How to use meropenem in pediatric patients undergoing CKRT? Integrated meropenem pharmacokinetic model for critically ill children.

Standard dosing could fail to achieve adequate systemic concentrations in ICU children or may lead to toxicity in children with acute kidney injury. The population pharmacokinetic analysis was used to simultaneously analyze all available data (plasma, prefilter, postfilter, effluent, and urine concentrations) and provide the pharmacokinetic characteristics of meropenem. The probability of target fT > MIC attainment, avoiding toxic levels, during the entire dosing interval was estimated by simulation of different intermittent and continuous infusions in the studied population. A total of 16 critically ill children treated with meropenem were included, with 7 of them undergoing continuous kidney replacement therapy (CKRT). Only 33% of children without CKRT achieved 90% of the time when the free drug concentration exceeded the minimum inhibitory concentration (%fT > MIC) for an MIC of 2 mg/L. In dose simulations, only continuous infusions (60-120 mg/kg in a 24-h infusion) reached the objective in patients <30 kg. In patients undergoing CKRT, the currently used schedule (40 mg/kg/12 h from day 2 in a short infusion of 30 min) was clearly insufficient in patients <30 kg. Keeping the dose to 40 mg/kg q8h without applying renal adjustment and extended infusions (40 mg/kg in 3- or 4-h infusion every 12 h) was sufficient to reach 90% fT > MIC (>2 mg/L) in patients >10 kg. In patients <10 kg, only continuous infusions reached the objective. In patients >30 kg, 60 mg/kg in a 24-h infusion is sufficient and avoids toxicity. This population model could help with an individualized dosing approach that needs to be adopted in critically ill pediatric patients. Critically ill patients subjected to or not to CKRT may benefit from the administration of meropenem in an extended or continuous infusion.

Volumetric capnography and return of spontaneous circulation in an experimental model of pediatric asphyxial cardiac arrest.

A secondary analysis of a randomized study was performed to study the relationship between volumetric capnography (VCAP) and arterial CO2 partial pressure (PCO2) during cardiopulmonary resuscitation (CPR) and to analyze the ability of these parameters to predict the return of spontaneous circulation (ROSC) in a pediatric animal model of asphyxial cardiac arrest (CA). Asphyxial CA was induced by sedation, muscle relaxation and extubation. CPR was started 2 min after CA occurred. Airway management was performed with early endotracheal intubation or bag-mask ventilation, according to randomization group. CPR was continued until ROSC or 24 min of resuscitation. End-tidal carbon dioxide (EtCO2), CO2 production (VCO2), and EtCO2/VCO2/kg ratio were continuously recorded. Seventy-nine piglets were included, 26 (32.9%) of whom achieved ROSC. EtCO2 was the best predictor of ROSC (AUC 0.72, p < 0.01 and optimal cutoff point of 21.6 mmHg). No statistical differences were obtained regarding VCO2, VCO2/kg and EtCO2/VCO2/kg ratios. VCO2 and VCO2/kg showed an inverse correlation with PCO2, with a higher correlation coefficient as resuscitation progressed. EtCO2 also had an inverse correlation with PCO2 from minute 18 to 24 of resuscitation. Our findings suggest that EtCO2 is the best VCAP-derived parameter for predicting ROSC. EtCO2 and VCO2 showed an inverse correlation with PCO2. Therefore, these parameters are not adequate to measure ventilation during CPR.

Population pharmacokinetics of piperacillin in critically ill children including those undergoing continuous kidney replacement therapy.

