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Remote Ischemic Preconditioning for Prevention of Acute Kidney Injury in Patients Undergoing On-Pump Cardiac Surgery: A Systematic Review and Meta-Analysis

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Remote ischemic preconditioning (RIPC) may attenuate acute kidney injury (AKI). However, results of studies evaluating the effect of RIPC on AKI after cardiac surgery have been controversial and contradictory. The aim of this meta-analysis is to examine the association between RIPC and AKI after on-pump cardiac surgery. The authors searched relevant studies in PubMed, EMBASE, and the Cochrane Library through December 2015. We considered for inclusion all randomized controlled trials that the role of RIPC in reducing AKI and renal replacement therapy (RRT) among patients underwent on-pump cardiac surgical procedures. We collected the data on AKI, initiation of RRT, serum creatinine (sCr) levels, and in-hospital mortality. Random- and fixed-effect models were used for pooling data. Nineteen trials including 5100 patients were included. The results of this meta-analysis showed a significant benefit of RIPC for reducing the incidence of AKI after cardiac interventions (odds ratio [OR] = 0.84; 95% confidence interval [CI], 0.73–0.98; P = 0.02). No significant difference was found in the incidence of RRT between RIPC and control (OR, 0.76, 95% CI, 0.46–1.24; P = 0.36). In addition, compared with standard medical care, RIPC showed no significant difference in postoperative sCr (IV 0.07; 95% CI, −0.03 to 0.16; P = 0.20; postoperative day 1; IV 0.00; 95% CI, −0.08 to 0.09; P = 0.92; postoperative day 2; IV 0.04; 95% CI, −0.05 to 0.12; P = 0.39; postoperative day 3), and in-hospital mortality (OR, 1.21, 95% CI, 0.64–2.30; P = 0.56). According to the results from present meta-analysis, RIPC was associated with a significant reduction AKI after on-pump cardiac surgery but incidence of RRT, postoperative sCr, and in-hospital mortality. Further high-quality randomized controlled trials and experimental researches comparing RIPC are desirable.
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Remote Ischemic Preconditioning for Prevention of Acute
Kidney Injury in Patients Undergoing On-Pump
Cardiac Surgery
A Systematic Review and Meta-Analysis
Yabing Zhang, MD, Xiyang Zhang, MD, Dongmei Chi, MD, Siyang Wang, MD, Hua Wei,
Hong Yu, MD, Qian Li, MD, and Bin Liu, MD
Abstract: Remote ischemic preconditioning (RIPC) may attenuate
acute kidney injury (AKI). However, results of studies evaluating the
effect of RIPC on AKI after cardiac surgery have been controversial and
contradictory.
The aim of this meta-analysis is to examine the association between
RIPC and AKI after on-pump cardiac surgery.
The authors searched relevant studies in PubMed, EMBASE, and
the Cochrane Library through December 2015.
We considered for inclusion all randomized controlled trials that the
role of RIPC in reducing AKI and renal replacement therapy (RRT)
among patients underwent on-pump cardiac surgical procedures.
We collected the data on AKI, initiation of RRT, serum creatinine
(sCr) levels, and in-hospital mortality. Random- and fixed-effect models
were used for pooling data.
Nineteen trials including 5100 patients were included. The results of
this meta-analysis showed a significant benefit of RIPC for reducing the
incidence of AKI after cardiac interventions (odds ratio [OR]¼0.84;
95% confidence interval [CI], 0.73–0.98; P¼0.02). No significant
difference was found in the incidence of RRT between RIPC and control
(OR, 0.76, 95% CI, 0.46– 1.24; P¼0.36). In addition, compared with
standard medical care, RIPC showed no significant difference in post-
operative sCr (IV 0.07; 95% CI, 0.03 to 0.16; P¼0.20; postoperative
day 1; IV 0.00; 95% CI, 0.08 to 0.09; P¼0.92; postoperative day 2; IV
0.04; 95% CI, 0.05 to 0.12; P¼0.39; postoperative day 3), and in-
hospital mortality (OR, 1.21, 95% CI, 0.64–2.30; P¼0.56).
According to the results from present meta-analysis, RIPC was
associated with a significant reduction AKI after on-pump cardiac
surgery but incidence of RRT, postoperative sCr, and in-hospital
mortality. Further high-quality randomized controlled trials and exper-
imental researches comparing RIPC are desirable.
(Medicine 95(37):e3465)
Abbreviations: AKI = acute kidney injury, BUN = blood urea
nitrogen, CI = confidence interval, CPB = cardiopulmonary bypass,
ICU = intensive care unit, IR = ischemia and reperfusion, OR =
odds ratio, RCTr = andomized controlled trial, RIPCr = emote
ischemic preconditioning, RR = relative ratio, RRT = renal
replacement therapy, sCr = serum creatinine.
INTRODUCTION
Up to 30% patients developed acute kidney injury (AKI)
after cardiac surgery and approximately 1% to 2% of all the
patients require renal replacement therapy (RRT).
1,2
The devel-
opment of AKI following cardiac surgery is associated with
substantial morbidity and mortality, as well as prolonged inten-
sive care unit and hospital stays.
3,4
The pathophysiology of
AKI following cardiac surgery is complex and multifactorial.
During cardiopulmonary bypass (CPB), a variety of insults
participated the development of tubular injury, including
systemic inflammatory response, ischemia–reperfusion (IR)
injury, macroscopic and microscopic emboli, exposing blood
to nonphysiologic surfaces, significant hemodynamic changes,
and exposure to contrast media.
5–7
Although numerous clinical trials of prophylactic inter-
ventions have been used, most of the interventions to prevent
AKI after cardiac surgery are not supported definitively by
evidence, and some have even proved harmful.
8–10
Remote ischemic preconditioning (RIPC) is a phenomenon
that brief intermittent periods of IR of a distant organ or tissue
provide protection to distant organs from subsequent episode of
lethal IR.
11,12
The mechanisms underlying RIPC are incomple-
tely understood. RIPC might preserve kidney function in
patients undergoing cardiac and vascular interventions through
restraining production of oxygen-free radicals and attenuating
the inflammatory cascade response involved in pathogenesis of
AKI.
13– 15
The randomized controlled trials (RCTs) concerning the
renal protective effect of RIPC in patients undergoing cardio-
vascular surgery during CPB were inconsistent, and the results
remained controversial and contradictory. In this study, we
conducted a meta-analysis including complete results from
recently published RCT to investigate whether an RIPC pro-
tocol prevents AKI after on-pump cardiac surgery. There was no
registered protocol.
Editor: Kazuo Hanaoka.
Received: February 15, 2016; revised: March 26, 2016; accepted: March
31, 2016.
From the Department of Anesthesiology, West China Hospital of Sichuan
University, Chengdu, Sichuan (YZ, XZ, DC, SW, HY, QL, BL), and
Department of Anesthesiology, First Affiliated Hospital of Zhengzhou
University, Zhengzhou (HW), China.
