in eGFR in the treatment group [226]. Fur-
thermore, there was a trend towards increased need for
Metabolic interventions RRT which corresponds to findings from the EPaNIC
Recommendations trial where early parenteral nutrition increased the
1. We recommend not using high-dose IV selenium for duration of RRT probably driven by higher urea levels
renal protection in critically ill patients (1B). [227]. Correspondingly, lower caloric intake (defined
2. We suggest not using N-acetylcysteine to prevent as receiving less than 60% of requirements, also called
contrast-associated AKI in critically ill patients permissive underfeeding) has been found to be associ-
because of conflicting results and possible adverse ated with a lower risk for RRT (RR 0.711, 95% CI 0.545–
effects (Grade 2B). 0.928) [228].
3. We suggest that all patients with or at risk of acute A host of RCTs have been performed comparing NAC
kidney injury have adequate nutritional support pref- to placebo or other interventions with or without hydra-
erably through the enteral route (BPS). tion in non-critically ill patients receiving radiocontrast
media [229–237]. Results are controversial as alluded
Rationale to earlier but the latest meta-analysis assessing the effi-
Starvation accelerates protein breakdown and impairs cacy of intravenous NAC only showed no reduction of
protein synthesis in the kidney, whereas feeding might AKI or RRT [238]. The ACT trial, currently the largest
exert the opposite effects and promote renal regen- RCT including 2308 patients undergoing coronary and
eration. In animal experiments increased protein intake peripheral vascular angiography, failed to demonstrate
has been shown to reduce tubular injury [219, 220], and any beneficial effect of NAC [239]. RCTs in the critically
enteral versus parenteral nutrition improved the reso- ill population are not available.
lution of AKI [221]. On the other hand, amino acids RCTs examining the role of NAC in the prevention
infused before or during ischaemia may also enhance of renal dysfunction in high-risk contexts like car-
tubular damage and accelerate loss of renal function diac surgery showed controversial results [240–246]
[222]. This may also extend to high-dose glutamine when (ESM_2 Table S13). In addition IV NAC may be harm-
given to patients during the injury phase of AKI [223]. ful leading to allergic reactions [247] and decreased
Furthermore, brief periods of reduced food intake appear cardiac output or survival in patients with septic shock
to increase resistance against ischaemia–reperfusion [248, 249].
injury in rodents [224]. This “amino acid paradox” may A small RCT in 42 patients showed that selenium sup-
be related to the increase in metabolic work for trans- plementation decreased the requirement for RRT from
port processes which may aggravate ischaemic injury. 43% to 14% in patients with SIRS [250]. These finding
Enhanced autophagy, induced by nutrient deprivation could, however, not be reproduced in consecutive trials
and promoting the repair of cellular damage, may be an [251] including two larger RCTs involving 249 and 1089
alternative explanation. In this context permissive under- patients with sepsis [252, 253].
feeding during the acute phase of critical illness may be
protective against AKI. Statins
One aspect of nutrition is the adequate supply of nutri- Recommendations
tional co-factors and antioxidants such as the glutathione 1. We recommend against the perioperative use of high-
precursor N-acetylcysteine (NAC), antioxidant vitamins dose statins to prevent postoperative AKI in cardiac
(vitamin E (α-tocopherol) and vitamin C (ascorbic acid)) surgery (Grade 1A).
as well as selenium. However, these antioxidants have 2. We suggest the short-term use of atorvastatin or
also been investigated in pharmacological doses with the rosuvastatin to prevent contrast-associated AKI in
intention to provide protection against damage by oxy- high-risk patients undergoing coronary contrast
gen radicals. angiography (Grade 2B).

Clinical studies Rationale

Protein(s) and amino acids augment renal perfusion and The pleiotropic effect of statins, including antioxidant,
improve renal function, representing recruitment of anti-inflammatory and antithrombotic effects, may con-
“renal reserve capacity” [225]. An RCT investigating the tribute to nephroprotection [254].
 739

