Alicja Bartkowska-Śniatkowska

Assessing circadian rhythms during prolonged midazolam infusion in the pediatric intensive care unit (PICU) children

BACKGROUND This study evaluates possible circadian rhythms during prolonged midazolam infusion in 27 pediatric intensive care unit (PICU) children under mechanical ventilation. METHODS Blood samples for midazolam and 1-OH-midazolam assay were collected throughout the infusion at different times of the day. The blood pressure, heart rate and body temperature were recorded every hour for the rhythms analysis. Population nonlinear mixed-effect modeling with NONMEM was used for data analysis. RESULTS A two-compartment model for midazolam pharmacokinetics and a one-compartment model for midazolam metabolite adequately described the data. The 24 h profiles of all monitored physiological parameters were greatly disturbed/abolished in comparison with the well-known 24 h rhythmic patterns in healthy subjects. There was no significant circadian rhythm detected with respect to midazolam pharmacokinetics, its active metabolite pharmacokinetics and all monitored parameters. CONCLUSIONS We concluded that the light-dark cycle did not influence midazolam pharmacokinetics in intensive care units children. Also, endogenous rhythms in critically ill and sedated children are severely disturbed and desynchronized. Our results confirmed that it is necessary to adjust the dose of midazolam to the patients body weight. The low value of midazolam clearances observed in our study was probably caused by mechanical ventilation, which was shown to decrease the cardiac output.

Pharmacokinetics of sufentanil during long‐term infusion in critically ill pediatric patients

The aim of this study was to develop a population pharmacokinetic model of sufentanil and to assess the influence of covariates in critically ill children admitted to a pediatric intensive care unit. After institutional approval, 41 children were enrolled in the study. Blood samples for pharmacokinetic (PK) assessment were collected from routinely placed arterial catheters during and after discontinuation of infusion. Population nonlinear mixed‐effects modeling was performed using NONMEM. A 2‐compartment model described sufentanil PK sufficiently. Typical values of the central and peripheral volume of distribution and the metabolic and intercompartmental clearance for a theoretical patient weighing 70 kg were VC = 7.90 l, VT = 481 L, Cl = 45.3 L/h, and Q = 38.3 L/h, respectively. High interindividual variability of all PK parameters was noted. Allometric/isometric principles to scale sufentanil PK revealed that to achieve the same steady‐state sufentanil concentrations in plasma for pediatric patients of different body weights, the infusion rate should follow the formula (infusion rate for a 70‐kg adult patient, μg/h) × (body weight/70 kg)0.75. Severity of illness described by PRISM score, the monitored physiological and laboratory parameters, and coadministered drugs such as vasopressors were not found to be significant covariates.

Do we really know the pharmacodynamics of anaesthetics used in newborns, infants and children? A review of the experimental and clinical data on neurodegeneration.

The practices of anaesthesiology and intensive therapy are difficult to imagine without sedation or general anaesthesia, regardless of whether the patient is a newborn, baby, child or adult. The relevant concerns for children are distinct from those for adults, primarily due to the effects of anatomical, physiological and pharmacokinetic-pharmacodynamic (PK/PD) differences, which become increasingly important in the brains of children as they develop. The process of central nervous system maturation in humans lasts for years, but its greatest activity (myelination and synaptogenesis) occurs during the fetal period and the first two years of life. Many experimental studies have demonstrated that exposure to anaesthetic drugs during this period can induce neurodegenerative changes in the central nervous systems of animals. The extrapolation of these results directly to humans must be performed with great caution, but anaesthesiologists around the world must begin to debate the safety of general anaesthesia in humans. Prospective trials should continue being carried out, and anaesthesia and surgery, delayed if possible among the smallest patients. The simultaneous use of different anaesthetics with the same potential neurotoxicities should also be avoided, potentially in favour of regional anaesthesia techniques, in this group of patients.

