The lectin-like domain of tumor necrosis factor improves lung function after rat lung transplantation--potential role for a reduction in reactive oxygen species generation

To test the hypothesis that the lectin-like domain of tumor necrosis factor, mimicked by the TIP peptide, can improve lung function after unilateral orthotopic lung isotransplantation. Because of a lack of a specific treatment for ischemia reperfusion-mediated lung injury, accompanied by a disrupted barrier integrity and a dysfunctional alveolar liquid clearance, alternative therapies restoring these parameters after lung transplantation are required.

500 ml of blood loss does not decrease non-invasive tissue oxygen saturation (StO2) as measured by near infrared spectroscopy - A hypothesis generating pilot study in healthy adult women

Background The goal when resuscitating trauma patients is to achieve adequate tissue perfusion. One parameter of tissue perfusion is tissue oxygen saturation (StO2), as measured by near infrared spectroscopy. Using a commercially available device, we investigated whether clinically relevant blood loss of 500 ml in healthy volunteers can be detected by changes in StO2 after a standardized ischemic event. Methods We performed occlusion of the brachial artery for 3 minutes in 20 healthy female blood donors before and after blood donation. StO2 and total oxygenated tissue hemoglobin (O2Hb) were measured continuously at the thenar eminence. 10 healthy volunteers were assessed in the same way, to examine whether repeated vascular occlusion without blood donation exhibits time dependent effects. Results Blood donation caused a substantial decrease in systolic blood pressure, but did not affect resting StO2 and O2Hb values. No changes were measured in the blood donor group in the reaction to the vascular occlusion test, but in the control group there was an increase in the O2Hb rate of recovery during the reperfusion phase. Conclusion StO2 measured at the thenar eminence seems to be insensitive to blood loss of 500 ml in this setting. Probably blood loss greater than this might lead to detectable changes guiding the treating physician. The exact cut off for detectable changes and the time effect on repeated vascular occlusion tests should be explored further. Until now no such data exist.

[Acute myocardial infarction: importance of the networking in the initial management]

Early reperfusion with prompt re-establishment of coronary blood flow improves survival in patients suffering from acute ST-elevation myocardial infarction (STEMI). Leaving systemic thrombolysis for primary percutaneous coronary intervention (PCI) is justified by clinical results in favor of PCI. Nevertheless, primary PCI necessitates additional transfer time and requires an efficient territorial networking. The present article summarizes the up-to-dated management of patients with acute STEMI and/or overt cardiogenic shock.

Combined use of pulsed arterial spin-labeling and susceptibility-weighted imaging in stroke at 3T

Background and Purpose: In acute stroke it is no longer sufficient to detect simply ischemia, but also to try to evaluate reperfusion/recanalization status and predict eventual hemorrhagic transformation. Arterial spin labeling (ASL) perfusion may have advantages over contrast-enhanced perfusion-weighted imaging (cePWI), and susceptibility weighted imaging (SWI) has an intrinsic sensitivity to paramagnetic effects in addition to its ability to detect small areas of bleeding and hemorrhage. We want to determine here if their combined use in acute stroke and stroke follow-up at 3T could bring new insight into the diagnosis and prognosis of stroke leading to eventual improved patient management. Methods: We prospectively examined 41 patients admitted for acute stroke (NIHSS >1). Early imaging was performed between 1 h and 2 weeks. The imaging protocol included ASL, cePWI, SWI, T2 and diffusion tensor imaging (DTI), in addition to standard stroke protocol. Results: We saw four kinds of imaging patterns based on ASL and SWI: patients with either hypoperfusion and hyperperfusion on ASL with or without changes on SWI. Hyperperfusion was observed on ASL in 12/41 cases, with hyperperfusion status that was not evident on conventional cePWI images. Signs of hemorrhage or blood-brain barrier breakdown were visible on SWI in 15/41 cases, not always resulting in poor outcome (2/15 were scored mRS = 0–6). Early SWI changes, together with hypoperfusion, were associated with the occurrence of hemorrhage. Hyperperfusion on ASL, even when associated with hemorrhage detected on SWI, resulted in good outcome. Hyperperfusion predicted a better outcome than hypoperfusion (p = 0.0148). Conclusions: ASL is able to detect acute-stage hyperperfusion corresponding to luxury perfusion previously reported by PET studies. The presence of hyperperfusion on ASL-type perfusion seems indicative of reperfusion/collateral flow that is protective of hemorrhagic transformation and a marker of favorable tissue outcome. The combination of hypoperfusion and changes on SWI seems on the other hand to predict hemorrhage and/or poor outcome.

