Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64)

BACKGROUND: The progression of nephropathy from diagnosis of type 2 diabetes has not been well described from a single population. This study sought to describe the development and progression through the stages of microalbuminuria, macroalbuminuria, persistently elevated plasma creatinine or renal replacement therapy (RRT), and death. METHODS: Using observed and modeled data from 5097 subjects in the UK Prospective Diabetes Study, we measured the annual probability of transition from stage to stage (incidence), prevalence, cumulative incidence, ten-year survival, median duration per stage, and risk of death from all-causes or cardiovascular disease. RESULTS: From diagnosis of diabetes, progression to microalbuminuria occurred at 2.0% per year, from microalbuminuria to macroalbuminuria at 2.8% per year, and from macroalbuminuria to elevated plasma creatinine (>or=175 micromol/L) or renal replacement therapy at 2.3% per year. Ten years following diagnosis of diabetes, the prevalence of microalbuminuria was 24.9%, of macroalbuminuria was 5.3%, and of elevated plasma creatinine or RRT was 0.8%. Patients with elevated plasma creatinine or RRT had an annual death rate of 19.2% (95% confidence interval, CI, 14.0 to 24.4%). There was a trend for increasing risk of cardiovascular death with increasing nephropathy (P < 0.0001), with an annual rate of 0.7% for subjects in the stage of no nephropathy, 2.0% for those with microalbuminuria, 3.5% for those with macroalbuminuria, and 12.1% with elevated plasma creatinine or RRT. Individuals with macroalbuminuria were more likely to die in any year than to develop renal failure. CONCLUSIONS: The proportion of patients with type 2 diabetes who develop microalbuminuria is substantial with one quarter affected by 10 years from diagnosis. Relatively fewer patients develop macroalbuminuria, but in those who do, the death rate exceeds the rate of progression to worse nephropathy.     

Gentamicin pharmacokinetics during slow daily home hemodialysis

BACKGROUND: Gentamicin is commonly used in hemodialysis patients. Gentamicin pharmacokinetics during traditional hemodialysis have been described. Slow daily home (SDH) hemodialysis (7 to 9 hours a day/6 days a week) use is increasing due to benefits observed with increased hemodialysis. We determined gentamicin pharmacokinetics for SDH hemodialysis patients. METHODS: Eight patients (four male and four female) received a single intravenous dose of 0.6 mg/kg gentamicin post-hemodialysis. Blood samples were collected at 5, 10, 15, 30, and 60 minutes after dose. The next day patients underwent a typical SDH hemodialysis (high-flux F50NR dialyzer) session. Blood samples were taken at 0, 5, 15, 60, 120, 240, 360, 480 minutes during and 15, 30 and 60 minutes post-hemodialysis. Baseline and 24-hour urine samples were collected. Pharmacokinetic parameters were calculated assuming a one-compartment model. RESULTS: Patients were 42.5 +/- 13.1 years old (mean +/- SD). Inter-, intra-, and post-hemodialysis collection periods were 17.0 +/- 2.1 hours, 8.1 +/- 0.4 hours, and 1.1 +/- 0.1 hours, respectively. Intra-, and interdialytic gentamicin half-lives were different (intradialytic, 3.7 +/- 0.8 hours; interdialytic, 20.4 +/- 4.7 hours; P < 0.0001). Hemodialysis clearance accounted for 70.5% gentamicin total clearance. Renal clearance correlated with glomerular filtration rate (GFR) (renal clearance=1.2 GFR; r2=0.98; P < 0.001). Mean peak and trough of hemodialysis concentrations were 1.8 +/- 0.6 microg/mL and 0.5 +/- 0.2 microg/mL, respectively. Post-hemodialysis rebound was 3.1 +/- 8.8% at 1 hour. CONCLUSION: Pharmacokinetic model predicts 2.0 to 2.5 mg/kg dose gentamicin post-hemodialysis would provide peak (1 hour post-dose) and trough (end of SDH hemodialysis session) concentrations of 6.0 to 7.5 microg/mL and 0.7 to 0.8 microg/mL, respectively. This would provide adequate coverage for most gram-negative organisms in SDH hemodialysis patients.     

