Clinical decision-making training using the Script Concordance Test and simulation: A pilot study for pediatric residents.

BACKGROUND: Each year, new pediatric residents begin their shifts in the pediatric emergency room. While technical skills are often acquired during workshops, non-technical skills such as communication, professionalism, situational awareness, or decision-making are rarely tested. Simulation enables non-technical skills to be developed in situations frequently encountered in pediatric emergencies. Adopting an innovative approach, we combined two pedagogical methods: the Script Concordance Test (SCT) and simulation to improve clinical reasoning and non-technical skills of first-year pediatric residents in dealing with clinical situations involving febrile seizures. The aim of this work is to report the feasibility of such a combined training. METHODS: The first-year pediatric residents participated in a training session on how to manage a child attending the emergency department with a febrile seizure. At the beginning of the session, the trainees had to complete the SCT (seven clinical situations) and then participated in three simulation scenarios. Student satisfaction was assessed by means of a questionnaire at the end of the session. RESULTS: In this pilot study, 20 residents participated in the training. The SCT scores for the first-year pediatric residents were lower and more widely distributed than those of the experts with better concordance for diagnostic items compared to investigation or treatment items. All were satisfied with the teaching methods employed. Further sessions on additional topics relating to the management of pediatric emergency cases were requested. CONCLUSION: Although limited by the small size of our study, this combination of teaching methods was possible and seemed promising for the development of non-technical skills of pediatric residents. These methods are in line with the changes being made to the third cycle of medical studies in France and can be adapted to other situations and other specialties.

Syndrome of inappropriate anti-diuresis induces volume-dependent hypercalciuria.

Hyponatremia is associated with bone demineralization. We hypothesized that, during hyponatremia, calciuria and calcium balance depend on volemic status. We evaluated calciuria in patients with hyponatremia, secondary to SIAD or hypovolemia. Patients with SIAD exhibited a volemic expansion that was associated with hypercalciuria. Calciuria was proportional to markers of volemia. INTRODUCTION: Chronic mild hyponatremia has been associated with bone demineralization of unknown mechanisms. During chronic hyponatremia, arginine-vasopressin secretion can result from hypovolemia or from syndrome of inappropriate anti-diuresis (SIAD) that leads to a slightly volemic expansion. Since volemia determines renal calcium excretion and balance, we evaluated calcium homeostasis in patients with chronic hyponatremia, related to SIAD or to hypovolemia. METHODS: We retrospectively included all patients referred to our Department between May 2006 and May 2014 for hyponatremia, resulting from SIAD or chronic hypovolemia. None had edema, cirrhosis, cardiac, or renal insufficiency. Exploration included estimation of volemia, extracellular fluid volume (ECFV) measurement with inulin, and calcium homeostasis. RESULTS: In total, the SIAD and hypovolemic groups included 22 and 7 patients, respectively. The SIAD group exhibited signs of increased volemia: higher glomerular filtration rate, higher fractional excretion of uric acid, and lower plasma renin. ECFV exceeded that of the hypovolemic group and was above usual values. There was no difference between the two groups regarding plasma calcium, PTH, and vitamin D. However, in the SIAD group, calciuria was higher than in the hypovolemic group, reaching levels of hypercalciuria. Furthermore, there was a positive correlation between calciuria and markers of volemia. CONCLUSIONS: Our results show that SIAD results in a volemic expansion tendency that is associated with a decrease in renal calcium reabsorption and thus hypercalciuria, whereas in the hypovolemic group, calciuria was not increased. Therefore, renal loss of calcium and bone demineralization in SIAD patients could be partly induced by volemic expansion.

[Urinary tract infections: Economical impact of water intake]. / Infections des voies urinaires : impact économique de la consommation d'eau.

