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.

Prevalence, Risk Factors and Impact of Nutrition Interruptions in Critically Ill Children.

Background: Enteral nutrition interruptions (ENI) are prevalent in the pediatric intensive care unit (PICU), but there is little evidence of their characteristics. Methods: This is a cross-sectional multicenter study including critically ill children on enteral nutrition. ENIs were classified as PICU procedures, procedures performed outside the PICU (PPOP), feeding intolerance and other criteria. The number and features of ENIs were collected. Results: A total of 75 children were enrolled. There were 41 interruptions affecting 37.3% of the patients with a median duration of 5 ± 9.4 h. The most common reason for ENI was PPOP (41.5%), followed by other criteria. Interruptions were considered preventable in 24.4% of the cases, but only eight were compensated. ENIs were more prevalent among children with cardiac disease (p = 0.047), higher PRISM (p = 0.047) and longer PICU stay (p = 0.035). There was association between PRISM and total interruption time (p = 0.02) and lower caloric intake (p = 0.035). Patients with respiratory illness (p = 0.022) and on noninvasive ventilation (p = 0,028) had fewer ENIs. ENI total time was associated with lower caloric (p = 0.001) and protein (p = 0.02) intake. Conclusions: ENIs are prevalent in PICU, especially in children with higher PRISM, longer PICU stays and cardiac disease, and result in lower caloric and protein intake.

Early vs late enteral nutrition in pediatric intensive care unit: Barriers, benefits, and complications.

BACKGROUND: This study aimed to define the existing barriers for early enteral nutrition (EEN) in critically ill children and to analyze the differences in nutrient supply, complications, and outcomes between EEN and late EN (LEN). METHODS: This is a secondary analysis of a multicenter observational, prospective study including critically ill children receiving EN. Variables analyzed included demographic and anthropometric features, caloric and nutrient supply, outcomes, and complications according to the EN onset. Patients were classified into two groups according to the start of EN: 24-EEN vs EN started after 24 h (24-LEN) and 48-EEN vs EN started after 48 h (48-LEN). RESULTS: Sixty-eight children were enrolled; 22.1% received 24-EEN, and 67.6% received 48-EEN. EN was most frequently delayed in patients older than 12 months, in patients with cardiac disease, and in those requiring mechanical ventilation (MV). Children in the 24-EEN group had shorter duration of MV compared with those in the 24-LEN group (P = 0.04). The 48-EEN group received a higher caloric intake (P = 0.04), reached the caloric target earlier (P < 0.01), and had lower incidence of constipation (P = 0.01) than the 48-LEN group. There was a positive correlation between the time required to reach the maximum caloric intake and the length of pediatric intensive care stay (r = 0.46; P < 0.01). CONCLUSION: EEN may improve nutrient delivery, reduce time on MV, and prevent constipation in critically ill children. No relevant differences between 24-EEN and 48-EEN were found. Cardiac disease, MV, and age older than 12 months were risk factors associated with LEN.

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.

Effects of airway management and tidal volume feedback ventilation during pediatric resuscitation in piglets with asphyxial cardiac arrest.

To compare the effect on the recovery of spontaneous circulation (ROSC) of early endotracheal intubation (ETI) versus bag-mask ventilation (BMV), and expiratory real-time tidal volume (VTe) feedback (TVF) ventilation versus without feedback or standard ventilation (SV) in a pediatric animal model of asphyxial cardiac arrest. Piglets were randomized into five groups: 1: ETI and TVF ventilation (10 ml/kg); 2: ETI and TVF (7 ml/kg); 3: ETI and SV; 4: BMV and TVF (10 ml/kg) and 5: BMV and SV. Thirty breaths-per-minute guided by metronome were given. ROSC, pCO2, pO2, EtCO2 and VTe were compared among groups. Seventy-nine piglets (11.3 ± 1.2 kg) were included. Twenty-six (32.9%) achieved ROSC. Survival was non-significantly higher in ETI (40.4%) than BMV groups (21.9%), p = 0.08. No differences in ROSC were found between TVF and SV groups (30.0% versus 34.7%, p = 0.67). ETI groups presented lower pCO2, and higher pO2, EtCO2 and VTe than BMV groups (p < 0.05). VTe was lower in TVF than in SV groups and in BMV than in ETI groups (p < 0.05). Groups 1 and 3 showed higher pO2 and lower pCO2 over time, although with hyperventilation values (pCO2 < 35 mmHg). ETI groups had non significantly higher survival rate than BMV groups. Compared to BMV groups, ETI groups achieved better oxygenation and ventilation parameters. VTe was lower in both TVF and BMV groups. Hyperventilation was observed in intubated animals with SV and with 10 ml/kg VTF.

Nutritional status and nutrition support in critically ill children in Spain: Results of a multicentric study.

OBJECTIVES: Critically ill children are often malnourished and require nutrition support (NS). Early enteral nutrition (EEN) seems to be safe in critically ill patients. However, there is a scarcity of data about the management of EEN in sick pediatric patients. The aim of this study was to analyze the nutritional status, NS characteristics, macronutrient supply, and associations between NS and outcomes in critically ill children in Spain. METHODS: This was a multicentric, prospective, cross-sectional study involving critically ill children who received NS and with an expected length of stay (LOS) in the pediatric intensive care unit of ≥3 d. Anthropometric variables, characteristics of NS, EEN, nutrient supply, and complications were recorded. RESULTS: We enrolled 86 children. Undernutrition and overweight were more prevalent in children ≤2 y of age than in older children (undernutrition: 40 versus 19%, respectively; overweight: 22.2 versus 14.3%, respectively). Being overweight was associated with a shorter PICU LOS (5.8 ± 2 versus 9.8 ± 6.5; P = 0.005). EN was the preferred method for nutrient delivery. EEN was administered to 58.1% of patients and was more common in children >2 y of age than in younger patients (73.1 versus 44.4%; P = 0.015). EEN was safe and was associated with a higher caloric intake (81.6 ± 35.3 versus 59.6 ± 36.6; P = 0.019). There was a negative correlation between mean time to EN initiation and maximum energy supply (r = -0.32; P = 0.07). CONCLUSIONS: Malnutrition was prevalent among critically ill children in Spain. Being overweight was associated with a shorter PICU LOS. EEN was safe and was associated with a higher caloric intake; however, it is rarely used in PICUs in Spain.