Catherine Litalien

Risk factors of acute renal failure in critically ill children: A prospective descriptive epidemiological study*

Objective: Acute renal failure is a serious condition in critically ill patients, but little literature is available on acute renal failure in critically ill children. The aim of the study was to determine incidence rate, identify risk factors, and describe the clinical outcome of acute renal failure in the pediatric intensive care unit (PICU). Design: Prospective, descriptive study. Setting: A tertiary PICU. Patients: Patients were 1,047 consecutively admitted children over a 1-yr period. Interventions: None. Measurements and Main Results: Acute renal failure was defined as doubling of baseline serum creatinine. A comparison between patients with acute renal failure and without acute renal failure was carried out, and the risk factors playing a significant role in the manifestation of acute renal failure were analyzed. There were 985 cases included in the study, with the incidence rate of acute renal failure in PICU being 4.5%. The most common PICU admission diagnoses in acute renal failure cases were hemolytic uremic syndrome (18.2%), oncologic pathologies (18.2%), and cardiac surgery (11.4%). Significant risk factors for acute renal failure following multivariate analysis were thrombocytopenia (odds ratio, 6.3; 95% confidence interval, 2.5, 16.2), age >12 yrs (odds ratio, 4.9; 95% confidence interval, 1.9, 13), hypoxemia (odds ratio, 3.2; 95% confidence interval, 1.3, 8.0), hypotension (odds ratio, 3.0; 95% confidence interval, 1.2, 7.5), and coagulopathy (odds ratio, 2.7; 95% confidence interval, 1.3, 5.6). The mortality rate was estimated to be higher in patients with acute renal failure compared with patients without acute renal failure (29.6% vs. 2.3%, p < .001). Conclusions: Although not frequent in the PICU, acute renal failure is associated with a significant increase in mortality. The risk factors of acute renal failure are multiple and are often present before PICU admission. A multiple-center study is planned with the intention to confirm these results.

LOCALIZATION AND mRNA EXPRESSION OF CYP3A AND P-GLYCOPROTEIN IN HUMAN DUODENUM AS A FUNCTION OF AGE

Cytochromes P450 3A (CYP3A) and P-glycoprotein (P-gp) are mainly located in enterocytes and hepatocytes. The CYP3A/P-gp system contributes to the first-pass metabolism of many drugs, resulting in a limited bioavailability. During the neonatal period, a shift between CYP3A7, the fetal form, and CYP3A4 occurs in the liver, but data on the expression of the CYP3A/P-gp complex in the intestine are very limited. A total of 59 normal duodenal biopsies from white children aged 1 month to 17 years were studied. Localization of the proteins by immunohistochemistry analysis was performed using a polyclonal antibody, Nuage anti-CYP3A, and a monoclonal antibody, C494 anti-P-gp. The mRNA quantification was performed using highly specific real-time reverse transcription-polymerase chain reaction. Villin mRNA quantification was used for normalization. CYP3A protein was detected in all enterocytes in the samples from patients over 6 months of age, whereas it was not in younger samples. P-gp protein was expressed at the apical and upper lateral surfaces of the enterocytes. CYP3A isoforms and P-gp mRNA levels were highly variable. CYP3A4 and CYP3A5 mRNA levels were high during the first year of life and decreased with age, whereas CYP3A7 was detected at a low level in 64% of samples, whatever the age. P-gp mRNA expression level was also highly variable. Our results showed that neonates and infants had a significant expression of CYP3A and P-gp mRNA in the intestine, suggesting a different maturation profile of CYP3A and P-gp with age in the liver and the intestine.

