Slow release antibiotics for treatment of septic arthritis in large animals

The search for an effective treatment for septic arthritis is ongoing. Current therapies are expensive since they require repeated joint lavage and long term antibiotic treatment. Local application of antimicrobial drugs is advantageous because high concentrations can be attained at the infection site, although repeated injections increase the risk of superinfection of the joint. Thus, slow release formulations, which have the advantage of local treatment yet single application of the drug, are appealing. Antibiotics used in slow release formulations are selected for tissue compatibility, an appropriate antibacterial spectrum, and stability both during the mixing procedure and within the carrier during the release period. Ideally the carriers should be bioresorbable. Promising reports on the clinical use of poly(methyl methacrylate) (PMMA) mixed with several different antibiotics, and of collagen sponges impregnated with gentamicin, should encourage the search for formulations optimally adapted to veterinary medical requirements.

[Arginine-vasopressin in septic and vasodilatorial shock]

Current therapy of septic/vasodilatory cardiovascular failure includes volume resuscitation and infusion of inotropic and vasopressor agents. Norepinephrine is the first-line vasoconstrictor, and can stabilize hemodynamic variables in most patients. Nonetheless, irreversible cardiovascular failure which is resistant to conventional hemodynamic therapies still is the main cause of death in patients with severe sepsis and septic shock. In such advanced, catecholamine-resistant shock states, arginine-vasopressin (AVP) has repeatedly caused an increase in mean arterial blood pressure, a decrease in toxic norepinephrine-dosages, as well as further beneficial hemodynamic, endocrinologic and renal effects. Although AVP exerted negative inotropic effects in previous clinical trials and in selected animal experiments, a continuous low-dose AVP infusion during advanced septic/vasodilatory shock caused a decrease in cardiac index only in patients with a hyperdynamic circulation. Adverse effects on gastrointestinal circulation and the systemic microcirculation can not be excluded, but have not yet been confirmed in clinical prospective trials. Negative side effects of a supplementary AVP therapy are an increase in total bilirubin concentrations, and a decrease in platelet count. A transient increase in hepatic transaminases during AVP infusion is most likely related to preceding hypotensive episodes. Important points which must be considered when using AVP as a "rescue vasopressor" in septic/vasodilatory shock states are: 1) AVP infusion only in advanced shock states that can not be adequately reversed by conventional hemodynamic therapy (e.g. norepinephrine >0,5-0,6 mug/kg/min), 2) presence of normovolemia, 3) AVP infusion only in combination with norepinephrine, 4) strict avoidance of bolus injections and dosages >4 IU/h. Effects of a supplementary AVP infusion in advanced vasodilatory shock on survival are currently examined in a large, prospective multicenter trial in North America and Australia.

A case of necrotizing fasciitis with septic shock in a cat caused by Acinetobacter baumannii

A 4-year-old, neutered female, domestic shorthair cat admitted to the animal hospital for recurrent constipation presumed to be due to post-traumatic injuries, went into shock with signs including fever and ataxia followed by stupor. On the fifth day of hospitalization, the cat developed severe, diffuse oedema of the ventral abdomen with multifocal to coalescing erythematous areas and small vesicle formation. The results of bacteriological cultures of liver, spleen and kidney specimens led to the diagnosis of Acinetobacter baumannii sepsis. Histopathological findings of skin samples taken during necropsy showed an extensive epidermal and dermal necrosis with septic vasculitis and numerous intralesional gram-negative bacteria. Detection of the bla(OXA-51-like) gene specific for A. baumannii by PCR, performed retrospectively on samples of the deep layers of the skin, confirmed the presence of A. baumannii also in the cutaneous lesions. To our knowledge this is the first report of a necrotizing fasciitis with septic shock in a cat caused by A. baumannii.

ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock

BACKGROUND: Insufficient control of von Willebrand factor (VWF) multimer size as a result of severely deficient ADAMTS-13 activity results in thrombotic thrombocytopenic purpura associated with microvascluar thrombosis and platelet consumption, features not seldom seen in severe sepsis and septic shock. METHODS: ADAMTS-13 activity and VWF parameters of 40 patients with severe sepsis or septic shock were compared with those of 40 healthy controls of the same age and gender and correlated with clinical findings and sepsis outcome. RESULTS: ADAMTS-13 activity was significantly lower in patients than in healthy controls [median 60% (range 27-160%) vs. 110% (range 63-200%); P < 0.001]. VWF parameters behaved reciprocally and both VWF ristocetin cofactor activity (RCo) and VWF antigen (VWF:Ag) were significantly (P < 0.001) higher in patients compared with controls. Neither ADAMTS-13 activity nor VWF parameters correlated with disease severity, organ dysfunction or outcome. However, a contribution of acute endothelial dysfunction to renal impairment in sepsis is suggested by the significantly higher VWF propeptide and soluble thrombomodulin levels in patients with increased creatinine values as well as by their strong positive correlations (creatinine and VWF propeptide r(s) = 0.484, P < 0.001; creatinine and soluble thrombomodulin r(s) = 0.596, P < 0.001). CONCLUSIONS: VWF parameters are reciprocally correlated with ADAMTS-13 activity in severe sepsis and septic shock but have no prognostic value regarding outcome.

Factor XIII in severe sepsis and septic shock

OBJECTIVE: In sepsis, activation of coagulation and inhibition of fibrinolysis lead to microvascular thrombosis. Thus, clot stability might be a critical issue in the development of multiple organ dysfunction syndrome. Activated FXIII (FXIIIa) forms stable fibrin clots by covalently cross-linking fibrin monomers. Therefore, we investigated the impact of FXIII antigen and activity levels on disease severity and fatality in sepsis patients. PATIENTS AND METHODS: FXIII subunit A (FXIIIA) and FXIII cross-linking activity (FXIIICA) were measured in 151 controls, in 32 patients with severe sepsis and 8 with septic shock. In addition, FXIII subunit B (FXIIIB) was measured in the sepsis patients. Moreover, clotting parameters were determined. RESULTS: Patients suffering from sepsis (n=40) had significantly (p<0.005) lower FXIIIA levels (median [range]: 36.5% [8.8-127.4%]) and FXIIICA levels (76.5% [9.4-266%]) as compared to healthy controls (n=151, 119% [31.3-283.2] and 122.4% [40.6-485.3], respectively). No difference in FXIIIA, FXIIIB and FXIIICA levels between survivors and non-survivors, nor between patients with severe sepsis and septic shock was found. The specific activity of FXIII (FXIIICA/FXIIIA, SA(FXIII)) was significantly (p<0.001) higher in sepsis patients (2.0 [0.8-5.3]) as compared to healthy controls (1.0 [0.4-5.1]). SA(FXIII) significantly (p<0.05) increased with fatality (non-survivors [n=13] vs. survivors [n=27]: 3.3 [1.2-5.0] vs. 1.9 [0.8-5.3]) and disease severity (septic shock vs. severe sepsis: 3.4 [1.8-4.3] vs. 1.9 [0.8-5.3]). CONCLUSION: We show decreased FXIIICA and FXIIIA levels, but higher SA(FXIII) in sepsis as compared to controls. Increased SA(FXIII) correlates with disease severity and fatality in sepsis patients.

Vasopressin in septic shock: effects on pancreatic, renal, and hepatic blood flow

INTRODUCTION: Vasopressin has been shown to increase blood pressure in catecholamine-resistant septic shock. The aim of this study was to measure the effects of low-dose vasopressin on regional (hepato-splanchnic and renal) and microcirculatory (liver, pancreas, and kidney) blood flow in septic shock. METHODS: Thirty-two pigs were anesthetized, mechanically ventilated, and randomly assigned to one of four groups (n = 8 in each). Group S (sepsis) and group SV (sepsis/vasopressin) were exposed to fecal peritonitis. Group C and group V were non-septic controls. After 240 minutes, both septic groups were resuscitated with intravenous fluids. After 300 minutes, groups V and SV received intravenous vasopressin 0.06 IU/kg per hour. Regional blood flow was measured in the hepatic and renal arteries, the portal vein, and the celiac trunk by means of ultrasonic transit time flowmetry. Microcirculatory blood flow was measured in the liver, kidney, and pancreas by means of laser Doppler flowmetry. RESULTS: In septic shock, vasopressin markedly decreased blood flow in the portal vein, by 58% after 1 hour and by 45% after 3 hours (p < 0.01), whereas flow remained virtually unchanged in the hepatic artery and increased in the celiac trunk. Microcirculatory blood flow decreased in the pancreas by 45% (p < 0.01) and in the kidney by 16% (p < 0.01) but remained unchanged in the liver. CONCLUSION: Vasopressin caused marked redistribution of splanchnic regional and microcirculatory blood flow, including a significant decrease in portal, pancreatic, and renal blood flows, whereas hepatic artery flow remained virtually unchanged. This study also showed that increased urine output does not necessarily reflect increased renal blood flow.