Correspondence: Bin Liu, Department of Anesthesiology, West China
Hospital of Sichuan University, No. 37, Wai Nan Guo Xue Xiang,
Chengdu, Sichuan 610041, China (e-mail: liubinhxyy@163.com).
YZ, XZ, DC, and SW contribute equally to this research.
This research was carried out with the support of National Natural Science
Foundation of China (Grant Nos. 81300110 and 30972862) and the
Sichuan Province Science and Technology Supporting Program (Grant
No. 2012FZ0121).
The authors have no conflicts of interest to disclose.
Copyright #2016 the Author(s). Published by Wolters Kluwer Health, Inc.
All rights reserved.
This is an open access article distributed under the Creative Commons
Attribution License 4.0, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
ISSN: 0025-7974
DOI: 10.1097/MD.0000000000003465
Medicine®
SYSTEMATIC REVIEW AND META-ANALYSIS
Medicine Volume 95, Number 37, September 2016 www.md-journal.com |1
METHODS
Search Strategy
The systematic review was performed in accordance with
PRISMA (Preferred Reporting Items for Systematic reviews
and Meta-Analyses) guidelines.
16
Ethical approval was not
required considering the nature of the study.
We searched, without language restriction, MEDLINE,
EMBASE, and the Cochrane Library through December
2015. The search terms were ischemic preconditioning, RIPC,
cardiac surgical procedures, cardiac surgery, coronary artery
bypass graft surgery, valve surgery, CPB, and RCTs. Reference
lists of retrieved articles were manually searched to
avoid omissions.
Types of Outcome Measures
The primary outcomes were development of AKI,
initiation of RRT. Serum creatinine (sCr) levels and in-hospital
mortality after surgery were secondary outcomes.
Study Selection
The inclusion criteria were as follows: patients underwent
on-pump cardiac surgical procedures, including coronary artery
bypass graft surgery and valve surgery; and studies comparing
RIPC with control, and sufficient data available to calculate a
relative ratio (RR) or mean difference (MD) with 95% confi-
dence interval (95% CI). The following exclusion criteria were
used: RIPC was performed in all patients undergoing major
vessel surgery; study protocols; pediatric patients; nonhuman
studies; and percutaneous coronary interventions/coronary
angiography studies.
Two investigators (YZ and XZ) independently reviewed all
abstracts and included the full-text each trial independently and
recorded eligibility, quality, and outcomes. Disagreements
between the reviewers concerning the decision to include or
exclude a study were resolved through discussion. If necessary,
the 3rd reviewer (DC) was consulted. We excluded duplicate
reports, non-RCTs, and experimental design. Conference
abstracts were also excluded, unless published as full-text
reports in journals.
Quality Assessment
Two reviewers (YZ and XZ) independently performed
quality assessment. We used the Jadad scoring system to assess
the quality of the trails according to randomization; blinding;
withdrawals; and dropouts.
17
According to this scale, we judged
the trails as low-quality study with 2 or less points and high-
quality study with 3 or more points.
Data Synthesis and Analysis
Before the analysis, data were standardized into equiv-
alent units. We calculated and subsequently pooled in inde-
pendent meta-analyses, risk ratio (RR) with 95% CI for
dichotomous outcomes and MD with 95% CI for continuous
outcomes. Heterogeneity among pooled studies was evalu-
ated using the Mantel–Haenszel, x
2
,andtheI
2
statistic to
assess the degree of interstudy variation. I
2
values exceeding
25%, 50%, and 75% were considered evidence of low,
moderate, and severe statistical heterogeneity, respectively.
18
Homogeneity assumption was measured by Pvalue. A P
value <0.10 indicates statistically significant heterogeneity
and synthesis of each study was performed using the random-
effects model.
Publication bias was evaluated by Begg test and Egger test.
Sensitivity analysis was conducted by sequentially deleting a
single study each time in an attempt to identify the potential
influence of an individual study. A 2-tailed Pvalue of <0.05
was considered a criterion for statistical significance. Analyses
were carried out with Review Manager 5.3 (RevMan, The
Cochrane Collaboration, Oxford, UK) and STATA 12.0 (Sta-
taCorp, College Station, TX).
RESULTS
Study Characteristics
The study selection process is presented in Figure 1. The
search strategy identified 1093 studies, of which data from 19
trials
19– 37
were used comprising 5100 patients (Table 1).
Among the 19 studies, 1 was a conference abstract,
21
which
has not been published as full-text reports in a peer-reviewed
journal. One study by Walsh and his colleagues included 7
patients (accounting 2.7%) with off-pump procedure.
37
Two
studies
19,21
had a Jadad score of <3 (Table 2). For the primary
endpoints, the incidence of AKI was reported in 14 trails.
20–
25,28– 30,32– 36
In this part, the multicenter randomized study by
Meybohm et al
27
was not analyzed, because the patient of AKI
grade 1 were not recorded according their supplementary
materials. The incidence of renal-replacement therapy was
reported in 9 trails.
19,23,26,27,29– 32,35
Effect of RIPC on the Incidence of AKI
A total of 15 RCTs including 3487 patients reported data
on the incidence of AKI, and the overall incidence was 32.4%
(532/1732 in RIPC group and 599/1755 in control group). There
was a significantly lower risk of AKI in the RIPC group
compared with control group using the fixed-effect model (odds
ratio [OR] ¼0.84; 95% CI, 0.73–0.98; P¼0.02), with low
heterogeneity (x
2
¼22.34, I
2
¼37%) (Figure 2). Sensitivity
analysis sequentially deleting a single study each time revealed
that most individual study was consisted. The RR did not
change markedly in sensitivity analyses, ranging from 0.69
(0.51, 0.81) with lower heterogeneity (I
2
¼20%) when the trial
FIGURE 1. Flow chart of selection process of eligible studies.
RCT ¼randomized controlled trial.
Zhang et al Medicine Volume 95, Number 37, September 2016
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TABLE 1. Demographic Data of Studies Included in Meta-Analysis (RIPC Group/Control Group)
Study
No. of
Patients DM, No.
