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Long-standing controversy has surrounded aspirin as an antithrombotic modality to prevent venous thromboembolism (VTE), particularly in the orthopedic surgery arena. New data are emerging on the use of aspirin for both primary VTE prevention and secondary prevention of recurrent VTE after an initial anticoagulation course. This review article will provide the history behind the controversy, information regarding recent or ongoing clinical trials of aspirin for primary VTE prevention in major orthopedic surgery, evidence for aspirin in secondary prevention of recurrent VTE, and suggestions for future research. Aspirin may be a reasonable option for VTE prevention in certain major orthopedic surgery patients. Additionally, investigation among non-orthopedic populations such as the acutely ill medical patient and the non-orthopedic surgery patient is encouraged to provide further safety and efficacy data.

Loop diuretics are central to the management of fluid overload in acute decompensated heart failure. However, a variance in the response to loop diuretics can alter a patient's clinical course and has an adverse effect on clinical outcomes. Thus, a diminished response to loop diuretics is an important clinical issue. Factors thought to contribute to diuretic resistance include erratic oral absorption in congested states and postdiuretic sodium retention. Further contributing to diuretic resistance in patients with advanced heart failure are decreases in renal perfusion and alterations in sodium handling that occur in an attempt to maintain circulatory homeostasis. Several pharmacologic interventions have been used to improve diuretic response. Intravenous diuretic administration, increasing diuretic doses, or changing diuretic agents can potentially overcome pharmacokinetic obstacles which contribute to drug resistance. Combination diuretic therapy may be useful to overcome increased sodium retention, dopamine may improve renal perfusion, and hypertonic saline may transiently increase intravascular volume and improve sodium delivery to the tubules of the nephron. Despite the prevalence of diuretic resistance, there remains a paucity of clinical trial evidence to help guide therapy in these patients.

There has been much research linking elevated resting heart rate to cardiovascular morbidity and mortality. Based on these findings, a lower resting heart rate would be of theoretical benefit in patients with cardiovascular disease. From a pathophysiologic perspective, a lower resting heart rate would be of particular benefit in patients with ischemic heart disease and/or heart failure. Although β-blockers and nondihydropyridine calcium channel blockers are effective at lowering heart rate, they have many other pharmacologic effects that may not be desirable in some patients, such as negative inotropy. Ivabradine is a drug designed to lower heart rate without any other demonstrable pharmacologic effects; in other words, a pure heart rate-lowering drug. It functions by blocking the hyperpolarization-activated cyclic nucleotide gated channels (f-channels) specific for the sinoatrial node and disrupting If ion current flow. This effectively prolongs diastolic depolarization and slows firing in the sinoatrial node, which lowers heart rate. The effects of ivabradine are most pronounced at higher heart rates (use-dependence), which is important in minimizing the development of symptomatic bradycardia. Clinical trials have demonstrated ivabradine to be an effective antianginal drug both alone and in combination with β-blocker therapy, although it has not been shown to produce a demonstrable effect on reducing major adverse cardiovascular events. In patients with heart failure, ivabradine has demonstrated many hemodynamic benefits, but its effect on clinical outcomes have been mixed and dependent on baseline heart rate, ie, the drug may be of benefit with higher baseline heart rates, but detrimental with low baseline heart rates. The adverse effects of ivabradine are not uncommon, but are rarely severe and include visual disturbances, bradycardia, and atrial fibrillation. Although ivabradine is a very interesting new agent, its variable benefits in large-scale clinical trials leave its exact place in therapy still somewhat nebulous. Unanswered questions include which patient populations would benefit most from this drug, and which concomitant medications would produce the best clinical outcomes when used with ivabradine.

Background Peri-spinal subarachnoid (intrathecal; i.t.) injection of non-viral naked plasmid DNA encoding the anti-inflammatory cytokine, IL-10 (pDNA-IL-10) suppresses chronic neuropathic pain in animal models. However, two sequential i.t. pDNA injections are required within a discrete 5 to 72-hour period for prolonged efficacy. Previous reports identified phagocytic immune cells present in the peri-spinal milieu surrounding the i.t injection site that may play a role in transgene uptake resulting in subsequent IL-10 transgene expression. Methods In the present study, we aimed to examine whether factors known to induce pro-phagocytic anti-inflammatory properties of immune cells improve i.t. IL-10 transgene uptake using reduced naked pDNA-IL-10 doses previously determined ineffective. Both the synthetic glucocorticoid, dexamethasone, and the hexose sugar, D-mannose, were factors examined that could optimize i.t. pDNA-IL-10 uptake leading to enduring suppression of neuropathic pain as assessed by light touch sensitivity of the rat hindpaw (allodynia). Results Compared to dexamethasone, i.t. mannose pretreatment significantly and dose-dependently prolonged pDNA-IL-10 pain suppressive effects, reduced spinal IL-1β and enhanced spinal and dorsal root ganglia IL-10 immunoreactivity. Macrophages exposed to D-mannose revealed reduced proinflammatory TNF-α, IL-1β, and nitric oxide, and increased IL-10 protein release, while IL-4 revealed no improvement in transgene uptake. Separately, D-mannose dramatically increased pDNA-derived IL-10 protein release in culture supernatants. Lastly, a single i.t. co-injection of mannose with a 25-fold lower pDNA-IL-10 dose produced prolonged pain suppression in neuropathic rats. Conclusions Peri-spinal treatment with D-mannose may optimize naked pDNA-IL-10 transgene uptake for suppression of allodynia, and is a novel approach to tune spinal immune cells toward pro-phagocytic phenotype for improved non-viral gene therapy.