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Aim: This study aimed to compare outcomes post-admission to a Swedish paediatric intensive care unit (PICU) in children with complex chronic conditions (CCC) and without CCC., Methods: In this observational registry-based study, consecutive admissions to the Astrid Lindgren Children's Hospital PICU from 1 January 2008 to 31 December 2016 were analysed. Data on demographics, predicted death rates (PDR), admission diagnoses and causes of death were collected. Mortality was recorded up to 15 years after admission and compared between groups., Results: Patients with CCC constituted 64.6% (n = 3026) of PICU admissions and 83.5% (n = 111) of PICU deaths. The crude mortality rate in PICU was 2.84% overall. CCC-patients were 2.83 times more likely to die in PICU compared to non-CCC (OR 2.83; 95% CI: 1.78-4.49). Mortality increased in the CCC-cohort up to 5 years after PICU discharge, while non-CCC patients generally survived if they survived in PICU. Of the patients who died in PICU, the median PDR was 22.9% for CCC-patients and 66.5% in the non-CCC cohort., Conclusion: Children with CCC accounted for most admissions and deaths in PICU. Despite lower severity of illness scores upon admission, CCC patients were nearly three times more likely to die in PICU compared to non-CCC patients., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: The shift of treatment of paediatric cancer patients to include more care at home puts a lot of pressure on health care professionals (HCPs) to prepare and train parents on safe and correct drug handling at home. Parents must take in and understand the information presented to them while coping with their own fear related to their child's cancer diagnosis. In Sweden, parents are expected to handle and manipulate oral anticancer drugs (OADs) in the home setting. There is however a lack of a standardized method to inform and educate parents on how to handle OADs in a correct way at home., Aim: To describe parents' experiences of handling OADs at home after participating in an educational intervention., Method: Educational intervention in the present study aimed to improve parents' knowledge in key concepts that is, handling OADs at home by using information presented in different forms. Fifteen parents to 12 children with cancer were recruited from a paediatric oncology ward in Sweden to participate in an interview. The interviews were transcribed verbatim and subjected to qualitative content analysis., Results: Parents' experiences are presented in categories: Relieved stress, Awareness of own exposure, Facilitated my everyday life, Parents need continued support individually. The educational intervention resulted in both positive and negative feelings, increased awareness of drug exposure and correct drug handling at home. Practical training and information presented in different ways facilitated the process of drug handling. To handle the drug correctly at home parents requested to be trained and informed in the beginning of their child's oral drug treatment. In addition, parents requested to be individually approached by HCP to get answers to questions and concerns., Conclusions: This educational intervention study shows promising results for the method used by HCPs to inform and educate parents on complicated topics such as handling OADs at home., (© 2024 The Author(s). Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.)

Aim: Studies on frequencies of manipulated medicines in paediatric care are common, but there is little knowledge of experiences of pharmacists and registered nurses in this area. The aim of this study was to explore registered nurses' and pharmacists' reasoning in the manipulation of medicines to paediatric inpatients., Methods: Semistructured interviews with twelve registered nurses and seven pharmacists were performed at a Swedish paediatric university hospital. The interviews were transcribed verbatim and analysed using content analysis., Results: Four major categories emerged from the analysis of the interviews: medicines management, knowledge, consulting others and organisation. Medicines management involved the process of drug handling, which is prescribing, reconstitution or manipulation and administration. Knowledge concerned both the knowledge base and how healthcare personnel seek information. Consulting others involved colleagues, registered nurses and pharmacists, between registered nurses, pharmacists and physicians and between registered nurses, pharmacists and caregivers. Organisation covered documentation, time and working environment., Conclusion: Both pharmacists and registered nurses stated that manipulation of medicines to paediatric patients was often necessary but felt unsafe due to lack of supporting guidelines. Pharmacists were natural members of the ward team, contributing with specific knowledge about medicines and formulations., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Lack of child-friendly dosage forms and strengths often leads to manipulation of medicines at hospital units or by caregivers in the home setting. One alternative to manipulating dosage forms is the use of extemporaneous preparations. In Sweden, these are produced according to good manufacturing practice by a few extemporaneous pharmacies., Objectives: To compare frequencies of patients administered extemporaneous preparations in two separate years, 10 years apart., Methods: This registry-based study describes and compares the frequency of extemporaneous oral preparations administered to paediatric patients in 2009 and 2019 at a Swedish university hospital.The study included 117 023 oral administrations (to 4905 patients) and 128 638 oral administrations (to 4718 patients) from 2009 and 2019, respectively., Results: The frequency of inpatients administered one or more extemporaneous preparations increased from 22% in 2009 to 40% in 2019 (p<0.0001). The increase was observed in all age groups. The use of some active pharmaceutical ingredients increased (eg, captopril, clonidine, hydrocortisone, melatonin and propranolol), and some active pharmaceutical ingredients decreased between the study years (eg, midazolam and sildenafil)., Conclusions: The introduction of new authorised products has decreased the need for manipulation or extemporaneous preparations in some therapeutic groups. There remains, however, a pronounced lack of commercially available child-friendly dosage forms and suitable strengths enabling safe administration of medicines to children, indicated by the large percentage of patients receiving at least one extemporaneous preparation., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Alpha-1-acid glycoprotein is an acute-phase protein with a high affinity for amide local anesthetics. Compared to adults, neonates have lower concentrations of this glycoprotein in plasma, and are therefore at higher risk of developing local anesthetic toxicity. Alpha-1-acid glycoprotein concentrations rise in adults after surgery as a response to stress as well as in inflammatory conditions. Previous studies have shown that concentrations of alpha-1-acid-glycoprotein in neonates vary postpartum, influenced by gestational age and mode of delivery., Aim: This study aims to determine the concentrations of alpha-1-acid glycoprotein pre- and postoperatively in neonates undergoing major surgery. This information is important for determining safe and effective dosage of local anesthetic in this vulnerable group of patients., Methods: In this prospective observational study, 25 neonates (median 3 days of age) undergoing major surgery were included. Blood sampling was performed preoperatively and at four occasions postoperatively. Alpha-1-acid-glycoprotein plasma concentrations were analyzed using an immunoturbidimetric assay. Mann-Whitney U test, Kruskal-Wallis and Spearman ranking correlation test were used for the statistical analysis., Results: Higher plasma concentrations of alpha-1-acid-glycoprotein were found 48 h postoperatively compared to preoperatively [median (inter-quartile range) 0.815 g L -1 (0.663-0.983 g L -1 ) vs. 0.300 g L -1 (0.205-0.480 g L -1 p < 0.001)], respectively. It was not possible to detect any influence of sex, postnatal age, gestational age, or delivery mode on alpha-1-acid-glycoprotein concentrations in our data., Conclusions: Alpha-1-acid-glycoprotein concentrations increase in neonates as a response to surgery regardless of gestational age, sex, or mode of delivery., (© 2023 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd.)

Background: Long term treatment of pediatric patients with oral anticancer drugs (OADs) requires the parents/caregivers to prepare the drug at home. The handling procedures in the home setting are, however, not regulated by Swedish law and the parents are often left without guidance on how to handle OADs in a safe way., Aim: The aim of this study was to increase understanding of how OADs are handled by parents/caregivers in the home setting before and after an intervention., Methods: Parents of pediatric cancer patients were observed and videotaped during their handling of OADs in the home setting before and after the intervention. During the intervention, the parents were provided with written instructions, movie clips and practical training on handling the OADs. Four checklists were used to compare and score the four handling procedures (measuring an oral suspension, cutting tablets, dissolving tablets, and opening capsules) for each parent before and after the intervention., Results: The intervention significantly improved the OAD handling procedures among the studied parents. The median score for correct handling was 19% (IQR: 3.6 to 30%) before the intervention and 89.5% (IQR: 71.5 to 94.5%) after the intervention (p < 0.0001)., Conclusions: An intervention comprising practical training and information presented in different forms improved the handling of OADs at home by parents. There is an urgent need to implement this method in all oncology centers in Sweden, educate HCPs to standardize the presentation of information. There is also a great need to provide parents with age-appropriate oral drug formulations from the local hospital pharmacies in Sweden.