OBJECTIVES: Despite that piperacillin-tazobactam combination is commonly used in critically ill children, increasing evidence suggests that the current dosing schedules are not optimal for these patients. The aim of this work is to develop a population pharmacokinetic model for piperacillin to evaluate the efficacy of standard dosing in children with and without continuous kidney replacement therapy (CKRT) and to propose alternative dosing schemes maximizing target attainment. METHODS: Four hundred twenty-nine piperacillin concentrations measured in different matrices, obtained from 32 critically ill children (19 without CKRT, 13 with CKRT) receiving 100 mg/kg of piperacillin/tazobactam every 8 hours (increased to 12 hours after the fourth dose) were modelled simultaneously using the population approach with NONMEM 7.4. The percentage of patients with 90% fT > MIC and target attainment (percentage of dosing interval above MIC) were estimated for different intermittent and continuous infusions in the studied population. RESULTS: Piperacillin pharmacokinetic was best described with a two-compartment model. Renal, nonrenal, and hemofilter clearances were found to be influenced by the glomerular filtration rate, height (renal clearance), weight (nonrenal clearance), and filter surface (hemofilter clearance). Only seven (37%) children without CKRT and seven (54%) with CKRT achieved 90% fT > MIC with the current dosing schedule. Of the alternative regimens evaluated, a 24-hour continuous infusion of 200 mg/kg (CKRT) and 300 mg/kg (no CKRT) provided 100% fT > MIC (percent of time free drug remains above the minimum inhibitory concentration) (≤16 mg/L) and target attainments ≥90% across all evaluated MICs. DISCUSSION: In children with and without CKRT, standard dosing failed to provide an adequate systemic exposure, while prolonged and continuous infusions showed an improved efficacy.

Continuous Incisional Lidocaine in Pediatric Patients following Open Heart Surgery.

Continuous incisional lidocaine infusion has been proposed as an adjunctive therapy in the management of postoperative pain in adult patients. The aim of this study was to determine the efficacy and safety of a continuous subcutaneous lidocaine infusion in pediatric patients following open heart surgery. All patients receiving a subcutaneous lidocaine infusion in median sternotomy incisions after open heart surgery during 2 consecutive years were included in the study. A historical cohort of patients was used as a control group. Demographic variables (age, size, and surgical procedure), variables related to sedation and analgesia (COMFORT and analgesia scales, drug doses, and duration), and complications were registered. 106 patients in the lidocaine infusion group and 79 patients in the control group were included. Incisional analgesia was effective for the treatment of pain as it reduced the dose and duration of intravenous fentanyl (odds ratio (OR) 6.26, confidence interval (CI) 95%: 2.48-15.97, p = 0.001; OR 4.30, CI 95%: 2.09-8.84, p = 0.001, respectively). The reduction in fentanyl use was more important in children over two years of age. Adverse effects were seen in three children (2.8%): they all had decreased level of consciousness, and one of them presented seizures as well. Two of these three patients had lidocaine levels over 2 mcg/ml. A continuous lidocaine incisional infusion is effective for the treatment of pain after open heart surgery. This procedure reduced intravenous analgesic drug requirements in pediatric patients undergoing a median sternotomy incision. Although the incidence of secondary effects is low, monitoring of neurologic status and lidocaine blood levels are recommended in all patients.

Effect of ventilation rate on recovery after cardiac arrest in a pediatric animal model.

AIMS: To assess the impact of two different respiratory rates in hemodynamic, perfusion and ventilation parameters in a pediatric animal model of cardiac arrest (CA). METHODS: An experimental randomized controlled trial was carried out in 50 piglets under asphyxial CA. After ROSC, they were randomized into two groups: 20 and 30 respirations per minute (rpm). Hemodynamic, perfusion and ventilation parameters were measured 10 minutes after asphyxia, just before ROSC and at 5, 15, 30 and 60 minutes after ROSC. Independent medians test, Kruskal-Wallis test and χ2 test, were used to compare continuous and categorical variables, respectively. Spearman's Rho was used to assess correlation between continuous variables. A p-value <0.05 was considered significant. RESULTS: Arterial partial pressure of carbon dioxide (PaCO2) was significantly lower in the 30 rpm group after 15 minutes (41 vs. 54.5 mmHg, p <0.01), 30 minutes (39.5 vs. 51 mmHg, p < 0.01) and 60 minutes (36.5 vs. 48 mmHg, p = 0.02) of ROSC. The percentage of normoventilated subjects (PaCO2 30-50 mmHg) was significantly higher in the 30 rpm group throughout the experiment. pH normalization occurred faster in the 30 rpm group with significant differences at 60 minutes (7.40 vs. 7.34, p = 0.02). Lactic acid levels were high immediately after ROSC in both groups, but were significantly lower in the 20 rpm group at 30 (3.7 vs. 4.7 p = 0.04) and 60 minutes (2.6 vs. 3.6 p = 0.03). CONCLUSIONS: This animal model of asphyxial CA shows that a respiratory rate of 30 rpm is more effective to reach normoventilation than 20 rpm in piglets after ROSC. This ventilation strategy seems to be safe, as it does not cause hyperventilation and does not affect hemodynamics or cerebral tissue perfusion.