Clinical studies statin-naïve patients with CKD had a higher incidence of

Statins may have a beneficial role in high-risk patients AKI when treated with statin [268] (ESM_2 Table S15).
exposed to contrast administration for angiography, as Finally, an even larger placebo-controlled RCT in 1922
suggested by three recent RCTs [255–257]. In a mul- cardiac surgery patients that included AKI as a second-
ticentre trial in China, 2998 patients with type 2 diabe- ary outcome demonstrated renal harm in those receiv-
tes or mild to moderate CKD undergoing coronary or ing rosuvastatin 20 mg/day in the perioperative period
peripheral arterial angiography were randomised to a [270].
5-day course of rosuvastatin versus no statin [255]. The
incidence of CA-AKI was significantly lower in those Remote ischaemic preconditioning
receiving rosuvastatin (2.3% vs. 3.9%, respectively, Recommendations
p = 0.01). In a single-centre study [256], 504 statin-naïve 1. We suggest not using remote ischaemic precondi-
patients with acute coronary syndrome (ACS) scheduled tioning for prevention of AKI in critically ill patients
to undergo an early invasive strategy were randomised (Grade 2A).
to high-dose rosuvastatin at the time of admission ver-
sus treatment with atorvastatin commenced at hospital Rationale
discharge; 6.7% of patients in the early high-dose statin Remote ischaemic preconditioning (RIPC) or several
group developed CA-AKI compared to 15.1% in the con- short cycles of limb ischaemia is achieved through infla-
trol group. The 30-day rate of adverse cardiovascular and tion of a blood pressure cuff. The mechanism by which
renal events was also significantly reduced in the rosu- RIPC prevents AKI is incompletely understood.
vastatin group (3.6% vs. 7.9%, respectively, p = 0.036).
An RCT in 410 CKD patients showed less CA-AKI in Clinical studies
patients randomised to a single dose of atorvastatin In cardiac surgery several single-centre RCTs demon-
within 24 h before contrast exposure compared to the strated reduced incidence of AKI and need for RRT
control group (4.5% vs. 17.8%, p = 0.005) [257]. Two [271–273]. However, several others, including four larger
more recent RCTs found similar effects of statins in dia- and multicentric RCTs [274–277] did not confirm these
betics with CKD [258, 259]. These positive findings were beneficial effects, nor was a change in creatinine or
confirmed by several meta-analyses combining studies mortality demonstrated. The conflicting results in car-
in patients undergoing coronary angiography [260–263] diac surgery may be explained by inclusion of low-risk
(ESM_2 Table S14). One of these meta-analyses con- patients in trials that showed no benefit, and the use of
cluded that short-term, pre-procedural, intensive statin propofol and opioids, treatments that may blunt the ben-
treatment only reduced CA-AKI in ACS patients and eficial effects of RIPC.
recommended further studies in non-ACS patients [264]. In 13 recent meta-analyses the effect of RIPC was eval-
This meta-analysis, however, did not include the largest uated in different cohorts and definitions of AKI [178,
RCT [255]. Although, these results lend support to the 278–289]. Though several meta-analyses found a reduc-
short-term use of statins before procedures involving tion of AKI [278, 279, 281–284, 286, 287, 289, 290] this
intra-arterial contrast exposure in patients with coronary was restricted to stage 1 AKI [289], or subgroups such as
artery disease with or without diabetes and/or CKD, it percutaneous coronary interventions [278, 279], or car-
must be considered that most of the studies were per- diac surgery with propofol-free anaesthesia [283]. The
formed outside the ICU, thereby warranting downgrad- meta-analyses are limited by risk of bias, heterogeneity
ing of the level of evidence. in definitions of AKI, low event rates and underestima-
In patients undergoing cardiac surgery, two large tion of influence of co-morbidities [283, 289]. Finally, a
meta-analyses including data from observational studies Cochrane review including studies on patients undergo-
found conflicting evidence regarding the role of preop- ing surgery could not show a benefit on renal outcomes
eratve statin in preventing postoperative AKI [265, 266], [178] (ESM_2 Table S16).
and a Cochrane analysis of small RCTs found no effect In summary, the effects by which RIPC prevents AKI
[267]. Two recent placebo-controlled RCTs investigated are incompletely understood. RIPC for prevention of AKI
the effects of perioperative high-dose atorvastatin (i.e. has mainly been evaluated in cardiovascular surgery and
80 mg, followed by 40 mg daily) in elective cardiac sur- after contrast administration. Larger studies and meta-
gery [268] and valvular heart surgery [269] and showed analyses are not consistent in demonstrating a preventive
no renal benefit. Furthermore, in the largest trial, effect of RIPC for AKI.
740