When reporting individual drug concentrations or proper pharmacokinetic data, it is important to adequately report the circumstances associated with sampling, storing, analysis methodology and pharmacokinetic modelling. If this is not done in sufficient detail it will be impossible to properly evaluate the validity of the results. The present text represents a suggested approach on what to report when you are contemplating to submit a manuscript to regional anesthesia and pain medicine, this to achieve relevant standards in this context., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Critically ill Covid-19 patients are likely to develop the sequence of acute pulmonary hypertension (aPH), right ventricular strain, and eventually right ventricular failure due to currently known pathophysiology (endothelial inflammation plus thrombo-embolism) that promotes increased pulmonary vascular resistance and pulmonary artery pressure. Furthermore, an in-hospital trans-thoracic echocardiography (TTE) diagnosis of aPH is associated with a substantially increased risk of early mortality. The aim of this retrospective observational follow-up study was to explore the mortality during the 1-24-month period following the TTE diagnosis of aPH in the intensive care unit (ICU)., Methods: A previously reported cohort of 67 ICU-treated Covid-19 patients underwent an electronic medical chart-based follow-up 24 months after the ICU TTE. Apart from the influence of aPH versus non-aPH on mortality, several TTE parameters were analyzed by the Kaplan-Meier survival plot technique (K-M). The influence of biomarkers for heart failure (NTproBNP) and myocardial injury (Troponin-T), taken at the time of the ICU TTE investigation, was analyzed using receiver-operator characteristics curve (ROC) analysis., Results: The overall mortality at the 24-month follow-up was 61.5% and 12.8% in group aPH and group non-aPH, respectively. An increased relative mortality risk continued to be present in aPH patients (14.3%) compared to non-aPH patients (5.6%) during the 1-24-month period. The easily determined parameter of a tricuspid valve regurgitation, allowing a measurement of a systolic pulmonary artery pressure (regardless of magnitude), was associated with a similar K-M outcome as the generally accepted diagnostic criteria for aPH (systolic pulmonary artery pressure >35 mmHg). The biomarker values of NTproBNP and Troponin-T at the time of the TTE did not result in any clinically useful ROC analysis data., Conclusion: The mortality risk was increased up to 24 months after the initial examination in ICU-treated Covid-19 patients with a TTE diagnosis of aPH, compared to non-aPH patients. Certain individual TTE parameters were able to discriminate 24-month risk of morality., (© 2022 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Aim: The aim of this study was to describe the experiences of parents handling oral anticancer drugs in a home setting., Methods: Parents of children with cancer were recruited from a paediatric oncology ward in Sweden to participate in an interview. The interviews were transcribed verbatim and subjected to qualitative content analysis., Results: We found the following categories and subcategories: parents' views on the provided information-lack of, too little or contradictory information, and parents' preferences for information delivery; safety over time; correct drug dose; and drug administration. As time passed, most parents adapted to their child's illness, felt safer and found it easier to take in and process any given information. Parents preferred information in different formats (written, movie clips and orally) and in their mother tongue. Many parents were aware of the importance of giving an accurate dose to their child and described the process of drug administration as overwhelming., Conclusion: Parents need to be provided with accurate, timely, nonconflicting and repeated information-in different forms and in their mother tongue-on how to handle oral anticancer drugs at home., (© 2022 The Authors. Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.)

This is a registry-based study with the aim of describing and comparing the frequency of manipulations of solid oral and rectal medicines in 2009 and 2019 at inpatient units and an emergency department in a paediatric hospital within a Swedish university hospital. All patients aged 1 month−18 years with oral or rectal administrations were included. In total, 140,791 oral and rectal administrations were included in 2009, and 167,945 oral and rectal administrations were included in 2019. The frequency of patients receiving at least one manipulated oral medicine decreased between the study years, both in inpatient units and in the emergency department (from 19% to 17%, p = 0.0029 and from 11% to 5%, p < 0.0001, respectively). The frequency of patients receiving a manipulated rectal medicine also decreased between the study years, both in inpatient units and in the emergency department (from 22% to 10%, p < 0.0001 and from 35% to 7% 2019, p < 0.0001, respectively). The results show a decrease in the manipulation of both oral and rectal medicines to paediatric patients in 2019 compared to 2009. Even though this implies a safer practice, there is still a pronounced lack of child-friendly dosage forms and suitable strengths enabling the safe administration of medicines to sick children.

Objective/aim: The aim of the study was to quantify excess mortality in children after admission to a Pediatric Intensive Care Unit (PICU), compared to the age and sex matched general Swedish population., Design: Single-center, retrospective cohort study., Setting: Registry study of hospital registers, a national population register and Statistics Sweden., Patients: Children admitted to a tertiary PICU in Sweden in 2008-2016., Interventions: None., Main Results: In total, 6,487 admissions (4,682 patients) were included in the study. During the study period 444 patients died. Median follow-up time for the entire PICU cohort was 7.2 years (IQR 5.0-9.9 years). Patients were divided into four different age groups (0-28 d, > 28 d -1 yr, > 1-4 yr, and > 4 yr) and four different risk stratification groups [Predicted Death Rate (PDR) intervals: 0-10%, > 10-25%, > 25-50%, and > 50%] at admission. Readmission was seen in 929 (19.8%) patients. The Standardized Mortality Ratios (SMRs) were calculated using the matched Swedish population as a reference group. The SMR for the entire study group was 49.8 (95% CI: 44.8-55.4). For patients with repeated PICU admissions SMR was 108.0 (95% CI: 91.9-126.9), and after four years 33.9 (95% CI: 23.9-48.0). Patients with a single admission had a SMR of 35.2 (95% CI: 30.5-40.6), and after four years 11.0 (95% CI: 7.0-17.6). The highest SMRs were seen in readmitted children with oncology/hematology (SMR = 358) and neurologic (SMR = 192) diagnosis. Children aged >1-4 years showed the highest SMR (325). In PDR group 0-10% children with repeated PICU admissions (n = 798), had a SMR of 100., Conclusion: Compared to the matched Swedish population, SMRs were greatly elevated up to four years after PICU admission, declining from over 100 to 33 for patients with repeated PICU admissions, and from 35 to 11 for patients with a single PICU admission., Competing Interests: The authors have declared that no competing interests exist.

Background: Survival rate increases for preterm infants, but long-term neurodevelopmental outcome predictors are lacking. Our primary aim was to determine whether a specific proteomic profile in cerebrospinal fluid (CSF) of preterm infants differs from that of term infants and to identify novel biomarkers of neurodevelopmental outcome in preterm infants., Methods: Twenty-seven preterm infants with median gestational age 27 w + 4 d and ten full-term infants were enrolled prospectively. Protein profiling of CSF were performed utilizing an antibody suspension bead array. The relative levels of 178 unique brain derived proteins and inflammatory mediators, selected from the Human Protein Atlas, were measured., Results: The CSF protein profile of preterm infants differed from that of term infants. Increased levels of brain specific proteins that are associated with neurodevelopment and neuroinflammatory pathways made up a distinct protein profile in the preterm infants. The most significant differences were seen in proteins involved in neurodevelopmental regulation and synaptic plasticity, as well as components of the innate immune system. Several proteins correlated with favorable outcome in preterm infants at 18-24 months corrected age. Among the proteins that provided strong predictors of outcome were vascular endothelial growth factor C, Neurocan core protein and seizure protein 6, all highly important in normal brain development., Conclusion: Our data suggest a vulnerability of the preterm brain to postnatal events and that alterations in protein levels may contribute to unfavorable neurodevelopmental outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Leifsdottir, Jost, Siljehav, Thelin, Lassarén, Nilsson, Haraldsson, Eksborg and Herlenius.)

