Efficacy of incisional negative pressure therapy in preventing post-sternotomy wound complications.

BACKGROUND: Sternal wound infections represent a source of significant morbidity and mortality following median sternotomy. The use of incisional negative pressure wound therapy in prevention has yet to be elucidated. METHODS: A retrospective study was conducted before and after a universal wound care protocol was implemented including the prophylactic use of negative pressure wound therapy (NPWT). The primary endpoint was sternal infections within 90 days of the index operation. RESULTS: In the control period, there was a 3.0% rate of sternal infection within 90 days compared to 0.8% in the intervention period (p < 0.001). An odds ratio of 0.25 (95% confidence interval 0.11, 0.57; p < 0.001) in the intervention period as compared to the control period was demonstrated. CONCLUSIONS: The use of a standardized wound care protocol including the universal application of NPWT for patients undergoing cardiac surgery with median sternotomy was an independent predictor of decreased rates of sternal infection.

How much is too much? Outcomes in patients using high-dose insulin glargine.

BACKGROUND AND OBJECTIVES: Many patients with type 2 diabetes mellitus (T2DM) do not achieve glycaemic control targets on basal insulin regimens. This analysis investigated characteristics, clinical outcomes and impact of concomitant oral antidiabetes drugs (OADs) in patients with T2DM treated with high-dose insulin glargine. METHODS: Patient-level data were pooled from 15 randomised, treat-to-target trials in patients with T2DM treated with insulin glargine ± OADs for ≥ 24 weeks. Data were stratified according to whether patients exceeded three insulin dose cut-off levels (> 0.5, > 0.7 and > 1.0 IU/kg). End-points included glycated haemoglobin A1c (A1C), fasting plasma glucose, body weight, and overall, nocturnal and severe hypoglycaemia. RESULTS: Data from 2837 insulin-naïve patients were analysed. Patients with insulin titrated beyond the three doses investigated had significantly higher baseline A1C levels and were younger, with shorter diabetes duration than those at/below cut-offs (p < 0.05 for all cut-offs); they also had greater weight gain (p < 0.001 for the > 0.5 and > 0.7 IU/kg cut-offs) than those who did not exceed the cut-offs, regardless of concomitant OAD. Patients on concomitant metformin alone had higher insulin doses at Week 24, but achieved greater reductions in A1C, less weight gain and lower hypoglycaemia rates than patients on a concomitant sulfonylurea or metformin plus a sulfonylurea, regardless of whether cut-offs were exceeded. CONCLUSION: In patients with T2DM, increasing basal insulin doses above 0.5 IU/kg may not improve glycaemic control; treatment strategies targeting postprandial glucose control should be considered for such patients.

More satisfied, but why? A pooled patient-level analysis of treatment satisfaction following the initiation of insulin glargine vs. comparators in insulin-naïve patients with type 2 diabetes mellitus.

AIM: To assess patient-reported outcomes associated with initiating insulin glargine among insulin-naïve patients with type 2 diabetes mellitus (T2DM). METHODS: This was a pooled analysis of patient-level data from Phase 3, randomized controlled trials evaluating once-daily insulin glargine vs. comparator treatment for ≥24 weeks in previously insulin-naïve adult patients with T2DM and poor glycaemic control. Eligible studies utilized strict, predefined insulin titration algorithms with weekly dose-adjustment to achieve fasting plasma glucose (FPG) levels of ≤5.6 mmol/l. Treatment satisfaction was measured using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) change (c) and status (s) versions. RESULTS: A total of 1577 patients from four studies were included; 830 patients treated with insulin glargine and 747 with comparators. At week 24, DTSQc scores improved in both groups with a significantly higher increase in treatment satisfaction for insulin glargine vs. comparators (13.5 vs. 12.1; p < 0.0001). Multivariate regression analysis revealed that significant predictors of DTSQc improvement at week 24 were insulin glargine treatment (p < 0.0001), higher baseline DTSQs (p < 0.0001), and lower baseline body weight (p = 0.0103). Greater improvement in DTSQc at week 24 was significantly associated with decrease from baseline in glycosylated haemoglobin (p < 0.001) and FPG (p = 0.0001); a numerically more positive change in weight from baseline approached significance (p = 0.07). CONCLUSION: Initiation of insulin glargine in insulin-naïve patients with T2DM is associated with greater improvements in treatment satisfaction than alternative interventions, with perceived improvements in glycaemic control and baseline weight likely to be important factors.

Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia.

BACKGROUND: This multicentre, double-blind, placebo-controlled study compared the opioid-sparing effectiveness and clinical safety of parecoxib sodium over 48 h, in 195 postoperative patients after routine total knee replacement surgery. METHODS: Elective total primary knee arthroplasty was performed under spinal anaesthesia, with a single dose of spinal bupivacaine 10-20 mg, and intraoperative sedation with midazolam 0.5-1.0 mg i.v., or propofol <6 mg kg(-1)h(-1). Patients were randomized to receive either parecoxib sodium 20 mg twice daily (bd) i.v. (n=65), parecoxib sodium 40 mg bd i.v. (n=67), or placebo (n=63) at the completion of surgery, and after 12, 24, and 36 h. Morphine (1-2 mg) was taken by patient-controlled analgesia or by bolus doses after 30 min. RESULTS: Patients receiving parecoxib sodium 20 mg bd and 40 mg bd consumed 15.6% and 27.8% less morphine at 24 h than patients taking placebo (both P<0.05). Both doses of parecoxib sodium administered with morphine provided significantly greater pain relief than morphine alone from 6 h (P<0.05). A global evaluation of study medication demonstrated a greater level of satisfaction among patients taking parecoxib sodium than those taking placebo. Parecoxib sodium administered in combination with morphine was well tolerated. However, a reduction in opioid-type side-effects was not demonstrated in the parecoxib sodium groups. CONCLUSION: Parecoxib sodium provides opioid-sparing analgesic effects in postoperative patients.

Cell analysis for hematopoietic stem/progenitor cell transplantation.

Cytometric analysis has become an important aspect in the quality control of cells in all phases of hematopoietic cell transplantation. In the stage of donor conditioning the counting of stem and progenitor cells is important and several reliable single platform tests for CD34+ cells have become available recently. It has been shown, that the count of certain subsets of CD34 may predict best time for harvesting stem cells better than just CD34. In many cases manipulation of the cell sample after collection from the donor is necessary before the cells are adequate for transplantation. Characterization of the resulting cell preparations requires reliable quantitative analysis of a variety of cell types like the enumeration of T-cells at the level of one in ten thousand for some allogeneic transplantations. It is discussed how these clinical requirements will need a refinement of cytometric procedures to achieve adequate clinical decisions.

Nitric oxide generation mediates lipid A-induced oxidant injury in renal proximal tubules.

In previous studies, we found that lipid A, the biologically active component of lipopolysaccharide, triggers a rapid release of intracellular calcium, the activation of nitric oxide synthase (NOS), and nitric oxide (NO) production in rat proximal tubules. This pathway leads ultimately to cell death [as measured by the release of lactate dehydrogenase (LDH)], initiated by early generation of NO. In the present studies we found that lipid A produces a time- and concentration-dependent increase in lipid peroxidation [malondialdehyde (MDA) formation] prior to cell death. Furthermore, preventing lipid peroxidation protected against cell death. Lipid A (50 micro;g/ml) produced significant MDA formation in 30 min. The addition of two antioxidants 5 min prior to lipid A completely inhibited MDA formation and LDH release at 90 min. Preincubation with 5 mm GSH also significantly reduced MDA formation. The involvement of NOS activation in lipid A-induced lipid peroxidation was established when an NOS inhibitor and an inhibitor of intracellular calcium release completely blocked MDA formation. In addition, superoxide generation was significantly increased in the presence of lipid A, and the involvement of superoxide was established when superoxide dismutase protected against oxidant injury. The iron chelators deferoxamine (also a scavenger of peroxynitrite) and diethylenetriaminepentaacetic acid prevented lipid A-induced lipid peroxidation and cell death, indicating a role for iron and peroxynitrite. The addition of an NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl, prior to lipid A also completely protected tubule cells from lipid peroxidation and subsequent cell death. These results indicate that lipid A-stimulated NO generation in the rat proximal tubule initiates oxidant injury.

Superoxide generation by renal proximal tubule nitric oxide synthase.

