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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. [ABSTRACT FROM AUTHOR]

Background Aim Method Results Conclusions 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.To describe parents' experiences of handling OADs at home after participating in an educational intervention.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.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.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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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−1p < 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (PvO2 ). Therefore, it has been suggested that increasing PvO2 by veno-venous extracorporeal membrane oxygenation (V-V ECMO) would adequately reduce PVR in V-V ECMO patients.Objective: Whether increased PvO2 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 (FI O2 ) was stepwise reduced to establish different degrees of alveolar hypoxia. PvO2 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 FI O2 of 0.15. At lower FI O2 , PVR increased; at FI O2 0.10 to 4.9 [4.2-7.0], P = .036, at FI O2 0.05 to 6.0 [4.3-8.6], P = .002, and at FI O2 0 to 5.4 [3.5 - 7.0] mm Hg L-1  min, P = .05.Conclusions: The effect of increased PvO2 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. [ABSTRACT FROM AUTHOR]

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 (TFH) 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 TFH 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 TFH 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. [ABSTRACT FROM AUTHOR]

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 (PaO2 ) and fraction of inspired oxygen (FiO2 ) was extracted from 990 admissions.Results: There was close agreement between PIM2 score and PDR regardless of whether the PaO2 /FiO2 ratio was omitted or not. In the subgroup of admissions with a respiratory admission diagnosis, the inclusion of the PaO2 /FiO2 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 PaO2 /FiO2 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Adult meta-analyses have verified that adjunct use of alpha-2 adrenoceptor agonists (A2 AA) together with local anesthetics ( LA) will prolong the duration of peripheral nerve blocks. The standard use of A2 AAs 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 A2 AAs [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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives/Aim: To investigate whether nasal aerosol clonidine can reduce the onset time of preoperative sedation. Background: Premedication is common in the pediatric population, but the optimal agent and administration route is still a matter of debate. Clonidine has many beneficial effects in the perioperative period. Clonidine nasal drops produce a similar sedative effect as after oral administration but do not reduce the onset time. Nasal aerosol administration of drugs is generally more effective than drops and an option to decrease the onset time of clonidine. Methods: Pediatric ASA status 1 and 2 patients were randomized to receive placebo (P), clonidine 3-4 μg kg−1 (C4), or clonidine 7-8 μg kg−1 (C7) as a nasal aerosol. Acceptance of administration, pre- and postoperative sedation, and adverse events were assessed. Results: A total of 60 patients were enrolled with a median age of 3.5 years (range 0.7-6.9) and median weight of 14.8 kg (range 10-25). In the C7 group, 55% of the children were found adequately sedated at 30 min as compared to 32% in the C4 group ( P = 0.1202). At 45 min, adequate sedation was seen in 65% of the patients in both C4 and C7 groups, which were both found to be significantly higher compared with the placebo control group (14%) ( P-values = 0.0027 and 0.0013, respectively). The postoperative sedation profile did not differ between the three study groups. Conclusions: Clonidine administered as nasal aerosol (3-8 μg kg−1) was not found to achieve adequate preoperative sedation within 30 min of administration. Despite its sedative properties, no prolongation of postoperative sedation was noted compared with placebo. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to validate the Mosteller formula for the estimation of body surface area (BSA) in various childhood ages. Many physiological processes including drug metabolism correlate with values for BSA. In addition, dosing of many drugs, especially drugs with low therapeutic index, for example, anti-neoplastics, are based on estimated values of BSA. Methods: Published data from measured BSA in 268 children and infants (median age: 8 month; range: 0-18 years) were compared with BSA values estimated by the Mosteller formula. Correlation between estimated and measured BSA values was performed by the Spearman rank correlation. Bias and precision were evaluated as outlined by Sheiner and Beal. Measured and estimated BSA values were compared by the Eksborg's plot. Results: Measured values of BSA and BSA values estimated by the Mosteller formula were closely correlated (rs = 0.973; p < 0.0001). The formula of Mosteller had with a precision of 9.38% and underestimated BSA by 4.06%. The quotients Estimated/Measured BSA were within the range 0.9-1.1 in 71.3% of the observations, but deviation up to 35% occurred. Conclusion: The Mosteller formula underestimates BSA in the paediatric population and must be used with precautions because of low precision, most pronounced in neonates and infants. [ABSTRACT FROM AUTHOR]