Aim: Perinatal asphyxia, resulting in hypoxic-ischaemic encephalopathy (HIE), has been associated with high mortality rates and severe lifelong neurodevelopmental disabilities. Our aim was to study the association between the proteomic profile in cerebrospinal fluid (CSF) and the degree of HIE and long-term outcomes., Methods: We prospectively enrolled 18-term born infants with HIE and 10-term born controls between 2000 and 2004 from the Karolinska University Hospital. An antibody suspension bead array and FlexMap3D analysis was used to characterise 178 unique brain-derived and inflammation associated proteins in their CSF., Results: Increased CSF concentrations of several brain-specific proteins were observed in the proteome of HIE patients compared with the controls. An upregulation of neuroinflammatory pathways was also noted and this was confirmed by pathway analysis. Principal component analysis revealed a gradient from favourable to unfavourable HIE grades and outcomes. The proteins that provided strong predictors were structural proteins, including myelin basic protein and alpha-II spectrin. The functional proteins included energy-related proteins like neuron-specific enolase and synaptic regulatory proteins. Increased CSF levels of 51 proteins correlated with adverse outcomes in infants with HIE., Conclusion: Brain-specific proteins and neuroinflammatory mediators in CSF may predict HIE degrees and outcomes after perinatal asphyxia., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: The aim of this study was to use Body Surface Area (BSA) data calculated with the Mosteller equation to test potential new equations that estimate BSA using Body Weight (BW) alone in children aged 0-18 years.Mosteller's equation, the golden standard at our hospital, was used to calculate the BSA in infants and children aged 0-18 years using BW and height data from 27,440 hospital visits by 20,635 patients over one year., Methods: The best fit of three nonlinear regression equations (third-order polynomial, Meeh-type, and modified Boyd self-adjusting-type) to a plot of the calculated Mosteller BSA values versus BW was then investigated. The correlation between the BSA values estimated by these equations and the Mosteller BSA values was established by the Spearman rank correlation test. Bias and precision were evaluated as outlined by Sheiner and Beal. Measured and estimated BSA values were compared using the Eksborg plot., Results: The estimated BSA values from all three equations and the BSA values from the Mosteller equation were closely correlated ( P  < .0001). The third-order polynomial and Meeh-type equations overestimated BSA by 0.13% and 0.40%, respectively, while the Boyd self-adjusted-type equation underestimated BSA by 0.060%. For the entire pediatric population, the best fit was obtained with the Meeh-type equation: 99.2% of the Meeh/Mosteller BSA ratios were within the range of 0.9-1.1 when compared with 98.3% and 97.2% for the polynomial and Boyd-type equations, respectively., Conclusion: A single Meeh-type equation can be used to predict the results of Mosteller equation when H is not available with high precision and accuracy in children aged 0-18 years, including term neonates. We now plan to include the results of this study in CPOE systems in Sweden to improve drug dosage in all children., Competing Interests: None., (© 2020 Publishing services provided by Elsevier B.V. on behalf of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.)

Background: Naloxone has a high affinity for the µ-opioid receptor and acts as a competitive antagonist, thus reversing the effects of opioids. Naloxone is often administrated intravenously, but there is a growing interest in the intranasal route in treating patients with opioid overdose, and in reversing effects after therapeutic use of opioids. As administration is painless and no intravenous access is needed, the intranasal route is especially useful in children., Aim: The aim of this study was to investigate the uptake of naloxone 0.4 mg/ml during the first 20 min after administration as a nasal spray in a pediatric population, with special focus on the time to achieve maximum plasma concentration., Methods: Twenty children, 6 months-10 years, were included in the study. The naloxone dose administered was 20 µg/kg, maximum 0.4 mg, divided into repeated doses of 0.1 ml in each nostril. Venous blood samples were collected at 5, 10, and 20 min after the end of administration., Results: All patients had quantifiable concentrations of naloxone in venous blood at 5 min, and within 20 min, peak concentration had been reached in more than half of the children. At 20 min after intranasal administration, the plasma naloxone concentrations were within the range of 2-6 nanogram/ml., Conclusion: This study confirms the clinical experience that the rapid effect of naloxone after intranasal administration in children was reflected in rapid systemic uptake to achieve higher peak plasma concentrations than previously reported in adults., (© 2021 John Wiley & Sons Ltd.)

Background: High-volume (1.5 ml kg -1 ) caudal block in infants results in major reductions of cerebral blood flow velocity (CBFV) and cerebral oxygenation, caused by rostral CSF movement which increases intracranial pressure. The primary aim of this study was to determine the relationship between injected volume and CBFV changes. We hypothesised that this volume-blood flow relationship would have a similar albeit inverted shape to the well-known intracranial pressure volume-pressure curve., Methods: Fifteen subjects, age 0-6 months, mean (range) weight 4.9 (2.1-6.4) kg, were studied. A 1.5 ml kg -1 caudal injection of 0.2% ropivacaine was administered in three phases separated by two pauses. Subjects were randomised into five groups, in whom the pauses were implemented at different pre-set proportions of the total injected volume. Middle cerebral artery Doppler ultrasonography was used for CBFV measurements (V max , peak CBF velocity; V min , lowest CBF velocity; velocity time index). Mean flow velocity, pulsatility index, and resistivity index were calculated, and haemodynamic parameters were recorded., Results: CBFV parameters decreased in all patients. The most affected parameter, V min , was reduced by ∼50% (range 15-68%) compared with baseline. There was a nonlinear relationship between the volume of the first phase injection and the CBFV measurement during the first pause. Across all time points, there was a linear relationship between volume administered and CBFV. Systemic haemodynamic parameters remained stable throughout the study., Conclusions: Injection pauses appear to attenuate adverse CBFV increases during administration of a high-volume caudal block., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of the current study was to investigate how cerebral and splanchnic oxygen saturation (rSO2-C and rSO2-A) in critically ill children transported in air ambulance was affected by flight with cabin pressurization corresponding to ≥ 5000 feet. A second aim was to investigate any differences between cyanotic and non-cyanotic children in relation to cerebral and splanchnic oxygen saturation during flight ≥ 5000 feet. The variability of the cerebral and splanchnic Near Infrared Spectroscopy (NIRS) sensors was evaluated., Design: NIRS was used to measure rSO2-C and rSO2-A during transport of critically ill children in air ambulance. rSO2 data was collected and stored by the NIRS monitor and extracted and analyzed off-line after the transport. Prior to evaluation of the NIRS signals all zero and floor-effect values were removed., Setting: The Pediatric Intensive Care Unit (PICU) at Astrid Lindgren Children's Hospital, Karolinska University Hospital in Stockholm, Sweden., Patients: In total, 44 critically ill children scheduled for inter-hospital transport by a specialized pediatric transport team were included in the study between January 2014 and January 2019 (convenience sampling)., Intervention: No interventions were conducted., Measurements: All study patients were monitored with a cerebral NIRS-sensor placed over the forehead and an abdominal NIRS-sensor placed in the infra-umbilical area for cerebral and splanchnic regional oxygen saturation monitoring, rSO2-C and rSO2-A, respectively., Main Results: Complete rSO2-C and rSO2-A data was obtained in 39 patients. Median age was 12 days. Cyanotic congenital heart malformations were present in 9 patients (23%). In 22 patients (56%) rSO2-C decreased at altitude ≥ 5000 feet and in 24 patients (61%) rSO2-A decreased at altitude ≥ 5000 feet compared to baseline (p<0.0001). In 25 patients (64%) the rSO2-C/rSO2-A ratio was greater at altitude ≥ 5000 feet than at baseline. A ratio ≥ 1 was seen in 77% of patients at altitude ≥ 5000 feet compared to in 67% of patients at baseline., Conclusion: Both cerebral and splanchnic oxygen saturation decreased at altitude ≥ 5000 feet compared to baseline. In most patients, both cyanotic and non-cyanotic, cerebral oxygen saturation was preserved more than splanchnic oxygen saturation., Competing Interests: The authors have declared that no competing interests exist.