Baseline
Creatinine, mg/dL
Surgical
Procedures
RIPC
Methods
AKI
Definition
Cabrera-Fuentes et al
19
6/6 NR NR CABG, valve surgery 1 Upper limb NR
Candilio et al
21
90/90 NR NR CABG, valve surgery NR NR
Candilio et al
20
89/89 28/24 NR CABG, valve surgery 1 Upper thigh AKIN
Choi et al
22
38/38 1/4 0.91/0.92 CABG, valve surgery 1 Upper leg AKIN
Gallagher et al
23
43/43 27/28 1.37/1.37 CABG, valve surgery 1 Upper limb AKIN
Hausenloy et al
24
801/811 203/790 1.07/1.07 CABG, valve surgery 1 Upper limb AKIN
Hu et al
25
101/100 0/0 NR Valve surgery Right thigh AKIN
Lucchinetti et al
26
27/28 0/0 1.04/1 CABG Right thigh NR
Meybohm et al
28
90/90 21/17 0.82/0.88 CABG, valve surgery 1 Upper limb AKIN
Meybohm et al
27
692/693 166/178 NR CABG, valve surgery 1 Upper limb Modified RIFLE
Pinaud et al
29
50/49 6/8 NR Aortic valve surgery 1 Upper limb AKIN
Rahman et al
30
80/82 0/0 1.11/1.09 CABG 1 Upper limb Creatinine rise
>0.5 mg/dL
Thielmann et al
31
27/26 0/0 1.13/1.17 CABG 1 Upper limb NR
Venugopal et al
32
38/40 0/0 0.96/0.95 CABG, valve surgery 1 Upper limb AKIN
Walsh et al
37
128/130 39/40 1.10 CABG, valve surgery, or other 1 Thigh AKIN
Wang et al
33
15/16 0/0 0.78/0.78 Valve surgery Right lower limb AKIN
Young et al
34
48/48 NR 1.15/1.07 CABG, valve surgery 1 Upper limb RIFLE
Zarbock et al
35
120/120 46/44 1.1/1.2 CABG, valve surgery 1 Upper arm AKIN
Zimmerman et al
36
59/59 24/21 0.93/0.95 CABG, valve surgery 1 Thigh AKIN
AKI ¼acute kidney injury, AKIN ¼acute kidney injury network, CABG ¼coronary artery bypass grafting, DM ¼diabetes mellitus, NR ¼no
report, RIFLE ¼Risk Injury Failure Loss End-stage renal disease, RIPC ¼remote ischemic preconditioning.
TABLE 2. Quality of Studies Included in Meta-Analysis
Study Randomization Method
Allocation
Concealment Blinding
Intention-to-Treat
Analysis
Completeness of
Follow-Up
Jadad
Score
Cabrera-Fuentes
et al
19
NR Yes Double blind Yes Yes 2
Candilio et al
21
NR Yes Double blind NR NR 2
Candilio et al
20
Computer-generated randomization
procedure
Yes Double blind Yes Yes 5
Choi et al
22
Computer-generated randomization table Yes Double blind Yes Yes 4
Gallagher et al
23
NR Yes Single blind Yes Yes 3
Hausenloy et al
24
Computer-generated randomization
procedure
Yes Double blind Yes Yes 5
Hu et al
25
NR Yes Double blind Yes No 3
Lucchinetti et al
26
Computer-generated random numbers Yes Double blind Yes Yes 4
Meybohm et al
28
NR Yes Double blind Yes Yes 5
Meybohm et al
27
Computer-generated randomization
procedure
Yes Double blind Yes Yes 5
Pinaud et al
29
Computer-generated randomization table No Single blind Yes Yes 4
Rahman et al
30
Computer-generated randomization schedule Yes Double blind Yes Yes 4
Thielmann et al
31
Randomized by anesthesiologist No Single blind No Yes 3
Venugopal et al
32
Computer-generated random numbers No Single blind Yes Yes 3
Walsh et al
37
Computer-generated randomization
procedure
Yes Triple blind Yes Yes 5
Wang et al
33
Computer-generated randomization schedule Yes Triple blind Yes Yes 3
Young et al
34
Block randomization generated by online
randomization sequence generator
Yes Double blind Yes Yes 4
Zarbock et al
35
Computer-generated randomization code Yes Double blind Yes Yes 5
Zimmerman et al
36
Block randomization generated by study
coordinator
No Single blind Yes Yes 3
NR ¼no report.
Medicine Volume 95, Number 37, September 2016 Remote Ischemic Preconditioning for Acute Kidney Injury
Copyright #2016 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com |3
by Hausenloy et al
24
was omitted to 0.88 (0.75, 1.02) (I
2
¼17%)
when the trial by Zimmerman et al.
36
No significant publication
bias was detected, with P¼0.843 in Begg test and P¼0.055 in
Egger test.
Effect of RIPC on RRT
The initiation of RRT was reported in 2428 study subjects.
In 4 of the 10 trials, none of patients required postoperative
hemodialysis or hemofiltration. In total, 65 patients, 2.68%,
received RRT after surgery (28, RIPC group; 37, control group).
There was no significant difference in the incidence of RRT
between 2 groups (OR, 0.76, 95% CI, 0.46 –1.24; P¼0.27) with
nonsignificant heterogeneity (x
2
¼10.90, I
2
¼54%) (Figure 3).
In sensitivity analysis, there was no significant difference
between 2 groups for replacement therapy requirement. No
evidence of publication bias was detected for initiation of RRT
by either funnel plots, Begg test (P¼1.000), or Egger test
(P¼0.237).
Postoperative sCr Levels
Available information on the hospital postoperative sCr
was analyzed. No statistically significant difference was
observed on 1, 2, or 3 days after operation (Figure 4).
Mortality
A total of 13 studies including 2710 patients reported data
on the in-hospital mortality. There was no statistically
significant difference in the overall mortality between 2 groups
(OR, 1.21, 95% CI, 0.64–2.30; P¼0.56) with no heterogeneity
(x
2
¼6.97, I
2
¼0%) (Figure 5).
DISCUSSION
This study reports detailed analyses of 19 trails that
compared RIPC to the control group in prevention of AKI
for patients undergoing cardiac interventions. The results of this
meta-analysis showed a significant benefit of RIPC for reducing
the incidence of AKI after cardiac interventions. No significant
differences were found in the incidence of RRT, postoperative
sCr, and in-hospital mortality.
AKI is a potential complication among patients under-
going cardiac surgery that can arise from a variety of causes.
Data suggest that even a small increase (0.3 –0.5 mg/dL) in sCr
after cardiac surgery is associated with a substantial decrease in
survival.
38
The protection was supported by numerous precli-
nical studies in animals showing that RIPC, compared with
controls, was associated with reduction of blood urea nitrogen
(BUN), sCr, and histologic renal damage.
39,40
The present analysis is in accordance with the findings of a
previous meta-analysis, and helps further understand the effect
of RIPC.
41
In addition to experimental evidence, several clinical
trials have suggested the potential protection of RIPC on
reducing kidney damage in humans,
20,36
while some studies
found the contrary.
25,29
Lack of knowledge of RIPC and con-
flicting results of small sample sizes trials
20,21,30,33
may explain
FIGURE 2. Forest plot for acute kidney injury.
FIGURE 3. Forest plot for renal replacement therapy.