Oral clonidine is used as premedication in children. The bioavailability of clonidine given orally in adults is 75-100% but is unknown in children. Children (3-10 years) undergoing adenotonsillectomy were administered oral clonidine 4 mcg·kg mixed with apple fruit drink as premedication. Intravenous plasma was assayed for clonidine concentration at 5, 15, 30, 45 min and 1, 2, 4, 6, 12, 18 h after administration. Clonidine plasma concentrations were determined by liquid chromatography-mass spectroscopy, and pharmacokinetic parameters were calculated using nonlinear effects mixed-effects models. Current data were pooled with published time-concentration profiles from children ( n = 49) administered intravenous clonidine to determine oral bioavailability. There were eight children studied (age 3-10 years, weight 10.5-36 kg). A two-compartment model with first-order absorption and elimination was used to describe time-concentration profiles. Population parameter estimates (CV%; 95% CI), standardized to a 70-kg person, were absorption half-life (Tabs), 0.45 (85.1; 0.221-0.884) h, absorption lag time (Tlag), 0.148 (91.2; 0.002-0.316) h, Clearance (CL) 17.9 (30.3; 16-20.3) l·h per 70 kg, between compartment clearance (Q) 121 (44.3; 80.1-165) l·h per 70 kg, central volume (V1) 81.2 (71.5; 60.7-105) l·70 kg, peripheral volume of distribution (V2) 113 (33.9; 91-131) l·70 kg. The oral bioavailability was 55.4% (CV 6.4%; 95% CI 0.469, 0.654). Clonidine administered with an apple fruit drink displays a variable and relatively slow absorption after oral administration ( T 1.04 h, C 0.77 mcg·l). The oral bioavailability was 55.4%, which is less than reported in adults. Consequently, higher oral doses of clonidine (per kg) are required when this formulation is used to achieve concentrations similar to those reported in adults. [ABSTRACT FROM AUTHOR]

The aim of this prospective, age-stratified, observational study was to determine the cranial extent of spread of a large volume (1.5 ml·kg, ropivacaine 0.2%), single-shot caudal epidural injection using real-time ultrasonography. Fifty ASA I-III children were included in the study, stratified in three age groups; neonates, infants (1-12 months), and toddlers (1-4 years). The caudal blocks were performed during ultrasonographic observation of the spread of local anesthetic (LA) in the epidural space. A significant inverse relationship was found between age, weight, and height, and the maximal cranial level reached by 1.5 ml·kg of LA. In neonates, 93% of the blocks reached a cranial level of ≥Th12 vs 73% and 25% in infants and toddlers, respectively. Based on our data, a predictive equation of segmental spread was generated: Dose (ml/spinal segment) = 0.1539·(BW in kg)-0.0937. This study found an inverse relationship between age, weight, and height and the number of segments covered by a caudal injection of 1.5 ml·kg of ropivacaine 0.2% in children 0-4 years of age. However, the cranial spread of local anesthetics within the spinal canal as assessed by immediate ultrasound visualization was found to be in poor agreement with previously published predictive equations that are based on actual cutaneous dermatomal testing. [ABSTRACT FROM AUTHOR]

Background: Opioids are common drugs for pain treatment in preterm newborn infants, in spite of several adverse effects. Constipation is a frequent problem when opioids are used in both adults and neonates. Although several studies indicate that the oral administration of naloxone hydrochloride (NH) improves intestinal motility during opioid therapy, there is still a lack of evidence in newborns. Aim: The aim of this study was to assess the efficacy of NH against reduced intestinal motility during opioid treatment. Methods: A retrospective cohort study was performed. We analysed the medical records of fifteen infants (Group 1) treated with continuous morphine (MO) infusion and fourteen infants (Group 2) treated with both oral NH (3 μg/kg 4 times daily) and MO. Results: There was no statistically significant difference in the total MO dose. Infants treated both with NH and MO had a tendency to improve their mean stool frequency/day. A statistically significant improvement was observed in the mean total food intake (mL/kg/day) of the infants treated with NH (p = 0.014). No difference in the mean food retention between the two groups was observed. Conclusion: Orally administrated NH seems to improve intestinal motility resulting in increased food intake/day and improved stool frequency/day in premature newborn infants treated with MO. Further studies are needed to corroborate these findings. [ABSTRACT FROM AUTHOR]

