Breast milk oxycodone concentrations in mothers given oxycodone for post-Caesarean delivery pain management.

AIMS: Both effective analgesia and early breastfeeding play an important role in maternal and neonatal well-being after Caesarean delivery. We studied controlled-release oxycodone tablet treatment for postoperative pain management and determined the excretion of oxycodone into breast milk. METHODS: Controlled-release oxycodone/naloxone 10/5-mg tablets (n = 21) or controlled-release oxycodone 10-mg tablets (n = 22) were administered to mothers twice a day for the first 3 days after elective Caesarean delivery as a part of multimodal analgesia. Maternal plasma and breast milk samples were collected daily. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed with ultra-performance liquid chromatography-mass spectrometry. Maternal pain intensity was recorded with an 11-point Numeric Rating Scale (0-10). Neonatal oxycodone exposure was estimated by simulating five different exposure scenarios, including the highest possible exposure through breast milk. RESULTS: The mean oxycodone and noroxycodone milk-to-maternal plasma ratios were 3.2 and 3.0, respectively. A strong correlation was found between plasma and breast milk oxycodone (R2 = 0.87) and noroxycodone concentrations (R2 = 0.91). In the simulated highest neonatal exposure scenario, the neonate's maximum plasma concentration was estimated to be 5.4 ng/mL and the estimated weight-adjusted infant oxycodone dose was less than 10% of the maternal dose. Pain intensities were similarly low between the two treatment groups. CONCLUSIONS: The oxycodone dose received from colostrum and breast milk during the first three postoperative days after Caesarean delivery is assumed safe for healthy, term neonates, but in extreme cases it is possible for the neonate to receive a dose through breast milk that may elicit opioid effects.

Buprenorphine plasma and cerebrospinal fluid concentrations in osteoarthritis patients during low-dose transdermal patch dosing.

METHODS: Fifty-six (56) patients scheduled for arthroplasty, received 7-day extended-release buprenorphine transdermal patches (5 µg/h) for five consecutive weeks, starting two weeks prior to the surgery. Simultaneous plasma and cerebrospinal fluid (CSF) samples were collected during spinal anesthesia. RESULTS: Median buprenorphine plasma and CSF concentrations at steady-state were 54 pg/mL (range 8.6 - 167 pg/mL) and 1.6 pg/mL (0.30 - 7.3 pg/mL), respectively. The median CSF/plasma -ratio was 3% (range 0.35 - 16%). Large between-subject variability was observed in the measured buprenorphine concentrations within the study population.

Oxycodone does not affect placental circulatory physiology during the early first stage of labor-A randomized trial.

INTRODUCTION: Opioids are used for pain relief during the first stage of labor. Oxycodone can cause maternal hypotension that may modify utero- and fetoplacental circulatory physiology. We hypothesized that maternal intravenous (i.v.) oxycodone has no detrimental effect on utero- and fetoplacental hemodynamics during the early first stage of labor. MATERIAL AND METHODS: Twenty-two parturients requiring pain relief during the first stage of labor were randomized in a double-blinded and placebo-controlled study. By Doppler ultrasonography, both uterine artery (Ut) and umbilical vein (UV) volume blood flows (Q), Ut pulsatility index (PI), and Ut vascular resistance (RUt) were calculated. Blood flow velocity waveforms were obtained between uterine contractions. After baseline measurements, women received oxycodone 0.05 mg/kg or a placebo intravenous. Doppler ultrasonography was repeated up to 120 min after the first drug administration. The second dose of oxycodone 0.05 mg/kg was allowed at 60 min to all parturients with contraction pain ≥5/10. Maternal plasma samples were collected at each study phase and after delivery with umbilical cord plasma samples, to measure oxycodone concentrations. CLINICALTRIALS: gov identifier (NCT no. NCT02573831). RESULTS: At baseline, mean QUt and QUV did not differ significantly between the placebo-first (478 mL/min and 57 mL/min/kg) and the oxycodone-first (561 mL/min and 71 mL/min/kg) groups. In addition, RUt and Ut PI were comparable between the groups. Following oxycodone at 60 min, mean QUt and QUV (714 mL/min and 52 mL/min/kg) were similar to the placebo-first (520 mL/min and 55 mL/min/kg) group. Furthermore, all the measured parameters were comparable to the baseline values. At 60 min after the first study drug administration, all the parturients in the placebo-first group needed intravenous oxycodone 0.05 mg/kg. At 120 min, we found no statistically significant change in any of the measured parameters. No significant correlation was found between maternal oxycodone concentration and QUt or QUV. Furthermore, newborn oxycodone concentration did not correlate with QUV. CONCLUSIONS: Oxycodone did not have any detrimental effect on either utero- or fetoplacental circulatory physiology during the early first stage of labor. Maternal plasma oxycodone did not correlate with utero- and fetoplacental hemodynamics. No correlation was found between newborn oxycodone concentration and fetoplacental hemodynamics.

