Richard J. Rivers

Inducible NO Synthase–Dependent S-Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction

Endothelial function is impaired in aging because of a decrease in NO bioavailability. This may be, in part, attributable to increased arginase activity, which reciprocally regulates NO synthase (NOS) by competing for the common substrate, l-arginine. However, the high Km of arginase (>1 mmol/L) compared with NOS (2 to 20 &mgr;mol/L) seemingly makes direct competition for substrate unlikely. One of the mechanisms by which NO exerts its effects is by posttranslational modification through S-nitrosylation of protein cysteines. We tested the hypothesis that arginase1 activity is modulated by this mechanism, which serves to alter its substrate affinity, allowing competition with NOS for l-arginine. We demonstrate that arginase1 activity is altered by S-nitrosylation, both in vitro and ex vivo. Furthermore, using site-directed mutagenesis we demonstrate that 2 cysteine residues (C168 and C303) are able to undergo nitrosylation. S-Nitrosylation of C303 stabilizes the arginase1 trimer and reduces its Km value 6-fold. Finally, arginase1 nitrosylation is increased (and thus its Km decreased) in blood vessels from aging rats, likely contributing to impaired NO bioavailability and endothelial dysfunction. This is mediated by inducible NOS, which is expressed in the aging endothelium. These findings suggest that S-nitrosylated arginase1 can compete with NOS for l-arginine and contribute to endothelial dysfunction in the aging cardiovascular system.

Variability in Blood and Blood Component Utilization as Assessed by an Anesthesia Information Management System

Background: Data can be collected for various purposes with anesthesia information management systems. The authors describe methods for using data acquired from an anesthesia information management system to assess intraoperative utilization of blood and blood components. Methods: Over an 18-month period, data were collected on 48,086 surgical patients at a tertiary care academic medical center. All data were acquired with an automated anesthesia recordkeeping system. Detailed reports were generated for blood and blood component utilization according to surgical service and surgical procedure, and for individual surgeons and anesthesiologists. Transfusion hemoglobin trigger and target concentrations were compared among surgical services and procedures, and between individual medical providers. Results: For all patients given erythrocytes, the mean transfusion hemoglobin trigger was 8.4 ± 1.5, and the target was 10.2 ± 1.5 g/dl. Variation was significant among surgical services (trigger range: 7.5 ± 1.2–9.5 ± 1.1, P = 0.0001; target range: 9.1 ± 1.2–11.3 ± 1.4 g/dl, P = 0.002), surgeons (trigger range: 7.2 ± 0.7–9.8 ± 1.0, P = 0.001; target range: 8.8 ± 0.9–11.8 ± 1.3 g/dl, P = 0.001), and anesthesiologists (trigger range: 7.2 ± 0.8–9.6 ± 1.2, P = 0.001; target range: 9.0 ± 0.9–11.7 ± 1.3 g/dl, P = 0.0004). The use of erythrocyte salvage, fresh frozen plasma, and platelets varied threefold to fourfold among individual surgeons compared with their peers performing the same surgical procedure. Conclusions: The use of data acquired from an anesthesia information management system allowed a detailed analysis of blood component utilization, which revealed significant variation among surgical services and surgical procedures, and among individual anesthesiologists and surgeons compared with their peers. Incorporating these methods of data acquisition and analysis into a blood management program could reduce unnecessary transfusions, an outcome that may increase patient safety and reduce costs.

Optimizing preoperative blood ordering with data acquired from an anesthesia information management system

Background:The maximum surgical blood order schedule (MSBOS) is used to determine preoperative blood orders for specific surgical procedures. Because the list was developed in the late 1970s, many new surgical procedures have been introduced and others improved upon, making the original MSBOS obsolete. The authors describe methods to create an updated, institution-specific MSBOS to guide preoperative blood ordering. Methods:Blood utilization data for 53,526 patients undergoing 1,632 different surgical procedures were gathered from an anesthesia information management system. A novel algorithm based on previously defined criteria was used to create an MSBOS for each surgical specialty. The economic implications were calculated based on the number of blood orders placed, but not indicated, according to the MSBOS. Results:Among 27,825 surgical cases that did not require preoperative blood orders as determined by the MSBOS, 9,099 (32.7%) had a type and screen, and 2,643 (9.5%) had a crossmatch ordered. Of 4,644 cases determined to require only a type and screen, 1,509 (32.5%) had a type and crossmatch ordered. By using the MSBOS to eliminate unnecessary blood orders, the authors calculated a potential reduction in hospital charges and actual costs of

Network Vascular Communication Initiated by Increases in Tissue Adenosine

211,448 and

Compliance with Surgical Care Improvement Project for Body Temperature Management (SCIP Inf-10) Is Associated with Improved Clinical Outcomes.

43,135 per year, respectively, or

Conducted arteriolar dilations persist in the presence of nitroarginine

8.89 and

Technique for using video microscopy and indicator dilution for repeated measurements of cardiac output in small animals.