Drug record discrepancies in an outpatient electronic medical record: frequency,type, and potential impact on patient care at a hemodialysis center

BACKGROUND: Patients who require hemodialysis take many drugs. Electronic drug records may be discrepant with what patients are actually taking. Record discrepancies are a potential source of drug-related problems. We sought to determine the extent to which drug record discrepancies occur in a hemodialysis population. METHODS: This was a prospective observational study of patients enrolled in a pharmacist clinic at an outpatient hemodialysis center from August-December 2001. Patients participated in monthly drug interviews conducted by a pharmacist, during which patient drug use was determined. Data collected consisted of patient demographics, drug type, and number of drugs. Drug record discrepancies were classified and assigned a potential drug-related problem. Results were compared with the electronic drug record. Patients with documented drug record discrepancies were compared with those patients for whom no discrepancy was identified. RESULTS: Over the 5-month period, 215 drug interviews were conducted in 63 patients. One hundred thirteen drug record discrepancies were identified in 38 patients (60%). Discrepancies (mean +/- SD 1.7 +/- 1.3, range 1-7) were identified during 65 drug interviews (30.2%). Electronic drug records were discrepant by one drug record, two drug records, and more than two drug records 60.0%, 26.2%, and 13.8% of the time, respectively. Drug record discrepancies placed patients at risk for adverse drug events and dosing errors in 49.6% and 34.5%, respectively, of 113 discrepancies. Patient age negatively correlated with the number of drug record discrepancies identified (r = -0.27, p = 0.04). CONCLUSIONS: Drug record discrepancies occur frequently among patients undergoing hemodialysis. Incorporation of a pharmacist into the patient care team may increase the accuracy of the electronic drug record and avert unnecessary drug-related problems.     

Cannulation of the axillary artery for cardiopulmonary bypass: safeguards and pitfalls

BACKGROUND: The ascending aorta is the customary site for arterial cannulation for cardiopulmonary bypass. Favorable experience at our institution and elsewhere using axillary artery cannulation in treating type A aortic dissections has caused us to broaden our indications for using this site for arterial cannulation for cardiopulmonary bypass. METHODS: Medical records, operative notes, and perfusion records were reviewed in all patients in whom the axillary artery was cannulated directly or by a graft for cardiopulmonary bypass from January 1, 2000 through August 30, 2002. RESULTS: Seventy-five patients underwent axillary artery cannulation during the 32-month interval. Eleven patients had ascending aortic dissections, 20 had extensively diseased ascending aortas, and 44 were individuals undergoing repeat cardiac procedures. The right axillary artery was used in 72 patients and the left in 3. In 16 patients the artery was cannulated directly, and in 59 the arterial cannula was inserted into a prosthetic graft that had been anastomosed to the axillary artery. Axillary artery cannulation was satisfactory in 95% (71 of 75) of the cases in which it was used. CONCLUSIONS: Cannulation of the axillary artery for cardiopulmonary bypass is a dependable approach for procedures including reoperations, aortic dissections, and extensively diseased ascending aortas.     

Tissue oxygen monitoring during hemorrhagic shock and resuscitation: a comparison of lactated Ringer's solution,hypertonic saline dextran,and HBOC-201

BACKGROUND: The ideal resuscitation fluid for the trauma patient would be readily available to prehospital personnel, universally compatible, effective when given in small volumes, and capable of reversing tissue hypoxia in critical organ beds. Recently developed hemoglobin-based oxygen-carrying solutions possess many of these properties, but their ability to restore tissue oxygen after hemorrhagic shock has not been established. We postulated that a small-volume resuscitation with HBOC-201 (Biopure) would be more effective than either lactated Ringer's (LR) solution or hypertonic saline dextran (HSD) in restoring baseline tissue oxygen tension levels in selected tissue beds after hemorrhagic shock. We further hypothesized that changes in tissue oxygen tension measurements in the deltoid muscle would reflect the changes seen in the liver and could thus be used as a monitor of splanchnic resuscitation. METHODS: This study was a prospective, blinded, randomized resuscitation protocol using anesthetized swine (n = 30), and was modeled to approximate an urban prehospital clinical time course. After instrumentation and splenectomy, polarographic tissue oxygen probes were placed into the liver (liver PO2) and deltoid muscle (muscle PO2) for continuous tissue oxygen monitoring. Swine were hemorrhaged to a mean arterial pressure (MAP) of 40 mm Hg over 20 minutes, shock was maintained for another 20 minutes, and then 100% oxygen was administered. Animals were then randomized to receive one of three solutions: LR (12 mL/kg), HSD (4 mL/kg), or HBOC-201 (6 mL/kg). Physiologic variables were monitored continuously during all phases of the experiment and for 2 hours postresuscitation. RESULTS: At a MAP of 40 mm Hg, tissue PO2 was 20 mm Hg or less in both the liver and muscle beds. There were no significant differences in measured liver or muscle PO2 values after resuscitation with any of the three solutions in this model of hemorrhagic shock. When comparing the hemodynamic effects of resuscitation, the cardiac output was increased from shock values in all three animal groups with resuscitation, but was significantly higher in the animals resuscitated with HSD. Similarly, MAP was increased by all solutions during resuscitation, but remained significantly below baseline except in the group of animals receiving HBOC-201 (p < 0.01). HBOC-201 was most effective in both restoring and sustaining MAP and systolic blood pressure. There was excellent correlation between liver and deltoid muscle tissue oxygen values (r = 0.8, p < 0.0001). CONCLUSION: HBOC-201 can be administered safely in small doses and compared favorably to resuscitation with HSD and LR solution in this prehospital model of hemorrhagic shock. HBOC-201 is significantly more effective than HSD and LR solution in restoring MAP and systolic blood pressure to normal values. Deltoid muscle PO2 reflects liver PO2 and thus may serve as an index of the adequacy of resuscitation in critical tissue beds.     