Background: During severe respiratory failure, hypoxic pulmonary vasoconstriction (HPV) is partly suppressed, but may still play a role in increasing pulmonary vascular resistance (PVR). Experimental studies suggest that the degree of HPV during severe respiratory failure is dependent on pulmonary oxygen tension (PvO 2 ). Therefore, it has been suggested that increasing PvO 2 by veno-venous extracorporeal membrane oxygenation (V-V ECMO) would adequately reduce PVR in V-V ECMO patients., Objective: Whether increased PvO 2 by V-V ECMO decreases PVR in global alveolar hypoxia., Methods: Nine landrace pigs were ventilated with a mixture of oxygen and nitrogen. After 15 minutes of stable ventilation and hemodynamics, the animals were cannulated for V-V ECMO. Starting with alveolar normoxia, the fraction of inspiratory oxygen (F I O 2 ) was stepwise reduced to establish different degrees of alveolar hypoxia. PvO 2 was increased by V-V ECMO., Results: V-V ECMO decreased PVR (from 5.5 [4.5-7.1] to 3.4 [2.6-3.9] mm Hg L -1  min, P = .006) (median (interquartile range),) during ventilation with F I O 2 of 0.15. At lower F I O 2 , PVR increased; at F I O 2 0.10 to 4.9 [4.2-7.0], P = .036, at F I O 2 0.05 to 6.0 [4.3-8.6], P = .002, and at F I O 2 0 to 5.4 [3.5 - 7.0] mm Hg L -1  min, P = .05., Conclusions: The effect of increased PvO 2 by V-V ECMO on PVR depended highly on the degree of alveolar hypoxia. Our results partly explain why V-V ECMO does not always reduce right ventricular afterload at severe alveolar hypoxia., (© 2020 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Objectives: Loss of vaccine-induced antibodies (Abs) after chemotherapy against paediatric acute lymphoblastic leukaemia (ALL) is common and often necessitates re-immunisation after cessation of treatment. Even so, some ALL survivors fail to mount or to maintain protective Abs. Germinal centres (GCs) are clusters of proliferating B cells in follicles of secondary lymphoid tissues (SLTs) formed during adaptive immune responses and the origins of long-lived memory B and plasma cells that are the source of Abs. Furthermore, productive GC reactions depend on T follicular helper (T FH ) cells. To understand why chemotherapy induces deficits in Ab responses, we examined how SLTs were affected by chemotherapy., Methods: Rhesus macaques were infused with either three cycles of the anthracycline doxorubicin or saline, followed by immunisation with a de novo and booster antigen. Spleen and lymph nodes were removed, and memory B, bulk T and T FH cells were examined., Results: Despite adequate GC morphology, a diminished memory and IgG + B-cell population along with diminished total and booster vaccine-specific IgG-producing memory B cells were noted in the spleens of macaques with past doxorubicin exposure compared to the saline-treated controls ( P  < 0.05). Intact bulk T and T FH cells were found in the SLTs of treated macaques, which displayed higher CD40L upregulation capacity by their splenic CXCR5 + helper T cells ( P  < 0.01). In contrast to the spleen, the immune cell populations studied were comparable between the lymph nodes of both saline- and doxorubicin-treated macaques., Conclusion: Our findings suggest that the splenic memory B-cell subset, compared to its lymph node counterpart, is more severely altered by anthracycline treatment., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Objectives: Data on long-term survival in children after interhospital transport to a PICU are scarce. The main objective was to investigate short- and long-term outcome after acute interhospital transport to a PICU for different age and risk stratification groups. Secondary aims were to investigate whether neonatal patients would have higher mortality and be more resource demanding than older patients., Design: Single-center, retrospective cohort study., Setting: Specialist pediatric transport team and a tertiary PICU in Sweden., Patients: Critically ill children 0-18 years old, acutely transported by a specialist pediatric transport team to a PICU in Sweden (January 1, 2008, to December 31, 2016)., Interventions: None., Measurements and Main Results: A total of 401 acute transport events were included. Overall mortality was 15.7% with a median follow-up time of 3.4 years (range, 0-10.2 yr). Median predicted death rate was 4.9%. There was no mortality during transport. Cumulative mortality almost doubled within the first 6 months after PICU discharge, from 6.5% to 12.0%. Of late deaths, 66.7% occurred in the risk stratification group predicted death rate 0-10%, and 95% suffered from severe comorbidity. There were no deaths after PICU discharge in the neonatal group. Cumulative mortality in multiple transported patients was 36.4%., Conclusions: This is the first report on long-term survival after acute pediatric interhospital transport. For the entire cohort, there was significant mortality after PICU discharge, especially in multiple transported patients. In contrast, survival in the subgroup of neonatal patients was high after PICU discharge.

Higher chloroquine doses can effectively treat up to 93 to 96% of malaria infections caused by Plasmodium falciparum carrying the resistance-conferring chloroquine resistance transporter ( pfcrt ) 76T allele. The tolerability of 50 (double the standard dose) and 70 mg/kg total chloroquine doses were assessed in this study. Fifteen 4- to 8-year-old children with uncomplicated malaria were given 10 mg/kg of chloroquine twice daily for 2 days and 5 mg/kg twice daily on the third day. Fifteen additional children were given 5 mg/kg twice daily for 2 more days. Chloroquine concentrations, blood pressure, electrocardiograms (ECGs), parasite density, and adverse events were assessed until day 28. Both dosages were well tolerated, and symptoms resolved by day 3 in parallel with increasing chloroquine concentrations. The median corrected QT (QTc) interval was 12 to 26 ms higher at expected peak concentrations than at day 0 ( P  < 0.001). Pfcrt 76T was associated with delayed parasite clearance. Day 28 clinical and parasitological responses against P. falciparum with pfcrt 76T were 57% (4/7) and 67% (4/6) after treatment with 50 and 70 mg/kg, respectively. Dosages were well tolerated, and no severe cardiac adverse events occurred. The QTc interval increase was similar to that found in adults taking 25 mg/kg of chloroquine. (This study has been registered at ClinicalTrials.gov under identifier NCT01814423.)., (Copyright © 2020 American Society for Microbiology.)