BACKGROUNDS: This study aims to estimate the impact of preventing urinary tract infections (UTI), using a strategy of increased water intake, from the payer's perspective in the French health care system. METHODS: A Markov model enables a comparison of health care costs and outcomes for a virtual cohort of subjects with different levels of daily water intake. The analysis of the budgetary impact was based on a period of 5years. The analysis was based on a 25-year follow-up period to assess the effects of adequate water supply on long-term complications. RESULTS: The authors estimate annual primary incidence of UTI and annual risk of recurrence at 5.3% and 30%, respectively. Risk reduction associated with greater water intake reached 45% and 33% for the general and recurrent populations, respectively. The average total health care cost of a single UTI episode is €1074; for a population of 65 millions, UTI management represents a cost of €3.700 millions for payers. With adequate water intake, the model indicates a potential cost savings of €2.288 millions annually, by preventing 27 million UTI episodes. At the individual level, the potential cost savings is approximately €2915. CONCLUSIONS: Preventing urinary tract infections using a strategy of adequate water intake could lead to significant cost savings for a public health care system. Further studies are needed to assess the effectiveness of such an approach.

Relation between urinary hydration biomarkers and total fluid intake in healthy adults.

BACKGROUND/OBJECTIVES: In sedentary adults, hydration is mostly influenced by total fluid intake and not by sweat losses; moreover, low daily fluid intake is associated with adverse health outcomes. This study aimed to model the relation between total fluid intake and urinary hydration biomarkers. SUBJECTS/METHODS: During 4 consecutive weekdays, 82 adults (age, 31.6±4.3 years; body mass index, 23.2±2.7 kg/m(2); 52% female) recorded food and fluid consumed, collected one first morning urine (FMU) void and three 24-h (24hU) samples. The strength of linear association between urinary hydration biomarkers and fluid intake volume was evaluated using simple linear regression and Pearson's correlation. Multivariate partial least squares (PLS) modeled the association between fluid intake and 24hU hydration biomarkers. RESULTS: Strong associations (|r| ≥ 0.6; P<0.001) were found between total fluid intake volume and 24hU osmolality, color, specific gravity (USG), volume and solute concentrations. Many 24hU biomarkers were collinear (osmolality versus color: r=0.49-0.76; USG versus color: r=0.46-0.78; osmolality versus USG: 0.86-0.97; P<0.001). Measures in FMU were not strongly correlated to intake. Multivariate PLS and simple linear regression using urine volume explained >50% of the variance in fluid intake volume (r(2)=0.59 and 0.52, respectively); however the error in both models was high and the limits of agreement very large. CONCLUSIONS: Hydration biomarkers in 24hU are strongly correlated with daily total fluid intake volume in sedentary adults in free-living conditions; however, the margin of error in the present models limits the applicability of estimating fluid intake from urinary biomarkers.

Increased water intake as a prevention strategy for recurrent urolithiasis: major impact of compliance on cost-effectiveness.

PURPOSE: We evaluated the economic impact of preventing recurrent stones using a strategy of increased water intake and determined the impact of compliance on cost-effectiveness for the French health care system. MATERIALS AND METHODS: A Markov model was constructed to compare costs and outcomes for recurrent kidney stone formers with less than 2 L vs 2 L or more daily fluid intake. Model assumptions included an annual prevalence of 120,000 stone episodes in France, 14.4% annual risk of stone recurrence and a 55% risk reduction in subjects with adequate water intake. Costs were based on resource use as estimated by a panel of experts and official national price lists. Outcomes were from the perspective of the public health payer, and encompassed direct and indirect costs. RESULTS: The total cost of an episode of urolithiasis was estimated at €4,267 including the cost of treatment and complications. This corresponds to an annual budget impact of €88 million for recurrent stones based on 21,000 stone events. Assuming 100% compliance with fluid intake recommendations of 2 L daily, 11,572 new stones might be prevented, resulting in a cost savings of €49 million. Compliance with water intake in only 25% of patients would still result in 2,893 fewer stones and a cost savings of €10 million. Varying the costs of managing stones had a smaller impact on outcomes since in many patients stones do not form. Varying the incidence of complications did not change the incidence of stones and had a negligible effect on overall cost. CONCLUSIONS: Preventing recurrent urolithiasis has a significant cost savings potential for a payer as a result of a reduced stone burden. However, compliance is an important factor in determining cost-effectiveness.

Ondansetron does not block paracetamol-induced analgesia in a mouse model of fracture pain.

