Evaluation of the abuse potential of difelikefalin, a selective kappa-opioid receptor agonist, in recreational polydrug users.

Difelikefalin, a selective kappa-opioid receptor agonist with limited central nervous system penetration, is being developed for the treatment of chronic pruritic conditions. This randomized, double-blind, active- and placebo-controlled, four-way crossover study was designed to evaluate the abuse potential of difelikefalin in healthy recreational polydrug users. Using a 4 × 4 Williams design, nondependent adult users of opioids and hallucinogens (N = 44) were randomized to receive single intravenous (i.v.) injections of difelikefalin at supratherapeutic doses (5 and 15 mcg/kg); pentazocine (0.5 mg/kg), a schedule IV mu-opioid partial agonist and kappa-opioid receptor agonist; and placebo. The abuse potential of difelikefalin was compared with pentazocine and placebo using the maximal score (maximum effect [Emax ]) of the Drug Liking visual analog scale (VAS; primary end point), along with multiple secondary end points of subject-rated measures and pupillometry. Difelikefalin produced significantly lower Drug Liking VAS Emax , and lower peak positive, sedative, and perceptual effects compared with pentazocine. These effects of difelikefalin were small, brief, and not dose-dependent, although marginally greater than those observed with placebo. Neither dose of difelikefalin elicited significant negative or hallucinogenic effects. On end-of-session measures of overall drug liking and willingness to take the drug again, difelikefalin did not differ from placebo, indicating subjects neither liked nor disliked the effects overall and did not feel motivated to take the drug again. Consistent with its lack of mu agonist activity, difelikefalin did not induce miosis compared with pentazocine. All treatments were generally well-tolerated. This study indicates that difelikefalin presents a low potential for abuse.

RIPC Remains a Promising Technique for Protection of the Myocardium during Open Cardiac Surgery: A Meta-Analysis and Systematic Review.

BACKGROUND: Remote ischemic preconditioning (RIPC) is the process of inducing brief ischemia in a tissue to prevent ischemic damage in another. This preconditioning can be induced simply by inflating a blood pressure cuff on a limb. Previous randomized controlled trials (RCT) have suggested that RIPC may infer myocardial protection during open cardiac surgery. One method of assessing the degree of myocardial damage incurred in these studies is to assay troponin concentration. Troponin is a cardiac enzyme released by damaged myocardiocytes. With the recent publication of several large RCTs in this area, a meta-analysis of the evidence was undertaken. METHODS: A systematic search of PubMed, EMBASE, and clinicaltrials.gov.uk was conducted using MeSH terms "ischaemic preconditioning" and "cardiac surgery." RCTs that examined post-surgery troponin concentrations were included in this review. The primary outcome investigated was troponin levels at six hours post-cardiac surgery. Secondary outcomes included six to eight hour and twenty-four hour troponin release. RESULTS: Thirteen RCTs, comprising 1398 participants, were identified for inclusion in this meta-analysis. Twelve hour postoperative troponin was significantly reduced by RIPC, standardized mean difference 1.29 (95% CI 0.34-2.24). Six to eight and twenty-four hour troponin were also significantly reduced, standardized mean differences 1.23 (95% CI 0.62-1.84) and 1.25 (95% CI 0.31-2.19) respectively. CONCLUSIONS: The reduction in troponin concentration suggests that RIPC reduces myocardial damage during open cardiac surgery, however, the degree of bias in the studies assessed may have had a significant impact on this result.

The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics. RESULTS: Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56-1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07-0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34-0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis. CONCLUSIONS: Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery. CLINICALTRIALSGOV ID: NCT00845364.

Prospective peer review of regional percutaneous interventional procedures: a tool for quality control and revalidation.

AIMS: Current quality measures of percutaneous coronary intervention (PCI) procedures are based on the incidence of major adverse cardiac events (MACE). This crude marker ignores the many clinical nuances that make for sound decision making in PCI. We have established a prospective peer review audit tool to determine the quality of PCI within our cardiac network, which consists of five PCI hospitals serving a population of 1.4 million people in Sussex, UK. METHODS AND RESULTS: Analysis of 10% of all PCI cases selected at random each month by a non-clinical audit manager is made by a rotating panel of two PCI operators and one cardiac surgeon. Each PCI case is assessed for anatomical suitability, lesion severity, strategic appropriateness and final outcome. Panel findings were reported back to the operator and the audit manager. A total of 326 cases were assessed by the review committee. Results were disseminated to individual operators. Coronary anatomy and lesion severity were considered appropriate for PCI in 94.2% and 96.0% of cases, respectively. Appropriateness of strategy was confirmed in 86.2% and the outcome considered satisfactory in 90.8%. A total of 242 subsequent cases were analysed to assess practice trends. This analysis demonstrated a statistically significant improvement in clinical decision making with respect to appropriateness of strategy (from 86.2% to 92.6%; p=0.004). CONCLUSIONS: Prospective peer review of percutaneous coronary intervention cases by a rotating regional committee is valuable in ensuring procedural quality.

The efficacy of intraoperative atrial radiofrequency ablation for atrial fibrillation during concomitant cardiac surgery-the Surgical Atrial Fibrillation Suppression (SAFS) Study.