Zhang et al Medicine Volume 95, Number 37, September 2016
4|www.md-journal.com Copyright #2016 Wolters Kluwer Health, Inc. All rights reserved.
the absence of RIPC in the operating room. The inconsistent
outcomes across RIPC trials might also have been due to
differences in study protocols, different patient populations,
comorbid diseases, anesthetic regimens, and surgical tech-
nique.
40
To achieve widespread clinical acceptance of RIPC,
it has been suggested that focus should be kept on patients at
high risk of global tissue damage including AKI.
42
They might
benefit most from protection by RIPC.
A prospective double-blind study performed by Zarbock
et al reported that patients undergoing cardiac surgery were at
high risk of AKI with a Cleveland Clinic score 6. Their study
included 240 subjects in which the rate and severity of AKI
influenced by RIPC was compared with a sham procedure.
35
They found fewer patients in the RIPC group received RRT
(5.8% vs 15.8%, respectively) and shorter intensive care unit
stay length than our study. As for there was no significance on
the secondary end points including of in-hospital, and 30-day
mortality, mechanical ventilation, myocardial infarction, or
stroke no significant difference was detected.
However, the result should be interpreted with caution.
The definitions of AKI adopted in respective trials included in
the present meta-analysis were different which might influence
the global results. The adopted definitions included the AKIN
criterion, RIFLE criterion, and other similar definitions.
Although all the adopted AKI definitions were similar, the
conclusions drawn should be treated with caution. However, the
subgroup analysis based on definitions of AKI of a previous
meta-analysis indicated a nonsignificant effect of RIPC on AKI
prevention.
41
The absence of an association between RIPC and RRT
could be expected, since requirement of replacement therapy is
very low in general, and only 2.68% patients developed into a
severe dialysis-dependent AKI in our present analysis.
Limitations
The present meta-analysis has several limitations that
should be considered. First, the definitions of AKI adopted
in respective trials were different, although no significant effect
FIGURE 4. Forest plot for postoperative serum creatinine levels. (A) Serum creatinine levels on the 1st postoperative day; (B) serum
creatinine levels on the 2nd postoperative day; and (C) serum creatinine levels on the 3rd postoperative day.
FIGURE 5. Forest plot for relative risk of mortality.
Medicine Volume 95, Number 37, September 2016 Remote Ischemic Preconditioning for Acute Kidney Injury
Copyright #2016 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com |5
was found. Second, comorbidities among the studies were
different such as hyperlipidemia, diabetes, and hypertension.
They may raise protective threshold and to some extent resist to
various conditioning strategies. In our analysis, the heterogen-
eity is low and acceptable. Third, preoperative kidney function
of the studies was different, and patients at high risk of AKI
following cardiac surgery were supposed to benefit from RIPC
most. We lacked corresponding trails to make a subgroup
analysis and whether preexisting decreased kidney function
could influence the effect of RIPC on AKI. Fourth, different
anesthetic protocols might confound the effect of RIPC. Both
propofol anesthesia and volatile anesthetics were shown to
attenuate protection by RIPC.
27,43
Opioid analgesics can inter-
fere with cardioprotective efficacy of RIPC and raise the
threshold for an additional benefit by their independently
cardioprotection.
42
CONCLUSION
In present systematic meta-analysis, RIPC was associated
with a significant reduction AKI after on-pump cardiac surgery
but incidence of RRT, postoperative sCr, and in-hospital
mortality. Numerous clinical trials using several interventions
to prevent AKI have been somewhat disappointing. In clinical
practice, RIPC appears to be a safe procedure, as no adverse
events related to RIPC application were reported to date.
To verify the beneficial effects of RIPC, more efforts
should be made to form a better evidentiary basis for RIPC.
Before RIPC is adopted for clinical use, large-scale, probably
multicenter, and high-quality studies will be needed to change
practice. Meanwhile more experimental research is needed on
the potential mechanisms responsible for improved AKI.
REFERENCES
1. Hobson CE, Yavas S, Segal MS, et al. Acute kidney injury is
associated with increased long-term mortality after cardiothoracic
surgery. Circulation. 2009;119:2444–2453.
2. Koyner JL, Bennett MR, Worcester EM, et al. Urinary cystatin C as
an early biomarker of acute kidney injury following adult cardiothor-
acic surgery. Kidney Int. 2008;74:1059–1069.
3. Ryckwaert F, Boccara G, Frappier JM, et al. Incidence, risk factors,
and prognosis of a moderate increase in plasma creatinine early after
cardiac surgery. Crit Care Med. 2002;30:1495–1498.
4. Stafford-Smith M, Podgoreanu M, Swaminathan M, et al. Associa-
tion of genetic polymorphisms with risk of renal injury after
coronary bypass graft surgery. Am J Kidney Dis. 2005;45:519–530.
5. Cremer J, Martin M, Redl H, et al. Systemic inflammatory response
syndrome after cardiac operations. Ann Thorac Surg. 1996;61:1714–
1720.
6. Moat NE, Evans TE, Quinlan GJ, et al. Chelatable iron and copper
can be released from extracorporeally circulated blood during
cardiopulmonary bypass. FEBS Lett. 1993;328:103–106.
7. Rosner MH, Okusa MD. Acute kidney injury associated with cardiac
surgery. Clin J Am Soc Nephrol. 2006;1:19–32.
8. Burns KE, Chu MW, Novick RJ, et al. Perioperative N-acetylcysteine
to prevent renal dysfunction in high-risk patients undergoing CABG
surgery: a randomized controlled trial. JAMA. 2005;294:342–350.
9. Landoni G, Bove T, Szekely A, et al. Reducing mortality in acute
kidney injury patients: systematic review and international web-
based survey. J Cardiothorac Vasc Anesth. 2013;27:1384–1398.
10. Ranucci M, Soro G, Barzaghi N, et al. Fenoldopam prophylaxis of
postoperative acute renal failure in high-risk cardiac surgery patients.
Ann Thorac Surg. 2004;78:1332–1337discussion 1337– 1338.
11. Gho BC, Schoemaker RG, van den Doel MA, et al. Myocardial
protection by brief ischemia in noncardiac tissue. Circulation.
1996;94:2193–2200.
12. Przyklenk K, Bauer B, Ovize M, et al. Regional ischemic
‘‘preconditioning’’ protects remote virgin myocardium from subse-
quent sustained coronary occlusion. Circulation. 1993;87:893–899.
13. Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote
ischaemic preconditioning on myocardial injury in patients under-
going coronary artery bypass graft surgery: a randomised controlled
trial. Lancet (Lond, Engl). 2007;370:575–579.
14. Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning:
underlying mechanisms and clinical application. Cardiovasc Res.
2008;79:377–386.
15. Pickard JMJ, Bøtker HE, Crimi G, et al. Remote ischemic
conditioning: from experimental observation to clinical application:
report from the 8th Biennial Hatter Cardiovascular Institute Work-
shop. Basic Res Cardiol. 2015;110:453.
16. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. PLoS
Med. 2009;6:e1000097.
17. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality
and discrepancies between large and small randomized trials in
meta-analyses. Ann Intern Med. 2001;135:982–989.
18. Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring incon-
sistency in meta-analyses. BMJ (Clin Res ed). 2003;327:557–560.
19. Cabrera-Fuentes HA, Niemann B, Grieshaber P, et al. RNase1 as
a potential mediator of remote ischaemic preconditioning for
cardioprotectiondagger. Eur J Cardiothorac Surg. 2015;48:
732–737.
20. Candilio L, Malik A, Ariti C, et al. Effect of remote ischaemic
preconditioning on clinical outcomes in patients undergoing cardiac
bypass surgery: a randomised controlled clinical trial. Heart (British
Cardiac Society). 2015;101:185–192.
21. Candilio L, Malik A, Ariti C, et al. The effects of multi-limb remote
ischaemic preconditioning in patients undergoing cardiac bypass
surgery. Heart (British Cardiac Society). 2013;99:A74.
22. Choi YS, Shim JK, Kim JC, et al. Effect of remote ischemic
preconditioning on renal dysfunction after complex valvular heart
surgery: a randomized controlled trial. J Thorac Cardiovasc Surg.
2011;142:148–154.
23. Gallagher SM, Jones DA, Kapur A, et al. Remote ischemic
preconditioning has a neutral effect on the incidence of kidney
injury after coronary artery bypass graft surgery. Kidney Int.
2015;87:473–481.
24. Hausenloy DJ, Candilio L, Evans R, et al. Remote ischemic
preconditioning and outcomes of cardiac surgery. N Engl J Med.
2015;373:1408–1417.
25. Hu Q, Luo W, Huang L, et al. Multiorgan protection of remote
ischemic perconditioning in valve replacement surgery. J Surg Res.
2016;200:13–20.
26. Lucchinetti E, Bestmann L, Feng J, et al. Remote ischemic
preconditioning applied during isoflurane inhalation provides no
benefit to the myocardium of patients undergoing on-pump coronary
artery bypass graft surgery: lack of synergy or evidence of
antagonism in cardioprotection? Anesthesiology. 2012;116:296–310.
27. Meybohm P, Bein B, Brosteanu O, et al. A multicenter trial of
remote ischemic preconditioning for heart surgery. N Engl J Med.
2015;373:1397–1407.
28. Meybohm P, Renner J, Broch O, et al. Postoperative neurocognitive
dysfunction in patients undergoing cardiac surgery after remote
ischemic preconditioning: a double-blind randomized controlled pilot
study. PLoS ONE. 2013;8:e64743.
Zhang et al Medicine Volume 95, Number 37, September 2016
6|www.md-journal.com Copyright #2016 Wolters Kluwer Health, Inc. All rights reserved.
29. Pinaud F, Corbeau JJ, Baufreton C, et al. Remote ischemic
preconditioning in aortic valve surgery: results of a randomized
controlled study. J Cardiol. 2016;67:36–41.
30. Rahman IA, Mascaro JG, Steeds RP, et al. Remote ischemic
preconditioning in human coronary artery bypass surgery: from
promise to disappointment? Circulation. 2010;122(Suppl):S53–S59.
31. Thielmann M, Kottenberg E, Boengler K, et al. Remote ischemic
preconditioning reduces myocardial injury after coronary artery
bypass surgery with crystalloid cardioplegic arrest. Basic Res
Cardiol. 2010;105:657–664.
32. Venugopal V, Laing CM, Ludman A, et al. Effect of remote
ischemic preconditioning on acute kidney injury in nondiabetic
patients undergoing coronary artery bypass graft surgery: a second-
ary analysis of 2 small randomized trials. Am J Kidney Dis.
2010;56:1043–1049.
33. Wang Q, Luo W, Zhou Q. Intervention of NGAL and HO-1 in valve
replacement surgery-induced acute kidney injury. J Cent S Univ Med
Sci. 2014;39:1001–1007.
34. Young PJ, Dalley P, Garden A, et al. A pilot study investigating the
effects of remote ischemic preconditioning in high-risk cardiac
surgery using a randomised controlled double-blind protocol. Basic
Res Cardiol. 2012;107:256.
35. Zarbock A, Schmidt C, Van Aken H, et al. Effect of remote
ischemic preconditioning on kidney injury among high-risk patients
undergoing cardiac surgery: a randomized clinical trial. JAMA.
2015;313:2133–2141.
36. Zimmerman RF, Ezeanuna PU, Kane JC, et al. Ischemic precondi-
tioning at a remote site prevents acute kidney injury in patients
following cardiac surgery. Kidney Int. 2011;80:861–867.
37. Walsh M, Whitlock R, Garg AX, et al. Effects of remote ischemic
preconditioning in high-risk patients undergoing cardiac surgery
(Remote IMPACT): a randomized controlled trial. CMAJ.
2016;188:329–336.
38. Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes
of serum creatinine predict prognosis in patients after cardiothoracic
surgery: a prospective cohort study. J Am Soc Nephrol.
2004;15:1597–1605.
39. Wever KE, Menting TP, Rovers M, et al. Ischemic preconditioning
in the animal kidney, a systematic review and meta-analysis. PLoS
ONE. 2012;7:e32296.
40. Zarbock A, Kellum JA. Remote ischemic preconditioning and
protection of the kidneya novel therapeutic option. Crit Care Med.
2016;44:607–616.
41. Yang Y, Lang XB, Zhang P, et al. Remote ischemic preconditioning
for prevention of acute kidney injury: a meta-analysis of randomized
controlled trials. Am J Kidney Dis. 2014;64:574–583.
42. Heusch G, Botker HE, Przyklenk K, et al. Remote ischemic
conditioning. J Am Coll Cardiol. 2015;65:177–195.
43. Kottenberg E, Thielmann M, Bergmann L, et al. Protection by
remote ischemic preconditioning during coronary artery bypass graft
surgery with isoflurane but not propofola clinical trial. Acta
Anaesthesiol Scand. 2012;56:30–38.
Medicine Volume 95, Number 37, September 2016 Remote Ischemic Preconditioning for Acute Kidney Injury
Copyright #2016 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com |7
... but no impact on RRT requirement. 201 However, a similar-sized meta-analysis (21 trials, n = 5,262) found no reduced CSA-AKI incidence (a co-primary outcome), and a Cochrane Database Systematic Review (primary outcome, 28 studies, n = 6,851) found similar, reporting a minimal impact for one AKI criteria alone (Acute Kidney Injury Network: risk ratio 0.76 [0.57-1.0]). 202,203 In contrast, another RCT (the RenalRIPC study) reported reductions in CSA-AKI and major adverse kidney events with RIPC compared with a sham intervention (AKI: 38% v 53%, p = 0.02; major adverse kidney events: 14% v 25%, p = 0.03). ...