BACKGROUND: The aim of this study was to assess any interaction between ondansetron and paracetamol on a model of post-fracture pain in mice. METHODS: In protocol A, after fracture of the tibia, mice were assigned to four groups: paracetamol 30 mg kg⁻¹, paracetamol 50 mg kg⁻¹, paracetamol 100 mg kg⁻¹, or a saline vehicle i.p. In protocol B, after fracture of the tibia, mice were randomized to receive either paracetamol (100 mg kg⁻¹) plus saline (vehicle), paracetamol (100 mg kg⁻¹) plus ondansetron (1 mg kg⁻¹), paracetamol (100 mg kg⁻¹) plus ondansetron (2 mg kg⁻¹), saline plus ondansetron (2 mg kg⁻¹), or saline plus saline i.p. Three tests were used to assess pain behaviour: von Frey filament application, hot-plate test, and a subjective pain scale. Rescue analgesia with morphine was administered as necessary. RESULTS: In protocol A, paracetamol (100 mg kg⁻¹)-treated animals had less mechanical nociception, thermal nociception, and a lower subjective pain scale rating, when compared with those receiving paracetamol at 30 or 50 mg kg⁻¹ or saline [ED50 paracetamol=46.3 (6.34) mg kg⁻¹]. No difference was found between paracetamol (30 mg kg⁻¹) and saline-treated animals. In protocol B, the mechanical withdrawal threshold, the thermal withdrawal latency, and the subjective pain scale were lower after injection of paracetamol (100 mg kg⁻¹)+saline, paracetamol (100 mg kg⁻¹)+ondansetron (1 mg kg⁻¹), and paracetamol (100 mg kg⁻¹)+ondansetron (2 mg kg⁻¹), whereas in mice receiving saline+ondansetron (2 mg kg⁻¹) or saline+saline, there was no difference. CONCLUSION: We found that paracetamol 100 mg kg⁻¹ blocked the development of hyperalgesia and allodynia after fracture pain and ondansetron did not modify the antinociceptive effect of paracetamol in this model.

Acute and sub-chronic oral toxicity studies of an aqueous stem bark extract of Pterocarpus soyauxii Taub (Papilionaceae) in rodents.

UNLABELLED: Pterocarpus soyauxii Taub (Papilionaceae) is used in Cameroonian traditional medicine and pharmacopoeia to treat hypertension, diabetes, gastrointestinal parasitizes and cutaneous diseases. AIM OF THE STUDY: The present investigation was carried out to evaluate the safety of an aqueous stem bark extract of Pterocarpus soyauxii by determining toxicity after acute and sub-chronic oral administration in male and female rodents. MATERIALS AND METHODS: The acute toxicity test was conducted in mice. An aqueous extract of barks was administrated by gavage in single doses of 2.5-12.5 g/kg. General behaviour and mortality were examined for up to 7 days. The sub-chronic toxicity test was performed in rats. The plant extract was administered by daily gavage of 150-600 mg/kg for 42 days. Body weight, food and water intakes were followed weekly. Haematological, biochemical and organ parameters were determined at the end of the 42-day administration. RESULTS: In the acute study in mice, oral administration of the aqueous extract of Pterocarpus soyauxii caused dose-dependent general behaviour adverse effects and mortality. The no-observed adverse effect level (NOAEL) of the extract was 5.0 g/kg. The lowest-observed adverse effect level (LOAEL) was 7.5 mg/kg. Mortality increased with the dose, LD(50) was>10.75 g/kg for the mouse. In the sub-chronic study in rats, daily oral administration of the aqueous extract of Pterocarpus soyauxii did not result in death or significant changes in haematological or biochemical parameters, excepted increased hepatic catalase activity (P<0.05) at the dose of 600 mg/kg. No alteration was observed in body weight, food and water intake. Liver, kidney, lung and pancreas histopathology did not reveal morphological alteration. CONCLUSIONS: The results showed that the aqueous stem bark extract of Pterocarpus soyauxii Taub had very low toxicity in oral acute high dose administration and no toxicity in oral sub-chronic low dose administration and indicate that the plant could be considered safe for oral medication.

Hypoglycaemic effects of Mammea africana (Guttiferae) in diabetic rats.

