Intravenous fosfomycin for pulmonary exacerbation of cystic fibrosis: Real life experience of a large adult CF centre.

BACKGROUND: The increased prevalence of multi-drug resistant strains of P.aeruginosa and allergic reactions among adult patients with cystic fibrosis (CF) limits the number of antibiotics available to treat pulmonary exacerbations. Fosfomycin, a unique broad spectrum bactericidal antibiotic, might offer an alternative therapeutic option in such cases. AIM: To describe the clinical efficacy, safety and tolerability of intravenous fosfomycin in combination with a second anti-pseudomonal antibiotic to treat pulmonary exacerbations in adult patients with CF. METHOD: A retrospective analysis of data captured prospectively, over a 2-years period, on the Unit electronic medical records for patients who received IV fosfomycin was performed. Baseline characteristics in the 12 months prior treatment, lung function, CRP, renal and liver function and electrolytes at start and end of treatment were retrieved. RESULTS: 54 patients received 128 courses of IV fosfomycin in combination with a second antibiotic, resulting in improved FEV1 (0.94 L vs 1.24 L, p < 0.01) and reduced CRP (65 mg/L vs 19.3 mg/L, p < 0.01). Renal function pre- and post-treatment remained stable. 4% (n = 5) of courses were complicated with AKI at mid treatment, which resolved at the end of the course. Electrolyte supplementation was required in 18% of cases for potassium and magnesium and 7% for phosphate. Nausea was the most common side effect (48%), but was well controlled with anti-emetics. CONCLUSION: Antibiotic regimens including fosfomycin appear to be clinically effective and safe. Fosfomycin should, therefore, be considered as an add-on therapy in patients who failed to respond to initial treatment and with multiple drug allergies.

Lentivirus vectors encoding both central polypurine tract and posttranscriptional regulatory element provide enhanced transduction and transgene expression.

Incorporation of a central polypurine tract (cPPT) and a posttranscriptional regulatory element (PRE) into lentivirus vectors provides increased transduction efficiency and transgene expression. We compared the effects of these elements individually and together on transduction efficiency and gene expression, using lentivirus vectors pseudotyped with vesicular stomatitis virus G protein (VSV-G) and encoding enhanced green fluorescent protein (GFP) and rat erythropoietin (EPO). The transduction efficiency was greater than 2-fold higher in the vector containing the PRE element, 3-fold higher in vector encoding the cPPT element, and 5-fold increased in the GFP virus containing both cPPT and PRE elements relative to the parent virus. In comparison with parent vector the mean fluorescence intensity (MFI) of GFP expression was 7-fold higher in cells transduced with virus containing PRE, 6-fold increased in cells transduced with virus containing cPPT, and 42-fold increased in GFP-virus containing both cPPT and PRE elements. EPO-virus containing a PRE element showed a nearly 5-fold increase in EPO secretion over the parent vector, and the vector encoding both PRE and cPPT showed a 65-fold increase. Thus, lentivirus vectors incorporating both PRE and cPPT showed expression levels significantly increased over the sum of the components alone, suggesting a synergistic effect.

Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis.

BACKGROUND: The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart. METHODS AND RESULTS: After diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 microgram/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5+/-0.8 mm(3)/mm vessel (range 0.6 to 13.7 mm(3)/mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside (P<0.001), although coronary sinus plasma tPA antigen and activity concentrations increased only during substance P infusion (P<0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA (r=-0.61, P=0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31+/-23 IU/min; ex-smokers, 50+/-33 IU/min; nonsmokers 202+/-73 IU/min; P<0.05). CONCLUSIONS: We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.

Drugs, guns, and kids: the association between substance use and injury caused by interpersonal violence.

BACKGROUND: Drug and alcohol uses have been linked to the frequency of injury events, recurrent hospital admission for injury, and interpersonal violence. Data regarding the association of recent substance use and injury type and frequency in children and young adults are not available. Such data probably would be valuable in planning interventions to prevent substance use and reduce the risks of injuries. METHODS: Evidence of substance use was assessed in trauma patients presenting to the authors' level 1 trauma center over a 6-month interval. Demographic data, mechanisms of injury, revised trauma scores (RTS), injury severity scores (ISS), hospital days, and mortality rate were evaluated. Chi square analysis and 2-tailed, paired t tests were used for statistical analysis. Multivariate logistic regression was utilized to determine the influence of individual variables. RESULTS: From a total group of 743 patients with life-threatening injuries, trauma registry records of 186 patients less than 21 years old were eligible for evaluation, and 126 of these had complete blood and urine drug assessments completed on admission to the trauma center. Forty-two percent (53 of 126) patients tested positive for alcohol or drugs. No patients less than 14 years of age (n = 61) had positive drug screen results. However, in the cohort of patients aged 14 and 15 (n = 17), 71% tested positive. Also, 72% of adolescents (age < 18) who were victims of injuries from gunshot wounds had evidence of substance use. Multivariate analysis showed gunshot wounds (P <.003) to be associated independently with positive drug screens. No statistical differences were observed in ethnic distribution, ISS, RTS, hospital days, or mortality rate when patients with positive screen results were compared with those without evidence of substance use. CONCLUSIONS: Trauma victims had evidence of substance use in early teen age years especially in the 14 and 15-year-old age groups. Toxicology screening disclosed that substance use is associated strongly with gunshot wounds. Substance use, along with poverty, inadequate family support, and peer pressure are factors that influence injury risk. Interventions to prevent substance use in young children may reduce the risk of injury.