Pharmacokinetics of Proton Pump Inhibitors in Children

The use of proton pump inhibitors (PPIs) has become widespread in children and infants for the management of paediatric acid-related disease. Pharmacokinetic profiles of only omeprazole and lansoprazole have been well characterised in children over 2 years of age with acid-related diseases. Few data have been recently published regarding the pharmacokinetics of pantoprazole in children, and none are available for rabeprazole or esomeprazole. The metabolism of PPI enantiomers has never been studied in the paediatric population.A one-compartment model best describes the pharmacokinetic behaviour of omeprazole, lansoprazole and pantoprazole in children, with important interindividual variability for each pharmacokinetic parameter. Like adults, PPIs are rapidly absorbed in children following oral administration; the mean time to reach maximum plasma concentration varies from 1 to 3 hours. Since these agents are acid labile, their oral formulations consist of capsules containing enteric-coated granules. No liquid formulation is available for any of the PPIs. Thus, for those patients unable to swallow capsules, extemporaneous liquid preparations for omeprazole and lansoprazole have been reported; however, neither the absolute nor the relative bioavailabilities of these oral formulations have been studied in children. Intravenous formulations are available for omeprazole (in Europe), lansoprazole and pantoprazole.PPIs are rapidly metabolised in children, with short elimination half-lives of around 1 hour, similar to that reported for adults. All PPIs are extensively metabolised by the liver, primarily by cytochrome P450 (CYP) isoforms CYP2C19 and CYP3A4, to inactive metabolites, with little unchanged drug excreted in the urine. Similar to that seen in adults, the absolute bioavailability of omeprazole increases with repeated dosing in children; this phenomenon is thought to be due to a combination of decreased first-pass elimination and reduced systemic clearance. The apparent clearance (CL/F) of omeprazole, lansoprazole and pantoprazole appears to be faster for children than for adults. A higher metabolic capacity in children as well as differences in the extent of PPI bioavailability are most likely responsible for this finding. This may partly account for the need in children for variable and sometimes considerably greater doses of PPIs, on a per kilogram basis, than for adults to achieve similar plasma concentrations. Furthermore, no studies have been able to demonstrate a statistically significant correlation between age and pharmacokinetic parameters among children. Despite the small number of very young infants studied, there is some evidence for reduced PPI metabolism in newborns. The limited paediatric data regarding the impact of CYP2C19 genetic polymorphism on PPI metabolism are similar to those reported for adults, with poor metabolisers having 6- to 10-fold higher area under the concentration-time curve values compared with extensive metabolisers.Finally, because a pharmacokinetic/pharmacodynamic relationship exists for PPIs, the significant interindividual variability in their disposition may partly explain the wide range of therapeutic doses used in children. Further studies are needed to better define the pharmacokinetics of PPIs in children <2 years of age.

Protected specimen brush or bronchoalveolar lavage to diagnose bacterial nosocomial pneumonia in ventilated adults : A meta-analysis

OBJECTIVE We conducted a meta-analysis by using summary receiver operating characteristic curves to compare the diagnostic value for bacterial nosocomial pneumonia of the following: a) quantitative culture (colony-forming units per milliliter or CFU/mL) of respiratory secretions collected with a bronchoscopic protected specimen brush (PSB); b) quantitative culture of a bronchoscopic bronchoalveolar lavage (BAL); and c) the percentage of infected cells (IC) in BAL. DATA SOURCES All studies published in the English or the French language, through January 1, 1995, on the evaluation of PSB or BAL for the diagnosis of pneumonia were considered for analysis. The relevant literature was identified through computer and reference searching and by experts in the field. STUDY SELECTION A study was included if at least two of three independent readers regarded its purpose as the evaluation of CFU-PSB, CFU-BAL, or IC-BAL for the diagnosis in human beings of bacterial nosocomial pneumonia in ventilated adults and if the study was prospective and published in a peer-reviewed journal. DATA EXTRACTION Three readers reviewed all published articles and decided whether to include each study; consensus was defined as agreement by at least two readers. The authors of each original article included in the meta-analysis were asked to complete a questionnaire in which they were asked to check and to correct the data extracted by one of the independent readers. DATA SYNTHESIS Summary receiver operating characteristic curves were used to compare the efficacy of three diagnostic tests. Eighteen studies on CFU-PSB (795 patients) were included, as well as 11 studies on CFU-BAL (435 patients) and 11 on IC-BAL (766 patients). The accuracy of these tests was not different. However, it seems that administration of previous antibiotics markedly decreased accuracy of CFU-PSB (p = .0002) but not the accuracy of CFU-BAL and that of IC-BAL. CONCLUSION Both PSB and BAL are reliable to diagnose bacterial nosocomial pneumonia. Because CFU-BAL and IC-BAL seemed more resistant to the effects of antibiotics, we recommend BAL rather than PSB if the patient is already receiving antibiotics.