AIM OF THE STUDY: The stem bark of Mammea africana Sabine (Guttiferae) is used in African rain forest to treat various diseases, including diabetes mellitus. We investigated whether Mammea africana extract induced hypoglycaemic activity in rats. MATERIALS AND METHODS: We tested the effects of acute (5h) and sub-acute (21 days) oral administrations of the CH(2)Cl(2)-MeOH stem bark extract of Mammea africana (19-300 mg/kg body weight) on blood glucose levels of normal and streptozotocin (STZ)-induced type 1 diabetic rats. The effects were compared with those of glibenclamide. RESULTS: Acute administration reduced blood glucose in the diabetic rats only (33.87%, P<0.01). Sub-acute treatment for 21 days also reduced blood glucose level in diabetic rats (73.29%, P<0.01). A reduction or stabilization in total serum protein, triglyceride, cholesterol and alanine amino transferase levels was also observed. No effect was observed on body weight loss but food and water intakes were significantly reduced (P<0.01) in diabetic rats. The maximal anti-diabetic effect was obtained with the dose of 75 mg/kg and was more important than that of glibenclamide. CONCLUSION: It can be concluded that extracts of Mammea africana exhibited a significant anti-hyperglycaemic activity and improved the metabolic alterations in STZ-diabetic rats. These results provide a rationale for the use of Mammea africana to treat diabetes mellitus and hypercholesterolemia.

Opioid-induced hyperalgesia in a mice model of orthopaedic pain: preventive effect of ketamine.

BACKGROUND: The aim of this study was to assess the preventative effect of ketamine on the exaggerated postoperative pain observed in sufentanil-treated mice and its ability to improve the analgesic effectiveness of morphine during the postoperative period in an orthopaedic model of pain. METHODS: In this study, we assessed the effects of ketamine on sufentanil enhancement of pain behaviour induced by fracture and the effects of ketamine on postoperative morphine-induced analgesia. Three tests were used to assess pain behaviour: von Frey filament application, hot-plate test, and a subjective pain scale. RESULTS: When administered 1 day after surgery in mice treated with sufentanil on D0 (before surgery), morphine induced an analgesic effect as observed by the nociceptive threshold increase in saline- and ketamine-treated mice. Morphine was more effective in ketamine-treated (1 and 50 mg kg(-1)) mice. CONCLUSIONS: Our results suggest that pre-emptive use of ketamine is useful in orthopaedic surgery in this mice model to diminish short- and long-term hyperalgesia, but also to improve morphine effectiveness leading to a better mobilization and more rapid rehabilitation.

Renal side effects of adefovir in hepatitis B virus-(HBV) positive kidney allograft recipients.

