Antiarrhythmics in Cardiac Arrest: A Systematic Review and Meta-Analysis.

INTRODUCTION: It is widely accepted that antiarrhythmics play a role in cardiopulmonary resuscitation (CPR) universally, but the absolute benefit of antiarrhythmic use and the drug of choice in advanced life support remains controversial. AIM: To perform a thorough, in-depth review and analysis of current literature to assess the efficacy of antiarrhythmics in advanced life support. MATERIAL AND METHODS: Two authors systematically searched through multiple bibliographic databases including CINAHL, SCOPUS, PubMed, Web of Science, Medline(Ovid) and the Cochrane Clinical Trials Registry. To be included studies had to compare an antiarrhythmic to either a control group, placebo or another antiarrhythmic in adult cardiac arrests. These studies were independently screened for outcomes in cardiac arrest assessing the effect of antiarrhythmics on return of spontaneous circulation (ROSC), survival and neurological outcomes. Data was extracted independently, compared for homogeneity and level of evidence was evaluated using the Cochrane Collaboration's tool for assessing the risk of bias. The Mantel-Haenszel (M-H) random effects model was used and heterogeneity was assessed using the I2 statistic. RESULTS AND DISCUSSION: The search of the literature yielded 30 studies, including 39,914 patients. Eight antiarrhythmic agents were identified. Amiodarone and lidocaine, the two most commonly used agents, showed no significant effect on any outcome either against placebo or each other. Small low quality studies showed benefits in isolated outcomes with esmolol and bretylium against placebo. The only significant benefit of one antiarrhythmic over another was demonstrated with nifekalant over lidocaine for survival to admission (p=0.003). On sensitivity analysis of a small number of high quality level one RCTs, both amiodarone and lidocaine had a significant increase in survival to admission, with no effect on survival to discharge. CONCLUSIONS: This systematic review and meta-analysis suggests that, based on current literature and data, there has been no conclusive evidence that any antiarrhythmic agents improve rates of ROSC, survival to admission, survival to discharge or neurological outcomes. Given the side effects of some of these agents, we recommend further research into their utility in current cardiopulmonary resuscitation guidelines.

Overtime claiming among Australian doctors-in-training.

Objective To quantify patterns of overtime among doctors-in-training in New South Wales and to explore the reasons doctors-in-training cite for not claiming overtime worked. Methods A confidential online self-reporting survey was conducted of post-graduate doctors-in-training, working in hospitals in NSW, from post-graduate year 1 through to completion of specialist training. Questions sought to determine the average amount of overtime worked, overtime claiming patterns, and reasons why overtime was not claimed. Comparisons were made by level of training and specialty training pathway. Results A total of 1351 valid responses were received. Unrostered overtime was extremely common, as was underpayment for work completed. Though 73.5% of respondents reported working at least 5 h of unrostered overtime per fortnight, only 15.6% of respondents reported claiming all their unrostered overtime, and among those who did claim overtime, only 45.5% reported being paid the amount in full. Common reasons for not claiming overtime included workplace cultural expectations (37.0%), and overtime not falling under approved reasons (32.6%). There were statistically significant differences (P < 0.001) in all response categories between critical care, physician and surgical training pathways. Conclusions The survey data demonstrated a significant disconnect between expectations and reality of working hours among doctors-in-training. This is indicative of concerns regarding loss of income, impaired ability to plan workforce allocation due to hidden workload, and possibly impaired wellbeing.

Achieving self-sufficiency: training Australia's future medical workforce.

There is an oversupply of Australian junior doctors, but significant training bottlenecks are developing, and geographical maldistribution in rural and remote areas remains. Last year, the Federal Minister for Immigration rejected a Department of Health recommendation for the removal of 41 health roles from the Skilled Occupation List after concerns that rural and regional communities would be left without access to medical services in areas currently serviced by international medical graduates. In an effort to achieve workforce self-sufficiency, Australia must ensure access to high-quality vocational training places in rural and regional settings while managing immigration of overseas-trained health professionals.

Dependence of neovascularization mechanisms on the molecular microenvironment.