Evolution in the management of hepatic trauma: a 25-year perspective.

OBJECTIVE: To define the changes in demographics of liver injury during the past 25 years and to document the impact of treatment changes on death rates. SUMMARY BACKGROUND DATA: No study has presented a long-term review of a large series of hepatic injuries, documenting the effect of treatment changes on outcome. A 25-year review from a concurrently collected database of liver injuries documented changes in treatment and outcome. METHODS: A database of hepatic injuries from 1975 to 1999 was studied for changes in demographics, treatment patterns, and outcome. Factors potentially responsible for outcome differences were examined. RESULTS: A total of 1,842 liver injuries were treated. Blunt injuries have dramatically increased; the proportion of major injuries is approximately 16% annually. Nonsurgical therapy is now used in more than 80% of blunt injuries. The death rates from both blunt and penetrating trauma have improved significantly through each successive decade of the study. The improved death rates are due to decreased death from hemorrhage. Factors responsible include fewer major venous injuries requiring surgery, improved outcome with vein injuries, better results with packing, and effective arterial hemorrhage control with arteriographic embolization. CONCLUSIONS: The treatment and outcome of liver injuries have changed dramatically in 25 years. Multiple modes of therapy are available for hemorrhage control, which has improved outcome.

Laparoscopic retroperitoneal repair of recurrent postoperative lumbar hernia.

A patient who previously underwent an attempt at open mesh repair of a lumbar hernia that occurred following iliac crest bone harvesting was managed successfully by laparoscopic retroperitoneal fixation of the prosthetic material to the iliac crest using bone screws. A review of the literature supports the use of such a novel approach to manage this often vexing problem.

Initial experience with laparoscopic repair of incisional hernias.

BACKGROUND: Development of a safe, unobtrusive means to repair the large incisional hernia continues to represent a challenge to surgeons. METHODS: A retrospective analysis of the first 12 patients who underwent an attempt at laparoscopic repair of an incisional hernia at a single institution was carried out. RESULTS: Of the 12 attempts at laparoscopic repair, 11 were completed. No serious perioperative morbidity was encountered. During a mean follow-up of 12.5 months, one recurrence (due to a technical shortcoming that has since been overcome) was identified. CONCLUSIONS: The laparoscopic approach to incisional hernia repair is a safe alternative to open repair of abdominal wall defects.

Current clinical concepts in perioperative anticoagulation.

Management of patients with significant risks for thromboembolism in the perioperative period requires consideration of both risks of thromboembolism and risks of anticoagulant therapy. Patients who are receiving warfarin therapy because of recent venous thromboembolism, nonvalvular atrial fibrillation, and mechanical heart valves are at increased risk during the interval when the warfarin is discontinued and when the international normalized ratio is at a subtherapeutic level. In patients with an acute venous thromboembolic event within the past month, the use of intravenous heparin appears to be justified both preoperatively and postoperatively. If the venous thromboembolic event was within the past 2 to 3 months, use of intravenous heparin appears justified in the postoperative period. More than 3 months after an acute episode of venous thrombophlebitis, the relatively low risk of recurrence does not appear to justify the risks of complications from intravenous heparin. Patients with increased risks of arterial embolism, specifically those with nonvalvular atrial fibrillation and mechanical heart valves, are generally not at sufficient risk of arterial embolism to justify use of intravenous heparin during the perioperative subtherapeutic international normalized ratio interval when warfarin is withheld. A potential increased risk of recurrent arterial embolism when the preceding event was within a month suggests that elective surgery should be deferred beyond a month whenever possible in such patients. The use of fixed-dose, subcutaneous low molecular weight heparin has been observed to have advantages over use of unfractionated intravenous heparin both in terms of safety and efficiency. Further refinements in management of patients with significant risks of thromboembolism may occur with increased experience with low molecular weight heparin.