Article
Full-text available
Acute kidney injury is one of the most common major complications of cardiac surgery and it is associated with increased morbidity and mortality. Cardiac surgery-associated acute kidney injury has a complex, multifactorial etiology, including numerous factors such as the primary cardiac dysfunction, hemodynamic derangements of cardiac surgery and cardiopulmonary bypass, and the possibility of large volume blood transfusion. There are no truly effective pharmacological therapies for the management of acute kidney injury, and therefore anesthesiologists, intensivists and cardiac surgeons must remain vigilant, and attempt to minimise the risk of developing renal dysfunction. This narrative review describes the current state of the scientific literature concerning the specific aspects of cardiac surgery-associated acute kidney injury and presents it in a chronological fashion to aid the perioperative clinician in their approach to this high-risk patient group. The evidence is considered for risk prediction models, preoperative optimisation, and the intra- and postoperative management of cardiac surgery patients to improve renal outcomes.
... The different patterns observed in the muscle and in remote organs are possibly related to the underlying mechanisms of RIC. Longer cycles are necessary to activate different pathways supposed to be related to this technique and to evoke a protective effect in distant tissues, for instance, a neural pathway, in which sublethal ischemic stimulus provides an afferent signal to the central nervous system 16,20,21 . Consequently, there is an efferent response, through activation of parasympathetic nerves, that plays a role in modulating vascular activity and increasing antiinflammatory substances 16 . ...
Article
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Purpose: To clarify the best protocol for performing remote ischemic conditioning and to minimize the consequences of ischemia and reperfusion syndrome in brain, the present study aimed to evaluate different time protocols and the relation of the organs and the antioxidant effects of this technique. Methods: The rat's left femoral artery was clamped with a microvascular clamp in times that ranged from 1 to 5 minutes, according to the corresponding group. After the cycles of remote ischemic conditioning and a reperfusion of 20 minutes, the brain and the left gastrocnemius were collected. The samples were used to measure glutathione peroxidase, glutathione reductase and catalase levels. Results: In the gastrocnemius, the 4-minute protocol increased the catalase concentration compared to the 1-minute protocol, but the latter increased both glutathione peroxidase and glutathione reductase compared to the former. On the other hand, the brain demonstrated higher catalase and glutathione peroxidase in 5-minute group, and the 3-minute group reached higher values of glutathione reductase. Conclusions: Remote ischemic conditioning increases brain antioxidant capacity in a time-dependent way, while muscle presents higher protection on 1-minute cycles and tends to decrease its defence with longer cycles of intermittent occlusions of the femoral artery.
... Indeed, ischemic preconditioning (by vascular clamping) showed promising protective effects in animal models of I/R and the potential implication of HO-1 in the observed effects was suggested [239,240], since a priori augmentation of the expression of HO-1 induces resistance to apoptosis in human tubular cells [91]. However, HO-1 expression was not increased in such models [241,242] and the results of such procedures on AKI incidence in human cardiac surgery were also contradictory [243,244]. ...
Article
Full-text available
The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney’s filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1's functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1’s role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.
... It reduces the ischemia and reperfusion injury of target organs by stimulating endogenous protection [58,59]. Protective effects of RIPC have been reported on heart as well as kidney, brain, liver, skeletal muscle, small intestine and other organs [60]. Although molecular mechanisms underlying RIPC protective effects remain to be investigated, but as reflected by downregulation of Lcn2, a reduction of subclinical renal damage by RIPC, especially in the early stage of injury, has been reported [59]. ...
Article
Full-text available
Myocardial infarction (MI) is a leading cause of death worldwide and requires development of efficient therapeutic strategies . Mesenchymal stem cells (MSCs) -based therapy of MI has been promising but inefficient due to undesirable microenvironment of the infarct tissue. Hence, the current study was conducted to fortify MSCs against the unfavorable microenvironment of infarct tissue via overexpression of Lipocalin 2 (Lcn2) as a cytoprotective factor. The engineered cells (Lcn2-MSCs) were transplanted to infarcted heart of a rat model of MI. According to our findings, Lcn2 overexpression resulted in increased MSCs survival in the MI tissue (p < 0.05) compared to non-engineered cells. Furthermore, the infusion of Lcn2-MSCs mitigated Left ventricle (LV) remodeling, decreased fibrosis (p < 0.0001), and reduced apoptotic death of the LVs’ cells (p < 0.0001) compared to the control. Our findings suggest a potential novel therapeutic strategy for MI, however, further investigations such as safety and efficacy assessments in large animals followed by clinical trials are required.
... Importantly, RIPostC provides the possibility that cardioprotection may be initiated at a clinically relevant time, from an organ other than the heart, thereby avoiding damage to the heart. Since this discovery, IPC and RIPostC have been demonstrated to occur in mice, rats, dogs, sheep, pigs, and humans (26,37,38), and the mechanisms have been studied in detail (1,39,51,56), with many attempts to translate via clinical trials (6,8,12,13,25,26,28,29,32,33,36,37,55,60). Although clinical trials have shown some limited benefits, nothing has yet proven reliable and effective in large clinical trials. ...
Article
Full-text available
Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-. The similarity of the neuro-anatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease.
... Importantly, RIPostC provides the possibility that cardioprotection may be initiated at a clinically relevant time, from an organ other than the heart, thereby avoiding damage to the heart. Since this discovery, IPC and RIPostC have been demonstrated to occur in mice, rats, dogs, sheep, pigs, and humans (26,37,38), and the mechanisms have been studied in detail (1,39,51,56), with many attempts to translate via clinical trials (6,8,12,13,25,26,28,29,32,33,36,37,55,60). Although clinical trials have shown some limited benefits, nothing has yet proven reliable and effective in large clinical trials. ...
Preprint
Full-text available
Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-. The similarity of the neuro-anatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease.
... Importantly, RIPostC provides the possibility that cardioprotection may be initiated at a clinically relevant time, from an organ other than the heart, thereby avoiding damage to the heart. Since this discovery, IPC and RIPostC have been demonstrated to occur in mice, rats, dogs, sheep, pigs, and humans (26,37,38), and the mechanisms have been studied in detail (1,39,51,56), with many attempts to translate via clinical trials (6,8,12,13,25,26,28,29,32,33,36,37,55,60). Although clinical trials have shown some limited benefits, nothing has yet proven reliable and effective in large clinical trials. ...
Article
Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9−T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.
... 25,26 Results of recent meta-analyses have failed to demonstrate the efficacy of RIPC in reducing the incidence of AKI or the need for RRT. [197][198][199][200] Importantly, these metaanalyses included studies involving low-risk patients and studies that used propofol. In a subgroup of studies in which propofol was not used, a reduction in AKI was demonstrated, suggesting a possible interaction of propofol with the protective effects of RIPC. ...
