The effects of adenocaine (adenosine and lidocaine) on early post-resuscitation cardiac and neurological dysfunction in a porcine model of cardiac arrest.

AIM: Return of spontaneous circulation (ROSC) elicits ischaemia/reperfusion injury and myocardial dysfunction. The combination of adenosine and lidocaine (AL, adenocaine) has been shown to (1) inhibit neutrophil inflammatory activation and (2) improve left ventricular function after ischaemia. We hypothesized that resuscitation with adenocaine during early moments of cardiopulmonary resuscitation (CPR) attenuates leucocyte oxidant generation and myocardial dysfunction. METHODS: Pigs were randomized to: (1) sham (n=7), (2) cardiac arrest (CA; n=16), or 3) cardiac arrest+adenocaine (CA+AL; n=12). After 7 min of electrically induced ventricular fibrillation, start of CPR was followed by infusion of saline (CA) or adenocaine (CA+AL) for 6 min. Haemodynamics, cardiodynamics (pressure-volume loops) and leucocyte superoxide anion generation were assessed. Neurological function was evaluated after 24h by histology and neurological deficit score (0=normal; 500=brain dead). RESULTS: Rate of ROSC was comparable between groups: CA group 11/16 and CA+AL group 7/12 p=0.57). Cardiac index transiently increased after ROSC in both groups. Left ventricular dysfunction demonstrated by a rightward shift of the intercept of end-systolic pressure-volume relations in CA was avoided in the CA+AL group. Leucocyte superoxide anion generation 2h after ROSC was significantly attenuated in the CA+AL group compared to the CA group. Neurological deficit scores [CA: median: 17.5(IQR:0-75) and CA+AL: 35(IQR:15-150)] and histopathological damage were comparable in both groups (p=0.37). CONCLUSION: Infusion of adenocaine during early resuscitation from CA significantly improved early post-resuscitation cardiac function and attenuated leucocyte superoxide anion generation, without a change in post-ROSC neurological function. (IACUC protocol number 023-2009).

Ischemia-reperfusion increases transfection efficiency of intracoronary adenovirus type 5 in pig heart in situ.

Efficiency of intracoronary (IC) adenoviral vector transfection is impaired by the vascular endothelium. Ischemia and substances that increase vascular permeability (sodium nitroprusside, nitroglycerin) may augment adenoviral vector transfection efficiency (TE). We tested whether TE of adenoviral vector following IC infusion is improved by nitrates or by ischemia. Fluoroscopically guided angioplasty balloon catheters occluded the coronary artery in Yorkshire pigs and delivered adenoviral type 5 vector encoding the luciferase gene (Ad5Luc, 10(11) viral particles). TE (luciferase activity) was minimal and was not augmented by IC co-administration of 50 µg/min sodium nitroprusside to nonischemic myocardium. Two (but not one) 3-min episodes of occlusion tended to increase luciferase activity (p=0.06), and luciferase activity was further increased by IC co-administration of nitroglycerin (p<0.001). After 75 min of coronary artery occlusion, luciferase activity was greater than with shorter periods of ischemia, and was significantly greater in the ischemia-reperfused zone compared to the border zone 3 and 14 days after infusion; there was no transfection in nonischemic myocardium. IC delivery of Ad5Luc into post-ischemic myocardium caused no local inflammation or hemodynamic instability. We conclude that the uptake of IC Ad5 to ischemic reperfused myocardium validates use of IC Ad5 delivery protocols in future human gene therapy trials in patients following myocardial ischemia.

Adhesive epicardial corticosteroids prevent postoperative atrial fibrillation.

BACKGROUND: Postoperative atrial fibrillation remains a common cause of morbidity. Although epicardial drug delivery can increase efficacy and reduce side effects, it is impractical for postoperative atrial fibrillation because pericardial bleeding/effusion and drainage cause rapid drug elimination. Fibrin glue sprayed on the epicardium is vigorously adherent, allowing an admixed drug to remain in contact with the heart. The purpose of the present study was to evaluate a novel corticosteroid-fibrin glue mixture applied to the atrial epicardium at the time of surgery for prevention of postoperative atrial tachyarrhythmias. METHODS AND RESULTS: Talc was instilled into the pericardium in 15 dogs to simulate postoperative inflammation. Pacemakers were implanted to monitor arrhythmias. A mixture of triamcinolone and fibrin glue (Tisseel) was sprayed onto the atria of the treatment animals (n=9), whereas control animals (n=6) received Tisseel or nothing. After 1 week, pacemaker interrogation quantified postoperative atrial tachyarrhythmias (atrial rate >200 bpm) burden. Excised hearts underwent histological examination and tensile strength testing. postoperative atrial tachyarrhythmias occurred in 100% of control animals but only 33% of treatment animals (P=0.027). The median time (25th percentile, 75th percentile) in tachycardia was 5.5 hours (2.7, 12.6) per day in the control group, compared with 0 hours (0, 0.2) in the treatment group (P=0.001). Severe inflammation was present in 6 of 6 control animals and 1 of 9 treatment animals (P=0.001). The tensile strength of a healing left atriotomy was not significantly different between groups. Steroid levels at the time the animals were killed were very low (median of 0.22 µg/dL [0.18, 0.23]). CONCLUSIONS: A mixture of triamcinolone and fibrin glue sprayed onto the atria reduced postoperative atrial tachyarrhythmias and reduced inflammatory cell infiltration. There was no change in the tensile strength of a healing atriotomy and plasma steroid levels were low. Clinical trials of this approach are warranted.