Effects of vasopressin on microcirculatory blood flow in the gastrointestinal tract in anesthetized pigs in septic shock

BACKGROUND: Vasopressin increases arterial pressure in septic shock even when alpha-adrenergic agonists fail. The authors studied the effects of vasopressin on microcirculatory blood flow in the entire gastrointestinal tract in anesthetized pigs during early septic shock. METHODS: Thirty-two pigs were intravenously anesthetized, mechanically ventilated, and randomly assigned to one of four groups (n=8 in each; full factorial design). Group S (sepsis) and group SV (sepsis-vasopressin) were made septic by fecal peritonitis. Group C and group V were nonseptic control groups. After 300 min, group V and group SV received intravenous infusion of 0.06 U.kg.h vasopressin. In all groups, cardiac index and superior mesenteric artery flow were measured. Microcirculatory blood flow was recorded with laser Doppler flowmetry in both mucosa and muscularis of the stomach, jejunum, and colon. RESULTS: While vasopressin significantly increased arterial pressure in group SV (P<0.05), superior mesenteric artery flow decreased by 51+/-16% (P<0.05). Systemic and mesenteric oxygen delivery and consumption decreased and oxygen extraction increased in the SV group. Effects on the microcirculation were very heterogeneous; flow decreased in the stomach mucosa (by 23+/-10%; P<0.05), in the stomach muscularis (by 48+/-16%; P<0.05), and in the jejunal mucosa (by 27+/-9%; P<0.05), whereas no significant changes were seen in the colon. CONCLUSION: Vasopressin decreased regional flow in the superior mesenteric artery and microcirculatory blood flow in the upper gastrointestinal tract. This reduction in flow and a concomitant increase in the jejunal mucosa-to-arterial carbon dioxide gap suggest compromised mucosal blood flow in the upper gastrointestinal tract in septic pigs receiving low-dose vasopressin.

SHORT-TERM EFFECTS OF PHENYLEPHRINE ON SYSTEMIC AND REGIONAL HEMODYNAMICS IN PATIENTS WITH SEPTIC SHOCK: A CROSSOVER PILOT STUDY

Clinical studies evaluating the use of phenylephrine in septic shock are lacking. The present study was designed as a prospective, crossover pilot study to compare the effects of norepinephrine (NE) and phenylephrine on systemic and regional hemodynamics in patients with catecholamine-dependent septic shock. In 15 septic shock patients, NE (0.82 +/- 0.69 mug.kg.min) was replaced with phenylephrine (4.39 +/- 5.23 mug.kg.min) titrated to maintain MAP between 65 and 75 mmHg. After 8 h of phenylephrine infusion treatment was switched back to NE. Data from right heart catheterization, acid-base balance, thermo-dye dilution catheter, gastric tonometry, and renal function were obtained before, during, and after replacing NE with phenylephrine. Variables of systemic hemodynamics, global oxygen transport, and acid-base balance remained unchanged after replacing NE with phenylephrine except for a significant decrease in heart rate (phenylephrine, 89 +/- 18 vs. NE, 93 +/- 18 bpm; P < 0.05). However, plasma disappearance rate (phenylephrine, 13.5 +/- 7.1 vs. NE, 16.4 +/- 8.7%.min) and clearance of indocyanine green (phenylephrine, 330 +/- 197 vs. NE, 380 +/- 227mL.min.m), as well as creatinine clearance (phenylephrine, 81.3 +/- 78.4 vs. NE, 94.3 +/- 93.5 mL.min) were significantly decreased by phenylephrine infusion (each P < 0.05). In addition, phenylephrine increased arterial lactate concentrations as compared with NE infusion (1.7 +/- 1.0 vs. 1.4 +/- 1.1 mM; P < 0.05). After switching back to NE, all variables returned to values obtained before phenylephrine infusion except creatinine clearance and gastric tonometry values. Our results suggest that for the same MAP, phenylephrine causes a more pronounced hepatosplanchnic vasoconstriction as compared with NE.

