Cardiac Surgery, Aortocoronary Bypass Clinical Trial
Official title:
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.
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)?
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