Efficacy and safety of low-dose versus high-dose hydrocortisone to treat hypotension in neonates: a protocol for a systematic review and meta-analysis.

BACKGROUND: Impaired adrenal function is a well-described entity in critically ill term and preterm neonates with systemic hypotension. The standard treatment for neonatal hypotension includes volume expanders and vasopressors. Recent evidence supports the use of glucocorticoids for the primary or rescue treatment of neonatal hypotension associated with impaired adrenal function. However, inconsistency regarding the prescribed dosing regimen to provide the best balance between efficacy and safety in this vulnerable population remains an area of concern. METHODS: We will conduct a systematic review and meta-analysis to evaluate low-dosing compared with high-dosing regimens of hydrocortisone for the treatment of hypotension in critically ill term, preterm and very low birth weight neonates. Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Web of Science will be searched from inception to November 2021. Study screening and selection will be completed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Our primary outcomes will be (1) an improvement in end-organ perfusion, defined as an increase in blood pressure along with an increase in urine output or a reduction in serum lactate and (2) mortality prior to discharge. Our secondary outcomes will be the development of (1) major neurosensory abnormality, (2) bronchopulmonary dysplasia and (3) the occurrence of adverse events. DISCUSSION: Hydrocortisone may be beneficial in the treatment of hypotension associated with impaired adrenal function among critically ill neonates. However, its optimal dosing to balance desired efficacy with the risk of adverse events is yet to be determined. Our systematic review and meta-analysis aims to address this evidence gap, providing valuable knowledge for a large audience, including guideline developers, policy-makers and clinicians. PROSPERO REGISTRATION NUMBER: This protocol is submitted for registration to the international database of prospectively registered systematic reviews (PROSPERO, awaiting registration number).

Severe Acute Kidney Injury and Multiple Organ Failure in a 17-Day-Old Newborn: When Pathology Makes the Difference.

RATIONALE: Acute tubulointerstitial nephritis (ATIN) in children is most commonly due to allergic drug reactions. In neonates, diagnosis of ATIN is clinically suspected and a kidney biopsy is not routinely performed. PRESENTING CONCERN: A 17-day-old newborn presented with vomiting and dehydration, along with anuric acute kidney injury, severe electrolyte disturbances, hypocomplementemia, and thrombocytopenia. Abdominal ultrasound revealed bilateral nephromegaly and hepatosplenomegaly. The patient was promptly started on intravenous (IV) fluid and broad-spectrum antibiotics. His electrolyte disturbances were corrected as per standard guidelines. The rapid progressive clinical deterioration despite maximal treatment and the unclear etiology influenced the decision to proceed to a kidney biopsy. Histopathological findings revealed diffuse interstitial edema with a massive polymorphic cellular infiltrate and destruction of tubular structures, consistent with severe ATIN. Elements of thrombotic microangiopathy (TMA) were observed. DIAGNOSIS: The clinical presentation combined with imaging and histopathological findings was suggestive of ATIN caused by a severe acute bacterial pyelonephritis. INTERVENTION: Methylprednisolone pulses followed by oral prednisolone were administered. Antibiotics were continued for 10 days. The patient was kept on invasive mechanical ventilation and on peritoneal dialysis for 12 days. OUTCOME: His condition stabilized following steroid pulses. His renal function progressively improved, and renal replacement therapy was weaned off. His renal ultrasound normalized. He has maintained a normal blood pressure, urinalysis, and renal function over the past 5 years. NOVEL FINDING: This case reports a severe presentation of acute bacterial pyelonephritis in a neonate. It highlighted the involvement of complement activation in severe infectious process. Histopathological findings of ATIN and TMA played a crucial role in understanding the physiopathology and severity of the disease.