Lipid A, the biologically active component of lipopolysaccharide, initiates a specific cytotoxic signaling cascade in the renal proximal tubule that involves a rapid release of intracellular calcium, the activation of nitric oxide synthase (NOS) and NO production. Superoxide (O2-) generation is also a component of this cascade and both NO and O2- are required for the development of oxidant stress and cytotoxicity. Here we examined whether NOS activity was responsible for O2- generation. In renal proximal tubules isolated from the rat, the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) but not D-NMMA blocked lipid A (50 microg/ml)-stimulated O2- generation as measured by the reduction of cytochrome c during a 30-min incubation period. When L-arginine (2 mM) was added to the tubule suspensions, O2- generation was significantly inhibited, while NO2- (a marker of NO generation) was significantly increased. The addition of L-arginine also reduced lipid A-stimulated malondialdehyde formation at 30 min (a marker of lipid peroxidation) and lactate dehydrogenase release at 90 min (a marker of cell death). Thus, lipid A-stimulated the generation of both NO and O2- via NOS activation. Furthermore, increasing L-arginine availability shifted NOS activity toward NO generation and reduced oxidant injury. These results offer an explanation of why scavengers of NO or oxygen radicals ameliorate endotoxin-induced acute renal failure in vivo.

Nitric oxide generation by renal proximal tubules: role of nitric oxide in the cytotoxicity of lipid A.

Lipid A, the biologically active component of lipopolysaccharide, stimulated nitric oxide (NO) production by isolated rat proximal tubules (as measured by NO2- release) in a time-dependent manner. At a concentration of 50 micrograms/ml, lipid A stimulated NO2- generation and guanosine 3',5'-cyclic phosphate (cGMP) production within 5 min. Both of these effects were blocked by NG-methyl-L-arginine (L-NMMA), an inhibitor of NO synthase or by 8-(N,N'-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8), an inhibitor of intracellular Ca++ release. Because an increase in NO production may be cytotoxic, we examined the cytotoxic potential of lipid A. At 90 min, lipid A (50 micrograms/ml) produced significant lactate dehydrogenase release (42 +/- 5%) compared to control (25 +/- 5%; P < .05). Both L-NMMA (1 mM) and TMB-8 (100 microM) completely protected against lipid A-induced cytotoxicity. TMB-8 but not L-NMMA inhibited the rise intracellular Ca++ concentration ([Ca++]i) in isolated proximal tubules elicited by lipid A. L-NMMA but not TMB-8 inhibited proximal tubule soluble NO synthase activity. Thus, in the proximal tubule, lipid A stimulates a rise in [Ca++]i that in turn activates constitutive NO synthase. Furthermore, these events lead ultimately to NO-dependent cytotoxicity. Therefore, these findings suggest the potential for lipopolysaccharide to have a direct impact on proximal tubule physiology and renal function in vivo and support the potential therapeutic benefits of NO synthase inhibitors in the treatment of endotoxemia.

Effects of lipid A on calcium homeostasis in renal proximal tubules.

It is clear that lipopolysaccharides (LPS) are responsible for the multiorgan failure often associated with endotoxemia. However, little is known of the direct effects of LPS on kidney cells. We examined the effects of lipid A, the biologically active component of LPS, on rat proximal tubule Ca++ homeostasis. Lipid A produced a rapid, transient, concentration-dependent rise in intracellular Ca++ concentration, [Ca++]i, as monitored by fura-2. At 50 micrograms/ml [Ca++]i rose to 138 +/- 12 nM (n = 4) above basal [Ca++]i levels. The response to lipid A was not significantly inhibited by chelating extracellular Ca++ with EGTA (5 mM). However, the rise in [Ca++]i was significantly inhibited by 8-(N,N-dimethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride) and thapsigargin (17 +/- 7 nM and 13 +/- 9 nM rise, respectively; P < .05). These data indicate that the rise in [Ca++]i induced by lipid A is due to release of intracellular stores, and not extracellular influx. We also examined the role of inositol 1,4,5-trisphosphate in the lipid A response. Lipid A caused a time-dependent increase in inositol 1,4,5-trisphosphate that paralleled the rise in [Ca++]i, suggesting the release in [Ca++]i is through an inositol 1,4,5-trisphosphate-mediated release of intracellular stores. The ability of lipid A to alter Ca++ homeostasis suggests a potential for LPS to directly alter proximal tubule physiology and renal function in vivo.