Lung ultrasound and procalcitonin, improving antibiotic management and avoiding radiation exposure in pediatric critical patients with bacterial pneumonia: a randomized clinical trial.

BACKGROUND: Pneumonia is a major public health problem with an impact on morbidity and mortality. Its management still represents a challenge. The aim was to determine whether a new diagnostic algorithm combining lung ultrasound (LUS) and procalcitonin (PCT) improved pneumonia management regarding antibiotic use, radiation exposure, and associated costs, in critically ill pediatric patients with suspected bacterial pneumonia (BP). METHODS: Randomized, blinded, comparative effectiveness clinical trial. Children < 18y with suspected BP admitted to the PICU from September 2017 to December 2019, were included. PCT was determined at admission. Patients were randomized into the experimental group (EG) and control group (CG) if LUS or chest X-ray (CXR) were done as the first image test, respectively. Patients were classified: 1.LUS/CXR not suggestive of BP and PCT < 1 ng/mL, no antibiotics were recommended; 2.LUS/CXR suggestive of BP, regardless of the PCT value, antibiotics were recommended; 3.LUS/CXR not suggestive of BP and PCT > 1 ng/mL, antibiotics were recommended. RESULTS: 194 children were enrolled, 113 (58.2%) females, median age of 134 (IQR 39-554) days. 96 randomized into EG and 98 into CG. 1. In 75/194 patients the image test was not suggestive of BP with PCT < 1 ng/ml; 29/52 in the EG and 11/23 in the CG did not receive antibiotics. 2. In 101 patients, the image was suggestive of BP; 34/34 in the EG and 57/67 in the CG received antibiotics. Statistically significant differences between groups were observed when PCT resulted < 1 ng/ml (p = 0.01). 3. In 18 patients the image test was not suggestive of BP but PCT resulted > 1 ng/ml, all of them received antibiotics. A total of 0.035 mSv radiation/patient was eluded. A reduction of 77% CXR/patient was observed. LUS did not significantly increase costs. CONCLUSIONS: Combination of LUS and PCT showed no risk of mistreating BP, avoided radiation and did not increase costs. The algorithm could be a reliable tool for improving pneumonia management. CLINICAL TRIAL REGISTRATION: NCT04217980.

Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age.

In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic study in Spain. The N-acetyltransferase 2 gene was analyzed to determine the acetylation status. Samples were analyzed using a validated UPLC-UV assay. A non-compartmental pharmacokinetic analysis was performed. Twenty-three pharmacokinetic profiles were performed in 20 infants (8 females) at a median (IQR) age of 19.0 (12.6-23.3) weeks. The acetylator statuses were homozygous fast (n = 1), heterozygous intermediate (n = 12), and homozygous slow (n = 7). INH median (IQR) Cmax and AUC0-24h values were 4.8 (3.7-6.7) mg/L and 23.5 (13.4-36.7) h*mg/L and the adult targets (>3 mg/L and 11.6-26.3 h*mg/L) were not reached in three and five cases, respectively. The age at assessment or acetylator status had no impact on Cmax values, but a larger INH AUC0-24h (p = 0.025) and trends towards a longer half-life (p = 0.055) and slower clearance (p = 0.070) were observed in homozygous slow acetylators. Treatment was well tolerated; mildly elevated alanine aminotransferase levels were observed in three cases. In our series of young infants receiving isoniazid, no major safety concerns were raised, and the target adult levels were reached in most patients.

Intravenous branched-chain amino-acid-free solution for the treatment of metabolic decompensation episodes in Spanish pediatric patients with maple syrup urine disease.

Background: Metabolic decompensation episodes (DEs) in Maple Syrup urine disease (MSUD) result in brain accumulation of toxic branched-chain amino acids (BCAAs) and their respective branched-chain α-keto acids that could induce neuroinflammation, disturb brain bioenergetics, and alter glutamate and glutamine synthesis. These episodes require immediate intervention to prevent irreversible neurological damage. Intravenous (IV) administration of BCAA-free solution could represent a powerful alternative for emergency treatment of decompensations. Methods: This pediatric series discusses the management of DEs in MSUD patients with IV BCAA-free solution, as an emergency treatment for DEs or as a prophylactic in cases requiring surgery. Clinical evolution, amino acid profile and adverse effects were evaluated. Results: We evaluated the use of BCAA-free solution in 5 DEs in 5 MSUD pediatric patients, all with significantly elevated plasma leucine levels at admission (699-3296 µmol/L) and in 1 episode of risk of DE due to surgery. Leucine normalization was achieved in all cases with resolution or improvement of clinical symptoms following IV BCAA-free solution. The duration of administration ranged from 3-20 days. Administration of IV BCAA-free solution at the beginning of a DE could reverse depletion of the amino acids that compete with BCAAs for the LAT1 transporter, and the observed depletion of alanine, despite IV alanine supplementation. No related adverse events were observed. Conclusions: Administration of standardized IV BCAA-free solution in emergency settings constitutes an important and safe alternative for the treatment of DEs in MSUD, especially in pediatric patients for whom oral or enteral treatment is not viable.

Effects of a Paediatric Antimicrobial Stewardship Program on Antimicrobial Use and Quality of Prescriptions in Patients with Appendix-Related Intraabdominal Infections.

The effectiveness of antimicrobial stewardship programs (ASP) in reducing antimicrobial use (AU) in children has been proved. Many interventions have been described suitable for different institution sizes, priorities, and patients, with surgical wards being one of the areas that may benefit the most. We aimed to describe the results on AU and length of stay (LOS) in a pre-post study during the three years before (2014-2016) and the three years after (2017-2019) implementation of an ASP based on postprescription review with feedback in children and adolescents admitted for appendix-related intraabdominal infections (AR-IAI) in a European Referral Paediatric University Hospital. In the postintervention period, the quality of prescriptions (QP) was also evaluated. Overall, 2021 AR-IAIs admissions were included. Global AU, measured both as days of therapy/100 patient days (DOT/100PD) and length of therapy (LOT), and global LOS remained unchanged in the postintervention period. Phlegmonous appendicitis LOS (p = 0.003) and LOT (p < 0.001) significantly decreased, but not those of other AR-IAI diagnoses. The use of piperacillin-tazobactam decreased by 96% (p = 0.044), with no rebound in the use of other Gram-negative broad-spectrum antimicrobials. A quasisignificant (p = 0.052) increase in QP was observed upon ASP implementation. Readmission and case fatality rates remained stable. ASP interventions were safe, and they reduced LOS and LOT of phlegmonous appendicitis and the use of selected broad-spectrum antimicrobials, while increasing QP in children with AR-IAI.

Benefits of a Pediatric Antimicrobial Stewardship Program in Antimicrobial Use and Quality of Prescriptions in a Referral Children's Hospital.

OBJECTIVES: To evaluate the results of the first 24 months of a postprescription review with feedback-based antimicrobial stewardship program in a European referral children's hospital. STUDY DESIGN: We performed a pre-post study comparing antimicrobial use between the control (2015-2016) and the intervention periods (2017-2018) expressed in days of therapy/100 days present. Quality of prescriptions was evaluated by quarterly cross-sectional point-prevalence surveys. Length of stay, readmission rates, in-hospital mortality rates, cost of systemic antimicrobial agents, and antimicrobial resistance rates were included as complementary outcomes. RESULTS: Total antimicrobial use and antibacterial use significantly decreased during the intervention period (P = .002 and P = .001 respectively), and total antifungal use remained stable. A significant decline in parenteral antimicrobial use was also observed (P < .001). In 8 quarterly point-prevalence surveys (938 prescriptions evaluated), the mean prevalence of use of any antimicrobial among inpatients was 39%. An increasing trend in the rate of optimal prescriptions was observed after the first point-prevalence survey (P = .0898). Nonoptimal prescriptions were more common in surgical than in medical departments, in antibacterial prescriptions with prophylactic intention, and in empirical more than in targeted treatments. No significant differences were observed in terms of mortality or readmission rates. Only minor changes in antimicrobial resistance rates were noted. CONCLUSIONS: Our antimicrobial stewardship program safely decreased antimicrobial use and expenditure, and a trend toward improvement in quality of prescription was also observed.

Neuroprotection with hypothermia and allopurinol in an animal model of hypoxic-ischemic injury: Is it a gender question?

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of neonatal brain injury. Therapeutic hypothermia (TH) is the standard treatment for term newborns after perinatal hypoxic ischemic injury (HI). Despite this, TH does not provide complete neuroprotection. Allopurinol seems to be a good neuroprotector in several animal studies, but it has never been tested in combination with hypothermia. Clinical findings show that male infants with (HI) fare more poorly than matched females in cognitive outcomes. However, there are few studies about neuroprotection taking gender into account in the results. The aim of the present study was to evaluate the potential additive neuroprotective effect of allopurinol when administrated in association with TH in a rodent model of moderate HI. Gender differences in neuroprotection were also evaluated. METHODS: P10 male and female rat pups were subjected to HI (Vannucci model) and randomized into five groups: sham intervention (Control), no treatment (HI), hypothermia (HIH), allopurinol (HIA), and dual therapy (hypothermia and allopurinol) (HIHA). To evaluate a treatment's neuroprotective efficiency, 24 hours after the HI event caspase3 activation was measured. Damaged area and hippocampal volume were also measured 72 hours after the HI event. Negative geotaxis test was performed to evaluate early neurobehavioral reflexes. Learning and spatial memory were assessed via Morris Water Maze (MWM) test at 25 days of life. RESULTS: Damaged area and hippocampal volume were different among treatment groups (p = 0.001). The largest tissue lesion was observed in the HI group, followed by HIA. There were no differences between control, HIH, and HIHA. When learning process was analyzed, no differences were found. Females from the HIA group had similar results to the HIH and HIHA groups. Cleaved caspase 3 expression was increased in both HI and HIA. Despite this, in females cleaved caspase-3 was only differently increased in the HI group. All treated animals present an improvement in short-term (Negative geotaxis) and long-term (WMT) functional tests. Despite this, treated females present better long-term outcome. In short-term outcome no sex differences were observed. CONCLUSIONS: Our results suggest that dual therapy confers great neuroprotection after an HI event. There were functional, histological, and molecular improvements in all treated groups. These differences were more important in females than in males. No statistically significant differences were found between HIHA and HIH; both of them present a great improvement. Our results support the idea of different regulation mechanisms and pathways of cell death, depending on gender.