Cyclooxygenase-2, Asymmetric Dimethylarginine, and the Cardiovascular Hazard From Nonsteroidal Anti-Inflammatory Drugs.

BACKGROUND: Large-scale, placebo-controlled trials established that nonsteroidal anti-inflammatory drugs confer a cardiovascular hazard: this has been attributed to depression of cardioprotective products of cyclooxygenase (COX)-2, especially prostacyclin. An alternative mechanism by which nonsteroidal anti-inflammatory drugs might constrain cardioprotection is by enhancing the formation of methylarginines in the kidney that would limit the action of nitric oxide throughout the vasculature. METHODS: Targeted and untargeted metabolomics were used to investigate the effect of COX-2 deletion or inhibition in mice and in osteoarthritis patients exposed to nonsteroidal anti-inflammatory drugs on the l-arginine/nitric oxide pathway. RESULTS: Analysis of the plasma and renal metabolome was performed in postnatal tamoxifen-inducible Cox-2 knockout mice, which exhibit normal renal function and blood pressure. This revealed no changes in arginine and methylarginines compared with their wild-type controls. Moreover, the expression of genes in the l-arginine/nitric oxide pathway was not altered in the renal medulla or cortex of tamoxifen inducible Cox-2 knockout mice. Therapeutic concentrations of the selective COX-2 inhibitors, rofecoxib, celecoxib, and parecoxib, none of which altered basal blood pressure or renal function as reflected by plasma creatinine, failed to elevate plasma arginine and methylarginines in mice. Finally, plasma arginine or methylarginines were not altered in osteoarthritis patients with confirmed exposure to nonsteroidal anti-inflammatory drugs that inhibit COX-1 and COX-2. By contrast, plasma asymmetrical dimethylarginine was increased in mice infused with angiotensin II sufficient to elevate blood pressure and impair renal function. Four weeks later, blood pressure, plasma creatinine, and asymmetrical dimethylarginine were restored to normal levels. The increase in asymmetrical dimethylarginine in response to infusion with angiotensin II in celecoxib-treated mice was also related to transient impairment of renal function. CONCLUSIONS: Plasma methylarginines are not altered by COX-2 deletion or inhibition but rather are elevated coincident with renal compromise.

Impact of regional versus general anesthesia on the clinical outcomes of patients undergoing major lower extremity amputation.

BACKGROUND: Patients undergoing major lower extremity amputation (MLEA) for peripheral arterial disease are often elderly, debilitated, and fraught with medical comorbid conditions that place them at high risk for surgical intervention. Data from lower extremity revascularization surgeries are often extrapolated to determine which anesthetic modality to use for amputations, with preference given to regional anesthesia. However, there is little evidence to support the use of one mode of anesthesia over another. We conducted this study to determine the effect of anesthetic modality on the clinical outcomes of patients undergoing above- or below-knee amputations. METHODS: This study is a retrospective review of consecutive patients who underwent MLEA at a single center between 2002-2011. The study population was divided into 2 groups based on anesthetic modality (i.e., regional vs. general anesthesia). These groups were compared based on demographics and comorbidities. Major outcomes analyzed included death, myocardial infarction (MI), and pulmonary complications. Secondary outcome measures included cardiac arrhythmias, venous thromboembolism (VTE), and duration of stay in the intensive care unit and hospital. RESULTS: Four hundred sixty-three patients were identified; 56 patients were excluded for incomplete data, leaving 407 patients in the 2 groups combined. Of these, 259 patients underwent amputation under regional anesthesia; 148 underwent amputation under general anesthesia. Patients in the regional anesthesia group were older (76.6 vs. 71.6 years; P=0.001) and had a lower body mass index (25.2 vs. 26.9 kg/m2; P=0.013). They were also less likely to be on preoperative antiplatelet therapy (aspirin or clopidogrel) or anticoagulation (27% vs. 45%; P<0.001). Regional anesthesia was associated with a lower incidence of overall postoperative pulmonary complications (15% vs. 24%; P=0.02) and postoperative arrhythmia (14% vs. 25%; P=0.001). Duration of stay in the intensive care unit (1.92 vs. 3.85 days; P=0.001) and hospital (19.4 vs 23.1 days; P=0.037) were significantly longer in the group receiving general anesthesia. No significant differences in postoperative MI (12% vs. 9%; P=not significant [NS]), VTE (5% vs. 7%; P=NS) or mortality (10% vs. 13%; P=NS) was seen between groups. Controlling for procedure, above- versus below-knee amputation did not significantly alter these results. CONCLUSIONS: Regional anesthesia for patients undergoing MLEA is associated with a lower incidence of postoperative pulmonary complications and cardiac arrhythmias. It is also associated with lower resource use. As such, regional anesthesia should likely be the favored anesthetic modality for patients undergoing MLEA.

The future of emergency medicine.

Physician shortages are being projected for most medical specialties. The specialty of emergency medicine continues to experience a significant workforce shortage in the face of increasing demand for emergency care. The limited supply of emergency physicians, emergency nurses, and other resources is creating an urgent, untenable patient care problem. In July 2009, representatives of the leading emergency medicine organizations met in Dallas, TX, for the Future of Emergency Medicine Summit. This consensus document, agreed to and cowritten by all participating organizations, describes the substantive issues discussed and provides a foundation for the future of the specialty.

The future of emergency medicine.

BACKGROUND: The specialty of emergency medicine (EM) continues to experience a significant workforce shortage in the face of increasing demand for emergency care. SUMMARY: In July 2009, representatives of the leading EM organizations met in Dallas for the Future of Emergency Medicine Summit. Attendees at the Future of Emergency Medicine Summit agreed on the following: 1) Emergency medical care is an essential community service that should be available to all; 2) An insufficient emergency physician workforce also represents a potential threat to patient safety; 3) Accreditation Council for Graduate Medical Education/American Osteopathic Association (AOA)-accredited EM residency training and American Board of Medical Specialties/AOA EM board certification is the recognized standard for physician providers currently entering a career in emergency care; 4) Physician supply shortages in all fields contribute to-and will continue to contribute to-a situation in which providers with other levels of training may be a necessary part of the workforce for the foreseeable future; 5) A maldistribution of EM residency-trained physicians persists, with few pursuing practice in small hospital or rural settings; 6) Assuring that the public receives high quality emergency care while continuing to produce highly skilled EM specialists through EM training programs is the challenge for EM's future; 7) It is important that all providers of emergency care receive continuing postgraduate education.