Langendorff technique. Curve A - contractile function of the heart is greatly depressed after ischemia-reperfusion. Curve B - a set of short ischemic episodes (ischemic preconditioning) before prolonged ischemia provides functional recovery of contractile activity of the heart at<unk> . A study of aortic cross-clamping, a common procedure in cardiac surgery, demonstrated a strong potential benefit with further research ongoing. Therapeutic hypothermia An intriguing area of research demonstrates the ability of a reduction in body temperature to limit ischemic injuries. This procedure is called therapeutic hypothermia, and it has been shown by a number of large, high-quality randomised trials to significantly improve survival and reduce brain damage after birth asphyxia in newborn infants, almost doubling the chance of normal survival. For a full review see Hypothermia therapy for neonatal encephalopathy. However, the therapeutic effect of hypothermia does not confine itself to metabolism and membrane stability. Another school of thought focuses on hypothermia's ability to prevent the injuries that occur after circulation returns to the brain, or what is termed<unk> es. In fact an individual suffering from an ischemic insult continues suffering injuries well after circulation is restored. In rats it has been shown that neurons often die a full 24 hours after blood flow returns. Some theorize that this delayed reaction derives from the various inflammatory immune responses that occur during<unk> . These inflammatory responses cause intracranial pressure, pressure which leads to cell injury and in some situations cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effect of a patient's inflammatory immune responses during<unk> . Beyond this,<unk>  also increases free radical production. Hypothermia too has been shown to minimize a patient's production of deadly free radicals during<unk> . Many now suspect it is because hypothermia reduces both intracranial pressure and free radical production that hypothermia improves patient outcome following a blockage of blood flow to the brain. Hydrogen sulfide treatment There are some preliminary studies in mice that seem to indicate that treatment with hydrogen sulfide (H2S) can have a protective effect against<unk> . Cyclosporin In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporin at the time of percutaneous coronary intervention (PCI) has been found to deliver a 40 percent reduction in infarct size in a small group proof of concept study of human patients with<unk>  published in The New England Journal of Medicine in 2008. Cyclosporin has been confirmed in studies to inhibit the actions of cyclophilin D, a protein which is induced by excessive intracellular calcium flow to interact with other pore components and help open the MPT pore. Inhibiting cyclophilin D has been shown to prevent the opening of the MPT pore and protect the mitochondria and cellular energy production from excessive calcium inflows. However, the studies CIRCUS and CYCLE (published in September 2015 and February 2016 respectively) looked at the use of cyclosporin as a one time IV dose given right before perfusion therapy (PCI). Both studies found there is no statistical difference in outcome with cyclosporin administration. Research is ongoing.<unk>  leads to biochemical imbalances within the cell that lead to cell death and increased infarct size. More specifically, calcium overload and excessive production of reactive oxygen species in the first few minutes after<unk>  set off a cascade of biochemical changes that result in the opening of the so-called mitochondrial permeability transition pore (MPT pore) in the mitochondrial membrane of cardiac cells. The opening of the MPT pore leads to the inrush of water into the mitochondria, resulting in mitochondrial dysfunction and collapse. Upon collapse, the calcium is then released to overwhelm the next mitochondria in a cascading series of events that cause mitochondrial energy production supporting the cell to be reduced or stopped completely. The cessation of energy production results in cellular death. Protecting mitochondria is a viable cardioprotective strategy. In 2008, an editorial in the New England Journal of Medicine called for more studies to determine if cyclosporin can become a treatment to ameliorate<unk>  by protecting mitochondria. To that end, in 2011 the researchers involved in the original 2008 NEJM study initiated a phase III clinical study of<unk>  in 1000 myocardial infarction patients in centers throughout Europe. Results of that study were announced in 2015 and indicated that "intravenous ciclosporin did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year". This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse. Ciclosporin is currently in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage in traumatic brain injury. TRO40303 TRO40303 is a new cardioprotective compound that was shown to inhibit the MPT pore and reduce infarct size after ischemia-reperfusion. It was developed by Trophos company and currently is in Phase I clinical trial. Stem cell therapy Recent investigations suggest a possible beneficial effect of mesenchymal stem cells on heart and kidney<unk> . Superoxide dismutase Superoxide dismutase is an effective anti-oxidant enzyme which converts superoxide anions to water and hydrogen peroxide. Recent researches have shown significant therapeutic effects on pre-clinical models of<unk>  after ischemic stroke. Metformin A series of 2009 studies published in the Journal of Cardiovascular Pharmacology suggest that Metformin may prevent cardiac<unk>  by inhibition of Mitochondrial Complex I and the opening of MPT pore and in rats. Riboflavin In neonatal in vivo model of brain ischemia/reperfusion, tissue injury can be alleviated by the administration of FMN precursor, riboflavin that prevents inactivation of mitochondrial complex I. Cannabinoids A study published in 2012 show that the synthetic analogue of the phytocannabinoid Tetrahydrocannabivarin (THCV), Δ8-Tetrahydrocannabivarin (Δ8-THCV) and its metabolite 11-OH-Δ8-THCV, prevent hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors and thereby decrease tissue injury and inflammation with a protective effect against liver damage. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of Δ8-THCV, while a CB1 antagonist tended to enhance it. An earlier study published in 2011 found, that Cannabidiol (CBD) also protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response of oxidative and nitrative stress, and thereby cell death and tissue injury, but independent from classical CB1 and CB2 receptors.
Reperfusion injury
Ischemic cascade
Warfarin necrosis
Ischemia
Distributive shock
Second-impact syndrome
Crush injury
Myelonecrosis