AIMS: The purpose of this study was to evaluate the renal side-effects of adefovir therapy in kidney-transplant (KT) recipients with chronic hepatitis B virus (HBV) infection, who have become resistant to lamivudine therapy. PATIENTS AND METHODS: 11 kidney-transplant (KT) patients (10 men, 1 woman, median age 54 (46 - 67) years) had lamivudine-resistant chronic HBV infection. With respect to HBV markers, all were HBs Ag-positive, 8 were HBe Ag-negative/HBe antibody- (Ab) positive, i.e. precore mutant, and 3 were HBe Ag-positive/HBe Ab-negative. They were all given adefovir at 10 mg/d (3 cases) or 5 mg/d (6 cases) or 2.5 mg/d (2 cases) according to creatinine clearance. RESULTS: Compared to baseline without adefovir therapy, at last follow-up, adefovir therapy was associated, at 1 and 2 years post therapy, with a significant decrease in aspartate (AST) (28 (17 - 53), 28 (10 - 79) vs. 58 (24 - 1,282) IU/l, p = 0.001), alanine (ALT) (38 (13 - 55), 36 (17 - 92) vs. 72 (31 - 1,594) IU/l, p = 0.0032] aminotransferase levels, and gammaGT (31 (14 - 51), 25 (14 - 196) vs. 44 (25 - 742) IU/l, p = 0.03). With respect to HBV DNA, when compared to baseline, there was a significant decrease at both years 1 and 2 post therapy (p = 0.01). With respect to KT function at 2 years after starting adefovir, there was a significant increase in serum creatinine from 125 (+/- 35) to 141 (+/- 32) micromol/l, (p = 0.02) and a significant increase in 24-h proteinuria. With respect to renal tubular parameters, as compared to baseline without adefovir therapy, one year after adefovir therapy was commenced there was a significant decrease in urinary pH from 6.6 (+0.6) to 5.65 (+/- 0.7); p = 0.03, a significant decrease in bicarbonaturia (from 0.33 +/- 0.7 to 0.1 +/- 0.3 mmol/h, p = 0.01), an increase in urinary excretion of H+ (1.79 (+/- 1.33) to 2.44 (+/- 1.18) mmol/l (p = 0.03)), a significant decrease in phosphatemia (0.82 +/- 0.19 vs. 0.65 +/- 0.13 mmol/l, p = 0.04) and a significant decrease in phosphaturia threshold, a significant decrease in tubular phosphorus reabsorption (75.5 +/- 9.4% vs. 61.8 +/- 16%, p = 0.05), and a significant increase in the phosphorus index of excretion (0.18 +/- 0.114 vs. 0.35 +/- 0.164, p = 0.01). CONCLUSION: We have demonstrated that low-dosage adefovir therapy in kidney-transplant patients is relatively safe as far as renal parameters are concerned, even though we observed a slight impairment of renal proximal-tubular function.

Normal FGF23 levels in adult idiopathic phosphate diabetes.

Fibroblast growth factor 23 (FGF23), a recently discovered phosphaturic substance playing a key role in genetic and oncogenic phosphate diabetes, is involved in the physiological regulation of phosphate metabolism. Moderate idiopathic phosphate diabetes (IPD) leading to male osteoporosis and diffuse pain resembling fibromyalgia has been described. The aim of our study was to define the role of FGF23 in the mechanism of IPD. The study concerned 29 patients with IPD, mean age 53 +/- 11 years, of whom 72% were men. Fifteen subjects without bone disease and with normal serum phosphate and calcium levels were used as controls. Phosphate diabetes was confirmed by phosphate reabsorption level <85% and phosphate reabsorption threshold (TmPO4/GFR) <0.83. Known causes of phosphate diabetes were excluded. Fasting level of FGF23, serum phosphate, 1-25(OH)2D3, and parathyroid hormone were measured in patients and compared with FGF23 and serum phosphate in healthy controls. Spinal and hip bone mineral density (BMD) were measured by osteodensitometry. Sixteen of 29 patients had diffuse pain, 10 had osteoporosis according to the World Health Organization criteria, and 11 had osteopenia. Serum phosphate was significantly lower in patients than in controls, but FGF23 levels did not differ. Compared to patients with normal bone status, patients with osteopenia and osteoporosis had significantly decreased FGF23 levels, whereas serum phosphate was identical in the two groups. In all patients, serum phosphate and FGF23 were positively correlated and FGF23 and 1-25(OH)2D3 were negatively correlated. FGF23 seems not be a cause of IPD, and the FGF23/phosphate/1-25(OH)2D3 axis appeared to be functional.

Conversion from sirolimus to everolimus in maintenance renal transplant recipients within a calcineurin inhibitor-free regimen: results of a 6-month pilot study.