A role for GRK2 in myocardial ischemic injury: indicators of a potential future therapy and diagnostic

Morbidity and mortality of myocardial infarction remains significant with resulting left ventricular function presenting as a major determinant of clinical outcome. Protecting the myocardium against ischemia reperfusion injury has become a major therapeutic goal and the identification of key signaling pathways has paved the way for various interventions, but until now with disappointing results. This article describes the recently discovered new role of G-protein-coupled receptor kinase-2 (GRK2), which is known to critically influence the development and progression of heart failure, in acute myocardial injury. This article focuses on potential applications of the GRK2 peptide inhibitor βARKct in ischemic myocardial injury, the use of GRK2 as a biomarker in acute myocardial infarction and discusses the challenges of translating GRK2 inhibition as a cardioprotective strategy to a possible future clinical application.

The Bernese Hypothermia Algorithm: a consensus paper on in-hospital decision-making and treatment of patients in hypothermic cardiac arrest at an alpine level 1 trauma centre

INTRODUCTION: Guidelines for the treatment of patients in severe hypothermia and mainly in hypothermic cardiac arrest recommend the rewarming using the extracorporeal circulation (ECC). However,guidelines for the further in-hospital diagnostic and therapeutic approach of these patients, who often suffer from additional injuries—especially in avalanche casualties, are lacking. Lack of such algorithms may relevantly delay treatment and put patients at further risk. Together with a multidisciplinary team, the Emergency Department at the University Hospital in Bern, a level I trauma centre, created an algorithm for the in-hospital treatment of patients with hypothermic cardiac arrest. This algorithm primarily focuses on the decision-making process for the administration of ECC. THE BERNESE HYPOTHERMIA ALGORITHM: The major difference between the traditional approach, where all hypothermic patients are primarily admitted to the emergency centre, and our new algorithm is that hypothermic cardiac arrest patients without obvious signs of severe trauma are taken to the operating theatre without delay. Subsequently, the interdisciplinary team decides whether to rewarm the patient using ECC based on a standard clinical trauma assessment, serum potassium levels, core body temperature, sonographic examinations of the abdomen, pleural space, and pericardium, as well as a pelvic X-ray, if needed. During ECC, sonography is repeated and haemodynamic function as well as haemoglobin levels are regularly monitored. Standard radiological investigations according to the local multiple trauma protocol are performed only after ECC. Transfer to the intensive care unit, where mild therapeutic hypothermia is maintained for another 12 h, should not be delayed by additional X-rays for minor injuries. DISCUSSION: The presented algorithm is intended to facilitate in-hospital decision-making and shorten the door-to-reperfusion time for patients with hypothermic cardiac arrest. It was the result of intensive collaboration between different specialties and highlights the importance of high-quality teamwork for rare cases of severe accidental hypothermia. Information derived from the new International Hypothermia Registry will help to answer open questions and further optimize the algorithm.

Evaluation of multimeric tyrosine-O-sulfate as a cytoprotectant in an in vivo model of acute myocardial infarction in pigs

Intracoronary administration of glycosaminoglycan analogs, including the complement inhibitor dextran sulfate, attenuates myocardial ischemia/reperfusion injury (I/R injury). However, dextran sulfate has a distinct anticoagulatory effect, possibly limiting its use in specific situations in vivo. We therefore developed multimeric tyrosine sulfate (sTyr-PAA), a novel, minimally anticoagulatory, fully synthetic non-carbohydrate-containing polyacrylamide conjugate, for in vivo testing in an acute closed-chest porcine model of acute myocardial infarction.

Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients: a position paper endorsed by ESMINT and ESNR : Part I: Current situation and major research questions

A new era of stroke treatment may have begun with mechanical thrombectomy (MT) by fully deployed closed-cell self-expanding stents (stent-triever). Multiple case series and the first randomised controlled trials (RCTs) have now been published. More studies are under way involving large numbers of patients, which in turn has resulted in less strict "pragmatic" study protocols. Problems with current trials include a lack of standardisation in the conduct of the recanalisation procedure, the definition of primary endpoints such as the grade of arterial recanalisation and tissue reperfusion, and the post-surgical care provided. In Part 1 of this two part series, we outline the current situation and the major research questions.