JUSTIFICATION: La néphrite tubulo-interstitielle aiguë (NTIA) chez l'enfant est le plus souvent attribuée à une réaction allergique aux médicaments. Chez les nouveau-nés, le diagnostic de la NTIA est cliniquement suspecté et une biopsie des reins n'est pas pratiquée de façon systématique. PRÉSENTATION DU CAS: Un nouveau-né âgé de dix-sept jours pris de vomissements et déshydraté qui présentait une insuffisance rénale aiguë anurique, un grave déséquilibre électrolytique, une hypocomplémentémie et une thrombocytopénie. L'échographie abdominale a révélé une hypertrophie rénale bilatérale ainsi qu'une hépatosplénomégalie. Le patient a rapidement été traité avec des antibiotiques à large spectre par voie intraveineuse (IV), et les déséquilibres électrolytiques ont été corrigés conformément aux lignes directrices normalisées. La détérioration clinique rapide et progressive du patient malgré un traitement maximal et une étiologie incertaine a orienté la décision de procéder à une biopsie rénale. Les résultats histopathologiques ont révélé un œdème interstitiel diffus avec infiltrat cellulaire polymorphe et une destruction des structures tubulaires; des observations cohérentes avec une NTIA grave. Des éléments d'une microangiopathie thrombotique (MAT) avaient également été observés. DIAGNOSTIC: Le tableau clinique combiné aux résultats histopathologiques et d'imagerie suggérait une NTIA causée par une pyélonéphrite bactérienne grave. INTERVENTION: Le traitement a consisté en des injections répétées de méthylprednisolone suivies par l'administration orale de prednisolone. Le traitement aux antibiotiques s'est poursuivi sur une période de dix jours. Le patient a également été maintenu sous ventilation mécanique effractive et sous dialyse péritonéale pendant douze jours. RÉSULTATS: L'état du patient s'est stabilisé à la suite des injections répétées de stéroïdes; sa fonction rénale s'est progressivement améliorée et la thérapie de remplacement rénal a pu être cessée. L'échographie rénale s'est normalisée. Le patient a maintenu une tension artérielle, des analyses d'urine et une fonction rénale normales au cours des cinq dernières années. CONSTATATIONS: Ce rapport présente un cas grave de pyélonéphrite bactérienne aiguë chez un nouveau-né et a mis en lumière le rôle de l'activation du complément dans un processus infectieux grave. Les observations histopathologiques de la NTIA et de la MAT ont joué un rôle essentiel dans la compréhension de la physiopathologie et de la gravité de la maladie.

Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation.

AIMS: The aim of this study is to develop a population pharmacokinetic (PopPK) model for intravenous busulfan in children that incorporates variants of GSTA1, gene coding for the main enzyme in busulfan metabolism. METHODS: Busulfan concentration-time data was collected from 112 children and adolescents (median 5.4 years old, range: 0.1-20) who received intravenous busulfan during the conditioning regimen prior to stem cell transplantation. Weight, sex, baseline disease (malignant vs. non-malignant), age, conditioning regimen and GSTA1 diplotypes were evaluated as covariates of pharmacokinetic parameters by using nonlinear mixed effects analysis. The ability to achieve the target AUC24h (3600-6000 µM min-1 ) was assessed by estimating the first dose based on the present PopPK model and by comparing the results with other available models in children. RESULTS: A one-compartment model with first-order elimination best described the data. Allometric scaling of weight and a factor of busulfan metabolism maturation were included in the base model. GSTA1 diplotypes were found to be a significant covariate of busulfan clearance, which was 7% faster in rapid metabolizers and 12% slower in poor metabolizers, in comparison with normal ones. Busulfan doses calculated using the parameters of the proposed PopPK model were estimated to achieve the target AUC in 85.2% of the cases (95% CI 78.7-91.7%). CONCLUSION: This is the first PopPK for busulfan that successfully incorporated GSTA1 genotype in a paediatric population. Its use may contribute to better prediction of busulfan exposure in children and adolescents since the first dose, by tailoring the dose according to the individual metabolic capacity.

Impact of sampling time deviations on the prediction of the area under the curve using regression limited sampling strategies.

The regression limited sampling strategy approach (R-LSS), which is based on a small number of blood samples drawn at selected time points, has been used as an alternative method for the estimation of the area under the concentration-time curve (AUC). However, deviations from planned sampling times may affect the performance of R-LSS, influencing related therapeutic decisions and outcomes. The aim of this study was to investigate the impact of different sampling time deviation (STD) scenarios on the estimation of AUC by the R-LSS using a simulation approach. Three types of scenarios were considered going from the simplest case of fixed deviations, to random deviations and then to a more realistic case where deviations of mixed nature can occur. In addition, the sensitivity of the R-LSS to STD in each involved sampling point was evaluated. A significant impact of STD on the performance of R-LSS was demonstrated. The tolerance of R-LSS to STD was found to depend not only on the number of sampling points but more importantly on the duration of the sampling process. Sensitivity analysis showed that sampling points at which rapid concentration changes occur were relatively more critical for AUC prediction by R-LSS. As a practical approach, nomograms were proposed, where the expected predictive performance of R-LSS was provided as a function of STD information. The investigation of STD impact on the predictive performance of R-LSS is a critical element and should be routinely performed to guide R-LSS selection and use.

Limited sampling strategies for estimating intravenous and oral cyclosporine area under the curve in pediatric hematopoietic stem cell transplantation.