AIM: To provide data on conversion of kidney transplant patients from sirolimus to everolimus. MATERIALS AND METHODS: In this 6-month prospective, open-label pilot study, maintenance renal transplant patients receiving sirolimus, mycophenolic acid and corticosteroids without concomitant calcineurin inhibitor (CNI) therapy were converted to everolimus 8 mg/day (8 - 15 ng/ml), and followed for 6 months. Mycophenolic acid and corticosteroid therapy were continued unchanged. Patients with acute rejection within the previous 3 months were excluded. RESULTS: 11 patients were recruited and completed the study (mean 5.1 +/- 1.8 years post transplant). Mean everolimus trough level remained within target throughout the study. Mean GFR remained stable (Day 0, 48.4 +/- 8.4 ml/min/1.73 m2, Month 6, 49.5 +/- 17.3 ml/ min/1.73 m2 (p = 0.966), as did mean renal phosphate threshold (TmPO4/GFR) (Day 0, 0.41 +/- 0.15 mmol/l, Month 6, 0.40 +/- 0.17 mmol/l (p = 0.966)). Serum phosphates increased significantly from 0.71 to 0.77 mmol/l (p = 0.01), but tubular reabsorption of phosphates and 24-h phosphaturia remained unchanged and mean PTH concentration tended to decrease. No patient died, lost their graft or experienced biopsy-proven acute rejection after conversion. There were no cases of CMV infection. Tolerability remained similar post conversion. Hematological and lipid parameters remained stable. Liver enzymes and sex hormones remained within normal ranges. CONCLUSION: This pilot study suggests that converting kidney transplant patients receiving CNI-free maintenance immunosuppression from sirolimus to everolimus, at relatively high exposure levels, is safe and easily manageable. There was no consistent evidence for a change in GFR or proximal tubular function.

Influence of gender and body composition on hydration and body water spaces.

BACKGROUND & AIMS: Hydration disorders are frequent in clinical practice and can be a life threatening issue in frail patients. Mild dehydration (1-2% loss of body weight) appears to impair cognitive and muscular performance. There is, however, no infallible indicator of correct hydration, and of hydration disorders. This study aim at describing total body water (TBW), extra-cellular water (ECW) and intracellular water (ICW) in a cohort of healthy subjects varying in age, gender and body composition. Two indicators of cellular hydration (TBW over fat free mass, and ICW over fat free mass) were studied. METHODS: The study cohort was made of 944 men and 874 women (mean age 42.7+/-13.1 yrs, BMI 24.3+/-3.5 kg/m(2)). All were volunteers for a preventive health examination. TBW, ECW, ICW were measured with bioelectrical impedance analysis. Body composition was assessed with the 3-compartment model. RESULTS: Values for TBW, ECW, and ICW differed with gender and with BMI categories (lean, overweight, and obese). The ratio of TBW over weight decreased with increasing BMI and was lower in women than in men. ECW (as a proportion of TBW) increased with BMI. The ratio of TBW over fat free mass decreased in obese subjects. The ratio of ICW over fat free mass was normally distributed, and decreased with BMI, more so in women than in men. CONCLUSIONS: This study provides reference values for body water spaces in healthy adults that are negatively correlated with BMI. Women and obese people display indicators of cellular dehydration, and are more at risk of dehydration.

Hemodynamic and renal involvement of B1 and B2 kinin receptors during the acute phase of endotoxin shock in mice.

B1 kinin receptor (B1R) is up-regulated by endotoxins and thus may represent a therapeutic target in sepsis. We investigated the expression and role of B1R and B2R in the acute phase of lipopolysaccharide (LPS)-induced endotoxin shock in C57BL/6 mice (WT) and B1R and B2R knock out mice (B1KO, B2KO). B1R mRNA was enhanced from 6 to 48 h after LPS while B2R mRNA was further increased in B1KO. Maximal hypotension was found 24 h after LPS, and was more pronounced in B1KO, but was reduced in B2KO. Glomerular filtration rate was more reduced by LPS in B1KO than in WT and B2KO. Glycemia was reduced by LPS and particularly in B1KO and B2KO mice. Mortality was increased by LPS in B1KO. These data suggest that the up-regulated B1R plays, at least transiently, a significant beneficial role in acute LPS-induced hypotension. Conversely, supra activation of B2R could be also involved in the increased mortality observed in B1KO mice.

Pharmacokinetics of ceftazidime and cefepime in burn patients: the importance of age and creatinine clearance.

