2,3-Butanedione monoxime facilitates successful resuscitation in a dose-dependent fashion in a pig model of cardiac arrest.

PURPOSE: Ischemic contracture compromises the hemodynamic effectiveness of cardiopulmonary resuscitation (CPR) and resuscitability from cardiac arrest. In a pig model of cardiac arrest, 2,3-butanedione monoxime (BDM) attenuated ischemic contracture. We investigated the effects of different doses of BDM to determine whether increasing the dose of BDM could improve the hemodynamic effectiveness of CPR further, thus ultimately improving resuscitability. METHODS: After 16minutes of untreated ventricular fibrillation and 8minutes of basic life support, 36 pigs were divided randomly into 3 groups that received 50mg/kg (low-dose group) of BDM, 100mg/kg (high-dose group) of BDM, or an equivalent volume of saline (control group) during advanced cardiovascular life support. RESULTS: During advanced cardiovascular life support, the control group showed an increase in left ventricular (LV) wall thickness and a decrease in LV chamber area. In contrast, the BDM-treated groups showed a decrease in the LV wall thickness and an increase in the LV chamber area in a dose-dependent fashion. Mixed-model analyses of the LV wall thickness and LV chamber area revealed significant group effects and group-time interactions. Central venous oxygen saturation at 3minutes after the drug administration was 21.6% (18.4-31.9), 39.2% (28.8-53.7), and 54.0% (47.5-69.4) in the control, low-dose, and high-dose groups, respectively (P<.001). Sustained restoration of spontaneous circulation was attained in 7 (58.3%), 10 (83.3%), and 12 animals (100%) in the control, low-dose, and high-dose groups, respectively (P=.046). CONCLUSION: 2,3-Butanedione monoxime administered during CPR attenuated ischemic contracture and improved the resuscitability in a dose-dependent fashion.

Effects of the administration of 2,3-butanedione monoxime during conventional cardiopulmonary resuscitation on ischaemic contracture and resuscitability in a pig model of out-of-hospital cardiac arrest.

AIM OF THE STUDY: Ischaemic contracture compromises the haemodynamic effectiveness of cardiopulmonary resuscitation and resuscitability. 2,3-Butanedione monoxime (BDM) reduced ischaemic contracture by inhibiting actin-myosin crossbridge formation in an isolated heart model. We investigated the effects of BDM on ischaemic contracture and resuscitation outcomes in a pig model of out-of-hospital cardiac arrest (OHCA). METHODS: After 15min of untreated ventricular fibrillation, followed by 8min of basic life support, 16 pigs were randomised to receive either 2mlkg(-1) of BDM solution (25gl(-1)) or 2mlkg(-1) of saline during advanced cardiac life support (ACLS). RESULTS: During the ACLS, the control group showed an increase in left ventricular (LV) wall thickness from 10.0mm (10.0-10.8) to 13.0mm (13.0-13.0) and a decrease in LV chamber area from 8.13cm(2) (7.59-9.29) to 7.47cm(2) (5.84-8.43). In contrast, the BDM group showed a decrease in the LV wall thickness from 10mm (9.0-10.8) to 8.5mm (7.0-9.8) and an increase in the LV chamber area from 9.86cm(2) (7.22-12.39) to 12.15 cm(2) (8.02-14.40). Mixed model analyses of the LV wall thickness and LV chamber area revealed significant group effects and group-time interactions. Spontaneous circulation was restored in four (50%) animals in the control group and in eight (100%) animals in the BDM group (p=0.077). All the resuscitated animals survived during an intensive care period of 4h. CONCLUSION: BDM administered during cardiopulmonary resuscitation reversed ischaemic contracture in a pig model of OHCA.

[Closed treatment for type III humeral supracondylar fractures and prevention of ischemic contracture of forearm in children].

OBJECTIVE: To evaluate the curative effects of manipulative reduction for children's type III humeral supracondylar fracture and the preventions of ischemic contracture of forearm in the early period. METHODS: From September 2008 to September 2011, 38 patients with humeral supracondylar fractures were treated with manipulative reduction and plaster stabilization, including 20 males and 18 females with an average age of 7.5 years (ranged, 2 to 13 years); the average time from injury to visit was 1.8 days(ranged,0.5 h to 6 d). There were 21 cases in straighten-ulnar deviation type and 17 cases in straighten-radial deviation type, 1 case in flexion type,all of them without vascular nerve injury. It was important to process swelling correctly in early stage of fracture. To decide fixed position according to the original displacement, and make a regular X-ray review, if found another displacement to correct it in 1-2 weeks after injury in time. Dismantle the plaster on the basis of bone healing and guide the functional exercise of elbow joint. According to Dodgt standard to evaluate clinical effects. RESULTS: All patients were followed up from 3 months to 1 year with an average of 7 months. All fractures healed. According to Dodgt standard, 14 patients got an excellent results, 19 good, 4 fair and 1 poor. The excellent and good rate was 86.84%. CONCLUSION: It can obtain satisfactory clinical effects to treat humeral supracondylar fracture in children with closed manipulative reduction and plaster stabilization, while without vascular nerve injury. Early correct processing swelling and paying attention to gypsous angle can effectively prevent the ischemic contracture of forearm.

Dose-dependent effects of sildenafil on post-ischaemic left ventricular function in the rat isolated heart.