Ten-year results with hydroxyapatite-coated total hip femoral components in patients less than fifty years old. A concise follow-up of a previous report

We report the results of total hip arthroplasty with use of a proximally hydroxyapatite-coated femoral component after a minimum follow-up of ten years in a group of patients who were less than fifty years old at the time of the primary procedure. In the five years since the original publication of our study, two additional stems have undergone revision. Thus, a total of six stems have been revised. A small amount of erosive scalloping of the proximal part of the femur was seen in nearly one-half of the hips; however, all unrevised stems were radiographically stable and no hip had intramedullary osteolysis. The revision rate because of aseptic loosening of the stem was 0.9%, which compares favorably with that for other stems and other fixation methods in young patients at this point in time. This stem is currently being paired with a highly cross-linked polyethylene liner because of cup failures and the need for reoperation secondary to excessive polyethylene wear and proximal femoral osteolysis.     

Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK

Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.     

Practice development: purpose,methodology, facilitation and evaluation

Different approaches to practice development are associated with different assumptions, and these need to be made explicit if practice development is to be transparent, rigorous and systematic in its intentions and approaches. A practice development methodology underpinned by critical social science is advocated because it focuses on achieving sustainable change through practitioner enlightenment, empowerment and emancipation and an associated culture, rather than focusing only on technical practice development. Implications of different worldviews about practice development for facilitation and outcome evaluation are highlighted. Emancipatory practice development underpinned by critical social science is argued as synonymous to emancipatory action research.     

Carbon dioxide reactivity and pressure autoregulation of brain tissue oxygen

OBJECTIVE: To describe the normal relationships between brain tissue oxygen tension (PbrO2) and physiological parameters of systemic blood pressure and CO2 concentrations. METHODS: Licox Clark-type oxygen probes (GMS mbH, Kiel, Germany) were inserted in the frontal white matter of 12 swine maintained under general anesthesia with a 1.0 fraction of inspired oxygen (FiO2). In seven swine, alterations in end-tidal carbon dioxide (ET-CO2) concentration (range, 13-72 mm Hg) were induced via hyperventilation or instillation of CO2 into the ventilation circuit. In nine swine, mean arterial pressure (MAP) (range, 33-200 mm Hg) was altered; phenylephrine was used to induce hypertension, and a nitroprusside-esmolol combination or systemic hemorrhage was used for hypotension. Quantitative cerebral blood flow (CBF) was measured in two animals by using a thermal diffusion probe. RESULTS: Mean baseline PbrO2 was 41.9 +/- 11.3 mm Hg. PbrO2 varied linearly with changes in ET-CO2, ranging from 20 to 60 mm Hg (r2 = 0.70). The minimum PbrO2 with hypocarbia was 5.9 mm Hg, and the maximum PbrO2 with hypercarbia was 132.4 mm Hg. PbrO2 varied with MAP in a sigmoid fashion suggestive of pressure autoregulation between 60 and 150 mm Hg (r2 = 0.72). The minimum PbrO2 with hypotension was 1.4 mm Hg, and the maximum PbrO2 with hypertension was 97.2 mm Hg. In addition, CBF correlated linearly with PbrO2 during CO2 reactivity testing (r2 = 0.84). CONCLUSION: In the uninjured brain, PbrO2 exhibits CO2 reactivity and pressure autoregulation. The relationship of PbrO2 with ET-CO2 and MAP appears to be similar to those historically established for CBF with ET-CO2 and MAP. This suggests that, under normal conditions, PbrO2 is strongly influenced by factors that regulate CBF.