Aim: To investigate whether unnecessary harm could be avoided in children admitted to paediatric intensive care (PICU), we analysed the impact of arterial blood gas on the paediatric index of mortality score2 (PIM2) and the derived predicted death rate (PDR)., Methods: From January 1, 2008 to December 31, 2010, 1793 consecutive admissions, newborn infants to 16 years of age (median 0.71 years) from a single, tertiary PICU in Gothenburg Sweden, were collected. Admission information on arterial oxygen tension (PaO 2 ) and fraction of inspired oxygen (FiO 2 ) was extracted from 990 admissions., Results: There was close agreement between PIM2 score and PDR regardless of whether the PaO 2 /FiO 2 ratio was omitted or not. In the subgroup of admissions with a respiratory admission diagnosis, the inclusion of the PaO 2 /FiO 2 ratio increased the accuracy of the PIM2 score as well as the PDR. The standard mortality ratio was slightly but not significantly overestimated by excluding the PaO 2 /FiO 2 ratio., Conclusion: To avoid unnecessary harm to children admitted to PICU, an arterial blood gas analysis should only be performed if clinically indicated or if the child has a respiratory admission diagnosis. Estimation of the PIM2 score and PDR will not be less accurate by this approach., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: There is a significant long-term burden on survivors after acute respiratory distress syndrome, even 5 years after discharge. This is not well investigated in patients treated with extracorporeal membrane oxygenation. The objective of this study was to describe very-long-term (⩾3 years) disability in lung function and morphology, quality of life, mood disorders, walking capacity, and return to work status in extracorporeal membrane oxygenation survivors., Methods: Single-center retrospective cohort study on long-term survivors treated with extracorporeal membrane oxygenation for respiratory failure between 1995 and 2010 at a tertiary referral center in Sweden. Eligible patients were approached, and those who consented were interviewed and investigated during a day at the hospital., Results: A total of 38 patients were investigated with a median follow-up time of 9.0 years. Quality of life was reduced in several Short form 36 (SF-36) subscales and all domains of the St George's Respiratory Questionnaire, similar to previous studies in conventionally managed acute respiratory distress syndrome survivors. A reduced diffusion capacity of carbon monoxide was seen in 47% of patients, and some degree of residual lung parenchymal pathology was seen in 82%. Parenchymal pathology correlated with reductions in quality of life and diffusion capacity. Symptoms of anxiety and depression were seen in 22% and 14%, respectively., Conclusion: A significant long-term burden remains even 3-17 years after extracorporeal membrane oxygenation treatment, similar to conventionally managed acute respiratory distress syndrome survivors. Future prospective studies are needed to elucidate risk factors for these sequelae.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Currently, there is no standardized method to set the support level in neurally adjusted ventilatory assist (NAVA). The primary aim was to explore the feasibility of titrating NAVA to specific diaphragm unloading targets, based on the neuroventilatory efficiency (NVE) index. The secondary outcome was to investigate the effect of reduced diaphragm unloading on distribution of lung ventilation., Methods: This is a randomized crossover study between pressure support and NAVA at different diaphragm unloading at a single neurointensive care unit. Ten adult patients who had started weaning from mechanical ventilation completed the study. Two unloading targets were used: 40 and 60%. The NVE index was used to guide the titration of the assist in NAVA. Electrical impedance tomography data, blood-gas samples, and ventilatory parameters were collected., Results: The median unloading was 43% (interquartile range 32, 60) for 40% unloading target and 60% (interquartile range 47, 69) for 60% unloading target. NAVA with 40% unloading led to more dorsal ventilation (center of ventilation at 55% [51, 56]) compared with pressure support (52% [49, 56]; P = 0.019). No differences were found in oxygenation, CO2, and respiratory parameters. The electrical activity of the diaphragm was higher during NAVA with 40% unloading than in pressure support., Conclusions: In this pilot study, NAVA could be titrated to different diaphragm unloading levels based on the NVE index. Less unloading was associated with greater diaphragm activity and improved ventilation of the dependent lung regions.

The aim of the present study was to evaluate the performance of regional oxygen saturation (rSO 2 ) monitoring with near infrared spectroscopy (NIRS) during pediatric inter-hospital transports and to optimize processing of the electronically stored data. Cerebral (rSO 2 -C) and abdominal (rSO 2 -A) NIRS sensors were used during transport in air ambulance and connecting ground ambulance. Data were electronically stored by the monitor during transport, extracted and analyzed off-line after the transport. After removal of all zero and floor effect values, the Savitzky-Golay algorithm of data smoothing was applied on the NIRS-signal. The second order of smoothing polynomial was used and the optimal number of neighboring points for the smoothing procedure was evaluated. NIRS-data from 38 pediatric patients was examined. Reliability, defined as measurements without values of 0 or 15%, was acceptable during transport (> 90% of all measurements). There were, however, individual patients with < 90% reliable measurements during transport, while no patient was found to have < 90% reliable measurements in hospital. Satisfactory noise reduction of the signal, without distortion of the underlying information, was achieved when 20-50 neighbors ("window-size") were used. The use of NIRS for measuring rSO 2 in clinical studies during pediatric transport in ground and air-ambulance is feasible but hampered by unreliable values and signal interference. By applying the Savitzky-Golay algorithm, the signal-to-noise ratio was improved and enabled better post-hoc signal evaluation.

Background: Cerebral ischemia generates neuroinflammation that can induce neural cell death. This cohort study assessed whether Fas-ligand (FasL) and interleukin (IL)-6 levels in the cerebrospinal fluid (CSF) after hypoxic-ischemic encephalopathy (HIE) can serve as biomarkers of hypoxic brain injury in neonates., Methods: Term infants (> 37-week gestational age) who were admitted to the neonatal intensive care unit of Karolinska University Hospital in years 2002 to 2004 with perinatal asphyxia were enrolled prospectively. Control infants without brain pathology underwent lumbar puncture for suspected infection. FasL and IL-6 levels were measured in the CSF, by enzyme-linked immunosorbent assays. All patients underwent neurological assessment at 18 months. HIE was classified as mild, moderate, or severe (HIE I-III). Adverse neurological outcome at 18 months was defined as a mental developmental index < 85, deafness, blindness, cerebral palsy, or seizure disorder., Results: Of the 44 HIE patients, 14, 16, and 14 had HIE-I, HIE-II, and HIE-III, respectively. HIE-II and HIE-III patients had higher FasL and IL-6 levels than HIE-I patients and the 20 controls (all p < 0.0001). Patients with adverse outcomes had higher FasL and IL-6 levels than patients with normal outcomes and controls (both p < 0.0001). On receiver-operator curve analyses, FasL and IL-6 (alone and together) were highly predictive of HIE grade and outcome (areas under the curve range 0.86-0.94) and showed high sensitivity (66.7-100%). These biomarkers performed better than cord blood pH (areas under the curve: HIE grade = 0.80, adverse outcomes = 0.86)., Conclusion: CSF biomarkers FasL and IL-6 predicted severity of encephalopathy and long-term outcomes in post-asphyxiated infants better than a standard biomarker.

Objectives: To investigate the presence of cognitive dysfunction and brain lesions in long-term survivors after treatment with extracorporeal membrane oxygenation for severe respiratory failure, and to see whether patients with prolonged hypoxemia were at increased risk., Design: A single-center retrospective cohort study., Setting: Tertiary referral center for extracorporeal membrane oxygenation in Sweden., Patients: Long-term survivors treated between 1995 and July 2009. Seven patients from a previously published study investigated with a similar protocol were included., Interventions: Brain imaging, neurocognitive testing, interview., Measurements and Main Results: Thirty-eight patients (i.e., n = 31 + 7) were enrolled and investigated in median 9.0 years after discharge. Only memory tests were performed in 10 patients, mainly due to a lack of formal education necessary for the test results to be reliable. Median full-scale intelligence quotient, memory index, and executive index were 97, 101, and 104, respectively (normal, 100 ± 15). Cognitive function was not reduced in the group with prolonged hypoxemia. Brain imaging showed cerebrovascular lesions in 14 of 38 patients (37%), most commonly in the group treated with venoarterial extracorporeal membrane oxygenation (7/11, 64%). In this group, memory function and executive function were significantly reduced., Conclusions: Patients treated with extracorporeal membrane oxygenation for respiratory failure may have normal cognitive function years after treatment, if not affected by cerebrovascular lesions. Permissive hypoxemia was not correlated with long-term cognitive dysfunction in the present study. Further prospective studies with minimal loss to follow-up are direly needed to confirm our findings.

Objective: Factors predicting survival over time after pediatric intensive care unit (PICU) admissions are not fully understood. The primary aim of the current study was to investigate whether multiple admissions (MADM) compared to single PICU admissions (SADM) were associated with poor survival over time after being admitted to PICU facilities. Our secondary aim was to investigate if the presence of a complex chronic condition (CCC) would further impair prognosis., Design: A closed cohort of all children up to 16 years of age admitted to the three PICUs in Sweden between 2008 and 2010 was prospectively collected and followed until 2012, providing survival data for at least one but up to four years of follow-up., Setting: Three Swedish tertiary referral centers for pediatric intensive care and extracorporeal membrane oxygenation (ECMO) care were used., Patients: In total, 3,688 Swedish children with 5,019 PICU admissions were included., Interventions: No interventions were conducted., Measurements: An extensive data set was recorded, including up to four-year survival information following first PICU admission. The patients were assigned to seven admission diagnostic groups, which were then divided into SADM or MADM groups. The difference in survival over time and mortality rates (MR) and mortality rate ratios (MRR) were calculated. SADM and MADM groups with and without an existing CCC were formed. The difference in survival over time between groups was calculated., Main Results: A highly significant difference in survival over time was noted between SADM and MADM patients (p<0.0001), which was intensified by the presence of a CCC. MADM patients with a CCC had the worst outcome, while SADM patients without a CCC had the best outcome. MADM patients with no CCC demonstrated decreased survival over time compared to SADM patients with a CCC. Survival over time was statistically worsened for patients with MADM compared to SADM for the following admission diagnostic groups: Cardiovascular, Gastrointestinal/Renal, Respiratory, Neurological, and Miscellaneous. The mortality rate (deaths/patient year of follow-up) during the time of follow-up was 0.023 for SADM and 0.062 for MADM patients. The mortality rate ratio (MRR) between these groups was 2.69., Conclusion: Compared to single admissions, multiple admissions to PICU were associated with a significant decrease in survival over time in some but not all diagnostic groups. Regarding our secondary aim, we found that when the presence of a CCC is factored into the survival analysis, survival over time is further impaired.

