Remote Ischemic Preconditioning After Cardiac Surgery

Study Overview
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Brief Summary
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Acute kidney injury (AKI) is a well-recognized complication after cardiac surgery with cardiopulmonary bypass (CPB). The aim of this study is to reduce the incidence of AKI by implementing remote ischemic preconditioning and to evaluate the dose-response relationship using the biomarkers urinary [TIMP-2] *[IGFBP7] in high risk patients undergoing cardiac surgery.

Detailed Description
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Acute kidney injury (AKI) complicates 7-19% of cardiac surgical procedures. The investigators recently found that remote ischemic preconditioning (RIPC) using transient external compression of the upper arm prior to cardiac surgery was effective for reducing the occurrence of AKI (37.5% compared to 52.5% with sham; absolute risk reduction (ARR),15%; 95% CI, 2.56% to 27.44%; P=0.02). Fewer patients treated with RIPC received renal replacement therapy (RRT) (5.8% versus 15.8%; ARR, 10%; 95% CI, 2.25% to 17.75%; P=0.01). Moreover, the investigators found that the effectiveness of this intervention was strongly associated with the release of cell-cycle arrest biomarkers into the urine. Patients with urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 ([TIMP-2]•[IGFBP7]) ≥ 0.5 (ng/ml)(ng/ml)/1000 before surgery had a significantly reduced rate of AKI compared to patients with lower urinary [TIMP-2]•[IGFBP7] concentration (relative risk (RR), 67%; 95% CI, 53% to 83%, P<0.001) whereas the biomarker concentrations after surgery predicted AKI as previously shown. This effect makes sense because cell-cycle arrest is thought to be part of the protective mechanisms endothelial cells use when exposed to stress. Stimulating these responses with RIPC should reduce AKI. Importantly, only 56% of patients treated with RIPC achieved an increase in urine [TIMP-2]•[IGFBP7] to ≥ 0.5, and only in this group was the intervention effective-patients that did not achieve this level showed no benefit. Our goal is to eventually design and conduct a Bayesian 2-stage adaptive design sequence trial to evaluate the effectiveness of RIPC to prevent AKI in patients undergoing cardiac surgery. The dimensions of dose include duration, intensity and number of cycles. However, before this trial can be designed we need to answer 4 questions: i. Do baseline urinary [TIMP-2]•[IGFBP7] levels predict AKI (enrichment)? ii. Do [TIMP-2]•[IGFBP7] changes elicited by RIPC predict protection (RIPC efficacy measure)? iii. Is there a dose-response relationship between RIPC dose and [TIMP-2]•[IGFBP7]? iv. Is a dose-escalation RIPC protocol where doses are increased for non-responders, feasible and safe within the anesthesia workflow for cardiac surgery cases (practical)?

Official Title
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Remote Ischemic Preconditioning to Prevent Acute Kidney Injury in High Risk Patients After Cardiac Surgery (RIPCRenal)

Conditions
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Cardiac Surgery, Aortocoronary Bypass

Intervention / Treatment
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* Procedure: Remote ischemic preconditioning (RIPC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are scheduled to undergo cardiac surgery with cardiopulmonary bypass Cleveland Clinic Score >=6 Exclusion Criteria: Acute myocardial infarction up to 7 days before surgery Age < 18 years Off-pump cardiac surgery Preexisting AKI Chronic kidney disease (GFR < 30 ml/min) Kidney transplantation within the last 12 months Peripheral arterial occlusive disease Pregnancy Hepatorenal syndrome Sulfonamide or thiazide medication within the last 7 days Participation in another interventional trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Observational group<br>No intervention, standard care | |
| Sham Comparator: Sham RIPC<br>Three cycles of 5- min upper limb sham ischemia | Procedure: Remote ischemic preconditioning (RIPC)<br>* 3 cycles or more cycles of 5 to 10-min inflation of a blood-pressure cuff to 200 mm HG (or at least to a pressure 50 mmHG higher than the systolic arterial pressure) to one upper arm followed by 5 min reperfusion with the cuff deflated. In Non-Responder two additional cycles of 10 min cuff inflation will be performed in arm 6.<br>|
| Experimental: RIPC-Group 1<br>Three cycles of 5- min upper limb ischemia | Procedure: Remote ischemic preconditioning (RIPC)<br>* 3 cycles or more cycles of 5 to 10-min inflation of a blood-pressure cuff to 200 mm HG (or at least to a pressure 50 mmHG higher than the systolic arterial pressure) to one upper arm followed by 5 min reperfusion with the cuff deflated. In Non-Responder two additional cycles of 10 min cuff inflation will be performed in arm 6.<br>|
| Experimental: RIPC-Group 2<br>Three cycles of 7-min upper limb ischemia | Procedure: Remote ischemic preconditioning (RIPC)<br>* 3 cycles or more cycles of 5 to 10-min inflation of a blood-pressure cuff to 200 mm HG (or at least to a pressure 50 mmHG higher than the systolic arterial pressure) to one upper arm followed by 5 min reperfusion with the cuff deflated. In Non-Responder two additional cycles of 10 min cuff inflation will be performed in arm 6.<br>|
| Experimental: RIPC-Group 3<br>Three cycles of 10-min upper limb ischemia | Procedure: Remote ischemic preconditioning (RIPC)<br>* 3 cycles or more cycles of 5 to 10-min inflation of a blood-pressure cuff to 200 mm HG (or at least to a pressure 50 mmHG higher than the systolic arterial pressure) to one upper arm followed by 5 min reperfusion with the cuff deflated. In Non-Responder two additional cycles of 10 min cuff inflation will be performed in arm 6.<br>|
| Experimental: RIPC-Group 4<br>Three Cycles of 5-min upper limb ischemia. If there is no response this will be followed by 2 cycles of 10-min upper-limb ischemia | Procedure: Remote ischemic preconditioning (RIPC)<br>* 3 cycles or more cycles of 5 to 10-min inflation of a blood-pressure cuff to 200 mm HG (or at least to a pressure 50 mmHG higher than the systolic arterial pressure) to one upper arm followed by 5 min reperfusion with the cuff deflated. In Non-Responder two additional cycles of 10 min cuff inflation will be performed in arm 6.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in urinary [TIMP-2]*[IGFBP7] | Biomarkers will be measured at different time points after to evaluate the effect of RIPC on [TIMP-2]*[IGFBP7] | within 12 hours after CPB | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AKI within 72 hours |  | 72 h | 
| Dialysis within 7 days of surgery |  | 7 days | 
| All-cause-mortality at 90 days |  | 90 d | 
| Dialysis at day 90 |  | 90 days | 
| Renal recovery at day 90 |  | 90 days | 
| MAKE 90 | major adverse kidney events | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute kidney injury, cardiac surgery, Remote ischemic preconditioning, [TIMP-2]*[IGFBP7]