Background: The α2 agonist clonidine has become a popular drug for premedication in children. Effects and pharmacokinetics after oral, rectal, and intravenous administration are well known. The aim of this study was to investigate the absorption pharmacokinetics of clonidine nasal drops in children. Methods: Thirteen ASA I pediatric patients received after induction of anesthesia 4 mcg·kg−1 of clonidine by the nasal route. Blood samples were taken during a 12-h period and plasma levels of clonidine were analyzed by liquid chromatography–mass spectrometry. Data were calculated by a computer-aided curve-fitting program. Results: Plasma pharmacokinetics following administration of clonidine nasal drops showed a considerable interindividual variability and absorption was delayed and limited. A total of 95% confidence intervals for maximum plasma concentration and time to achieve maximum plasma concentration were 0.4–0.6 ng·ml−1 and 1.4–3.0 h, respectively. Conclusions: Clonidine nasal drops are erratically absorbed from the nasal mucosa and, thus, this mode of drug administration is not recommended for premedication purposes. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition with high mortality. We report an extremely premature girl, born in the 24th gestational week (BW 732 g), that during her second month developed a severe HLH subsequent to a Serratia marcescens septicemia, with hepatosplenomegaly, cytopenias, hyperbilirubinemia (mostly conjugated, total bilirubin 916 μmol/L), hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia (21266 μg/L), and elevated sIL-2 receptor levels. Genetic analysis revealed no PRF1, STX11 or UNC13D gene mutations. Treatment was provided according to the HLH-2004 protocol with etoposide, dexamethasone, and immunoglobulin, but no cyclosporin because of immature kidneys. She recovered fully from the HLH but developed a severe retinopathy as well as green teeth secondary to the hyperbilirubinemia. We conclude that secondary, bacteria-associated HLH can develop in premature infants, and that HLH can be treated with cytotoxic therapy also in premature infants. It is important to be aware of HLH in premature infants, since it is treatable. [ABSTRACT FROM AUTHOR]

Background: There are few data describing clonidine population pharmacokinetics in children (0–15 years) despite common use. Current pediatric data, described in terms of elimination half-life or Cmax and Tmax, poorly explain variability in drug responses among individuals representative of those in whom the drug will be used clinically. Methods: Published data from four studies investigating clonidine PK after intravenous (i.v.), rectal and epidural administration ( n = 42) were combined with an open-label study undertaken to examine the pharmacokinetics of i.v. clonidine 1–2 μg·kg−1 bolus in children after cardiac surgery ( n = 41). A population pharmacokinetic analysis of clonidine time–concentration profiles (380 observations) was undertaken using nonlinear mixed effects modeling. Estimates were standardized to a 70-kg adult using allometric size models. Results: Children had a mean age of 4 (sd 3.6 years, range 1 week–14 years) years and weight 17.8 (sd 12.6, range 2.8–60) kg. A two compartment disposition model with first-order elimination was superior to a one compartment model. Population parameter estimates (between subject variability) were clearance (CL) 14.6 (CV 35.1%) l·h−1 70 kg−1, central volume of distribution (V1) 62.5 (71.1%) l 70 kg−1, intercompartment clearance (Q) 157 (77.3%) l·h−1 70 kg−1 and peripheral volume of distribution (V2) 119 (22.9%) l 70 kg−1. Clearance at birth was 3.8 l·h−1 70 kg−1 and matured with a half-time of 25.7 weeks to reach 82% adult rate by 1 year of age. The volumes of distribution, but not clearance, were increased after cardiac surgery (V1 123%, V2 126%). There was a lag time of 2.3 (CV 73.2%) min before absorption began in the rectum. The absorption half-life from the epidural space was slower than that from the rectum (0.98 CV 24.5% h vs 0.26 CV 32.3% h). The relative bioavailability of epidural and rectal clonidine was unity ( F = 1). Conclusions: Clearance in neonates is approximately one-third that described in adults, consistent with immature elimination pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach. [ABSTRACT FROM AUTHOR]