Background: Septic shock is associated with high mortality. Aged and multimorbid patients are not always eligible for intensive care units. Norepinephrine is an accepted treatment for hypotension in septic shock. It is unknown whether norepinephrine has a place in treatment outside an intensive care unit and when given peripherally., Objectives: To describe mortality, Acute Physiology And Chronic Health Evaluation (APACHE-II), time to mean arterial pressure >65 mmHg, and adverse events in patients with septic shock receiving norepinephrine peripherally in an intermediate care unit., Methods: From a retrospective chart review of 91 patients with septic shock treated with norepinephrine for hypotension, ward mortality, 30-, 60- and 90-day mortality, standardized mortality ratio (SMR) and adverse events (necrosis and arrhythmia) were analysed. Administration route via peripheral venous catheter or central venous catheter was registered., Results: Median age was 81 (43-96) years and median APACHE-II score was 26 (12-42). Observed ward mortality was 27.5% (SMR 0.443, 95% CI: 0.287-0.654), and 30-day and 90-day mortality were 47.2% and 58.2%, respectively., Conclusions: Elderly patients with septic shock treated with norepinephrine displayed a better survival in the ward and at 30 days than expected. Our retrospective study did not indicate frequent complications when administering norepinephrine via a peripheral venous catheter.

Background: Information transfer to patients is an integral part of modern medicine. Internet-based alternatives represent a new and attractive way for information transfer., Methods: The study used a prospective observer-blinded design. Children (3-12 years) and parents were instructed to get further preoperative information either through an interactive web-based platform, the Anaesthesia-Web, or conventional brochure material until day of outpatient surgery. On the day of surgery, children and parents were separately asked six different questions. The primary end-point was to compare the total question score in children between the two information options (maximum score = 36). Secondary aims were the total question score for parents and the influence of age, sex, and time between the preoperative visit and day of surgery., Results: A total of 125 children were recruited, of which 103 were included in the final analysis (the Anaesthesia-Web group, n = 49; the brochure material group, n = 54). At the predetermined interim analysis, the total question score in children was found to be substantially higher in the Anaesthesia-Web group than in the brochure material group (median score: 27; IQR: 16.5-33 and median score: 19.5; IQR: 11.25-27.75, respectively, P = 0.0076). The median difference in score was 6; 95% CI: 0-9. The total question score in parents was also higher in the Anaesthesia-Web group than in the brochure material group. Increasing child age was associated with a higher total question score in both groups. Sex did not influence the total question score in the Anaesthesia-Web group, whereas girls scored better than boys in the brochure material group., Conclusions: Children in the age range 3-12 years of age as well as their parents do better attain preoperative information from an interactive web-based platform compared to conventional brochure material., (© 2017 John Wiley & Sons Ltd.)

Objective: Extracorporeal membrane oxygenation has been used in patients with severe circulatory or respiratory failure since the 1970s, but the knowledge on long-term survival in this group is scarce. The aim of the present study was to investigate the 10-year survival rates and causes of late death in children treated with extracorporeal membrane oxygenation., Design: Single-center, retrospective cohort study., Setting: Tertiary referral center for extracorporeal life support., Patients: Neonatal and pediatric patients treated with extracorporeal membrane oxygenation from 1987 to December 2013., Interventions: None., Measurements and Main Results: Survival status was obtained from the national Causes of Death registry. Patient background data along with data on survival and causes of death were collected. Survival rates were calculated using the Kaplan-Meier method. Of 400 subjects, 76% survived to discharge. The median follow-up time in survivors was 7.2 years. There was a high mortality rate within the first months after discharge. In the group of patients who survived the first 90 days after treatment, the 10-year survival rates were 93% in neonates and 89% in pediatric patients and were particularly beneficial in patients whose indication for extracorporeal membrane oxygenation was meconium aspiration syndrome, trauma, or infectious diseases. Late deaths were seen in some diagnostic groups, but the Kaplan-Meier curves plateaued over time., Conclusions: Children who survive the first months after treatment with extracorporeal membrane oxygenation have a high long-term survival rate. The prognosis is especially favorable in patients with reversible conditions.

Objective: The use of extracorporeal membrane oxygenation in adults with respiratory failure and sepsis is steadily increasing, but the knowledge on long-term survival in this group is scarce. The aim of the present study was to investigate the 5-year survival rates and causes of late death in this group of patients., Design: Single-center retrospective cohort study., Setting: Karolinska University Hospital, Stockholm, Sweden., Patients: Adult patients treated with extracorporeal membrane oxygenation for respiratory failure and sepsis between the service being established for adults in 1995 and December 2013., Interventions: None., Measurements and Main Results: Survival status was attained from a national Causes of Death registry. Minimal patient background data, along with data on survival and causes of death were collected. Survival rates were calculated using the Kaplan-Meier method. Of 255 subjects, 64% survived to discharge. The median follow-up time in survivors was 4.4 years. There was a high mortality rate within the first months after discharge. In the group of patients who survived the first 90 days after treatment, the 5-year survival rate was 87% and was particularly beneficial in patients treated for infectious diseases (88-100%). Late deaths were seen in most diagnostic groups, but the Kaplan-Meier curves flattened out over time., Conclusions: Extracorporeal membrane oxygenation treatment in adult patients with respiratory failure and sepsis can be lifesaving in appropriately selected patients. For patients who survive the first months after extracorporeal membrane oxygenation treatment, long-term survival seems good, especially in patients treated for infections.

To provide retrospective, descriptive information on patients with cervical necrotizing fasciitis treated at a single center during the years 1998-2014, and to evaluate the outcome of a newly introduced treatment strategy. Retrospective analysis of clinical data obtained from medical records. Mortality, pre-morbidity, severity of illness, primary site of infection, type of bacteria, time parameters. The observed 3-month mortality was 6/59 (10 %). The most common initial foci of the infection were pharyngeal, dental or hypopharyngeal. The most common pathogen was Streptococcus milleri bacteria within the Streptococcus anginosus group (66 % of the cases). Using a combined treatment with early surgical debridement combined with hyperbaric oxygen treatment, it is possible to reduce the mortality rate among patients suffering from cervical necrotizing fasciitis, compared to the expected mortality rate and to previous historical reports. Data indicated that early onset of hyperbaric oxygen treatment may have a positive impact on survival rate, but no identifiable factor was found to prognosticate outcome.