Comparison of novel synthetic materials with traditional methods to repair exposed abdominal wall fascial defects.

Repair of large abdominal wall defects is a challenge, particularly when full-thickness tissue loss prohibits coverage of the fascial repair. Two novel synthetic materials (TMS-1 and TMS-2) have been shown to be better accepted than expanded polytetrafluoroethylene (Gore-Tex), and polypropylene (Marlex) in the closure of clean and contaminated fascial wounds that are immediately covered by skin/soft tissue. Therefore, 1-cm2 abdominal wall defects were created in each of the four quadrants of rat groups. Gore-Tex, Marlex, and TMS-1 or TMS-2 were used to repair three defects, the fourth being primarily closed. To ensure that each repair remained exposed, skin edges were sutured to underlying muscle. Additional animal groups underwent the same protocol; however, peritonitis was induced at surgery using a fecal inoculum technique. Animals were sacrificed 2 weeks later, at which time a blinded observer assessed the surface area and severity of adhesions. In clean wounds, the surface area of formed adhesions was less (p < .004) after primary closure than each synthetic material; among the synthetics, TMS-2 caused significantly (p < .01) less extensive adhesions than Marlex. In addition, the severity of adhesions to TMS-2 was comparable to that of defects closed primarily, and less severe (p < .02) than those formed to Gore-Tex and Marlex. In animals with peritonitis, primary closure caused less extensive (p < .03) adhesions than Marlex and Gore-Tex and significantly (p < .002) less severe adhesions than Marlex, Gore-Tex, and TMS-2. However, the severity of adhesions formed to TMS-1 repairs proved comparable to primarily closed wounds. These experiments reaffirm the tenet that, whenever possible, abdominal wounds should undergo primary fascial closure. When soft tissue coverage over the repair cannot be achieved, TMS-2 is well tolerated in clean wounds. However, the superiority of TMS-1 over the other synthetic materials in contaminated wounds suggests it may also ultimately prove to be of clinical utility.

Efficacy of a novel synthetic material to close exposed fascial defects.

BACKGROUND: After developing a synthetic composite material (TMS-1) made from a porous polypropylene mesh (placed in apposition to fascia) coated on the "visceral" side with solid polyurethane, we compared its efficacy with that of porous polytetrafluoroethylene, polypropylene, and primary fascial closure when the repairs were left exposed to the environment. METHODS: We created 1 cm2 abdominal wall defects in each of the four abdominal quadrants of rats (n = 12). We used porous polytetrafluoroethylene, polypropylene, and TMS-1 to repair three defects; the fourth we primarily closed. The skin was left open in all cases, leaving the fascial closures exposed. A second group of rats (n = 24) had the same operation, except that peritonitis was induced using a standard fecal inoculation technique. When the rats were killed 2 weeks later, a "blinded" observer using a standard scale assessed the surface area and severity of adhesions formed. RESULTS: When compared with the other synthetic materials, the surface area of adhesions formed was significantly less after primary closure in clean conditions; in contaminated conditions, it was less than porous polytetrafluoroethylene, polypropylene, and the same as TMS-1. Furthermore, in contaminated conditions, the severity of adhesions beneath TMS-1 was the same as primary closure and significantly less than those beneath the polypropylene. CONCLUSION: The overall superiority of TMS-1 over porous polytetrafluoroethylene and polypropylene in septic conditions justifies further experiments to define its long-term efficacy in the repair of large defects.

Indomethacin-induced reduction in neonatal piglet mesenteric blood flow is blunted by dopexamine.

BACKGROUND: Dopexamine is a specific dopaminergic and beta2-adrenergic agonist. Using newborn piglets, we have previously shown that (1) dopexamine increases cardiac output and mesenteric blood flow; (2) indomethacin reduces mesenteric blood flow. METHODS: Ultrasonic blood flow probes were placed around the ascending aorta, cranial mesenteric artery, and a renal artery of 0 to 2-day-old and 2-week-old piglets. Animals of each age were grouped (5 to 8 animals per group) and subjected to one of three experimental protocols: (1) 0.4 mg/kg indomethacin infusion, (2) 10 microg/kg/min dopexamine infusion begun 10 minutes before indomethacin, or (3) no treatment. RESULTS: Control animals demonstrated no significant alterations in mesenteric blood flow. Compared with baseline, indomethacin produced significant (P< .05, analysis of variance) declines in cranial mesenteric artery blood flow in 0 to 2-day old (37.2+/-5.7 mL/min v 17.9+/-3.7 mL/min at 90 min), and 2-week-old (80.2+/-12.5 mL/min v 29.7+/-5.7 mL/min at 90 minutes) piglets. In both animal groups treated with dopexamine before indomethacin, the decreases in cranial mesenteric artery blood flow were eliminated (38.4+/-7.6 mL/min at baseline v 36.5+/-6.8 mL/min at 90 minutes in 0 to 2 day olds; 79.9+/-10.0 mL/min at baseline v 77.5+/-14.7 mL/min in 2 week olds). Indomethacin-induced declines in renal blood flow were similarly abrogated by dopexamine. CONCLUSION: Dopexamine may prove of clinical benefit when a neonate is considered a candidate for indomethacin therapy.