HPLC–MS/MS method for dexmedetomidine quantification with Design of Experiments approach: application to pediatric pharmacokinetic study

AIM The purpose of this work was to develop and validate a rapid and robust LC-MS/MS method for the determination of dexmedetomidine (DEX) in plasma, suitable for analysis of a large number of samples. METHOD Systematic approach, Design of Experiments, was applied to optimize ESI source parameters and to evaluate method robustness, therefore, a rapid, stable and cost-effective assay was developed. The method was validated according to US FDA guidelines. LLOQ was determined at 5 pg/ml. The assay was linear over the examined concentration range (5-2500 pg/ml), Results: Experimental design approach was applied for optimization of ESI source parameters and evaluation of method robustness. The method was validated according to the US FDA guidelines. LLOQ was determined at 5 pg/ml. The assay was linear over the examined concentration range (R2 > 0.98). The accuracies, intra- and interday precisions were less than 15%. The stability data confirmed reliable behavior of DEX under tested conditions. CONCLUSION Application of Design of Experiments approach allowed for fast and efficient analytical method development and validation as well as for reduced usage of chemicals necessary for regular method optimization. The proposed technique was applied to determination of DEX pharmacokinetics in pediatric patients undergoing long-term sedation in the intensive care unit.

Pharmacokinetics and pharmacodynamics of propofol in children undergoing different types of surgeries

BACKGROUND Propofol is a commonly used agent in total intravenous anesthesia (TIVA). However, the link between its pharmacokinetics and pharmacodynamics has not been fully characterized in children yet. Our aim was to determine the quantitative relationship between the venous plasma concentration and bispectral index (BIS) effect in a heterogeneous group of pediatric patients undergoing various surgical procedures (ASA status I-III). METHODS Nine male and nine female patients were anesthetized with propofol-fentanyl TIVA. Sparse venous samples for propofol concentrations assay and dense BIS measurements were collected during and after the end of infusion. Nonlinear mixed-effect modeling in NONMEM was used for data analysis. RESULTS A three-compartment model was linked with a classical Emax model through a biophase compartment to describe the available data. All clearance and volume terms were allometrically scaled to account for the body mass difference among the patients under study. A typical patient had their PK parameters observed within the range of literature values for children. The pharmacodynamic parameters were highly variable. The EC50 of 2.80 mg/L and the biophase distribution rate constant of 3.33 min(-1) were found for a typical patient. CONCLUSIONS The BIS values in children are highly correlated with the propofol effect compartment concentrations according to the classical Emax concentration-response relationship. Children had slightly lower sensitivity to propofol and slightly higher clearance, as compared with the adult data available in literature. The intra-patient variations in the BIS require the anesthesiologists attention in using BIS values alone to evaluate the depth of anesthesia in children.

Stanowisko Sekcji Pediatrycznej Polskiego Towarzystwa Anestezjologii i Intensywnej Terapii w sprawie znieczulenia ogólnego dzieci do 3. roku życia

1Department of Anaesthesiology and Intensive Therapy, Children`s Memorial Health Institute in Warsaw, Poland 2Department of Paediatric Anaesthesiology and Intensive Therapy, Karol Marcinkowski University of Medical Sciences in Poznan, Poland 3Department of Paediatric Anaesthesiology and Intensive Therapy, University Hospital in Wroclaw, Poland 4Department of Anaesthesiology and Intensive Therapy, University Children Hospital in Cracow-Prokocim, Poland 5Department of Intensive Therapy and Anaesthesiology, Medical University in Łodz 6Department of Paediatric and neonatal Anaesthesiology and Intensive Therapy, Regional Medical Centre in Opole, Poland 7Department of Anaesthesiology, Intensive Therapy and Post-operative Care, University Children Hospital in Warsaw, Poland

Assessment of the Usefulness of Multiplex Real-Time PCR Tests in the Diagnostic and Therapeutic Process of Pneumonia in Hospitalized Children: A Single-Center Experience