OBJECTIVES: Sildenafil may be beneficial during myocardial ischaemia/reperfusion, but this effect may be dose-dependent, accounting for previous conflicting results. We have explored the effects of two acute and one chronic administration regimen on left ventricular function. METHODS: The study was conducted on 36 Wistar rats (290 +/- 7 g). Sildenafil was administered 30 min before ischaemia at a low (0.7 mg/kg, n= 8) or high (1.4 mg/kg, n= 8)dosage. The chronic treatment arm (n= 8) consisted of two daily injections of sildenafil (0.7 mg/kg) for three weeks. The control group was formed by 12 rats. Ischaemic contracture, post-ischaemic recovery and hypercontracture were measured in isolated, Langendorff-perfused preparations. KEY FINDINGS: Ischaemic contracture tended to be lower after high-dose sildenafil, while remaining unchanged after low-dose or chronic sildenafil administration. Compared with controls (62.9 +/- 2.0% of baseline developed pressure), post-ischaemic recovery was higher (P= 0.0069) after low dose (75.1 +/- 2.4%), unchanged (P= 0.13) after high dose (69.1 +/- 2.1%), but lower (P < 0.001) after chronic (42.9 +/- 4.5%) sildenafil administration. Compared with controls (71.8 +/- 3.9 mmHg), hypercontracture was higher (P= 0.0052) after chronic sildenafil administration (89.5 +/- 4.1 mmHg), but similar after acute low dose (65.7 +/- 3.3 mmHg, P= 0.33) or high dose (67.1 +/- 4.7 mmHg, P= 0.43). CONCLUSIONS: The effects of sildenafil after ischaemia/reperfusion were strongly dose-dependent. Beneficial actions on left ventricular function were evident after acute pretreatment with a low dosage, but were lost after doubling the dose. Chronic sildenafil administration deteriorated left ventricular function during ischaemia and reperfusion.

Ischemic preconditioning of the whole heart confers protection on subsequently isolated ventricular myocytes.

Current cellular models of ischemic preconditioning (IPC) rely on inducing preconditioning in vitro and may not accurately represent complex pathways triggered by IPC in the intact heart. Here, we show that it is possible to precondition the intact heart and to subsequently isolate individual ventricular myocytes that retain the protection triggered by IPC. Myocytes isolated from Langendorff-perfused hearts preconditioned with three cycles of ischemia-reperfusion were exposed to metabolic inhibition and reenergization. Injury was assessed from induction of hypercontracture and loss of Ca(2+) homeostasis and contractile function. IPC induced an immediate window of protection in isolated myocytes, with 64.3 +/- 7.6% of IPC myocytes recovering Ca(2+) homeostasis compared with 16.9 +/- 2.4% of control myocytes (P < 0.01). Similarly, 64.1 +/- 5.9% of IPC myocytes recovered contractile function compared with 15.3 +/- 2.2% of control myocytes (P < 0.01). Protection was prevented by the presence of 0.5 mM 5-hydroxydecanoate during the preconditioning stimulus. This early protection disappeared after 6 h, but a second window of protection developed 24 h after preconditioning, with 54.9 +/- 4.7% of preconditioned myocytes recovering Ca(2+) homeostasis compared with 12.6 +/- 2.9% of control myocytes (P < 0.01). These data show that "true" IPC of the heart confers both windows of protection in the isolated myocytes, with a similar temporal relationship to in vivo preconditioning of the whole heart. The model should allow future studies in isolated cells of the protective mechanisms induced by true ischemia.

Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening.

BACKGROUND: In the majority of studies, metformin has been demonstrated to cardioprotect diabetic patients, the mechanism of which is unclear. We hypothesized that metformin cardioprotects the ischemic heart through the Akt-mediated inhibition of mitochondrial permeability transition pore (mPTP) opening. MATERIALS AND METHODS: Isolated perfused hearts from normoglycemic Wistar or from diabetic Goto-Kakizaki (GK) rats (N > or = 6/group) were subjected to 35 min ischemia and 120 min of reperfusion. Metformin (50 micromol/l) was added for 15 min at reperfusion, alone or with LY294002 (15 micromol/l), a PI3K inhibitor. Infarct size and Akt phosphorylation were measured. Furthermore, the effect of metformin on mPTP opening in adult cardiomyocytes isolated from both strains was determined. RESULTS: Metformin reduced infarct size in both Wistar (35 +/- 2.7% metformin vs. 62 +/- 3.0% control: P < 0.05) and GK hearts (43 +/- 4.7% metformin vs. 60 +/- 3.8% control: P < 0.05). This protection was accompanied by a significant increase in Akt phosphorylation. LY294002 abolished the metformin-induced Akt phosphorylation and the infarct-limiting effect of metformin in Wistar (61 +/- 6.7% metformin + LY294002 vs. 35 +/- 2.7% metformin: P < 0.05) and GK rats (56 +/- 5.7% metformin + LY294002 vs. 43 +/- 4.7% metformin: P < 0.05). In addition, metformin significantly inhibited mPTP opening and subsequent rigor contracture in both Wistar and GK cardiomyocytes subjected to oxidative stress, in a LY-sensitive manner. CONCLUSIONS: We report that metformin given at the time of reperfusion reduces myocardial infarct size in both the non-diabetic and diabetic heart and this protective effect is mediated through PI3K and is associated with Akt phosphorylation. Furthermore, cardioprotection appears to be executed through a PI3K-mediated inhibition of mPTP opening. These findings may explain in part the cardioprotective properties of metformin observed in clinical studies of diabetic patients.