Aim: We compared acute patients admitted to a single paediatric intensive care unit (PICU) following an emergency transfer by a specialist paediatric transport team and by other routes., Methods: This was a retrospective descriptive register-based study of consecutive admissions to a tertiary PICU in Sweden from 1 January 2008 to 31 December 2013. We compared the general characteristics of the cohorts, together with predicted death rates (PDR), PICU mortality, 30-day mortality, PICU length of stay (PICU LOS) and resource use., Results: Of the 3665 nonelective admissions, 221 patients received emergency transport from referring hospitals to the PICU by the specialist paediatric transport team. Their median age was lower (146 versus 482 days), PDR was higher (5.58% versus 1.39%), PICU LOS was longer (4.24 days versus 1.06 days), and they received more PICU-specific therapies. The standardised mortality ratio did not differ between the cohorts, and the PICU mortality was lower than predicted in both groups. The transport distance and mode of transport did not influence survival., Conclusion: Children admitted to the PICU following emergency transfers by the specialist paediatric transport team were younger, sicker, received more PICU-specific therapies and had longer PICU LOS than other acutely admitted critically ill patients. This indicates that these transfers were appropriate., (©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Spontaneous breathing during mechanical ventilation improves gas exchange by redistribution of ventilation to dependent lung regions. Neurally adjusted ventilatory assist (NAVA) supports spontaneous breathing in proportion to the electrical activity of the diaphragm (EAdi). NAVA has never been used in the operating room and no studies have systematically addressed the influence of different anaesthetic drugs on EAdi., Objectives: The aim of this study was to test the feasibility of NAVA under sedation and anaesthesia with two commonly used anaesthetics, sevoflurane and propofol, with and without remifentanil, and to study their effects on EAdi and breathing mechanics., Design: A crossover study with factorial design of NAVA during sedation and anaesthesia in pigs., Setting: University basic science laboratory in Uppsala, Sweden, from March 2009 to February 2011., Animals: Nine juvenile pigs were used for the experiment., Interventions: The lungs were ventilated using NAVA while the animals were sedated and anaesthetised with continuous low-dose ketamine combined with sevoflurane and propofol, with and without remifentanil., Main Outcome Measures: During the last 5  min of each study period (total eight steps) EAdi, breathing pattern, blood gas analysis, neuromechanical efficiency (NME) and neuroventilatory efficiency (NVE) during NAVA were determined., Results: EAdi was preserved and normoventilation was reached with both sevoflurane and propofol during sedation as well as anaesthesia. Tidal volume (Vt) was significantly lower with sevoflurane anaesthesia than with propofol. NME was significantly higher with sevoflurane than with propofol during anaesthesia with and without remifentanil. NVE was significantly higher with sevoflurane than with propofol during sedation and anaesthesia., Conclusion: NAVA is feasible during ketamine-propofol and ketamine-sevoflurane anaesthesia in pigs. Sevoflurane promotes lower Vt, and affects NME and NVE less than propofol. Our data warrant studies of NAVA in humans undergoing anaesthesia.

Background: Adult meta-analyses have verified that adjunct use of alpha-2 adrenoceptor agonists (A2AA) together with local anesthetics (LA) will prolong the duration of peripheral nerve blocks. The standard use of A2AAs for peripheral nerve blockade has recently been recommended also in children, but the evidence base in support of this suggestion has to date been equivocal. The purpose of this meta-analysis was to produce evidence-based data regarding the effect in children., Methods: Following a thorough literature search, five randomized controlled trials were included in a meta-analysis. Raw data from all studies were gathered and aggregated into patients randomized to receive plain LA (Group PLA) or LA mixed with either adjunct clonidine or dexmedetomidine (Group ADJ). The main outcome parameter was block duration (time to first administration of supplemental analgesic based on predetermined pain scores) analyzed by survival statistics. The total number of supplemental analgesic doses during the first 24 postoperative hours and serious side effects were included as secondary outcomes., Results: Pooling of the study data generated 141 patients in Group PLA and 142 patients in Group ADJ (overall n = 283; age: 0.8-13 years; weight 8-47 kg). Block duration was significantly prolonged (9.75 h vs 3.75 h) compared to the use of plain LA. Survival statistics verified a beneficial effect of using adjunct A2AAs [the log rank (Mantel-Cox) test (P = 0.0078), Gehan-Breslow-Wilcoxon test (P = 0.0027), and hazard ratio (1.653; 95% CI: 1.142 to 2.395)]. The number of patients that needed ≥ 2 doses of supplemental analgesics was higher in Group PLA (n = 19) compared to Group ADJ (n = 6) (P = 0.0088). No serious side effects were reported., Conclusion: This meta-analysis provides evidence-based support for the use of adjunct alpha-2 adrenoceptor agonists when performing peripheral nerve blocks in children., (© 2015 John Wiley & Sons Ltd.)

Background: A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors., Material and Methods: This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing., Results and Conclusion: Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.

Background: Adult meta-analysis has identified dexmedetomidine as a potentially useful adjunct to prolong the duration of peripheral nerve blocks. However, no data exist regarding the adjuvant use of dexmedetomidine in the setting of pediatric peripheral nerve blocks., Methods: Using a prospective, randomized, double-blind design, children (1½-8 years, ASA 1-2) scheduled for outpatient inguinal hernia repair were randomized to receive either an ultrasound-guided ilioinguinal/iliohypogastric nerve block (IINB) with plain ropivacaine 0.197% (Group LA; n = 21) or ropivacaine 0.197% with adjunct dexmedetomidine 0.3 μg·kg(-1) (Group LAD; n = 22). The primary endpoint of the study was time to first postoperative administration of supplemental analgesia (FPASA) triggered by a pain score ≥4 (CHIPPS or NRS scale). Intention-to-treat (ITT) analysis was decided as the primary statistical analysis of the data., Results: The median time to FPASA was prolonged by 88% following the use of adjunct dexmedetomidine (4.0 and 7.6 h in group LA and LAD, respectively) (P = 0.0717). Patients in Group LA displayed a significantly higher number of patients with a CHIPPS score ≥4 in the PACU (7 vs 0; P = 0.0029) as well as a higher incidence of PAED (4 vs 0; P = 0.0485) when compared to patients in Group LAD. No adverse events were recorded in any of the study groups., Conclusions: The use of dexmedetomidine as an adjunct to an IINB resulted in reduced incidences of CHIPPS pain scores ≥4 and PAED scores of ≥11 during early recovery following pediatric inguinal hernia repair. In addition, the use of adjunct dexmedetomidine was associated with a prolongation of the period to first supplemental analgesia demand. The results of the present exploratory study must be viewed as preliminary and need further validation by future larger sized studies and/or meta-analysis., (© 2015 John Wiley & Sons Ltd.)

Background: Clonidine has been advocated as a valid alternative for premedication in children but one of the few limitations is its association with reduced heart rate (HR), which thus raises the question of the safety of clonidine as premedication in children. The aim of this study was to investigate the incidence of bradycardia in children premedicated with oral or intravenous clonidine as compared to children not receiving pharmacologic premedication., Methods: An open, nonrandomized, observational study design was used. During the preoperative assessment visit the children were prescribed no premedication, intravenous or oral clonidine. On arrival to the operating room (OR) HR was recorded by connecting the patient to standard monitoring with pulseoximetry and/or Electrocardiogram. The primary outcome measure was the number of patients with a HR below 85% of the lower limit of the normal range (1st centile), which was defined as bradycardia that might need clinical intervention., Results: One thousand five hundred and seven patients were included in the analysis. 600 and 85 patients did not receive any premedication (Group 0), 305 patients received iv Clonidine (Group CIV), and 517 patients were given oral Clonidine (Group CPO). One patient in Group 0 (0.15%; 95% CI: 0-0.81%), none in Group CIV (0%; 95% CI: 0.00-0.98%), and 5 patients in Group CPO (0.97%; 95% CI: 0.31-2.24%) were observed to have a HR of <85% of the 1st centile., Conclusion: The incidence of bradycardia following oral or intravenous premedication with clonidine in a pediatric population scheduled for anesthesia is low. Thus, it does not appear rational to refrain from using clonidine as premedication in children only due to fear of bradycardia., (© 2015 John Wiley & Sons Ltd.)