INTRODUCTION: Studies assessing radiofrequency ablation (RFA) for atrial fibrillation (AF) performed at the time of concomitant cardiac surgery have reported high success rates. The efficacy of this treatment has primarily been determined by a single electrocardiogram (ECG) or 24-h Holter monitor at follow-up. We sought to assess the true efficacy of this procedure using prolonged cardiac rhythm monitoring. METHODS: One hundred patients with paroxysmal (n = 47) and persistent AF (n = 53) requiring cardiac surgery were enrolled. Patients were clinically reviewed 6 weeks post-operatively and were monitored with 7-day Holter with full disclosure, 6 months post-surgery. A cohort of 50 patients also underwent 7 day Holter monitoring preoperatively. AF recurrence was defined as >30 s of AF. RESULTS: At 6 months, 75% of patients were in sinus rhythm according to a single ECG. However, only 62% of patients were free from AF on 7-day Holter; all AF episodes in these patients were asymptomatic. The procedure resulted in a significant decrease in AF burden from 56.2% at baseline to 27.5% at 6 months follow-up, (p < 0.001). Predictors of AF recurrence were (1) pre-operative AF duration; (2) persistent compared with paroxysmal AF; (3) increasing left atrial diameter and (4) requirement for mitral valve surgery. CONCLUSIONS: Surgical RFA for the treatment of AF, during concomitant cardiac surgery, is a successful procedure and significantly reduces AF burden. However, 13% of patients have asymptomatic AF episodes only identified with continuous monitoring. This has important implications for post-operative anti-arrhythmic and anticoagulant management and for the definition of surgical AF ablation success.

Simultaneous aortic valve and arch replacement with bilateral nephrectomy for massive polycystic kidney disease, aortic regurgitation and dissecting aneurysm.

Aneurysmal dissection of the ascending aorta and arch may be associated with polycystic kidney disease. We report a case of massive polycystic kidneys leading to respiratory and gastrointestinal embarrassment in combination with aneurysmal dilatation of a chronic arch dissection managed by simultaneous bilateral nephrectomy and arch replacement.

Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: a randomized controlled trial.

OBJECTIVE: We sought to assess the role of glucose-insulin-potassium in providing myocardial protection in nondiabetic patients undergoing coronary artery surgery with cardiopulmonary bypass. METHODS: A prospective, randomized, double-blind, placebo-controlled trial was conducted at a single-center university hospital performing adult cardiac surgery. Two hundred eighty nondiabetic adult patients undergoing first-time elective or urgent isolated multivessel coronary artery bypass grafting were prospectively randomized to receive glucose-insulin-potassium infusion or placebo (dextrose 5%) before, during, and for 6 hours after surgical intervention. Anesthetic, cardiopulmonary bypass, myocardial protection, and surgical techniques were standardized. The primary end point was postreperfusion cardiac index. Secondary end points were systemic vascular resistance index, the incidence of low cardiac output episodes, inotrope and vasoconstrictor use, and biochemical-electrocardiographic evidence of myocardial injury. The incidence of dysrhythmias and infections requiring treatment was recorded prospectively. RESULTS: The glucose-insulin-potassium group experienced higher cardiac indices (P < .001) throughout infusion and reduced vascular resistance (P < .001). The incidence of low cardiac output episodes was 15.9% (22/138) in the glucose-insulin-potassium group and 27.5% (39/142) in the placebo group (P = .021). Inotropes were required in 18.8% (26/138) of the glucose-insulin-potassium group and 40.8% (58/142) of the placebo group (P < .001). Fewer patients in the glucose-insulin-potassium group (12.3% [16/133]) versus those in the placebo group (23.4% [32/137]) had significant myocardial injury (P = .017). Noncardiac morbidity was not different. CONCLUSION: Glucose-insulin-potassium therapy improves early postoperative cardiovascular performance, reduces inotrope requirement, and might reduce myocardial injury. These potential benefits are not at the expense of increased noncardiac morbidity.

The effects of hypothermia on human left ventricular contractile function during cardiac surgery.

OBJECTIVES: We investigated the interaction of heart rate (HR), temperature and contractility using a validated load independent method. BACKGROUND: Temperature manipulation is an integral part of cardiac surgery, and postoperative hypothermia is extremely common. Myocardial contraction is a series of enzymatic and physico-chemical reactions that may be differentially affected by temperature. METHODS: Ten patients undergoing coronary artery bypass grafting were studied during moderately hypothermic cardiopulmonary bypass. After conduit procurement and heparinization but before grafting, the patient was placed on cardiopulmonary bypass and rewarmed to 37 degrees C, and the left ventricle (LV) was instrumented with a conductance catheter allowing continuous pressure and volume measurement. The LV pressure volume relationship was examined to assess the contractility at 37, 35, 33 and 31 degrees C, with fixed atrial pacing (100 beats/min) in five patients and at 80 and 120 beats/min, at 33 and 37 degrees C in five patients. RESULTS: At a HR of 100 beats/min, lower temperature resulted in a highly significant decrease in maximal elastance (100% at 37 degrees C, 29 +/- 3.5% at 31 degrees C, p < 0.0001). At 37 degrees C, increasing HR increased contractility (80 beats/min 100%, 120 beats/min 205.9%, p = 0.0021); however, at 33 degrees C contractility fell with increasing HR (80 beats/min 100%, 120 beats/min, 53.7%, p = 0.0014). CONCLUSIONS: At normothermia LV contractility has a direct relationship with HR. In hypothermic conditions this relationship inverses. Clinical strategies maintaining higher HRs at colder temperatures result in reduced contractility. These factors are important in the management of cardiac surgical patients.