Circulating inflammatory cytokine levels in hemolytic uremic syndrome

Abstract Experimental data suggest that the host’s inflammatory response is involved in the pathophysiology of verotoxin-producing Escherichia coli (VTEC)-associated hemolytic uremic syndrome (HUS). We compared the circulating levels of pro- [interleukin (IL)-6, IL-8] and anti-inflammatory [IL-10 and IL-1 receptor antagonist (Ra)] mediators on enrollment among children with HUS due to E. coli O157:H7, according to the severity of renal dysfunction. The latter was evaluated by the occurrence of oligoanuria, the requirement for dialysis, and a glomerular filtration rate (GFR) ≤80 ml/min per 1.73 m2 measured 1 year later. Increased levels of IL-6 (P<0.0001), IL-10 (P<0.0001), and IL-1Ra (P<0.07) were found among patients with HUS compared with normal controls. Children with severe renal dysfunction also had tenfold increased levels of IL-6 and higher concentrations of IL-10 and IL-1Ra. Both the IL-6/IL-10 (4.9±8.3 vs. 0.5±0.4, P=0.01) and the IL-6/IL-1Ra ratios (0.10±0.20 vs. 0.01±0.01, P=0.04) were significantly increased. GFR correlated well with IL-6 levels, IL-6/IL-10 and IL-6/IL-1Ra ratios. Our data demonstrate that the inflammatory response of the host is associated with the severity of renal dysfunction during classic HUS. An imbalance between the pro- and the anti-inflammatory responses may be involved in the pathophysiology of VTEC-associated HUS.

Inflammatory mediators in Escherichia coli O157:H7 hemorrhagic colitis and hemolytic-uremic syndrome.

BACKGROUND Recent experimental data suggest that the inflammatory response of the host to verotoxin and/or lipopolysaccharides of Escherichia coli is involved in the pathophysiology of verotoxin-producing E. coli (VTEC) infections. METHODS We measured the circulating concentrations of cytokines [TNF-alpha, interleukin (IL)-1-beta, IL-1 receptor antagonist (Ra), IL-6, IL-8, IL-10] and soluble leukocyte adhesion molecules (L-selectin, P-selectin, E-selectin, intracellular cell adhesion molecule-1, vascular cell adhesion molecule-1) by sandwich enzyme-linked immunosorbent assay among (1) normal controls (n = 12), (2) disease controls with hemorrhagic colitis (HC) not associated with VTEC infections (n = 57), (3) patients with uncomplicated HC caused by E. coli O157:H7 (n = 30), and (4) children with hemolytic-uremic syndrome (HUS) (n = 28). Patients with HUS were matched with children who presented an uncomplicated HC caused by E. coli O157:H7 for the time interval elapsed between the onset of HC and that of blood sample collection. RESULTS Concentrations of TNF-alpha and IL-1-beta were undetectable. Children with HUS were characterized by increased amounts of IL-6 and IL-8, lower values of soluble L-selectin as well as increased levels of IL-10 and IL-1Ra. The circulating concentrations of IL-1Ra were higher among children with O157:H7 HC who subsequently developed HUS. CONCLUSIONS Increased pro- and antiinflammatory cytokine responses are produced by the host during the development of HUS among children with VTEC infections. Further studies are needed to determine their relative contribution to the pathophysiology of classic HUS.

Circulating levels of transforming growth Factor-β1 and lymphokines among children with hemolytic uremic syndrome

Verotoxin-producing Escherichia coli (VTEC) cause hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). The aim of this study was to compare the circulating levels of transforming growth factor-beta 1 (TGF-beta1), T helper (T(H))1 (interferon [IFN]-gamma, interleukin [IL]-2), and T(H)2-associated lymphokines (IL-4, IL-13) in children with uncomplicated Escherichia coli O157:H7 HC and patients who developed HUS. Circulating levels of IL-2, IL-4, and IL-13 were undetectable, and those of IFN-gamma were low and comparable among groups. Concentrations of TGF-beta1 were higher in children with uncomplicated O157:H7 HC than among those who developed HUS (934 +/- 680 versus 514 +/- 497 pg/mL, respectively; P < 0.04). The circulating levels of TGF-beta1 were also higher among children who did not take antidiarrheal agents (P < 0.008) and those who have been immediately discharged from the emergency room (P < 0.03). Our results did not show an imbalanced T(H)1/T(H)2-associated lymphokine response during the development of HUS. Increased circulating levels of TGF-beta1 in children with milder O157:H7 or uncomplicated HC most likely reflect appropriate intestinal tissue repair mechanisms rather than a remote systemic endocrine effect on the kidneys.

Quantification of busulfan in plasma by liquid chromatography-ion spray mass spectrometry : Application to pharmacokinetic studies in children

Optimisation of busulfan dosage in patients undergoing bone marrow transplantation is recommended in order to reduce toxic effects associated with high drug exposure. A new method was developed coupling liquid chromatography with mass spectrometry (LC-MS) and was validated for the determination of busulfan concentrations in plasma. Recovery was 86.7%, the limit of detection was 2.5 ng/ml and linearity ranged from 5 to 2500 ng/ml. The correlation between the busulfan concentrations measured by our previously published HPLC-UV method and the new HPLC-MS method was highly significant (P<0.0001). Sample volume was reduced and the method was rapid, sensitive and less expensive than the methods previously used in our laboratory. This method was used to determine the pharmacokinetic parameters of busulfan after the first administration of 1 mg/kg orally, in 13 children receiving the drug as part of the preparative regimen for bone marrow transplantation. Our results were similar to previously reported data. They showed that the apparent oral clearance of busulfan was 0.299+/-0.08 l/h/kg, and that it was significantly higher (P=0.02) in patients below the age of 5 years than in older children.