BACKGROUND: The optimal monitoring strategy for cyclosporine (CsA) in pediatric hematopoietic stem cell transplantation (HSCT) patients remains unclear. Although there is a growing interest in the use of the area under the concentration-time curve (AUC), measurement of AUC in clinical settings is often impractical. The objective of this study was to identify and validate limited sampling strategies (LSSs) for the prediction of CsA AUC after intravenous (IV) and oral (PO) administration in this population. METHODS: Sixty-eight pediatric patients who underwent HSCT and received CsA were investigated. Twelve-hour pharmacokinetic profiles (n = 138) performed per standard of care were collected. Weighted multiple linear regression was used to investigate all possible LSSs consisting of 4 or less concentration-time points. Their predictive performance was evaluated by leave one out cross validation and external validation by measuring the root mean squared relative error (RMSE%) and the 95th percentile of the absolute relative error (AE%). Values less than 20% were considered clinically acceptable. RESULTS: Nine LSSs (4 IV and 5 PO) convenient for clinical application proved to have clinically acceptable performance. Notably, LSS based on C0, C2, and C4 was found to be accurate for estimation of CsA exposure after both IV and PO administration with the 95th percentile of AE% of 19.7% and 17.5%, respectively. CONCLUSIONS: LSSs using 3 or 4 concentration-time points obtained within 4 hours postdose provide a convenient and reliable method to estimate CsA exposure in this population. These LSSs may facilitate future research aiming at better defining the relationship between AUC and clinical outcomes.

Bayesian approach for the estimation of cyclosporine area under the curve using limited sampling strategies in pediatric hematopoietic stem cell transplantation.

BACKGROUND: The optimal marker for cyclosporine (CsA) monitoring in transplantation patients remains controversial. However, there is a growing interest in the use of the area under the concentration-time curve (AUC), particularly for cyclosporine dose adjustment in pediatric hematopoietic stem cell transplantation. In this paper, we develop Bayesian limited sampling strategies (B-LSS) for cyclosporine AUC estimation using population pharmacokinetic (Pop-PK) models and investigate related issues, with the aim to improve B-LSS prediction performance. METHODS: Twenty five pediatric hematopoietic stem cell transplantation patients receiving intravenous and oral cyclosporine were investigated. Pop-PK analyses were carried out and the predictive performance of B-LSS was evaluated using the final Pop-PK model and several related ones. The performance of B-LSS when targeting different versions of AUC was also discussed. RESULTS: A two-compartment structure model with a lag time and a combined additive and proportional error is retained. The final covariate model does not improve the B-LSS prediction performance. The best performing models for intravenous and oral cyclosporine are the structure ones with combined and additive error, respectively. Twelve B-LSS, consisting of 4 or less sampling points obtained within 4 hours post-dose, predict AUC with 95th percentile of the absolute values of relative prediction errors of 20% or less. Moreover, B-LSS perform better for the prediction of the 'underlying' AUC derived from the Pop-PK model estimated concentrations that exclude the residual errors, in comparison to their prediction of the observed AUC directly calculated using measured concentrations. CONCLUSIONS: B-LSS can adequately estimate cyclosporine AUC. However, B-LSS performance is not perfectly in line with the standard Pop-PK model selection criteria; hence the final model might not be ideal for AUC prediction purpose. Therefore, for B-LSS application, Pop-PK model diagnostic criteria should additionally account for AUC prediction errors.

A specific and sensitive HPLC-MS/MS micromethod for milrinone plasma levels determination after inhalation in cardiac patients.

BACKGROUND: Milrinone administered through inhalation is an emerging method aimed at specifically reducing pulmonary hypertension without affecting systemic pressures. Its administration has been shown to be useful both in patients undergoing cardiac surgery and for persistent pulmonary hypertension of the newborn. These populations are prone to receive many concomitant medications and/or blood sampling may require a low volume quantification method. To address these issues in view of pharmacokinetic studies, this article aims to develop and validate a specific and sensitive analytical assay using high performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS) detection for the quantification of milrinone plasma concentrations after inhalation in patients undergoing cardiac surgery. METHODS: Plasma samples (50 µL) were extracted using ethyl acetate. Milrinone was separated on a C18 analytical column at 50°C. The mobile phase consisted of methanol and 10 mM ammonium acetate (45:55 vol/vol). The electrospray was operated in the negative ionization mode and monitored the following mass transitions: m/z 212.1 → 140.0 at 36 eV for milrinone and m/z 252.1 → 156.1 at 32 eV for olprinone. RESULTS: Calibration curves followed a quadratic regression in the concentration range of 0.3125-640 ng/mL. The lower limit of quantification is 0.3125 ng/mL and is based on a low plasma volume of 50 µL. Mean drug recovery and accuracy were ≥72.3% and 96.0%, respectively. Intraday and interday precision coefficient of variation (%) was ≤7.4% and ≤11.5%, respectively. The specificity allowed milrinone quantification in the multidrug administration conditions of cardiopulmonary bypass. CONCLUSIONS: This validated micromethod proved to be highly sensitive and specific while using a low volume of plasma. Its low volume and its lower limit of quantification indicate that this approach is suitable for further characterization of milrinone pharmacokinetics in both adults (inhalation) and neonates.

Pharmacogenetics and beyond: variability of voriconazole plasma levels in a patient with primary immunodeficiency.