In vivo vascularization of implanted (bio)artificial constructs is essential for their proper function. Vascularization may rely on sprouting angiogenesis, vascular incorporation of bone marrow-derived endothelial cells (BMDECs), or both. Here we investigated the relative contribution of these 2 mechanisms to neovascularization in a mouse model of a foreign body reaction (FBR) to subcutaneously implanted Dacron and in hind limb ischemia (HLI) in relation to the molecular microenvironment at these neovascularization sites. Neovascularization was studied in C57Bl/6 mice reconstituted with enhanced green fluorescent protein (EGFP) transgenic bone marrow. Sprouting angiogenesis, detected using nuclear incorporation of bromodeoxyuridine in endothelial cells was present in both models, whereas vascular incorporation of EGFP(+) BMDECs was restricted to HLI. In HLI, the presence of a pro-angiogenic molecular microenvironment comprising vascular endothelial growth factor, fibroblast growth factor 2, and granulocyte colony-stimulating factor corroborated the importance of these factors for vascular BMDEC incorporation, whereas this microenvironment was absent in FBR. Enhanced mobilization of BMDECs by granulocyte-macrophage colony-stimulating factor administration or by combining HLI and FBR with Dacron did not induce incorporation of BMDECs in FBR neovessels. We conclude that the efficacy of BMDEC-based therapy is not generally warranted, but it depends on the molecular microenvironment in the targeted tissue.

Electrophysiological consequence of skeletal myoblast transplantation in normal and infarcted canine myocardium.

OBJECTIVE: The purpose of this study is to test our hypothesis that injection of skeletal myoblasts (SkMbs) into viable tissue may alter impulse conduction but that injections into nonviable tissue (scar) will have negligible impact. BACKGROUND: Myocardial infarction (MI) is a major public health problem. SkMb transplantation after MI has been shown to have some beneficial effect on hemodynamic function. Previous studies have indicated that SkMbs do not electrically couple with viable host myocardium in vivo. METHODS: We used optical mapping to measure impulse propagation and arrhythmia inducibility in the canine left ventricular wedge preparation with and without MI. MI was created by temporary ligation of a branch of the left anterior descending coronary artery (LAD) (7.0 +/- 3.8 ng/mL troponin 24 hours after MI). Labeled SkMbs (10(8) in 4 mL of serum-free basal solution) were injected from the epicardium (20-40 0.1 mL injections) into normal myocardium (n = 8) or the central zone of the MI (n = 6). RESULTS: During endocardial pacing in the absence of MI, transmural conduction velocity was similar with (35.75 +/- 3.4 cm/s) and without (37.42 +/- 3.6 cm/s) SkMb transplantation. However, pacing from the epicardium resulted in conduction slowing in regions that were DiI-positive and associated with the expression of skeletal myosin (fast) but not connexin-43. In all preparations with MI (n = 13), abnormal impulse propagation was seen regardless of SkMb transplantation. Arrhythmias (at least one extra beat after standard programmed stimulation) occurred most frequently in preparations with MI independent of SkMb transplantation. In preparations without MI (n = 8), SkMb transplantation did not significantly increase arrhythmia inducibility. CONCLUSION: We conclude that SkMbs transplanted into normal myocardium can cause abnormal impulse propagation. These data suggest that the location of SkMb transplantation may influence arrhythmia vulnerability associated with MI.

Periluminal expression of a secreted transforming growth factor-ß type II receptor inhibits in-stent neointima formation following adenovirus-mediated stent-based intracoronary gene transfer.

Transforming growth factor-ß1 (TGF-ß1) has been shown unequivocally to enhance neointima formation in carotid and ileo-femoral arteries. In our previous studies, however, TGF-ß1 expression in coronary arteries actually reduced neointima formation without affecting luminal loss postangioplasty, while expression of a TGF-ß1 antagonist (RIIs) in balloon-injured coronary arteries reduced luminal loss without affecting neointima formation. These observed effects may be a consequence of the mode of coronary artery gene transfer employed, but they may also represent differences in the modes of healing of coronary, carotid, and ileo-femoral arteries after endoluminal injury. To help clarify whether a gene therapy strategy to antagonize TGF-ß might have application within the coronary vasculature, we have investigated the effect of high-level periluminal expression of RIIs using stent-based adenovirus-mediated intracoronary gene transfer. Porcine coronary arteries were randomized to receive a custom-made CoverStent preloaded with saline only, or with 1×10(9) infectious units of adenovirus expressing RIIs or ß-galactosidase (lacZ). Vessels were analyzed 28 days poststenting, at which time angiographic in-stent diameter was significantly greater in RIIs-treated arteries, and in-stent luminal loss significantly reduced. Computerized morphometric minimum in-stent lumen area was ~300% greater in RIIs-exposed vessels than in lacZ or saline-only groups. This was because of significantly reduced neointima formation in the RIIs group. RIIs had no demonstrable effect on cellular proliferation or apoptosis, but greater normalized neointimal/medial collagen content was observed in RIIs-exposed arteries. These data highlight the qualitatively similar effect of TGF-ß antagonism on neointima formation in injured coronary and noncoronary arteries, and suggest that since cellular proliferation is unaffected, TGF-ß1 antagonism might prevent in-stent restenosis without the delayed healing that is associated with drug-eluting stents in current clinical use.