AIM: The standard dosage recommendations for beta-lactam antibiotics can result in very low drug levels in intensive care (IC) patients and burn patients in the absence of renal dysfunction. We studied the pharmacokinetic parameters and serum concentrations of ceftazidime (CF) and cefepime (CE) in burn patients and analyzed the modifications according to clinical and biological parameters and in particular age and creatinine clearance. MATERIAL AND METHODS: Two pharmacokinetic studies were carried out with daily doses of 1 g x 6 for CF (n = 17) and 2 g x 3 for CE (n = 13). Creatinine clearance (CL(CR)) was both estimated and measured. Blood was sampled at steady state after an initial and a subsequent antibiotic dose. C(max) (maximal) and C(min) (minimal) concentrations were measured by HPLC. The influence of clinical and biological data was analyzed using ANOVA, ANCOVA and stepwise multiple linear regression. RESULTS: The ratio of C(min) to the low MIC break point (4 mg/l) was lower than 4 in 52% of subjects receiving CF and in 80% of subjects receiving CE. The C(min) of CF was correlated with measured CL(CR) and was higher in mechanically ventilated patients than in non-ventilated patients. The clearance of CF was correlated with age. The C(min) of CE was correlated with age and drug clearance with measured CL(CR). Therefore dosage adjustment of these drugs in burn patients needs to take into account age, measured creatinine clearance and the danger of low concentrations occurring when the creatinine clearance is greater than 120 ml x min(-1). CONCLUSION: In burn patients, the pharmacokinetic disposition of CF and CE was much more variable than in healthy subjects. Age and CL(CR) were predictors of the disposition of these antibiotics. Shortening the dosage interval or using continuous infusions will prevent low serum levels and keep trough levels above the MIC for longer periods of time. In view of the lack of a bedside measurement technique for ceftazidime and cefepime levels, we suggest a more frequent use of measured CL(CR) in order to attain efficacious clinical concentrations.

Assessment of renal function in clinical practice at the bedside of burn patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * In burn patients it has been shown ([2]), that there is a correlation between the creatinine clearance (CL(CR)) and the clearance of inulin. * The CL(CR) has never been studied in burn patients who have normal serum creatinine. * The Robert, Kirkpatrick and sMDRD formulae have never been evaluated in burn patients. WHAT THIS STUDY ADDS: * Despite burn patients having normal serum creatinine concentrations, the study showed that there are large variations in CL(CR) which cannot be detected by single serum creatinine measurements, and which have important implications for drug therapy. * It showed that the formulae currently used to calculate creatinine clearance on the basis of serum creatinine are inadequate for use in burn patients, and they should be abandoned in favour of direct measurement from a 24 h urine collection. AIMS: The aim of this study was to evaluate whether the renal function of burn patients could be correctly assessed using a single serum creatinine measurement, within normal limits, and three prediction equations of glomerular filtration taking into account, serum creatinine, age, weight and sex. METHODS: This was a prospective study comprising 36 adult burn patients with a serum creatinine <120 micromol l(-1), within the second or third week following the burn injury. Renal function was assessed using serum creatinine, 24 h urinary CL(CR), and the Cockcroft-Gault, Robert, Kirkpatrick and simplified MDRD equations. RESULTS: Despite normal serum creatinine concentrations in all patients, a significant number had a decreased CL(CR). The urinary CL(CR) was <80 ml(-1) min(-1) 1.73 m(-2) in nine patients (25%), and <60 ml(-1) min(-1) 1.73 m(-2) in five patients (14%). Between the groups having a CL(CR) lower or greater than 80 ml(-1) min(-1) 1.73 m(-2) there were no differences in gender, burn indices, percentage of mechanically ventilated patients or length of hospital stay, but a difference in age. The highest CL(CR) (>140 ml(-1) min(-1) 1.73 m(-2)) was found in 13 patients younger than 40 years. Regression analysis, residual and Bland-Altman plots revealed that neither the Cockcroft-Gault, Robert, Kirkpatrick nor sMDRD equations were specific enough for the assessment of renal function. CONCLUSIONS: In burn patients with normal serum creatinine during the hypermetabolic phase, serum creatinine and creatine based predictive equations are imprecise in assessing renal function.

Transient renal effects of sildenafil in male kidney transplant recipients.

