Remote Ischemic Preconditioning After Cardiac Surgery (RIPCRenal)

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

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.

Study Overview

• Status: Unknown
• Conditions: Cardiac Surgery, Aortocoronary Bypass
• Intervention / Treatment: Procedure: Remote ischemic preconditioning (RIPC)

Detailed Description

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)?

• Study Type: Interventional
• Enrollment (Anticipated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Melanie Meersch, MD; Phone Number: +49-251-8347282; Email: aki@anit.uni-muenster.de

Study Locations

• Germany
  • Muenster, Germany, D-48149
    • Recruiting
    • University Hospital Muenster
    • Contact: Alexander Zarbock, PhD, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Observational group; No intervention, standard care
Sham Comparator: Sham RIPC; Three cycles of 5- min upper limb sham ischemia	Procedure: Remote ischemic preconditioning (RIPC); 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.
Experimental: RIPC-Group 1; Three cycles of 5- min upper limb ischemia	Procedure: Remote ischemic preconditioning (RIPC); 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.
Experimental: RIPC-Group 2; Three cycles of 7-min upper limb ischemia	Procedure: Remote ischemic preconditioning (RIPC); 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.
Experimental: RIPC-Group 3; Three cycles of 10-min upper limb ischemia	Procedure: Remote ischemic preconditioning (RIPC); 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.
Experimental: RIPC-Group 4; 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); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Muenster
• Collaborators: Else Kröner Fresenius Foundation
• Investigators: Study Chair: Melanie Meersch, University Hospital Muenster

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Anticipated): June 1, 2019
• Study Completion (Anticipated): September 1, 2019

Study Registration Dates

• First Submitted: December 15, 2016
• First Submitted That Met QC Criteria: December 15, 2016
• First Posted (Estimate): December 20, 2016

Study Record Updates

• Last Update Posted (Actual): January 30, 2018
• Last Update Submitted That Met QC Criteria: January 29, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: cardiac surgery; acute kidney injury; Remote ischemic preconditioning; [TIMP-2]*[IGFBP7]
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Acute Kidney Injury
• Other Study ID Numbers: 04-AnIt-16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO