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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. [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]

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]

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. [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]

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]

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]

Abstract: The anticancer agent cisplatin (cis-diamminedichloroplatinum(II), cis-[PtCl2(NH3)2]) easily undergoes ligand-exchange reactions, resulting in mainly inactive Pt complexes. This paper presents a method for selective analysis of intact cisplatin in blood using LC and UV detection. Blood samples (hematocrit: 0.22–0.52) were spiked with cisplatin (final concentrations: 2.48×10−7 M–9.90×10−6 M) and subjected to centripetal ultrafiltration. The blood ultrafiltrate was separated (loop volume: 5μl) with a porous graphitic carbon column and a mobile phase of HEPES-buffer (pH 9.3). Prior to UV detection (344nm), the eluate was mixed with sodium N,N-diethyldithiocarbamate (DDTC) in a microwave field (115°C) in order to improve the UV absorptivity. Cisplatin eluted as a Pt–DDTC complex after 11.8min. The peak area was influenced primarily by the hematocrit, the DDTC concentration, and the temperature and residence time in the microwave cavity. The method was robust and sensitive provided preparing a fresh DDTC solution each day and, at the end of a day''s run, destroying DDTC remaining in the system. It offers the main advantages of high selectivity, sensitivity, and robustness, minimal sample processing, and the possibility to use small sample volumes. [Copyright &y& Elsevier]

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]

To evaluate the possibility of using near-infrared spectroscopy (NIRS) to measure tissue oxygenation (StO(2)) during hyperbaric oxygen (HBO) therapy. Nine healthy volunteers (1 female) age 25-37 years, breathed air or oxygen. Tissue oxygenation was measured using NIRS on the thumb. Subjects were blinded to breathing gas. A range of partial pressures of oxygen were administered in 10-min intervals: 21, 101, 21 kPa (compression to 280 kPa), 59, 280, 59 (decompression), 21 kPa. Data were averaged over last 5 min at each pressure. When switching from air to normobaric oxygen (NBO 101 kPa) StO(2) increased from 83% (82-85%, median and interquartile range) to 85% (84-87%) (P < 0.01), while when switching from air at pressure (59 kPa O(2)) to HBO (280 kPa), StO(2) increased from 85% (85-86%) to 88% (87-89%) (P < 0.001). There was no difference between baseline StO(2) while air breathing before NBO or after decompression. Values did not reach the maximal value of 100% at any point. The changes in hemoglobin oxygen saturation in tissue registered by the NIRS monitor when switching from air to oxygen followed inspired PO(2) under normobaric and hyperbaric conditions. [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]

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: 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 (Vmax, peak CBF velocity; Vmin, 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, Vmin, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [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 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]

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 [Gly14] 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 1.0 mg/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 [Cl] = 0.07 to 0.11 mm/day; vs 0.19 mm/day, 95% Cl = 0.15 to 0.23mm/day in vehicle; P< .001), an effect significantly prevented by the addition of HNG (0.15ram growth/day, 95% CI = 0.14 to 0.16mm/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 anti- cancer effects. [ABSTRACT FROM AUTHOR]

Purpose: Thiosulfate may reduce cisplatin-induced ototoxicity, most likely by relieving oxidative stress and by forming inactive platinum complexes. This study aimed to determine the concentration and protective effect of thiosulfate in the cochlea after application of a thiosulfate-containing high viscosity formulation of sodium hyaluronan (HYA gel) to the middle ear prior to i.v. injection of cisplatin in a guinea pig model. Methods: The release of thiosulfate (0.1 M) from HYA gel (0.5% w/w) was explored in vitro. Thiosulfate in the scala tympani perilymph of the cochlea 1 and 3 h after application of thiosulfate in HYA gel to the middle ear was quantified with HPLC and fluorescence detection. Thiosulfate in blood and CSF was also explored. The potential otoprotective effect was evaluated by hair cell count after treatment with thiosulfate in HYA gel applied to the middle ear 3 h prior to cisplatin injection (8 mg/kg b.w.). Results: HYA did not impede the release of thiosulfate. Middle ear administration of thiosulfate in HYA gel gave high concentrations in the scala tympani perilymph while maintaining low levels in blood, and it protected against cisplatin-induced hair cell loss. Conclusion: HYA gel is an effective vehicle for administration of thiosulfate to the middle ear. Local application of a thiosulfate-containing HYA gel reduces the ototoxicity of cisplatin most likely without compromising its antineoplastic effect. This provides a minimally invasive protective treatment that can easily be repeated if necessary. [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]

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]

Background Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained. Methods In HCT116 cells, cisplatin (20 µM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% Cl = 8.8- to 9.8-fold), to 5.1-fold (95% Cl = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided. Results In HCT116 cells, cisplatin (20 µM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% Cl = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% Cl = 8.8- to 9.8-fold, to 5.1-fold, 95% Cl = 4.4- to 5.8-fold). Oxaliplatin (20 µM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 µg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 µM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics. Conclusion Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity. [ABSTRACT FROM AUTHOR]