BACKGROUND: Sildenafil (Viagra) improves erection by sustaining Guanosine 3', 5'-cyclic monophosphate (cGMP)-mediated smooth muscle relaxation in the corpus cavernosum. It also induces systemic vasodilation, resulting in a minor decrease in blood pressure. We evaluated the effect of one dose of sildenafil on graft function and hemodynamics in impotent male transplant recipients. METHODS: Two sets of combined lithium, inulin, and p-amino hippurate clearance studies were conducted, with and without sildenafil (100 mg orally) in 11 male kidney transplant recipients (KTRs). RESULTS: Sildenafil increased glomerular filtration rate by 14+/-4 from the baseline value of 55+/-7 ml x min(-1) x 1.73 m2(-1) (P<0.01), whereas calculated renal vascular resistances decreased by 40+/-18 from the baseline value of 247+/-29 mmHg/L x min(-1) x 1.73 m2-1 (P<0.05). CONCLUSIONS: The oral administration of sildenafil in KTRs did not impair the function of the graft. In terms of renal physiology, the observed modifications did not warrant any specific precautions when offering sildenafil to KTRs suffering from erectile dysfunction.

Low-protein diet suppresses serum insulin-like growth factor-1 and decelerates the progression of growth hormone-induced glomerulosclerosis.

A low-protein (LP) diet has been associated with amelioration of renal function in glomerulosclerosis (GS). However, the mechanisms involved are still unclear. We have used a mouse transgenic for bovine growth hormone (GH), which develops progressive GS and exhibits consistently elevated levels of circulating GH and insulin-like growth factor (IGF)-1, to study the effect of dietary protein restriction. LP (6% protein) and normal-protein (NP, 20% protein) diets were maintained for 30 weeks in mice with established GS of mild/moderate degree. The degree of GS was markedly attenuated in LP compared to NP mice. Quantitative analysis revealed a significantly lower GS index (1.4 +/- 0.9 in LP vs. 2.8 +/- 0.8 in NP) and glomerular volume (0.8 x 10(6) +/- 0.1 x 10(6) microm(3) in LP vs. 1.2 x 10(6) +/- 0.1 x 10(6) microm(3) in NP) in mice with restricted protein intake. These morphologic changes were accompanied by a significant reduction in renal expression of alpha(1) type-IV collagen (2.4-fold) and tenascin (1.4-fold) in LP mice. Serum IGF-1 decreased by 40% and showed a significant correlation with alpha(1) type-IV collagen expression with the LP diet. The present finding supports the use of the LP diet to decelerate the progression of GS and furthermore suggests that one of the mechanisms involved in this process is the GH/IGF-1 regulation by protein intake.

Matrix accumulation in mesangial cells exposed to cyclosporine A requires a permissive genetic background.

BACKGROUND: Chronic nephrotoxicity is an important adverse effect of cyclosporine A (CsA) therapy. Tubulo-interstitial lesions and arteriolopathy are common histologic findings. Glomerular lesions are also described, but they are of variable severity. The aim of our study is to determine whether CsA has a direct effect on mesangial cells and whether the cellular response depends on the genetic background. METHODS: We studied mesangial cells isolated from mice susceptible (ROP/Le-+Es1(b)+Es1(a), ROP) and resistant to glomerulosclerosis (B6SJLF1, C57). We previously showed that sclerosis-prone and sclerosis-resistant phenotypes are maintained in vitro. We examined whether CsA exposure directly affected extracellular matrix turnover in mesangial cells and whether the response is determined by the genetic background. Extracellular matrix synthesis and degradation were studied by proline incorporation, ELISA, reverse transcription-polymerase chain reaction, zymography, and reverse zymography. We chose a CsA dose that induced neither cytotoxicity nor apoptosis (1 microg/ml). RESULTS: At the dose of 1 microg/ml total collagen accumulation was increased in ROP but not in C57 cells. Matrix metalloproteinase (MMP)-2 activity and mRNA levels were selectively decreased in ROP cells. CsA exposure did not affect tissue inhibitors of MMP (TIMP)-1 and -2 activity or TGF-beta1 mRNA expression and protein synthesis in either cell line. CONCLUSION: CsA increases total collagen accumulation in mesangial cells from sclerosis-prone mice by decreasing MMP-2 activity, but does not affect cells from sclerosis-resistant mice. Thus, CsA directly affects mesangial cells, but only those with a permissive genetic background for glomerulosclerosis.