Pediatric Remote Ischemic Pre-conditioning Prior to Complex Cardiac Surgery

Ischemic Preconditioning (IPC) refers to the phenomenon where a brief ischemia-reperfusion event to a tissue/organ can result in subsequent protection from a more severe ischemia-reperfusion event to that tissue/organ. There are many descriptions of IPC in animal models. Protection occurs in two phases: early after the IPC (<4hr), and later after the IPC (24-72hr). The protection is marked, with reduction in infarction sizes in brain and heart on the order of 50% or more. The later phase provides protection against infarction (lethal reperfusion injury) and stunning (post-ischemic myocardial dysfunction), while the early phase provides protection against infarction only. The mechanisms of IPC have been divided into 4 phases: preconditioning insult, stress sensors, signal transduction, and effectors of protection. Remote Ischemic PreConditioning (RIPC) refers to the finding that a brief ischemia-reperfusion event to a tissue/organ results in subsequent protection from a more severe ischemia-reperfusion event to a different tissue/organ. This is advantageous because the tissue subjected to the preconditioning stimulus can be more accessible and less vulnerable than the target organ to be protected, such as the brain or heart. Animal studies have demonstrated the efficacy of RIPC. The mechanisms and timing (early and late phases) appear to be the same as for IPC. There are several adult human studies of IPC. Studies of IPC in adults having coronary bypass surgery have found improvements in acute markers of myocardial injury and hemodynamic function. A meta-analysis of 22 trials of IPC during cardiac surgery in adults found a significant improvement in postoperative arrhythmias, inotrope requirements, and intensive care unit stay in the IPC group. There are adult studies showing that RIPC prevents ischemia-reperfusion injury. Currently, 3 large adult randomized control trial (RCT) are underway investigating the effects of RIPC after cardiac surgery and stroke. There are six studies of RIPC in children . In one study 37 children having cardiac surgery were randomized to RIPC induced by lower limb ischemia with a blood pressure cuff. The levels of troponin I and inotrope requirements were significantly greater in the control group vs. the RIPC group. In another study infants having repair of ventricular septal defect were randomized to receive RIPC 24 hr and 1 hr before CPB. The postoperative release of cytokines and heart enzymes were attenuated, there was better lung and heart function, and no adverse effects. A study in children with ventricular septal defect found that early RIPC and post-conditioning were associated with lower levels of troponin I, creatinine kinase and inotrope score post-operative. A recent RCT of children undergoing cardiac surgery found that late RIPC was associated with lower N-terminal pro-B-type natriuretic peptide but no difference in inflammatory markers or cardiac dysfunction. Similarly, a more recent small RCT of RIPC did not find any difference in troponin I levels or other short term outcomes. The largest RIPC pediatric RCT performed to date involved 113patients with the expectation that RIPC would reduce the incidence of acute kidney injury. This study found only a trend towards lower incidence of acute kidney injury in the RIPC group. The interpretation of most of these studies is difficult due to the small samples, and multiple analyses and without prestated primary or secondary outcomes. Recent reviews suggest studies be done with a larger sample size.

Potential Concerns in Children: In immature rodents, preconditioning with lipopolysaccharide, or oxygen-glucose deprivation, results in worse brain injury on ischemia-reperfusion. This raises the possibility of harm from IPC in neonates. This is very unlikely for the following reasons. First, this data applies to neonates at <32 weeks post-conception age. Second, lipopolysaccharide protected the brain when given 4 hr and 24hr before the ischemic event. Third, hypoxic preconditioning is protective to the immature brain.

Safety concerns: Based on the above discussion of potential concerns, and the studies reviewed, we anticipate no adverse effects from RIPC. Discomfort during RIPC is mild and will be treated with sedation if necessary. The dose of midazolam given for this purpose has been shown to be safe.

Potential Interference with Preconditioning: Animal studies have found that beta-blockers, sulfonylurea, caffeine, aminophylline, angiotensin converting enzyme inhibitors, and naloxone interfere with IPC. Patients on any of these drugs will be excluded. There are studies showing that inhalational anesthetics are pharmacologic preconditioning agents. The mechanism of action involves some of the same pathways as IPC. However, the response to IPC and anesthetic preconditioning involve a substantial subset of genes unique to each preconditioning stimulus. Studies of anesthetic preconditioning have found conflicting results suggesting that anesthetic preconditioning, if it occurs, is likely to be enhanced by IPC. Furthermore, in clinical studies with promising results discussed above, anesthetics were used during the surgical procedure.

Objectives: a) To demonstrate the feasibility of patient recruitment to a RIPC RCT at our center; and b) determine the effect of RIPC on the early postoperative course of infants after cardiac surgery. We aim to recruit 4 patients/month for a total of 50 patients in 1 year; this recruitment rate would make a larger trial feasible.