Safety and Tolerability Study of an Intravenously Administered Small Interfering Ribonucleic Acid (siRNA) Post On-Pump Cardiothoracic Surgery in Patients at Risk of Acute Kidney Injury.

INTRODUCTION: Patients undergoing on-pump cardiac surgery are at an increased risk of acute kidney injury. QPI-1002, a small interfering ribonucleic acid, is under clinical development for the prevention of acute kidney injury. The safety, tolerability, and pharmacokinetics of QPI-1002 was evaluated in this first-in-man, Phase 1 study of a small, interfering ribonucleic acid in patients at risk of acute kidney injury after on-pump cardiac surgery. METHODS: In this phase 1 randomized, placebo-controlled dose-escalation study, a single i.v. dose of QPI-1002 was administered in subjects undergoing on-pump cardiac surgery. Subjects received placebo (n = 4), or QPI-1002 in increasing doses of 0.5 mg/kg (n = 3), 1.5 mg/kg (n = 3), 5 mg/kg (n = 3), and 10 mg/kg (n = 3). RESULTS: A total of 16 subjects were enrolled in the study. The average maximum concentration and area under the curve from the time of dosing to the last measurable concentration of QPI-1002 were generally dose proportional, indicating that exposure increased with increasing dose. The average mean residence time (mean residence time to the last measurable concentration) was 10 to 13 minutes in all 4 drug-dosing cohorts. Adverse events occurred at a similar rate in all study groups. Of the total 109 reported adverse events, the events were distributed as 26 in the placebo group and 21, 19, 24, and 19 in the QPI-1002 0.5, 1.5, 5.0, and 10.0 mg/kg groups, respectively. Eight of the 16 subjects experienced at least 1 serious adverse event: 4 (100%) in the placebo group and 4 (33.3%) in the combined QPI-1002 cohorts. DISCUSSION: QPI-1002 was rapidly eliminated from plasma. QPI-1002 was safe and well tolerated across all dose groups. Overall, no dose-limiting toxicities or safety signals were observed in the study. Further development of QPI-1002 for prophylaxis of acute kidney injury is warranted.

Perioperative transoesophageal echocardiography: current status and future directions.

Transoesophageal echocardiography (TOE) is used in the perioperative arena to monitor patients during life-threatening emergencies, cardiac and high-risk non-cardiac surgeries. It provides qualitative and quantitative information on valvular and ventricular functions, and dynamic cardiac anatomy can be displayed with a physiological perspective. This technology has evolved from two-dimensional (2D) to the ready availability of real-time three-dimensional (RT-3D) imaging in the operating rooms. Enhanced spatial and temporal resolutions with 3D imaging have most significantly impacted the quality of intraoperative surgical valve repair and replacement decisions. Additionally, 3D imaging has facilitated the advent of minimally invasive and percutaneous interventions for structural heart disease. Information derived from TEE is routinely used to evaluate a patient's suitability for an intervention, provide guidance during the intervention and eventually comment on the quality and success of the procedure. Expertise in perioperative TEE is an integral component of a cardiac anaesthesiologist's skill sets. With structural heart disease interventions becoming more minimally invasive, the intraoperative guidance provided by TEE will continue to be a critical component of these procedures. With improving computational and processing power, the expectations from TEE will continue to be incremental in the perioperative arena.