Population pharmacokinetics of intravenous pantoprazole in paediatric intensive care patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The use of intravenous pantoprazole, a proton pump inhibitor, has been increasing in the paediatric intensive care unit. Despite this increased use, data on the disposition of intravenous pantoprazole in paediatric intensive care patients are very scarce. WHAT THIS STUDY ADDS Our population approach has determined the pharmacokinetic parameters of intravenous pantoprazole in paediatric intensive care patients and the relative importance of factors influencing its disposition. Pantoprazole clearance was significantly influenced by developmental changes and by the presence of systemic inflammatory syndrome, hepatic dysfunction and CYP2C19 inhibitors. AIMS To characterize the pharmacokinetics of intravenous pantoprazole in a paediatric intensive care population and to determine the influence of demographic factors, systemic inflammatory response syndrome (SIRS), hepatic dysfunction and concomitantly used CYP2C19 inducers and inhibitors on the drugs pharmacokinetics. METHODS A total of 156 pantoprazole concentration measurements from 20 patients (10 days to 16.4 years of age) at risk for or with upper gastrointestinal bleeding, who received pantoprazole doses ranging from 19.9 to 140.6 mg/1.73 m(2)/day, were analysed using a population pharmacokinetic approach (nonmem program). RESULTS The best structural model for pantoprazole was a two-compartment model with zero order infusion and first-order elimination. Body weight, SIRS, age, hepatic dysfunction and presence of CYP2C19 inhibitors were significant covariates affecting clearance (CL), accounting for 75% of interindividual variability. Only body weight significantly influenced central volume of distribution (V(c)). In the final population model, the estimated CL and V(c) were 5.28 l h(-1) and 2.22 l, respectively, for a typical 5-year-old child weighing 20 kg. Pantoprazole CL increased with weight and age, whereas the presence of SIRS, CYP2C19 inhibitors and hepatic dysfunction, when present separately, significantly decreased pantoprazole CL by 62.3, 65.8 and 50.5%, respectively. For patients aged between 6 months and 5 years without SIRS, CYP2C19 inhibitor or hepatic dysfunction, the predicted pantoprazole CL is faster than that reported in adults. CONCLUSION These results provide important information for physicians regarding selection of a starting dose and dosing regimens of pantoprazole for paediatric intensive care patients based on factors frequently encountered in this population.

Limited sampling strategies for monitoring tacrolimus in pediatric liver transplant recipients.

Objective: To develop and validate limited sampling strategies (LSSs) for tacrolimus in pediatric liver transplant recipients. Methods: Thirty-six 12-hour pharmacokinetic profiles from 28 pediatric liver transplant recipients (0.4-18.5 years) were collected. Tacrolimus concentrations were measured by immunoassay and area under the curve (AUC0-12) was determined by trapezoidal rule. LSSs consisting of 1, 2, 3, or 4 concentration-time points were developed using multiple regression analysis. Eight promising models (2 per category) were selected based on the following criteria: r2 ≥ 0.90, inclusion of trough concentration (C0), and time points within 4 hours postdose. The predictive performance of these LSSs was evaluated in an independent set of data by measuring the mean prediction error and the root mean squared prediction error. Results: Five models including 2-4 time points predicted AUC0-12 with a ±15% error limit. Bias (mean prediction error) and precision (root mean squared prediction error) of LSS involving C0, C1, and C4 (AUCpredicted = 9.30 + 3.69 × C0 + 2.19 × C1 + 4.69 × C4) were −4.98% and 8.29%, respectively. Among single time point LSSs, the model using C0 had a poor correlation with AUC0-12 (r2 = 0.53), whereas the one with C4 had the highest correlation with tacrolimus exposure (r2 = 0.84). Conclusions: Trough concentration is a poor predictor of tacrolimus AUC0-12 in pediatric liver transplant recipients. However, LSSs using 2-4 concentration-time points obtained within 4 hours postdose provide a reliable and convenient method to predict tacrolimus exposure in this population. The proposed LSSs represent an important step that will allow the undertaking of prospective trials aiming to better define tacrolimus target AUC in pediatric liver transplant recipients and to determine whether AUC-guided monitoring is superior to C0-based monitoring in terms of efficacy and safety.