Background: Administration of local anesthetics by a surgically placed wound catheter has recently been shown to reduce the need for postoperative morphine administration in extremely preterm infants undergoing ductus ligation. The primary aim of this randomized safety study was to define the plasma levels of levobupivacaine (LB) following two different intermittent infusion regimens., Methods: Eighteen preterm infants 23-27 gestational weeks, median birthweight 721 g scheduled for ductus ligation were included in the study. All patients were anesthetized according to a standardized protocol based on high-dose fentanyl (25-50 μg·kg(-1) ). Before skin closure, a subcutaneous catheter was inserted into the wound. The patients were randomized to receive one of the two intermittent infusion regimens: Group BII: Initial bolus plus early start of the intermittent infusion or Group DII: No bolus plus delayed start (8 h) of the intermittent infusion. Blood samples for determination of LB plasma concentrations were obtained on six occasions during the 24-h postoperative observation period, as well as hourly postoperative pain assessments using the Echelle Douleur Inconfort Noveau (EDIN) pain scale., Results: Plasma concentrations of LB ranged from 0.094 to 1.682 μg·ml(-1) and 0 to 0.549 μg·ml(-1) in group BII and DII, respectively. Both regimens were associated with low postoperative EDIN pain scores (24 h median of 0 and 1 in group BII and DII, respectively). No signs of systemic local anesthetic toxicity were noted., Conclusions: The two studied intermittent infusion regimens were associated with plasma levels below potentially toxic levels and were both associated with adequate postoperative pain scores., (© 2015 John Wiley & Sons Ltd.)

Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients' refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits., Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation., Results and Conclusion: MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

In this study, we determined the plasma concentration of ropivacaine by liquid chromatography-mass spectrometry for 30 hours after local infiltration analgesia in 15 patients with elective hip arthroplasty. The 95% upper prediction bound of maximal unbound plasma concentration of ropivacaine was 0.032 mg/L. Side effects sufficient to stop an IV infusion have been reported at arterial concentrations of 0.34 to 0.85 mg/L. Alpha-1-acid glycoprotein did not correlate with the fraction of unbound ropivacaine during the first 24 hours after local infiltration analgesia. No signs or symptoms of systemic local anesthetic toxicity were observed. The Clopper-Pearson 95% upper confidence limit for adverse signs was 0.218.

Background: The aim of this study was to report on the clinical outcome and safety of jejunostomy tube feeding used in our clinical setting for more than 14 years., Material and Methods: A retrospective study of all children who underwent a surgical catheter jejunostomy placement between July 1996 and March 2010 was conducted. Data were collected regarding the outcome and complications., Results: Thirty-three children (14 girls) were included. The median age at the time of primary surgery was 1.43 years (range, 0.15-17.7 years), and the median time of follow-up was 2.34 years (range, 0.27-12.6 years). Seventeen children were severely neurologically impaired (NI). Surgical insertion of a jejunostomy tube was performed due to 1 or more of the following indications: gastroesophageal reflux disease (GERD), failure to thrive, recurrent pneumonia, esophageal disease, or oral feeding difficulties. The effect of the indications showed a reduction in GERD and pneumonia. Feeding difficulties also decreased. Weaning was possible in 12 of 16 children without NI but in only 2 of 17 with NI. Major complications requiring surgical reoperation affected 8 children. No mortality was related to the jejunostomy feeding catheter., Conclusion: In selected cases, surgically placed jejunostomy tubes for feeding in children is an effective and safe method to overcome GERD, feeding difficulties, or recurrent pneumonia without major surgery., (© 2013 American Society for Parenteral and Enteral Nutrition.)

Background: Bortezomib is a proteasome inhibitor currently studied in clinical trials of childhood cancers. So far, no side effects on bone growth have been reported in treated children. However, bortezomib was recently found to induce apoptosis in growth plate chondrocytes and impair linear bone growth in treated mice. We hypothesize that [Gly(14)]-humanin (HNG), a 24-amino acid synthetic antiapoptotic peptide, can prevent bortezomib-induced bone growth impairment., Methods: Mice with human neuroblastoma or medulloblastoma tumor xenografts (9-13 animals/group) received one 2-week cycle (2 injections/week) of bortezomib (0.8 mg/kg or 1.0mg/kg), or HNG (1 µg/mouse), or the combination of HNG/bortezomib, or vehicle. Cultures of human growth plate cartilage, chondrogenic- and cancer cell lines, and immunohistochemistry for detection of proapoptotic proteins were also used. Statistical significance was evaluated by two-sided Mann-Whitney U test or by parametric or nonparametric analysis of variance., Results: Bortezomib efficiently blocked the proteasome and induced pronounced impairment of linear bone growth from day 0 to day 13 (0.09 mm/day, 95% confidence interval [CI] = 0.07 to 0.11 mm/day; vs 0.19 mm/day, 95% CI = 0.15 to 0.23 mm/day in vehicle; P < .001), an effect significantly prevented by the addition of HNG (0.15 mm growth/day, 95% CI = 0.14 to 0.16 mm/day; P < .001 vs bortezomib only; P = 0.03 vs vehicle). Bortezomib was highly toxic when added to cultures of human growth plate cartilage, with markedly increased apoptosis compared with control (P < .001). However, when combining with HNG, bortezomib-induced apoptosis was entirely prevented, as was Bax and PARP activation. Bortezomib delayed tumor growth, and HNG did not interfere with the anticancer effect when studied in human tumor xenografts or cell lines., Conclusions: HNG prevents bortezomib-induced bone growth impairment without interfering with bortezomib's desired anticancer effects.

Background: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations., Methods and Findings: Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m(2) were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10-14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662-988) and 758 (95% CI 640-876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10-14 taking 50 mg/kg and children aged 0-2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent., Conclusions: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10-14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.

Objectives: Pharmacokinetic studies are important for optimizing of drug dosing, but requires proper validation of the used pharmacokinetic procedures. However, simple and reliable statistical methods suitable for evaluation of the predictive performance of pharmacokinetic analysis are essentially lacking. The aim of the present study was to construct and evaluate a graphic procedure for quantification of predictive performance of individual and population pharmacokinetic compartment analysis., Methods: Original data from previously published pharmacokinetic compartment analyses after intravenous, oral, and epidural administration, and digitized data, obtained from published scatter plots of observed vs predicted drug concentrations from population pharmacokinetic studies using the NPEM algorithm and NONMEM computer program and Bayesian forecasting procedures, were used for estimating the predictive performance according to the proposed graphical method and by the method of Sheiner and Beal., Results: The graphical plot proposed in the present paper proved to be a useful tool for evaluation of predictive performance of both individual and population compartment pharmacokinetic analysis., Conclusion: The proposed method is simple to use and gives valuable information concerning time- and concentration-dependent inaccuracies that might occur in individual and population pharmacokinetic compartment analysis. Predictive performance can be quantified by the fraction of concentration ratios within arbitrarily specified ranges, e.g. within the range 0.8-1.2.

Background: In pediatric oncology, effective clinic-based management of acute and long-term distress in families calls for investigation of determinants of parents' psychological response to the child's cancer. We examined the relationship between parents' prior exposure to traumatic life events (TLE) and the occurrence of posttraumatic stress symptoms (PTSS) following their child's cancer diagnosis. Factors mediating the TLE-PTSS relationship were analyzed., Methodology: The study comprised 169 parents (97 mothers, 72 fathers) of 103 cancer diagnosed children (median age: 5,9 years; range 0.1-19.7 years). Thirty five parents were of immigrant origin (20.7%). Prior TLE were collated using a standardized questionnaire, PTSS was assessed using the Impact of Events-Revised (IES-R) questionnaire covering intrusion, avoidance and hyperarousal symptoms. The predictive significance of prior TLE on PTSS was tested in adjusted regression models., Results: Mothers demonstrated more severe PTSS across all symptom dimensions. TLE were associated with significantly increased hyperarousal symptoms. Parents' gender, age and immigrant status did not significantly influence the TLE-PTSS relationship., Conclusions: Prior traumatic life-events aggravate posttraumatic hyperarousal symptoms. In clinic-based psychological care of parents of high-risk pediatric patients, attention needs to be paid to life history, and to heightened vulnerability to PTSS associated with female gender.