Mild hypothermia during global cardiac ischemia opens a window of opportunity to develop heart donation after cardiac death

Although heart donation after cardiac death (DCD) could greatly improve graft availability, concerns regarding warm ischemic damage typically preclude transplantation. Improving tolerance to warm ischemia may thus open a window of opportunity for DCD hearts. We investigated the hypothesis that, compared with normothermia, mild hypothermia (32° C) initiated after ischemic onset improves cardiac functional recovery upon reperfusion. Isolated, working hearts from adult, male Wistar rats underwent global, no-flow ischemia, and reperfusion (n = 28). After ischemic onset, temperature was maintained at either 37° C for 20 or 30 min or reduced to 32° C for 40, 50, or 60 min. Recovery was measured after 60-min reperfusion. Following normothermic ischemia, recovery of rate-pressure product (RPP; per cent of preischemic value) was almost complete after 20-min ischemia (97 ± 9%), whereas no recovery was detectable after 30-min ischemia. After mildly hypothermic ischemia (32° C), RPP also recovered well after 40 min (86 ± 4%). Markers of metabolism and necrosis were similar in 37° C/20 min and 32° C/40 min groups. Simple reduction in cardiac temperature by a few degrees after the onset of global ischemia dramatically prolongs the interval during which the heart remains resistant to functional deterioration. Preservation of hemodynamic function is associated with improved metabolic recovery and reduced necrosis. The application of mild hypothermia may be a simple first step towards development of clinical protocols for DCD heart recovery.

Postreperfusion cardiac arrest and resuscitation during orthotopic liver transplantation: dynamic visualization and analysis of physiologic recordings

We recently reported on the Multi Wave Animator (MWA), a novel open-source tool with capability of recreating continuous physiologic signals from archived numerical data and presenting them as they appeared on the patient monitor. In this report, we demonstrate for the first time the power of this technology in a real clinical case, an intraoperative cardiopulmonary arrest following reperfusion of a liver transplant graft. Using the MWA, we animated hemodynamic and ventilator data acquired before, during, and after cardiac arrest and resuscitation. This report is accompanied by an online video that shows the most critical phases of the cardiac arrest and resuscitation and provides a basis for analysis and discussion. This video is extracted from a 33-min, uninterrupted video of cardiac arrest and resuscitation, which is available online. The unique strength of MWA, its capability to accurately present discrete and continuous data in a format familiar to clinicians, allowed us this rare glimpse into events leading to an intraoperative cardiac arrest. Because of the ability to recreate and replay clinical events, this tool should be of great interest to medical educators, researchers, and clinicians involved in quality assurance and patient safety.

Endovascular therapy in 201 patients with acute symptomatic occlusion of the internal carotid artery

Background and purpose Endovascular therapy is used increasingly for treatment of acute symptomatic internal carotid artery (ICA) occlusion, although randomized trials are lacking. Predictors of outcome are therefore of special interest. Methods From 1992 to 2010 we treated 201 patients with acute ICA occlusion with intra-arterial pharmacological thrombolysis (32), endovascular mechanical therapy (78) or a combination of both (91). All data were assessed prospectively. Results There were 76/38% patients with tandem occlusions [ICA plus middle (MCA) or anterior cerebral arteries (ACA)], 18/9% without concomitant occlusions of major intracranial arteries (ICA plus branch occlusion) and 107/53% with functional ICA-T occlusions (ICA plus MCA and ACA). Median baseline National Institute of Health Stroke Scale (NIHSS) score was 17. Good recanalization (Thrombolysis in Myocardial Infarction 2–3) was achieved in (157/201) 78% patients and good reperfusion (Thrombolysis in Cerebral Infarction 2–3) in (151/182) 83%. Better recanalization rates were obtained with mechanical approaches, with/without thrombolytics (78/91 = 86% and 64/78 = 82%) compared with pharmacological thrombolysis only (15/32 = 47%; P < 0.001). Twelve patients (6%) suffered symptomatic intracranial haemorrhages. The 3-month outcome was favourable [modified Rankin score (mRS) 0–2] in 54/28% patients and moderate (mRS 0–3) in 90/46%; 60/31% patients died. Only 17/16% patients with functional ICA-T occlusions had favourable outcomes compared with 32/44% with tandem occlusions and 5/31% with ICA plus cerebral branch occlusions (P = 0.001). In multivariate analysis age [odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.93–0.98], NIHSS on admission (OR = 0.9, 95% CI = 0.83–0.98) and functional ICA-T occlusion (OR = 0.35, 95% CI = 0.16–0.77) were non-modifiable predictors, and vessel recanalization was the only modifiable predictor of outcome (OR = 9.30, 95% CI = 2.03–42.63). Conclusions The outcome of acute symptomatic ICA occlusion is poor. However, recanalization is associated with better outcome, and recanalization rates with mechanical techniques were superior to merely pharmacological recanalization attempts.

Toll-like receptors in ischaemia and its potential role in the pathophysiology of muscle damage in critical limb ischaemia

Toll-like receptors (TLRs) are key receptors of the innate immune system which are expressed on immune and nonimmune cells. They are activated by both pathogen-associated molecular patterns and endogenous ligands. Activation of TLRs culminates in the release of proinflammatory cytokines, chemokines, and apoptosis. Ischaemia and ischaemia/reperfusion (I/R) injury are associated with significant inflammation and tissue damage. There is emerging evidence to suggest that TLRs are involved in mediating ischaemia-induced damage in several organs. Critical limb ischaemia (CLI) is the most severe form of peripheral arterial disease (PAD) and is associated with skeletal muscle damage and tissue loss; however its pathophysiology is poorly understood. This paper will underline the evidence implicating TLRs in the pathophysiology of cerebral, renal, hepatic, myocardial, and skeletal muscle ischaemia and I/R injury and discuss preliminary data that alludes to the potential role of TLRs in the pathophysiology of skeletal muscle damage in CLI.