Aim: One aspect of organizing medical follow-up for adult survivors of childhood cancer is to determine to what extent the former patient experiences a need for health services. In the present paper, we studied how the healthcare needs, both subjectively and objectively, were fulfilled for our former patients. Methods: 335 survivors over 18 y of age, with a follow-up time of more than 5 y after completion of therapy, were sent a questionnaire probing their present use of health services. Results: The response rate was 73%. A majority (60%) of the survivors had no regular follow-up visits, and 42% of these reported that they missed not having one. More than one third were thus far dissatisfied with the follow-up programme. Only 3% of those who had regular follow-ups found them “unnecessary”. Complaints subjectively related to their diseases or treatments were reported by 47%. Out of all responders, 34% did not miss having regular follow-up visits. Neither perceived disease-related complaints nor radiation therapy was a predictor for having a scheduled follow-up visit. Conclusion: In the absence of a long-term follow-up programme, many survivors were not receiving proper medical healthcare, whether from their perspective or from a professional one. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: Ototoxicity is a common side effect of high-dose cisplatin treatment. Thiol-containing chemoprotectors ameliorate cisplatin ototoxicity under experimental conditions. The trial was initiated to test the efficacy of amifostine protection in high-dose cisplatin treatment (125-150 mg/m2) for metastatic malignant melanoma, to correlate the ototoxic outcome with cisplatin pharmacokinetics, and to evaluate the importance of using a selective analytical method for the quantification of cisplatin. Study Design: Prospective study of 15 patients with stage IV malignant melanoma. Methods: Clinical follow-up of therapeutic response, pure-tone audiometry, and analysis of cisplatin and its monohydrated complex in blood ultrafiltrate by liquid chromatography with postcolumn derivatization were performed. Ultrafiltered blood platinum was analyzed by inductively coupled plasma mass spectrometry. Results: Ototoxicity and gastrointestinal toxicity were the most prominent side effects. Three patients ultimately required hearing aids. All patients had audiometric changes at one or more frequencies after the second treatment course, and all but one patient reported auditory symptoms. No correlation was found between hearing loss and blood cisplatin pharmacokinetics. Platinum levels determined by inductively coupled plasma mass spectrometry were higher than total platinum levels calculated from cisplatin and monohydrated complex concentrations obtained by liquid chromatography analysis. Conclusion: Ototoxicity was unacceptable despite amifostine treatment. Cisplatin pharmacokinetics during the first treatment course were not predictive of hearing loss. Amifostine caused a lowering of dose-normalized area under the concentration-time curve for cisplatin and monohydrated complex. Use of the unselective inductively coupled plasma mass spectrometry analysis leads to an overestimation of active drug. Selective analysis of cisplatin is especially important when evaluating cisplatin pharmacokinetics during chemoprotector treatment. [ABSTRACT FROM AUTHOR]

Investigates the body mass index (BMI) of all deceased illicit drug addicts (IDA) over a long period of time and evaluates the possible relationship between BMI and the drug of abuse, the HIV status and the unexpected death upon heroin administration. Increase in the prevalence of overweight in deceased IDA; Criteria in identifying IDA; Instruments used in performing complete postmortem examination on the subjects; Need for further studies to evaluate the causes of the increasing body weight in the drug addict population.

Aims To detect risk factors for sudden death from heroin injection. Design Evaluation of data from forensic investigations of all fatal cases of suspected heroin death in a metropolitan area. Only cases with detectable morphine and 6-monoacetylmorphine (6-MAM) in blood were included in order to select heroin intoxication cases. Setting Stockholm, Sweden. Measurements Autopsy investigation and toxicological analysis of blood and urine; and police reports. Findings In two-thirds of the 192 cases, death occurred in public places, and mostly without any time delay. Blood concentrations of morphine ranged from 50 to 1200 ng/g, and of 6-MAM from 1 to 80 ng/g. Codeine was detected in 96% of the subjects. In the majority of cases the forensic investigation indicated polydrug use, the most common additional findings being alcohol and benzodiazepines. However, in one-quarter of the cases other drug combinations were found. Previous abstinence from heroin and use of alcohol were identified as risk factors. For 6-MAM there was also a correlation with the presence of THC and benzodiazepines. Despite a high frequency of heart abnormalities (e.g. myocarditis and focal myocardial fibrosis), these conditions did not correlate with morphine or 6-MAM blood concentrations. Conclusions We confirm that alcohol intake and loss of tolerance are risk factors for death from heroin use, whereas no connection to heart pathology was observed. Further, prospective, studies should focus on other possible risk factors. [ABSTRACT FROM AUTHOR]

Aims NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. Methods A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. Results Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg kg-1 body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (± s.d.) AUC(0,∞) (capsule 602 ± 154 vs solution 602 ± 146 µg ml-1 h) or t½ (capsule 55 ± 13 vs solution 54 ± 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,∞) and Cmax increased linearly with dose. Following administration of 1 mg NTBC kg-1 in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol ml-1. Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol ml-1 following a dose of 4 mg kg-1 body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione kg-1, but returned to background levels during the following 24 h period. Conclusions NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use. [ABSTRACT FROM AUTHOR]