You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


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).^[@R1],[@R2]^ The development of AKI following cardiac surgery is associated with substantial morbidity and mortality, as well as prolonged intensive care unit and hospital stays.^[@R3],[@R4]^ 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.^[@R5]--[@R7]^

Although numerous clinical trials of prophylactic interventions 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.^[@R8]--[@R10]^

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.^[@R11],[@R12]^ The mechanisms underlying RIPC are incompletely 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.^[@R13]--[@R15]^

The randomized controlled trials (RCTs) concerning the renal protective effect of RIPC in patients undergoing cardiovascular 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 protocol prevents AKI after on-pump cardiac surgery. There was no registered protocol.

METHODS
=======

Search Strategy
---------------

The systematic review was performed in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines.^[@R16]^ 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% confidence 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.^[@R17]^ 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 equivalent units. We calculated and subsequently pooled in independent meta-analyses, risk ratio (RR) with 95% CI for dichotomous outcomes and MD with 95% CI for continuous outcomes. Heterogeneity among pooled studies was evaluated using the Mantel--Haenszel, χ^2^, and the I^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.^[@R18]^ Homogeneity assumption was measured by *P* value. 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 *P* value 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 (StataCorp, College Station, TX).

RESULTS
=======

Study Characteristics
---------------------

The study selection process is presented in Figure [1](#F1){ref-type="fig"}. The search strategy identified 1093 studies, of which data from 19 trials^[@R19]--[@R37]^ were used comprising 5100 patients (Table [1](#T1){ref-type="table"}). Among the 19 studies, 1 was a conference abstract,^[@R21]^ 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.^[@R37]^ Two studies^[@R19],[@R21]^ had a Jadad score of \<3 (Table [2](#T2){ref-type="table"}). For the primary endpoints, the incidence of AKI was reported in 14 trails.^[@R20]--[@R25],[@R28]--[@R30],[@R32]--[@R36]^ In this part, the multicenter randomized study by Meybohm et al^[@R27]^ 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.^[@R19],[@R23],[@R26],[@R27],[@R29]--[@R32],[@R35]^

![Flow chart of selection process of eligible studies. RCT = randomized controlled trial.](medi-95-e3465-g001){#F1}

###### 

Demographic Data of Studies Included in Meta-Analysis (RIPC Group/Control Group)

![](medi-95-e3465-g002)

###### 

Quality of Studies Included in Meta-Analysis

![](medi-95-e3465-g003)

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 \[OR\] = 0.84; 95% CI, 0.73--0.98; *P* = 0.02), with low heterogeneity (χ^2^ = 22.34, I^2^ = 37%) (Figure [2](#F2){ref-type="fig"}). 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^ = 20%) when the trial by Hausenloy et al^[@R24]^ was omitted to 0.88 (0.75, 1.02) (I^2^ = 17%) when the trial by Zimmerman et al.^[@R36]^ No significant publication bias was detected, with *P* = 0.843 in Begg test and *P* = 0.055 in Egger test.

![Forest plot for acute kidney injury.](medi-95-e3465-g004){#F2}

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; *P* = 0.27) with nonsignificant heterogeneity (χ^2^ = 10.90, I^2^ = 54%) (Figure [3](#F3){ref-type="fig"}). 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 (*P* = 1.000), or Egger test (*P* = 0.237).

![Forest plot for renal replacement therapy.](medi-95-e3465-g005){#F3}

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](#F4){ref-type="fig"}).

![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.](medi-95-e3465-g006){#F4}

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; *P* = 0.56) with no heterogeneity (χ^2^ = 6.97, I^2^ = 0%) (Figure [5](#F5){ref-type="fig"}).

![Forest plot for relative risk of mortality.](medi-95-e3465-g007){#F5}

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 undergoing 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.^[@R38]^ The protection was supported by numerous preclinical studies in animals showing that RIPC, compared with controls, was associated with reduction of blood urea nitrogen (BUN), sCr, and histologic renal damage.^[@R39],[@R40]^

The present analysis is in accordance with the findings of a previous meta-analysis, and helps further understand the effect of RIPC.^[@R41]^ In addition to experimental evidence, several clinical trials have suggested the potential protection of RIPC on reducing kidney damage in humans,^[@R20],[@R36]^ while some studies found the contrary.^[@R25],[@R29]^ Lack of knowledge of RIPC and conflicting results of small sample sizes trials^[@R20],[@R21],[@R30],[@R33]^ may explain 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 technique.^[@R40]^ 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.^[@R42]^ 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.^[@R35]^ 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.^[@R41]^

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 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 heterogeneity 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.^[@R27],[@R43]^ Opioid analgesics can interfere with cardioprotective efficacy of RIPC and raise the threshold for an additional benefit by their independently cardioprotection.^[@R42]^

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.

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.

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.