Development of a novel synthetic material to close abdominal wall defects.

To compare the efficacy of a novel synthetic material (TMS-2) with polytetrafluoroethylene, polypropylene (Marlex), and primary closure of experimentally fashioned clean and contaminated abdominal wounds, 1-cm2 abdominal wall defects were created in each of the four abdominal quadrants of rats (n = 10). Patches of each material were used to repair three of these defects, the fourth being primarily closed. A second group of rats (n = 7) underwent the same operative protocol; however, peritonitis was induced at the time of surgery using a fecal inoculation technique. Animals were killed 2 weeks later, and surface area and severity of formed adhesions were assessed by a "blinded" observer. All closure techniques were successful insofar as none demonstrated fascial dehiscence. Compared with each synthetic material, the surface area of formed adhesions was smaller after primary closure in clean and in contaminated conditions; however, the three synthetic materials were equally matched regarding surface area of adhesions under both conditions. In the face of fecal contamination, TMS-2 proved identical to primary closure, each generating significantly (P < 0.02) milder adhesions than the other prosthetic materials. It is concluded that the TMS-2 may prove of clinical benefit to repair abdominal wall defects.

Age-related differences in response to neutrophil-mediated reperfusion injury in the neonatal piglet heart.

BACKGROUND: Neonatal hearts have altered adhesion molecule interactions in response to ischemia-reperfusion. How this affects myocardial function is unknown. METHODS: Isolated, buffer perfused 0- to 2-day (newborn) and 2-week piglet hearts were first subjected to 20-minute global, normothermic ischemia, followed by 45 minutes of reperfusion during which 150 x 10(6) newborn or 2-week neutrophils were infused. In some hearts, an antibody to SLe(x) (CSLEX-1) was infused with neutrophils during reperfusion. Hemodynamic variables, including left ventricular developed pressure (LVDP), were recorded at timed intervals. Neutrophil CD-18, L-selectin, and SLe(x) contents were measured by flow cytometry. RESULTS: Full recovery of LVDP was observed in newborn hearts receiving newborn or 2-week-old neutrophils. Recovery of LVDP was depressed (p < 0.01, ANOVA) in 2-week-old hearts receiving 2-week old, not newborn, neutrophils. Infusion of CSLEX-1 in 2-week-old hearts restored LVDP to baseline. Whereas flow cytometry showed higher (p < 0.01, Student's t test) CD-18 and L-selectin expression on newborn versus 2-week-old neutrophils, newborn neutrophils expressed lower (p < 0.01) SLe(x) levels. CONCLUSIONS: Initial "loose" neutrophil-endothelial selectin interactions are a necessary prelude to "firm" adhesion and reperfusion injury. Operations performed soon after birth may be better tolerated than when surgery is delayed; anti-SLe(x) preparations may prove beneficial when performing cardiac procedures on older infants.

The incidence of secondary hernias diagnosed during laparoscopic total extraperitoneal inguinal herniorrhaphy.

During a 24-month period beginning in July of 1995, laparoscopic total extraperitoneal inguinal herniorrhaphy was attempted in 53 patients. All procedures were performed at a single institution, by senior-level general surgery residents, with the same attending surgeon functioning as first assistant. Three patients required conversion to an "open" procedure (all had a prior history of herniorrhaphy or lower abdominal surgery), leaving 50 patients for analysis. Preoperatively, a unilateral hernia was evident on clinical grounds in 29 patients, the remaining 21 presenting with signs of a bilateral hernia; of the total, 11 had a history of prior hernia repair on the presently affected side. At surgery, a total of 115 hernia defects (indirect, direct, femoral) were identified, 38% of which were discovered only at the time of surgery. Sixty-four percent of patients were found to have at least one of these "secondary" hernias. After reduction of the hernia(s), all defects were covered with polypropylene mesh secured with spiral tacks. There were 10 perioperative complications, one of which required corrective surgical intervention. Over 70% of patients were discharged on the day of surgery; 92% returned home within 23 h of their operation. The most common reason for delay of hospital discharge was urinary retention. There have been no recurrences in short-term follow-up. Most patients were pleased with the recovery time from and the cosmetic results of their surgery. These results suggest that laparoscopic total extraperitoneal herniorrhaphy represents a safe, effective, cosmetically appealing alternative to open hernia repair. Moreover, this approach may provide an added advantage insofar as identifying additional hernia defects that, when repaired, may ultimately yield a lower recurrence rate than might otherwise have been expected.