Renal function in children assisted with extracorporeal membrane oxygenation.

Acute kidney injury is a frequent complication in patients requiring extracorporeal membrane oxygenation. A single-center retrospective analysis from a prospective observational database assessing the incidence of acute kidney injury in children undergoing extracorporeal membrane oxygenation, the use of continuous renal replacement therapy and its association with outcomes was performed. One hundred children were studied. Creatinine was normal in 33.3% of children at the beginning of extracorporeal membrane oxygenation, between 1.5 and 2 times its baseline levels in 18.4% of children (stage I acute kidney injury), between 2 and 3 times baseline levels (stage II) in 20.7%, and over 3 times baseline levels or requiring continuous renal replacement therapy (stage III) in 27.6% of the patients. Eighteen patients were on continuous renal replacement therapy before the beginning of extracorporeal membrane oxygenation, 81 required continuous renal replacement therapy during extracorporeal membrane oxygenation, and 38 after weaning from extracorporeal membrane oxygenation, but none of them did at discharge from the pediatric intensive care unit. Fifty-one children survived to pediatric intensive care unit discharge. Mortality was lower in children with normal kidney function or with stage I acute kidney injury at the beginning of extracorporeal membrane oxygenation than in those with stage II or III acute kidney injury (33.3% vs 58.3%, p = 0.021). Mortality in children requiring continuous renal replacement therapy during extracorporeal membrane oxygenation was 54.3% and 21.1% in the rest of patients (p < 0.01). We conclude that kidney function is significantly impaired in a high percentage of children undergoing extracorporeal membrane oxygenation and many of them are treated with continuous renal replacement therapy. Patients treated with continuous renal replacement therapy have a higher mortality than those with normal kidney function or stage I acute kidney injury at the beginning of extracorporeal membrane oxygenation. Most patients surviving to pediatric intensive care unit discharge recover normal renal function after weaning from extracorporeal membrane oxygenation.

Correction: Cisplatin-Induced Non-Oliguric Acute Kidney Injury in a Pediatric Experimental Animal Model in Piglets.

[This corrects the article DOI: 10.1371/journal.pone.0149013.].

Evaluation of sublingual microcirculation in a paediatric intensive care unit: prospective observational study about its feasibility and utility.

BACKGROUND: Evaluation of the microcirculation in critically ill patients is usually done by means of indirect parameters. The aim of our study was to evaluate the functional state of the microcirculation by direct visualization of sublingual microcirculation using Sidestream Dark Field Imaging, to determine the correlation between these findings and other parameters that are commonly used in the clinical practice and to assess the applicability of the systematic use of this technique in critically ill children. METHODS: A prospective observational study was carried out in a Pediatric Intensive Care Unit (PICU) of a tertiary referral hospital. All patients admitted to the PICU during a three-month period were included in the study after obtaining the informed consent from the patient. Systematic evaluation of sublingual microcirculation was done in these patients (Total Vessel Density, Proportion of Perfused Vessels, Perfused Vessel Density, De Backer Score, Microvascular Flow Index, Heterogeneity Index) within the first day of admission (T1) and between the second and third day of admission (T2). Other clinical, hemodynamic, and biochemical parameters were measured and registered simultaneously. When the evaluation of the microcirculation was not feasible, the reason was registered. Descriptive analysis of our findings are expressed as means, medians, standard deviations and interquartile ranges. Mann-Whitney-Wilcoxon and Fisher tests were used to compare variables between patients with and without evaluation of the microcirculation. Pearson Correlation Coefficient (ρ) was used to evaluate the correlation between microcirculatory parameters and other clinical parameters. RESULTS: One hundred fine patients were included during the study period. Evaluation of the microcirculation was feasible in 18 patients (17.1%). 95.2% of them were intubated. The main reason for not evaluating microcirculation was the presence of respiratory difficulty or the absence of collaboration (95.1% on T1 and 68.9% on T2). Evaluated patients had a higher prevalence of intubation and ECMO at admission (72.2% vs. 14.9% and 16.6% vs. 1.1%, respectively), and longer median duration of mechanical ventilation (0 vs. 6.5 days), vasoactive drugs (0 vs. 3.5 days) and length of stay (3 vs. 16.5 days) than non-evaluated patients. There was a moderate correlation between microcirculatory parameters and systolic arterial pressure, central venous pressure, serum lactate and other biochemical parameters used for motoring critically ill children. CONCLUSIONS: Systematic evaluation of microcirculation in critically ill children is not feasible in the unstable critically ill patient, but it is feasible in stable critically ill children. Microcirculatory parameters show a moderate correlation with other parameters that are usually monitored in critically ill children.