Article
Background Post‐operative acute kidney injury after cardiopulmonary bypass (AKI‐CPB) for cardiac surgery is a frequent complication. It may require renal replacement therapy (RRT), which is associated with an increased morbidity and mortality. This review explores the efficacy of proposed pharmacological and non‐surgical renal protective strategies. Methods A comprehensive literature search was done using Ovid MEDLINE, Embase and Scopus databases. Keywords included were cardiopulmonary bypass, cardiac surgery, coronary artery bypass, renal protection and renal preservation. Eligible articles consisted of all studies on patients who had undergone cardiac surgery via CPB with an outcome of AKI and/or RRT reported. All studies underwent a quality check via the risk of bias tool. The three most researched interventions (based on number of randomized controlled trials and total patients analysed) and their renal outcomes were then analysed with Review Manager Software. Results Eighty‐eight articles were extracted. A total of 26 management strategies for renal protection following CPB were identified. N‐acetylcysteine (NAC), remote ischaemic preconditioning (RIPC) and the use of volatile anaesthetic agents (VAAs) were further analysed. NAC, RIPC and VAA had no statistically significant benefit in reducing either AKI‐CPB or the need for RRT following CPB. Conclusion NAC, RIPC and VAA were found to have no statistical significant benefit in reducing either AKI‐CPB or the need for RRT following CPB. There remains clinical uncertainty with all currently proposed pharmacological and non‐surgical renal protective strategies for CPB. Future research in this area should analyse the effects of combined interventions or specifically focus on ‘at‐risk’ patients.
Article
Background: P21, a cyclin kinase inhibitor, is upregulated by renal 'ischemic preconditioning' (IPC), and induces a 'cytoresistant' state. However, P21-induced cell cycle inhibition can also contribute to cellular senescence, a potential adverse renal event. Hence, this study assessed whether: (i) IPC-induced P21 upregulation is associated with subsequent renal senescence; and (ii) preconditioning can be established 'independent' of P21 induction and avoid a post-ischemic senescent state? Methods: CD-1 mice were subjected to either IPC (5-15 min) or to a recently proposed 'oxidant-induced preconditioning' (OIP) strategy (tin protoporphyrin-induced heme oxygenase inhibition +/- parental iron administration). P21 induction [messenger RNA (mRNA)/protein], cell proliferation (KI-67, phosphohistone H3 nuclear staining), kidney senescence (P16ink4a; P19Arf mRNAs; senescence-associated beta-galactosidase levels) and resistance to ischemic acute kidney injury were assessed. Results: IPC induced dramatic (10-25×) and persistent P21 activation and 'downstream' tubular senescence. Conversely, OIP did not upregulate P21, it increased, rather than decreased, cell proliferation markers, and it avoided a senescence state. OIP markedly suppressed ischemia-induced P21 up-regulation, it inhibited the development of post-ischemic senescence and it conferred near-complete protection against ischemic acute renal failure (ARF). To assess OIP's impact on a non-P21-dependent cytoprotective pathway, its ability to activate Nrf2, the so-called 'master regulator' of endogenous cell defenses, was assessed. Within 4 h, OIP activated each of three canonical Nrf2-regulated genes (NQO1, SRXN1, GCLC; 3- to 5-fold mRNA increases). Conversely, this gene activation pathway was absent in Nrf2-/- mice, confirming Nrf2 specificity. Nrf2-/- mice also did not develop significant OIP-mediated protection against ischemic ARF. Conclusions: OIP (i) activates the cytoprotective Nrf2, but not the P21, pathway; (ii) suppresses post-ischemic P21 induction and renal senescence; and (iii) confers marked protection against ischemic ARF. In sum, these findings suggest that OIP may be a clinically feasible approach for safely activating the Nrf2 pathway, and thereby confer protection against clinical renal injury.
Article
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BACKGROUND: Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. / METHODS: We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. / RESULTS: We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. / CONCLUSIONS: Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.)
Article
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Background: Remote ischemic preconditioning is a simple therapy that may reduce cardiac and kidney injury. We undertook a randomized controlled trial to evaluate the effect of this therapy on markers of heart and kidney injury after cardiac surgery. Methods: Patients at high risk of death within 30 days after cardiac surgery were randomly assigned to undergo remote ischemic preconditioning or a sham procedure after induction of anesthesia. The preconditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles. The sham procedure was identical except that ischemia was not induced. The primary outcome was peak creatine kinase- myocardial band (CK-MB) within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation). The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per litre). Patient-important outcomes were assessed up to 6 months after randomization. Results: We randomly assigned 128 patients to remote ischemic preconditioning and 130 to the sham therapy. There were no significant differences in postoperative CK-MB (absolute mean difference 0.15, 95% confidence interval [CI] -0.07 to 0.36) or creatinine (absolute mean difference 0.06, 95% CI -0.10 to 0.23). Other outcomes did not differ significantly for remote ischemic preconditioning relative to the sham therapy: for myocardial infarction, relative risk (RR) 1.35 (95% CI 0.85 to 2.17); for acute kidney injury, RR 1.10 (95% CI 0.68 to 1.78); for stroke, RR 1.02 (95% CI 0.34 to 3.07); and for death, RR 1.47 (95% CI 0.65 to 3.31). Interpretation: Remote ischemic preconditioning did not reduce myocardial or kidney injury during cardiac surgery. This type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery. Trial registration: ClinicalTrials.gov, no. NCT01071265.
Article
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Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
Article
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Systematic reviews and meta-analyses have become increasingly important in health care. Clinicians read them to keep up to date with their field [1],[2], and they are often used as a starting point for developing clinical practice guidelines. Granting agencies may require a systematic review to ensure there is justification for further research [3], and some health care journals are moving in this direction [4]. As with all research, the value of a systematic review depends on what was done, what was found, and the clarity of reporting. As with other publications, the reporting quality of systematic reviews varies, limiting readers' ability to assess the strengths and weaknesses of those reviews. Several early studies evaluated the quality of review reports. In 1987, Mulrow examined 50 review articles published in four leading medical journals in 1985 and 1986 and found that none met all eight explicit scientific criteria, such as a quality assessment of included studies [5]. In 1987, Sacks and colleagues [6] evaluated the adequacy of reporting of 83 meta-analyses on 23 characteristics in six domains. Reporting was generally poor; between one and 14 characteristics were adequately reported (mean = 7.7; standard deviation = 2.7). A 1996 update of this study found little improvement [7]. In 1996, to address the suboptimal reporting of meta-analyses, an international group developed a guidance called the QUOROM Statement (QUality Of Reporting Of Meta-analyses), which focused on the reporting of meta-analyses of randomized controlled trials [8]. In this article, we summarize a revision of these guidelines, renamed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), which have been updated to address several conceptual and practical advances in the science of systematic reviews (Box 1). Box 1: Conceptual Issues in the Evolution from QUOROM to PRISMA Completing a Systematic Review Is an Iterative Process The conduct of a systematic review depends heavily on the scope and quality of included studies: thus systematic reviewers may need to modify their original review protocol during its conduct. Any systematic review reporting guideline should recommend that such changes can be reported and explained without suggesting that they are inappropriate. The PRISMA Statement (Items 5, 11, 16, and 23) acknowledges this iterative process. Aside from Cochrane reviews, all of which should have a protocol, only about 10% of systematic reviewers report working from a protocol [22]. Without a protocol that is publicly accessible, it is difficult to judge between appropriate and inappropriate modifications.