1.81 per surgical patient, respectively. Conclusions:An institution-specific MSBOS can be created, using blood utilization data extracted from an anesthesia information management system along with our proposed algorithm. Using these methods to optimize the process of preoperative blood ordering can potentially improve operating room efficiency, increase patient safety, and decrease costs.

Development of a risk-adjusted blood utilization metric.

Vascular communication of vasomotor signals appears to coordinate the distribution of tissue blood flow. This study was performed to determine whether elevated tissue concentrations of adenosine or nitric oxide could induce vascular communicating signals. To test this, remote arteriolar responses were tested when drugs were applied either directly to an arteriole (∼20 μm diameter), or into the tissue in a region (with no vessels over 10 μm in diameter) that was 500 μm away from the arteriole and that bore no defined relationship to the flow path of the remote arteriole. In anesthetized hamster cheek pouch (n = 25), or cremaster muscle (n = 10), remote arteriolar responses were measured in response to nitric oxide (NO) donors (10–5 to 10–3 M), adenosine (10–5 to 10–3 M), or papaverine (10–5 to 10–2 M) applied for 40–120 s. Papaverine caused no remote response when applied directly while adenosine and NO donors caused similar, late-onset (10–20 s), dose-dependent, remote responses in both preparations. Remarkably however, only adenosine initiated a consistent remote arteriolar dilation when applied to the tissue site. Thus, increases in tissue adenosine may be critical for vascular communication of metabolic demands without regard to the specific blood flow path.

Multiple receptor subtypes and multiple mechanisms of dilation are involved in vascular network dilation caused by adenosine

Background:In an effort to measure and improve the quality of perioperative care, the Surgical Care Improvement Project (SCIP) was introduced in 2003. The SCIP guidelines are evidence-based process measures designed to reduce preventable morbidity, but it remains to be determined whether SCIP-measure compliance is associated with improved outcomes. Methods:The authors retrospectively analyzed the electronic medical record data from 45,304 inpatients at a single institution to assess whether compliance with SCIP Inf-10 (body temperature management) was associated with a reduced incidence of morbidity and mortality. The primary outcomes were hospital-acquired infection and ischemic cardiovascular events. Secondary outcomes were mortality and hospital length of stay. Results:Body temperature on admission to the postoperative care unit was higher in the SCIP-compliant group (36.6° ± 0.5°C; n = 44,064) compared with the SCIP-noncompliant group (35.5° ± 0.5°C; n = 1,240) (P < 0.0001). SCIP compliance was associated with improved outcomes in both nonadjusted and risk-adjusted analyses. SCIP compliance was associated with a reduced incidence of hospital-acquired infection (3,312 [7.5%] vs.160 [12.9%] events; risk-adjusted odds ratio [OR], 0.68; 95% CI, 0.54 to 0.85), ischemic cardiovascular events (602 [1.4%] vs. 38 [3.1%] events; risk-adjusted OR, 0.60; 95% CI, 0.41 to 0.92), and mortality (617 [1.4%] vs. 60 [4.8%] events; risk-adjusted OR, 0.41; 95% CI, 0.29 to 0.58). Median (interquartile range) hospital length of stay was also decreased: 4 (2 to 8) versus 5 (2 to 14) days; P < 0.0001. Conclusion:Compliance with SCIP Inf-10 body temperature management guidelines during surgery is associated with improved clinical outcomes and can be used as a quality measure.

Localized Adenovirus‐Mediated Gene Transfer Into Vascular Smooth Muscle in the Hamster Cheek Pouch

At least two mechanisms of arterial dilations are induced by the application of muscarinic agonists. One is caused by nitric oxide, and the second is the result of the release of an endothelium-dependent hyperpolarizing factor (EDHF) that has yet to be clearly defined. This study was performed to determine whether two modes of dilation also are present in the microcirculation. Arterioles (38 microns maximal diameter) in the cheek pouch of anesthetized hamsters were stimulated with the micropipette application of a muscarinic-receptor agonist (methacholine 10(-4) M; MCh). A single microapplication of MCh (5 s) caused dilation at the tip of the pipette, as well as a dilation remote from the site of application. Two modes of muscarinic receptor-induced dilation were suggested within arterioles because nitroarginine (10(-6)-10(-3) M) significantly decreased the local dilation from control of 14 +/- 1.8 microns to 5 +/- 0.9 microns in the presence of 10(-4) M nitroarginine, without significantly affecting the conducted response (control, 4.7 +/- 0.8 microns; with 10(-4) M nitroarginine, 3.1 +/- 0.5 microns). Therefore, in hamster check-pouch arterioles there are two modes of dilation caused by muscarinic agonists, and they are mediated by different mechanisms: one is nitric oxide and the other is consistent with a hyperpolarizing factor.