Cisplatin-Induced Non-Oliguric Acute Kidney Injury in a Pediatric Experimental Animal Model in Piglets.

OBJECTIVE: To design an experimental pediatric animal model of acute kidney injury induced by cisplatin. METHODS: Prospective comparative observational animal study in two different phases. Acute kidney injury was induced using three different doses of cisplatin (2, 3 and 5 mg/kg). The development of nephrotoxicity was assessed 2 to 4 days after cisplatin administration by estimating biochemical parameters, diuresis and renal morphology. Analytical values and renal morphology were compared between 15 piglets treated with cisplatin 3 mg/kg and 15 control piglets in the second phase of the study. RESULTS: 41 piglets were studied. The dose of 3 mg/kg administered 48 hours before the experience induced a significant increase in serum creatinine and urea without an increase in potassium levels. Piglets treated with cisplatin 3 mg/kg had significantly higher values of creatinine, urea, phosphate and amylase, less diuresis and lower values of potassium, sodium and bicarbonate than control piglets. Histological findings showed evidence of a dose-dependent increase in renal damage. CONCLUSIONS: a dose of 3 mg/kg of cisplatin induces a significant alteration in renal function 48 hours after its administration, so it can be used as a pediatric animal model of non-oliguric acute kidney injury.

Postoperative neutrophil gelatinase-associated lipocalin predicts acute kidney injury after pediatric cardiac surgery*.

OBJECTIVE: We investigated the temporal pattern and predictive value of neutrophil gelatinase-associated lipocalin for early identification of acute kidney injury in children undergoing cardiac surgery. DESIGN: Prospective observational cohort study. SETTING: One PICU in a tertiary medical center in Madrid, Spain. PATIENTS: One hundred six children older than 15 days and younger than 16 years undergoing surgery for congenital cardiac lesions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Urine samples were obtained before and at intervals after surgery. Acute kidney injury was defined according to pediatric Risk, Injury, Failure, Loss, and End-stage kidney disease criteria. The temporal pattern of both urine neutrophil gelatinase-associated lipocalin absolute concentration elevation and normalized to urine creatinine concentration was correlated with the development of acute kidney injury and other clinical outcomes. We evaluated the predictive ability of both urine neutrophil gelatinase-associated lipocalin and urine neutrophil gelatinase-associated lipocalin/creatinine by area under the curve, when added to a clinical predictive model. Data from 106 pediatric patients were analyzed. Acute kidney injury occurred in 42 patients (39.6%). Urine neutrophil gelatinase-associated lipocalin significantly increased in patients with acute kidney injury at 1, 3, and 15 hours postoperatively. Urine neutrophil gelatinase-associated lipocalin and urine neutrophil gelatinase-associated lipocalin/creatinine correlated with surgical variables and clinical outcomes. Acute kidney injury prediction improved when urine neutrophil gelatinase-associated lipocalin was added to a clinical model (area under the curve increased at 1 hr from 0.85 to 0.91 and at 3 hr to 0.92). Neither the urine neutrophil gelatinase-associated lipocalin nor the urine neutrophil gelatinase-associated lipocalin/creatinine values were significantly different between patients with prerenal and sustained acute kidney injury. CONCLUSIONS: Urine neutrophil gelatinase-associated lipocalin is a predictive biomarker for acute kidney injury after pediatric cardiac surgery, and it may permit earlier intervention that improves outcome of acute kidney injury. Urine neutrophil gelatinase-associated lipocalin normalized to urine creatinine improves the prediction of acute kidney injury severity but offers no advantage in acute kidney injury diagnosis.