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Background: Remote ischemic preconditioning (RIPC) is reported to reduce biomarkers of ischemic and reperfusion injury in patients undergoing cardiac surgery, but uncertainty about clinical outcomes remains. Methods: We conducted a prospective, double-blind, multicenter, randomized, controlled trial involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol. The trial compared upper-limb RIPC with a sham intervention. The primary end point was a composite of death, myocardial infarction, stroke, or acute renal failure up to the time of hospital discharge. Secondary end points included the occurrence of any individual component of the primary end point by day 90. Results: A total of 1403 patients underwent randomization. The full analysis set comprised 1385 patients (692 in the RIPC group and 693 in the sham-RIPC group). There was no significant between-group difference in the rate of the composite primary end point (99 patients [14.3%] in the RIPC group and 101 [14.6%] in the sham-RIPC group, P=0.89) or of any of the individual components: death (9 patients [1.3%] and 4 [0.6%], respectively; P=0.21), myocardial infarction (47 [6.8%] and 63 [9.1%], P=0.12), stroke (14 [2.0%] and 15 [2.2%], P=0.79), and acute renal failure (42 [6.1%] and 35 [5.1%], P=0.45). The results were similar in the per-protocol analysis. No treatment effect was found in any subgroup analysis. No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release, the duration of mechanical ventilation, the length of stay in the intensive care unit or the hospital, new onset of atrial fibrillation, and the incidence of postoperative delirium. No RIPC-related adverse events were observed. Conclusions: Upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery. (Funded by the German Research Foundation; RIPHeart ClinicalTrials.gov number, NCT01067703.).
Article
Full-text available
Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.).
Article
Objective: Acute kidney injury is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis, major surgery, and nephrotoxic drugs are the most common causes of acute kidney injury. There is currently no effective strategy available to prevent or treat acute kidney injury. Therefore, novel treatment regimens are required to decrease acute kidney injury prevalence and to improve clinical outcomes. Remote ischemic preconditioning, triggered by brief episodes of ischemia and reperfusion applied in distant tissues or organs before the injury of the target organ, attempts to invoke adaptive responses that protect against acute kidney injury. We sought to evaluate the clinical evidence for remote ischemic preconditioning as a potential strategy to protect the kidney and to review the underlying mechanisms in light of recent studies. Data sources: We searched PubMed for studies reporting the effect of remote ischemic preconditioning on kidney function in surgical patients (search terms: "remote ischemic preconditioning," "kidney function," and "surgery"). We also reviewed bibliographies of relevant articles to identify additional citations. Study selection: Published studies, consisting of randomized controlled trials, are reviewed. Data extraction: The authors used consensus to summarize the evidence behind the use of remote ischemic preconditioning. Data synthesis: In addition, the authors suggest patient populations and clinical scenarios in which remote ischemic preconditioning might be best applied. Conclusions: Several experimental and clinical studies have shown tissue-protective effects of remote ischemic preconditioning in various target organs, including the kidneys. Remote ischemic preconditioning may offer a novel, noninvasive, and inexpensive treatment strategy for decreasing acute kidney injury prevalence in high-risk patients. Although many new studies have further advanced our knowledge in this area, the appropriate intensity of remote ischemic preconditioning, its mechanisms of action, and the role of biomarkers for patient selection and monitoring are still unknown.
Article
Although remote ischemic preconditioning (RIPC) has emerged as an attractive strategy to reduce cardiac injury in patients undergoing diverse cardiac surgical procedures, it is unclear whether RIPC has protective effects in patients undergoing aortic valve replacement surgery without coronary artery bypass grafting (CABG). Hence, 100 adult patients undergoing elective aortic valve replacement for aortic valve stenosis, without combined surgery with CABG, were prospectively randomly assigned in a 1:1 ratio to either the RIPC group or the control group. The RIPC group underwent three cycles of 5-min inflation to 200mmHg and 5-min deflation of an automated upper-arm cuff inflator after induction of anesthesia. The control group had a deflated cuff placed on upper arm for 30min. The primary endpoint was 72-h area under curve (AUC) for troponin I (cTnI). Secondary endpoints were 72-h AUC for creatine kinase-MB isoenzyme (CK-MB) release, incidence of acute kidney injury, extubation time, length of stay in intensive care unit, and simplified acute physiology score (SAPS II). There were no significant differences in cTnI AUC [195±190 arbitrary units (a.u.) in RIPC group vs. 169±117 a.u. in the control group; p=0.41] and CK-MB AUC between groups. None of the other secondary endpoints differed between groups. Acute kidney injury occurred in 12 patients (24.5%) in the control group and in 13 (26.0%) in the RIPC group (p=0.86). RIPC did not exhibit significant cardiac or kidney protective effects in patients undergoing aortic valve replacement surgery without CABG. Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Article
Remote ischemic perconditioning (RIPerc) is a new alternative of remote ischemic conditioning and has not been well studied. RIPerc attenuates myocardial injury when applied during cardiac surgery. However, its protective effects on other organs remain unknown. Patients with rheumatic heart disease undergoing valve replacement surgery were randomized into the RIPerc group (n = 101) or the control group (n = 100). RIPerc was achieved by three cycles of 5-min ischemia-5-min reperfusion in the right thigh during surgery. Clinical data and the levels of injury biomarkers for the heart, lungs, liver, and kidneys within 48 h after surgery were compared using one-way or repeated measurement analysis of variance. In the RIPerc group, the release of serum cardiac troponin I (128.68 ± 102.56 versus 172.33 ± 184.38, P = 0.04) and the inotropic score (96.4 ± 73.8 versus 121.5 ± 89.6, P = 0.032) decreased compared with that of the control; postoperative drainage (458.2 ± 264.2 versus 545.1 ± 349.0 ml, P = 0.048) and the incidence of acute lung injury was reduced (36.6% versus 51%, P = 0.04), and the extent of hyperbilirubinemia was also attenuated. No significant difference was observed in the levels of biomarkers for renal injury and systemic inflammation response. RIPerc applied during the valve replacement surgery induced multiple beneficial effects postoperatively including reduced drainage and myocardial damage, lower incidence of acute lung injury, and attenuated hyperbilirubinemia. Copyright © 2015. Published by Elsevier Inc.