We report the case of a patient highly susceptible to invasive aspergillosis who received treatment with voriconazole (VRC). As part of therapeutic drug monitoring, VRC plasma trough concentrations were measured, showing undetectable levels (<0.16 µg/ml). Genotyping showed a heterozygous profile CYP2C19*1/*17, known to be associated with an ultrarapid-metabolism phenotype, contributing to the very low systemic exposure observed. Therefore, in this situation, the use of VRC treatment could be associated with therapeutic failure.

Critical illness polyneuromyopathy in a child with severe demyelinating myelitis.

We report a child presenting with severe demyelinating myelitis complicated with critical illness polyneuropathy. This previously healthy 8-month-old boy presented with acute superior limb weakness, absent tendon reflexes, and respiratory failure. Spinal magnetic resonance imaging showed an extensive cervical demyelinating lesion. Spinal cord trauma was suspected and high doses of dexamethasone were administered. Electromyography and nerve conduction studies showed absence of compound muscle action potentials and sural nerve sensory action potential, which was suggestive of a severe Guillain-Barré syndrome. However, intravenous immunoglobulins did not induce any improvement. Afterward, sural nerve biopsy showed a mild neuropathy, but muscle biopsy revealed abnormalities compatible with severe critical illness myopathy. After 5 months of evolution without improvement, the patient died following withdrawal of life support therapy. This case highlights the possible occurrence of critical illness polyneuromyopathy when treatment with corticosteroids are used in patients with acute demyelinating myelitis.

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.

Fluid balance of pediatric hematopoietic stem cell transplant recipients and intensive care unit admission.

Fluid administration is essential in patients undergoing hematopoietic stem cell transplant (HSCT). Admission to pediatric intensive care unit (PICU) is required for 11-29% of pediatric HSCT recipients and is associated with high mortality. The objective of this study was to determine if a positive fluid balance acquired during the HSCT procedure is a risk factor for PICU admission. The medical records of 87 consecutive children who underwent a first HSCT were reviewed retrospectively for the following periods: from admission for HSCT to PICU admission for the first group (PICU group), and from admission for HSCT to hospital discharge for the second group (non-PICU group). Fluid balance was determined on the basis of weight gain (WG) and fluid overload (FO). PICU group consisted of 19 patients (21.8%). Among these, 13 (68.4%) developed>or=10% WG prior to PICU admission compared with 15 (22.1%) in the non-PICU group (p<0.001). Thirteen patients (68.4%) developed>or=10% FO prior to PICU admission compared with 31 (45.6%) in the non-PICU group (p=0.075). Following multivariate analysis, >or=10% WG (p=0.018) and cardiac dysfunction on admission for HSCT (p=0.036) remained independent risk factors for PICU admission. Smaller children (p=0.033) and patients with a twofold increase in serum creatinine (p=0.026) were at risk of developing>or=10% WG. This study shows that WG is a risk factor for PICU admission in pediatric HSCT recipients. Further research is needed to better understand the pathophysiology of WG in these patients and to determine the impact of WG prevention on PICU admission.

Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy in children.

BACKGROUND: Propofol is commonly used to anesthetize children undergoing esophagogastroduodenoscopy. Opioids are often used in combination with propofol to provide total intravenous anesthesia. Because both propofol and remifentanil are associated with rapid onset and offset, the combination of these two drugs may be particularly useful for procedures of short duration, including esophagogastroduodenoscopy. The authors previously demonstrated that the median effective concentration (C50) of propofol during esophagogastroduodenoscopy in children is 3.55 microg/ml. The purpose of this study was to describe the pharmacodynamic interaction of remifentanil and propofol when used in combination for esophagogastroduodenoscopy in pediatric patients. METHODS: The authors studied 32 children aged between 3 and 10 yr who were scheduled to undergo esophagogastroduodenoscopy. Propofol was administered via a target-controlled infusion system using the STANPUMP software based on a pediatric pharmacokinetic model. Remifentanil was administered as a constant rate infusion of 25, 50, and 100 ng.kg(-1).min(-1) to each of three study groups, respectively. A sigmoid Emax model was developed to describe the interaction of remifentanil and propofol. RESULTS: There was a positive interaction between remifentanil and propofol when used in combination. The concentration of propofol alone associated with 50% probability of no response was 3.7 microg/ml (SE, 0.4 microg/ml), and this was decreased to 2.8 microg/ml (SE, 0.1 microg/ml) when used in combination with remifentanil. CONCLUSION: A remifentanil infusion of 25 ng.kg(-1).min(-1) reduces the concentration of propofol required for adequate anesthesia for esophagogastroduodenoscopy from 3.7 to 2.8 microg/ml. Increasing the remifentanil infusion yields minimal additional decrease in propofol concentration and may increase the risk of side effects.