DEVELOPMENT OF CONFORMABLE CNG TANK FOR AUTOMOTIVE APPLICATION

The purpose of this study is to design, develop and integrate a Compressed Natural Gas (CNG) tank that will have a conformable shape for efficient storage in a light-duty pick-up truck. The CNG tank will be a simple rectangular box geometry to demonstrate capability of non-cylindrical shapes. Using CAD drawings of the truck, a conformable tank will be designed to fit under the pick-up bed. The intent of the non-cylindrical CNG tank is to demonstrate improvement in size over the current solution, which is a large cylinder in the box of a pick-up truck. The geometry of the tank’s features is critical to its size and strength. The optimized tank design will be simulated with Finite Element Analysis (FEA) to determine critical stress regions, and appropriate design changes will be made to reduce stress concentration. Following the American National Standard Institute (ANSI) guide, different aluminum alloys will be optimized to obtain the best possible result for the CNG tank.

TANK SIZING AND OPTIMIZING LOOP PLACEMENT IN A BRANCHED WATER DISTRIBUTION SYSTEM

More than eighteen percent of the world’s population lives without reliable access to clean water, forced to walk long distances to get small amounts of contaminated surface water. Carrying heavy loads of water long distances and ingesting contaminated water can lead to long-term health problems and even death. These problems affect the most vulnerable populations, women, children, and the elderly, more than anyone else. Water access is one of the most pressing issues in development today. Boajibu, a small village in Sierra Leone, where the author served in Peace Corps for two years, lacks access to clean water. Construction of a water distribution system was halted when a civil war broke out in 1992 and has not been continued since. The community currently relies on hand-dug and borehole wells that can become dirty during the dry season, which forces people to drink contaminated water or to travel a far distance to collect clean water. This report is intended to provide a design the system as it was meant to be built. The water system design was completed based on the taps present, interviews with local community leaders, local surveying, and points taken with a GPS. The design is a gravity-fed branched water system, supplied by a natural spring on a hill adjacent to Boajibu. The system’s source is a natural spring on a hill above Boajibu, but the flow rate of the spring is unknown. There has to be enough flow from the spring over a 24-hour period to meet the demands of the users on a daily basis, or what is called providing continuous flow. If the spring has less than this amount of flow, the system must provide intermittent flow, flow that is restricted to a few hours a day. A minimum flow rate of 2.1 liters per second was found to be necessary to provide continuous flow to the users of Boajibu. If this flow is not met, intermittent flow can be provided to the users. In order to aid the construction of a distribution system in the absence of someone with formal engineering training, a table was created detailing water storage tank sizing based on possible source flow rates. A builder can interpolate using the source flow rate found to get the tank size from the table. However, any flow rate below 2.1 liters per second cannot be used in the table. In this case, the builder should size the tank such that it can take in the water that will be supplied overnight, as all the water will be drained during the day because the users will demand more than the spring can supply through the night. In the developing world, there is often a problem collecting enough money to fund large infrastructure projects, such as a water distribution system. Often there is only enough money to add only one or two loops to a water distribution system. It is helpful to know where these one or two loops can be most effectively placed in the system. Various possible loops were designated for the Boajibu water distribution system and the Adaptive Greedy Heuristic Loop Addition Selection Algorithm (AGHLASA) was used to rank the effectiveness of the possible loops to construct. Loop 1 which was furthest upstream was selected because it benefitted the most people for the least cost. While loops which were further downstream were found to be less effective because they would benefit fewer people. Further studies should be conducted on the water use habits of the people of Boajibu to more accurately predict the demands that will be placed on the system. Further population surveying should also be conducted to predict population change over time so that the appropriate capacity can be built into the system to accommodate future growth. The flow at the spring should be measured using a V-notch weir and the system adjusted accordingly. Future studies can be completed adjusting the loop ranking method so that two users who may be using the water system for different lengths of time are not counted the same and vulnerable users are weighted more heavily than more robust users.

The effect of demand, tank parameters, and pumping stations on energy use in municipal drinking water distribution systems