AAV-2-mediated expression of IGF-1 in skeletal myoblasts stimulates angiogenesis and cell survival.

The transplantation of skeletal myoblasts is being tested in various organ systems to facilitate tissue repair and regeneration. Previous studies have indicated that transplanted cells for varied reasons were not surviving in sufficient numbers following transplantation, thus negatively affecting overall therapeutic efficacy of the approach. We hypothesize that the genetic modification of myoblasts to express insulin-like growth factor 1 (IGF-1) locally may enhance the survival of transplanted cells by stimulating neo-vascularization, decreasing apoptosis, and promoting cell proliferation. Using an adeno-associated virus (adeno-associated virus type 2) vector system, the IGF-1 gene was introduced into canine skeletal myoblasts. As a negative control, myoblasts transduced with the green fluorescence protein (GFP) was used. Relative angiogenic response induced by IGF-1 myoblast was compared to VEGF165-induced neo-vascularization using Matrigel plugs under similar conditions. In vitro evaluation and characterization revealed that the secreted IGF-1 protein was biologically and functionally active in promoting endothelial cell proliferation, migration and assembly into vessel-like structures. Matrigel plugs containing the three test groups were implanted subcutaneously in nude mice (n = 5). After 3 weeks, analysis of explanted samples revealed an enhanced neo-vascularization with an average microvessel density per field for IGF-1 at 55.9 versus 33.4 for vascular endothelial growth factor and 24 for GFP. Additionally, apoptosis was significantly reduced (p

Continuous periaortic infusion improves doxycycline efficacy in experimental aortic aneurysms.

OBJECTIVE: We created a novel continuous infusion system to evaluate the efficacy of juxta-aortic doxycycline delivery as a transitional step toward developing hybrid drug/device treatment strategies for abdominal aortic aneurysm (AAA) disease. METHODS: Controlled comparison of treatment outcomes was studied in animal models with molecular and morphologic tissue analysis in a collaboration between university and corporate research laboratories. Rat AAAs were created via porcine pancreatic elastase (PPE) infusion and grouped and analyzed by subsequent treatment status (either doxycycline in vehicle or vehicle alone) and drug delivery method (continuous infusion via periaortic delivery system [PDS] or twice-daily subcutaneous injection). The main outcome measures were AAA diameter via direct measurement, medial elastin lamellar preservation via light microscopy, mural smooth muscle cell (SMC) proliferation and SMC and macrophage density via immunostaining and counting, expression of matrix metalloproteinases 2, 9, and 14 and tissue inhibitors of metalloproteinases 1 and 2 via real-time reverse transcriptase-polymerase chain reaction, and enzymatic activity via substrate zymography. Serum drug levels were analyzed via liquid chromatography/mass spectroscopy. RESULTS: PDS (1.5 mg/kg/day) and subcutaneous (60 mg/kg/day) delivery methods caused comparable reductions in AAA diameter during the period of 14 days after PPE infusion. PDS rats gained more weight during the postoperative period (P <.001), possibly as a result of reduced serum drug levels and systemic toxicity. Doxycycline treatment reduced AAA macrophage infiltration and SMC proliferation significantly. Despite reduced diameter, circumferential elastic lamellar preservation was not apparent in doxycycline-treated AAAs. CONCLUSIONS: Continuous periaortic infusion lowers the effective doxycycline dose for experimental AAA limitation. Alternative biologic inhibition strategies might also be amenable to direct intra-aortic or juxta-aortic delivery. Periaortic infusion might improve the clinical outcome of minimally invasive AAA treatment strategies. Clinical relevance Aneurysm remodeling may continue after successful endovascular AAA exclusion. Continued proteolytic activity within the aneurysm wall potentiates late graft migration and failure. The doxycycline infusion system developed in these experiments may serve as a prototype for adjuvant treatment modalities that complement endovascular AAA exclusion. Local delivery of doxycycline or other agents active in AAA disease, either continuously or at selected intervals after graft implantation, may stabilize the wall and aid in maintaining aneurysm exclusion. Alternative delivery methods could include passive diffusion from either the graft material itself or treatment reservoirs incorporated into endografts. Given the recognized limitations of current technologies, adjuvant biologic therapies have the potential to improve long-term patient outcome significantly after endovascular exclusion.