Alpha-trinositol reduces edema formation at the site of scald injury.

BACKGROUND: The effects of alpha-trinositol (1D-myo-inositol-1,2,6-triphosphate, IP3) on burn-induced edema formation were investigated. METHODS: Lymph flow (QL; microliter/min) and lymph-to-plasma protein ratio (CL/CP) were monitored in groups of five to six dogs before and 4 hours after (1) a 5-second 100 degrees C or 90 degrees C foot paw scald; (2) IP3 (45 mg/kg intravenous bolus, then a 20 mg/kg/hr infusion) 30 minutes before or after 100 degrees C scald, or 30 minutes after 90 degrees C scald. Hind paw venous pressure was elevated and maintained by outflow restriction until reaching steady state QL and (CL/CP)min. Macromolecular reflection coefficient (1-CL/CP) was measured. Fluid filtration coefficient (Kf; ml/min/mm Hg/100 gm) was calculated. Relative paw weight gain (%) was measured. RESULTS: Compared with preburn values, scald uniformly produced significant increases in QL, CL/CP, and Kf, IP3 significantly (p < 0.02, ANOVA) reduced paw weight gain when given before, but not after, 100 degrees C burn (41% +/- 5% versus 18% +/- 7% preburn IP3 and 31% +/- 3% postburn IP3). Compared with 90 degrees C burn animals, postburn treatment significantly (p < 0.017) attenuated 4-hour increases in QL (550 +/- 87 versus 252 +/- 29 microliters/min), Kf (0.016 +/- 00 versus 0.007 +/- 00 microliter/min/mm/Hg/100 gm), and relative paw weight gain (28% +/- 3% versus 12% +/- 5%). CONCLUSIONS: alpha-Trinositol given after a 90 degrees C scald blunted edema formation at the site of scald, likely through reduced transmembrane fluid flux.

Mitral valve replacement in Sickle C disease using intraoperative exchange transfusion.

Sickle C (SC) disease is a relatively uncommon hematologic disorder that poses special challenges when the patient requires a major surgical procedure. In particular, those who have a history of hemolytic crises require some type of intervention, usually homologous transfusion, to decrease the level of circulating hemoglobin S (HbS) and prevent intraoperative sickle crisis. We describe a 25-year-old man with SC disease and a history of multiple sickle cell crises who underwent mitral valve replacement using intraoperative exchange transfusion to decrease his HbS level from 53% to 7%.

Dopexamine maintains mesenteric blood flow during systemic hypoxemia in the neonatal piglet.

In adults, dopexamine is a specific dopaminergic and Beta2-adrenergic agonist; its effects in neonates are unknown. Ultrasonic flow probes were placed around the ascending and descending aorta and cranial mesenteric artery of 0- to 2-day-old and 2-week-old piglets. Animals of each age group (9 to 14 per group) were subjected to (1) dopexamine infusion (5 microg/kg/min); (2) 30 minutes of hypoxia (inspired oxygen content 0.12) followed by 30 minutes of reoxygenation; and (3) dopexamine infusion during hypoxia and reoxygenation. In both age groups dopexamine alone increased ascending aorta blood flow (cardiac output minus coronary artery blood flow), mildly decreased mean arterial pressure, and increased cranial mesenteric artery blood flow. Compared to baseline values, 30 minutes of hypoxia produced significant (P <0.05, analysis of variance) decreases in cranial mesenteric artery blood flow in 0- to 2-day-old (58 +/- 13 ml/min vs. 30 +/- 8 ml/min) and 2-week-old (125 +/- 18 ml/min vs. 60 +/- 11 ml/min) piglets. In all cases blood flow returned to baseline values after reoxygenation. In both animal groups treated with dopexamine before hypoxia, the decreases in cranial mesenteric artery blood flow were eliminated (47 +/- 5 ml/min vs. 44 +/- 6 ml/min in 0- to 2-day-old piglets; 140 +/- 27 ml/min vs. 117 +/- 18 ml/min in 2-week-old piglets). Dopexamine may prove to be of clinical benefit when neonates are threatened by hypoxemia-induced decreases in intestinal blood flow.