Two of the indicators of the UN Millennium Development Goals ensuring environmental sustainability are energy use and per capita carbon dioxide emissions. The increasing urbanization and increasing world population may require increased energy use in order to transport enough safe drinking water to communities. In addition, the increase in water use would result in increased energy consumption, thereby resulting in increased green-house gas emissions that promote global climate change. The study of multiple Municipal Drinking Water Distribution Systems (MDWDSs) that relates various MDWDS aspects--system components and properties--to energy use is strongly desirable. The understanding of the relationship between system aspects and energy use aids in energy-efficient design. In this study, components of a MDWDS, and/or the characteristics associated with the component are termed as MDWDS aspects (hereafter--system aspects). There are many aspects of MDWDSs that affect the energy usage. Three system aspects (1) system-wide water demand, (2) storage tank parameters, and (3) pumping stations were analyzed in this study. The study involved seven MDWDSs to understand the relationship between the above-mentioned system aspects in relation with energy use. A MDWDSs model, EPANET 2.0, was utilized to analyze the seven systems. Six of the systems were real and one was a hypothetical system. The study presented here is unique in its statistical approach using seven municipal water distribution systems. The first system aspect studied was system-wide water demand. The analysis involved analyzing seven systems for the variation of water demand and its impact on energy use. To quantify the effects of water use reduction on energy use in a municipal water distribution system, the seven systems were modeled and the energy usage quantified for various amounts of water conservation. It was found that the effect of water conservation on energy use was linear for all seven systems and that all the average values of all the systems' energy use plotted on the same line with a high R 2 value. From this relationship, it can be ascertained that a 20% reduction in water demand results in approximately a 13% savings in energy use for all seven systems analyzed. This figure might hold true for many similar systems that are dominated by pumping and not gravity driven. The second system aspect analyzed was storage tank(s) parameters. Various tank parameters: (1) tank maximum water levels, (2) tank elevation, and (3) tank diameter were considered in this part of the study. MDWDSs use a significant amount of electrical energy for the pumping of water from low elevations (usually a source) to higher ones (usually storage tanks). The use of electrical energy has an effect on pollution emissions and, therefore, potential global climate change as well. Various values of these tank parameters were modeled on seven MDWDSs of various sizes using a network solver and the energy usage recorded. It was found that when averaged over all seven analyzed systems (1) the reduction of maximum tank water level by 50% results in a 2% energy reduction, (2) energy use for a change in tank elevation is system specific, and (2) a reduction of tank diameter of 50% results in approximately a 7% energy savings. The third system aspect analyzed in this study was pumping station parameters. A pumping station consists of one or more pumps. The seven systems were analyzed to understand the effect of the variation of pump horsepower and the number of booster stations on energy use. It was found that adding booster stations could save energy depending upon the system characteristics. For systems with flat topography, a single main pumping station was found to use less energy. In systems with a higher-elevation neighborhood, however, one or more booster pumps with a reduced main pumping station capacity used less energy. The energy savings for the seven systems was dependent on the number of boosters and ranged from 5% to 66% for the analyzed five systems with higher elevation neighborhoods (S3, S4, S5, S6, and S7). No energy savings was realized for the remaining two flat topography systems, S1, and S2. The present study analyzed and established the relationship between various system aspects and energy use in seven MDWDSs. This aids in estimating the amount of energy savings in MDWDSs. This energy savings would ultimately help reduce Greenhouse gases (GHGs) emissions including per capita CO 2 emissions thereby potentially lowering the global climate change effect. This will in turn contribute to meeting the MDG of ensuring environmental sustainability.

Different patterns of Siglec-9-mediated neutrophil death responses in septic shock

Sialic-acid-binding immunoglobulin-like lectin (Siglec) 9 mediates death signals in neutrophils. The objective of this study was to determine the heterogeneity of neutrophil death responses in septic shock patients and to analyze whether these ex vivo data are related to the severity and outcome of septic shock. In this prospective cohort study, blood samples of patients with septic shock (n = 26) in a medical-surgical intensive care unit (ICU) were taken within 24 h of starting the treatment of septic shock (phase A), after circulatory stabilization (phase B), and 10 days after admission or at ICU discharge if earlier (phase C). Neutrophil death was quantified in the presence and absence of an agonistic anti-Siglec-9 antibody after 24 h ex vivo. In phase A, two distinct patterns of Siglec-9-mediated neutrophil death were observed: resistance to neutrophil death (n = 14; Siglec-9 nonresponders) and increased neutrophil death (n = 12; Siglec-9 responders) after Siglec-9 ligation compared with neutrophils from normal donors. Experiments using a pharmacological pan-caspase-inhibitor provided evidence for caspase-independent neutrophil death in Siglec-9 responders upon Siglec-9 ligation. There were no differences between Siglec-9 responders and nonresponders in length of ICU or hospital stay of survivors or severity of organ dysfunction. Taken together, septic shock patients exhibit different ex vivo death responses of blood neutrophils after Siglec-9 ligation early in shock. Both the resistance and the increased susceptibility to Siglec-9-mediated neutrophil death tend to normalize within 72 h after shock. Further studies are required to understand the role of Siglec-9-mediated neutrophil death in septic shock.