Severe Immune-Related Enteritis after In Utero Exposure to Pembrolizumab.

Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarrhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant's condition was successfully treated with prednisolone and infliximab.

How often do we perform painful and stressful procedures in the paediatric intensive care unit? A prospective observational study.

BACKGROUND: Adequate analgesia and sedation is crucial in critical care. There is little knowledge on the extent of painful and stressful procedures on children admitted to a paediatric intensive care unit (PICU) and its analgesic and/or sedative management. OBJECTIVE: The primary objective was to determine the number of painful and stressful procedures per patient per day in our PICU patients, including the numbers of attempts. A secondary objective was to map PICU nurses' perceptions of the painfulness of the included procedures. METHODS: A prospective, single-centre observational cohort study in a tertiary PICU. All patients admitted to the PICU over a 3-month period were eligible. Readmissions, polysomnography patients, and patients without any data have been excluded. The number of painful and stressful procedures was collected daily, and use of analgesics and sedatives was assessed and recorded daily. Twenty-five randomly assigned nurses rated the painfulness of procedures based on their personal experience using a numeric rating scale from 0 to 10. RESULTS: In a 3-month period, a total of 229 patients were included, accounting for 855 patient days. The median number of painful and stressful procedures per patient per day was 11 (interquartile range=5-23). Endotracheal suctioning was the most frequent procedure (45%), followed by oral and nasal suctioning. Arterial and lumbar puncture, peripheral IV cannula insertion, and venipuncture were scored as most painful ranging from 3 to 10. Procedural analgesia or sedation was often not used during these most painful procedures. CONCLUSIONS: Mechanically ventilated patients undergo more than twice as many painful procedures than non-ventilated patients, as endotracheal suctioning accounts for almost half of all. Nurses regarded skin-breaking procedures most painful; however, these were rarely treated by procedural analgosedation and only covered in the minority of cases by adequate background analgosedation.

Delirium in Critically Ill Children: An International Point Prevalence Study.

OBJECTIVES: To determine prevalence of delirium in critically ill children and explore associated risk factors. DESIGN: Multi-institutional point prevalence study. SETTING: Twenty-five pediatric critical care units in the United States, the Netherlands, New Zealand, Australia, and Saudi Arabia. PATIENTS: All children admitted to the pediatric critical care units on designated study days (n = 994). INTERVENTION: Children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the bedside nurse. Demographic and treatment-related variables were collected. MEASUREMENTS AND MAIN RESULTS: Primary study outcome measure was prevalence of delirium. In 159 children, a final determination of mental status could not be ascertained. Of the 835 remaining subjects, 25% screened positive for delirium, 13% were classified as comatose, and 62% were delirium-free and coma-free. Delirium prevalence rates varied significantly with reason for ICU admission, with highest delirium rates found in children admitted with an infectious or inflammatory disorder. For children who were in the PICU for 6 or more days, delirium prevalence rate was 38%. In a multivariate model, risk factors independently associated with development of delirium included age less than 2 years, mechanical ventilation, benzodiazepines, narcotics, use of physical restraints, and exposure to vasopressors and antiepileptics. CONCLUSIONS: Delirium is a prevalent complication of critical illness in children, with identifiable risk factors. Further multi-institutional, longitudinal studies are required to investigate effect of delirium on long-term outcomes and possible preventive and treatment measures. Universal delirium screening is practical and can be implemented in pediatric critical care units.

Pharmacological sedation management in the paediatric intensive care unit.

OBJECTIVE: This review addresses sedation management on paediatric intensive care units and possible gaps in the knowledge of optimal sedation strategies. We present an overview of the commonly used sedatives and their pharmacokinetic and pharmacodynamic considerations in children, as well as the ongoing studies in this field. Also, sedation guidelines and current sedation strategies and assessment methods are addressed. KEY FINDINGS: This review shows that evidence and pharmacokinetic data are scarce, but fortunately, there is an active research scene with promising new PK and PD data of sedatives in children using new study designs with application of advanced laboratory methods and modelling. The lack of evidence is increasingly being recognized by authorities and legislative offices such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). CONCLUSION: The population in question is very heterogeneous and this overview can aid clinicians and researchers in moving from practice-based sedation management towards more evidence- or model-based practice. Still, paediatric sedation management can be improved in other ways than pharmacology only, so future research should aim on sedation assessment and implementation strategies of protocolized sedation as well.

Paracetamol and morphine for infant and neonatal pain; still a long way to go?

INTRODUCTION: Pharmacologic pain management in newborns and infants is often based on limited scientific data. To close the knowledge gap, drug-related research in this population is increasingly supported by the authorities, but remains very challenging. This review summarizes the challenges of analgesic studies in newborns and infants on morphine and paracetamol (acetaminophen). Areas covered: Aspects such as the definition and multimodal character of pain are reflected to newborn infants. Specific problems addressed include defining pharmacodynamic endpoints, performing clinical trials in this population and assessing developmental changes in both pharmacokinetics and pharmacodynamics. Expert commentary: Neonatal and infant pain management research faces two major challenges: lack of clear biomarkers and very heterogeneous pharmacokinetics and pharmacodynamics of analgesics. There is a clear call for integral research addressing the multimodality of pain in this population and further developing population pharmacokinetic models towards physiology-based models.

Quality and clinical supply considerations of Paediatric Investigation Plans for IV preparations-A case study with the FP7 CloSed project.

A Paediatric Investigation Plan (PIP) is a development plan that aims to ensure that sufficient data are obtained through studies in paediatrics to support the generation of marketing authorisation of medicines for children. This paper highlights some practical considerations and challenges with respect to PIP submissions and paediatric clinical trials during the pharmaceutical development phase, using the FP7-funded Clonidine for Sedation of Paediatric Patients in the Intensive Care Unit (CloSed) project as a case study. Examples discussed include challenges and considerations regarding formulation development, blinding and randomisation, product labelling and shipment and clinical trial requirements versus requirements for marketing authorisation. A significant quantity of information is required for PIP submissions and it is hoped that future applicants may benefit from an insight into some critical considerations and challenges faced in the CloSed project.

Cardiovascular risk assessment in haemophilia patients.

Haemophilia patients have a reduced cardiovascular mortality, which may be the result of a lifelong deficiency of factor VIII or IX. On the other hand, the prevalence of risk factors may differ in these chronically ill patients compared to the general population. The prevalence of risk factors and expected risk of cardiovascular disease was compared in haemophilia patients and healthy controls. In adult haemophilia A and B patients, body mass index, blood pressure, cholesterol levels and fasting glucose levels were measured and compared to healthy age-matched males. The expected risk of mortality due to cardiovascular disease was calculated using a European risk prediction algorithm (SCORE). A total of 100 haemophilia A and B patients and 200 healthy controls were analysed. The mean age of the patients was 47 years (range 18-83). The number of haemophiliacs with hyperglycaemia (24%) and hypertension (51%) was higher than in the controls (p-values 0.001 and 0.03, respectively). The mean low-density lipoprotein (LDL) cholesterol level in cases was lower than the controls (3.02 mM (0.69-6.57) and 3.60 mM (1.68-5.95), respectively, p < 0.001). Fewer cases had increased LDL levels (p=0.045). No difference was found in the 10-year cardiovascular mortality risk >10% between cases and controls (12% and 7%, respectively, p = 0.18). The prevalence of risk factors and expected risk of cardiovascular disease in haemophilia patients is comparable to the general population. This strengthens the hypothesis that hypocoagulability may reduce cardiovascular mortality in haemophilia patients.