AKI care bundles most individuals without pre-existing chronic hyperten-

Recommendations sion. The potential role of vasopressin requires further
1. We suggest using the KDIGO recommendations to investigation. Together with these measures a review of
reduce the incidence of AKI after cardiac surgery all medications with the cessation of those known to be
(Grade 2C). nephrotoxic is mandatory. Diuretics should not be used
2. The use of AKI care bundles outside the intensive for prevention of AKI alone but may benefit the kidney by
care unit has some benefits, including the potential relieving renal congestion. Frank hyperglycaemia should
to improve the outcome of AKI (BPS). be avoided. The effect of statins appears to depend on the
setting, with promising results in contrast administra-
Rationale tion but no effect or even harm in cardiac surgery. There
Care bundles have been proposed as tools to improve is low-level evidence that the choice of the sedative may
the quality of care and outcome of patients with AKI. impact kidney function. The conflicting results on ischae-
Ideally, they should contain a small set of practices, pro- mic preconditioning preclude a firm recommendation.
cesses or treatments that are evidence-based, endorsed Heterogeneous definitions of AKI still hamper compari-
and/or recommended by guidelines and broadly son of different studies, despite the commendable efforts
accepted as appropriate and/or standard care by local by the ADQI, AKIN and KDIGO working groups [2, 296,
stakeholders. They are designed such that if one ele- 297]. In addition, AKI is frequently reported as a secondary
ment is not implemented, the remaining elements are outcome. Although several RCTs have fuelled the literature
not impacted. on prevention of AKI over the past 4–5 years, the available
evidence remains insufficient. Many recommendations are
Clinical studies therefore formulated as weak with low grade quality of evi-
Outside the critical care setting, different AKI care bun- dence. More high-quality studies with consensus AKI defi-
dles have been implemented with variable improvement nitions will be required to fill the knowledge gaps.
in clinical care, more efficient resource use and potentially
Electronic supplementary material
improved outcomes, especially if combined with educa- The online version of this article (doi:10.1007/s00134-017-4832-y) contains
tional measures and electronic alerting [291–293]. To date, supplementary material, which is available to authorized users.
care bundles comprising the KDIGO recommendations
Acknowlegements
have only been investigated in one study including 274 car- Open access funding provided by University of Innsbruck and Medical Univer‑
diac surgery patients at high risk for AKI as determined by sity of Innsbruck.
AKI biomarkers. The study showed less postoperative AKI
Author details
(although mainly by the urine output criteria) without, 1
Division of Intensive Care and Emergency Medicine, Department of Internal
however, influencing any major patient-centred outcome Medicine, Medical University Innsbruck, Anichstasse 35, 6020 Innsbruck, Aus‑
like RRT or renal recovery at day 30 [294]. The treatment tria. 2 Department of Internal Medicine III, University Hospital Vienna, Vienna,
Austria. 3 Department of Clinical and Experimental Medicine, Faculty of Health
strategy included avoidance of nephrotoxins and hypergly- and Medical Sciences, University of Surrey and Surrey Perioperative Anaes‑
caemia as well as applying goal-directed haemodynamic thesia and Critical Care Collaborative Research Group (SPACeR), Intensive
optimisation. It is unclear which element was effective Care Unit, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road,
Guildford GU2 7XX, United Kingdom. 4 Department of Intensive Care, Uni‑
because goal-directed therapy (GDT) neither prevented versitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
AKI nor reduced the need for RRT in septic shock, as 5
Department of Intensive Care Medicine, Ghent University Hospital, Ghent
shown by a secondary analysis [23] and a meta-analysis of University, De Pintelaan 185, 9000 Ghent, Belgium. 6 Department of Critical
Care and Nephrology, Guy’s and St Thomas’ Hospital, London, United King‑
three recent large RCTs [295], but avoiding nephrotoxins, dom. 7 Department of Adult Intensive Care, VU University Medical Centre, De
hyperglycaemia and hypovolaemia seems to be reasonable. Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands. 8 Clinical Department
and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular
Medicine, KU Leuven University, Leuven, Belgium.
Conclusions and summary
Prompt resuscitation of the circulation with fluids, vaso- Compliance with ethical standards
pressors and inotropes remains the cornerstone in the
Conflicts of interest
prevention of AKI. Volume expansion with isotonic MJ has received honoraria or research support from Baxter Healthcare Corp,
crystalloids is only recommended in states of true and AM-Pharma, CLS Behring, Fresenius and Astute Medical. WD declares no
suspected hypovolaemia. Uncontrolled volume expan- conflicts of interest. LF has received honoraria and research support from
Astute Medical, Fresenius, Baxter Gambro Renal and Orthoclinical Diagnostics.
sion and the use of starches and dextrans should be PH had received research grants from Baxter, AM Pharma, Bellco, and Pfizer EH
avoided. Following or together with fluid resuscitation received speaker’s fees from Alexion and Astute Medical, and a research grant
hypotensive patients should be given a vasoconstric- from Bellco. MO has received honoraria and research funding from Fresenius
Medical Care and Baxter Gambro. HO has financial congress support from
tor, preferably norepinephrine, and titrated individually Dirinco (Netherlands) and speaker’s honoraria from Fresenius and Gambro/
with a target MAP of 65–70 mmHg being adequate in Baxter. MS declares no conflicts of interest.
 741

Open Access 12. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P,
This article is distributed under the terms of the Creative Commons Attribu‑ Schunemann HJ (2008) GRADE: an emerging consensus on rating qual‑
tion-NonCommercial 4.0 International License (http://creativecommons.org/ ity of evidence and strength of recommendations. BMJ 336:924–926
licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and 13. Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, Alderson P,
reproduction in any medium, provided you give appropriate credit to the Glasziou P, Falck-Ytter Y, Schunemann HJ (2011) GRADE guidelines: 2.
original author(s) and the source, provide a link to the Creative Commons Framing the question and deciding on important outcomes. J Clin
license, and indicate if changes were made. Epidemiol 64:395–400
14. Guyatt GH, Schunemann HJ, Djulbegovic B, Akl EA (2015) Guideline
panels should not GRADE good practice statements. J Clin Epidemiol
Received: 10 April 2017 Accepted: 2 May 2017 68:597–600
Published online: 2 June 2017 15. de Mendonca A, Vincent JL, Suter PM, Moreno R, Dearden NM, Antonelli
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