The aim of the study was assessment of the usefulness of multiplex real-time PCR tests in the diagnostic and therapeutic process in children hospitalized due to pneumonia and burdened with comorbidities. Methods. The study group included 97 children hospitalized due to pneumonia at the Karol Jonscher Teaching Hospital in Poznań, in whom multiplex real-time PCR tests (FTD respiratory pathogens 33; fast-track diagnostics) were used. Results. Positive test results of the test were achieved in 74 patients (76.3%). The average age in the group was 56 months. Viruses were detected in 61 samples (82% of all positive results); bacterial factors were found in 29 samples (39% of all positive results). The presence of comorbidities was established in 90 children (92.78%). On the basis of the obtained results, 5 groups of patients were established: viral etiology of infection, 34 patients; bacterial etiology, 7 patients; mixed etiology, 23 patients; pneumocystis, 9 patients; and no etiology diagnosed, 24 patients. Conclusions. Our analysis demonstrated that the participation of viruses in causing severe lung infections is significant in children with comorbidities. Multiplex real-time PCR tests proved to be more useful in establishing the etiology of pneumonia in hospitalized children than the traditional microbiological examinations.

Cytomegalovirus pneumonia as the first manifestation of severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) is characterized by the absence of functional T lymphocytes and impairment of adaptive immunity. While heterogeneity of the genetic background in SCID leads to the variability of immune phenotypes, most of affected newborns appear healthy but within the first few months they develop life-threatening opportunistic respiratory or gastrointestinal tract infections. The objective of the study was to define the presenting features and etiology of infections in children with SCID. We retrospectively reviewed five children in whom the diagnosis of SCID had been established in our pediatric immunology clinic over the last 10-year period. A viral respiratory tract infection was the first manifestation of SCID in all the children studied. Cytomegalovirus (CMV) pneumonia was recognized in as many as 4 cases and coronavirus pulmonary infection was diagnosed in one case, whereas Pneumocystis jiroveci was identified as a co-pathogen in one CMV-infected patient. Severe combined immunodeficiency is a pediatric emergency condition and given the significant impact of pulmonary CMV infection in SCID children, establishing an accurate etiological diagnosis is of essential importance in instituting the specific treatment and improving the outcome.

Flip‐Flop Phenomenon in Epidural Sufentanil Pharmacokinetics: A Population Study in Children and Infants

The aims of this study were to develop a population pharmacokinetic model of sufentanil coadministered with 0.2% ropivacaine as an epidural infusion in infants and describe the sufentanil absorption profile from epidural space. Data from 2 previously published studies were merged for analysis—20 infants aged 3–36 months receiving sufentanil as an epidural infusion and 41 children 0–17 years old receiving sufentanil as a long‐term intravenous infusion. A population nonlinear mixed‐effects model was built in NONMEM. Sufentanil pharmacokinetics were described by a 2‐compartment model with first‐order absorption. The effect of body size on all volume and clearance parameters was included in the model according to allometric scaling with theoretical exponents. The maturation process of metabolic clearance was described by the Hill model. During the model‐building process the population was divided into 2 fractions with different typical values of metabolic clearance (CL1 and CL2). The typical values of systemic clearance scaled to a 70‐kg patient for the 2 subpopulations were CL1 = 52.6 L/h and CL2 = 158 L/h. The parameters of the Hill function were 54.9 weeks for the postmenstrual age of 50% clearance maturation and 0.802 for the Hill coefficient. The typical values of distribution clearance and volumes of the central and peripheral compartments for a patient with a weight of 70 kg were Q = 40.5 L/h, VC = 7.63 L, and VT = 473 L, respectively. The value of the absorption rate constant from the epidural space was 0.0459/h, which suggests flip‐flop pharmacokinetics of sufentanil after epidural administration.

Endovascular Treatment of an Adolescent Patient with a Ruptured Intracranial Aneurysm – Case Report and Review of Literature

Summary Background The occurence of aneurysms in young patients, under 18 years of age, is estimated at 0.5–2% of all diagnosed aneurysms. Case Report We reported on a case of a 16-year-old patient with subarachnoid hemorrhage diagnosed due to a ruptured cerebral vessel aneurysm. The angio-CT revealed an aneurysm of the middle cerebral artery, in its distal branch. An ad hoc coil embolization was performed with angiographic success. After 6 months following the ictus, the patient underwent a control angiography which confirmed total occlusion of the aneurysm with no residual inflow. Clinical examination revealed no neurological deficits and the patient was rated 0 in mRS (modified Rankin Scale). Conclusions In experienced departments of interventional neuroradiology the endovascular treatment should be the treatment of choice.