The Emerging Role of TLR and Innate Immunity in Cardiovascular Disease

Cardiovascular disease is a complex disorder involving multiple pathophysiological processes, several of which involve activation of toll-like receptors (TLRs) of the innate immune system. As sentinels of innate immunity TLRs are nonclonally germline-encoded molecular pattern recognition receptors that recognize exogenous as well as tissue-derived molecular dangers signals promoting inflammation. In addition to their expression in immune cells, TLRs are found in other tissues and cell types including cardiomyocytes, endothelial and vascular smooth muscle cells. TLRs are differentially regulated in various cell types by several cardiovascular risk factors such as hypercholesterolemia, hyperlipidemia, and hyperglycemia and may represent a key mechanism linking chronic inflammation, cardiovascular disease progression, and activation of the immune system. Modulation of TLR signaling by specific TLR agonists or antagonists, alone or in combination, may be a useful therapeutic approach to treat various cardiovascular inflammatory conditions such as atherosclerosis, peripheral arterial disease, secondary microvascular complications of diabetes, autoimmune disease, and ischemia reperfusion injury. In this paper we discuss recent developments and current evidence for the role of TLR in cardiovascular disease as well as the therapeutic potential of various compounds on inhibition of TLR-mediated inflammatory responses.

Coronary stent choice in patients with acute myocardial infarction

A prompt reperfusion with primary percutaneous coronary intervention represents the current gold standard treatment for patients with acute myocardial infarction. In this setting, coronary stents have been shown to improve outcomes compared to plain angioplasty and are routinely used. However, the stent selection among patients with acute myocardial infarction is still a matter of some debate. An increased risk of very late (>1-year) stent thrombosis has been associated with the use of early-generation drug-eluting stents (DES), leading to concerns regarding the long-term safety of these devices. Newer-generation DES were developed with the aim of addressing this safety issue, and were recently investigated in a few randomized studies in patients with acute myocardial infarction. The objective of the present review is to summarize the accumulated evidence, to guide the stent selection in patients with acute myocardial infarction.

Cardiac transplantation with hearts from donors after circulatory declaration of death: haemodynamic and biochemical parameters at procurement predict recovery following cardioplegic storage in a rat model

OBJECTIVES: Donation after circulatory declaration of death (DCDD) could significantly improve the number of cardiac grafts for transplantation. Graft evaluation is particularly important in the setting of DCDD given that conditions of cardio-circulatory arrest and warm ischaemia differ, leading to variable tissue injury. The aim of this study was to identify, at the time of heart procurement, means to predict contractile recovery following cardioplegic storage and reperfusion using an isolated rat heart model. Identification of reliable approaches to evaluate cardiac grafts is key in the development of protocols for heart transplantation with DCDD. METHODS: Hearts isolated from anaesthetized male Wistar rats (n = 34) were exposed to various perfusion protocols. To simulate DCDD conditions, rats were exsanguinated and maintained at 37°C for 15-25 min (warm ischaemia). Isolated hearts were perfused with modified Krebs-Henseleit buffer for 10 min (unloaded), arrested with cardioplegia, stored for 3 h at 4°C and then reperfused for 120 min (unloaded for 60 min, then loaded for 60 min). Left ventricular (LV) function was assessed using an intraventricular micro-tip pressure catheter. Statistical significance was determined using the non-parametric Spearman rho correlation analysis. RESULTS: After 120 min of reperfusion, recovery of LV work measured as developed pressure (DP)-heart rate (HR) product ranged from 0 to 15 ± 6.1 mmHg beats min(-1) 10(-3) following warm ischaemia of 15-25 min. Several haemodynamic parameters measured during early, unloaded perfusion at the time of heart procurement, including HR and the peak systolic pressure-HR product, correlated significantly with contractile recovery after cardioplegic storage and 120 min of reperfusion (P < 0.001). Coronary flow, oxygen consumption and lactate dehydrogenase release also correlated significantly with contractile recovery following cardioplegic storage and 120 min of reperfusion (P < 0.05). CONCLUSIONS: Haemodynamic and biochemical parameters measured at the time of organ procurement could serve as predictive indicators of contractile recovery. We believe that evaluation of graft suitability is feasible prior to transplantation with DCDD, and may, consequently, increase donor heart availability.