Quetiapine and other antipsychotic medications during pregnancy: a 15-year follow-up of a university hospital birth register.

PURPOSE: To survey trends of antipsychotic use during pregnancy and examine the associations between the use of quetiapine or any antipsychotic and adverse obstetric and neonatal outcomes. METHODS: Birth register study of 36,083 women who gave birth at Kuopio University Hospital, Finland, between 2002 and 2016. Obstetric and neonatal outcomes between women using quetiapine (N = 152) or any antipsychotic (N = 227) were compared to controls (N = 35,133). RESULTS: Altogether 246 (0.7%) women used antipsychotic medications during pregnancy and 153 (62,2%) of these women used quetiapine. Antipsychotic usage increased from 0.4% to 1.0% during the 15-year follow-up. Women using antipsychotics were more likely to smoke, drink alcohol, use illicit drugs, use other psychotropic medications, and have higher pre-pregnancy body mass index. Quetiapine use was associated with higher risk of increased postpartum bleeding in vaginal delivery (aOR 1.65; 95%CI 1.13-2.42), prolonged neonatal hospitalization (≥5 days) (aOR 1.54; 95%CI 1.10-2.15), and higher placental to birth weight ratio (PBW ratio) (aB 0.009; 95%CI 0.002-0.016). Use of any antipsychotic was associated with a higher risk of gestational diabetes mellitus (aOR 1.64; 95%CI 1.19-2.27), increased postpartum bleeding in vaginal delivery (aOR 1.50; 95%CI 1.09-2.07), prolonged neonatal hospitalization (≥5 days) (aOR 2.07; 95%CI 1.57-2.73), and higher PBW ratio (aB 0.007; 95%CI 0.001-0.012). CONCLUSION: The use of antipsychotic medications increased among Finnish pregnant women from 2002 to 2016. Pregnant women using antipsychotics appear to have a higher risk for some adverse pregnancy and birth outcomes and may benefit from more frequent maternity care follow-ups.

Postoperative pain in a prospectively assessed surgical short-stay cohort: A subgroup analysis.

BACKGROUND: There is sparse information about postoperative pain after short stay surgery. We explored the incidence of immediate postoperative pain and its relationship with persistent pain or opioid use 2 weeks after surgery. METHODS: This was a subgroup analysis of prospective and controlled data from adult patients (n = 931) who underwent short-stay surgery in a tertiary care hospital. Data comprised patient demographics, surgical category, pain scores and analgesic management during the recovery unit stay, before discharge on the postoperative morning after surgery and again 2 weeks after surgery. RESULTS: Half of the patients had severe dynamic pain in the recovery unit. It was commonest after orthopaedic (70% of patients), followed by gynaecological (54%), gastrointestinal (51%) and spine surgery (49%). Multimodal pain management was used for most patients (n = 811, 87%) with opioid use predominant. The median oxycodone dose during short-stay was the highest after orthopaedic surgery (39 mg). The first individual dynamic pain score after surgery was associated with follow-up pain score at rest (OR = 1.37), dynamic pain (OR = 1.35) and pain interference (OR = 1.34) at 2 weeks after surgery. Maximum dynamic pain reported in the recovery unit was associated with pain at rest (OR = 1.56), dynamic pain (OR = 1.65) and pain interference (OR = 1.45) at 2 weeks after surgery. Pain scores at 2 weeks were highest and analgesic use greatest in those patients who underwent spinal surgery. CONCLUSIONS: Intense postoperative pain remains common after short-stay surgery in some surgical categories including orthopaedic surgery and is associated with a greater likelihood of pain at 2 weeks.

Resilience, pain, and health-related quality of life in gynecological patients undergoing surgery for benign and malignant conditions: a 12-month follow-up study.

BACKGROUND: Gynecological surgery has many impacts on women's physical and mental health, and efforts to improve recovery from surgery are constantly under evaluation. Resilience is an ability to overcome stressors and adversities, such as traumas and surgeries. This study aimed to explore patients' resilience and psychological symptoms in relation to recovery, health-related quality of life (HRQoL), and pain one year after gynecological surgery. METHODS: In a prospective cohort study, we enrolled consecutive elective gynecologic surgery patients who completed questionnaires before and at one year after surgery: the Resilience Scale-25, the 15D instrument of HRQoL (15D), the Life Satisfaction Scale-4, and the Hospital Anxiety and Depression Scale. Their mean 15D scores were compared to those of an age-matched sample of women from the general Finnish population (n = 2743). RESULTS: We enrolled 271 women who underwent gynecological surgery due to benign (n = 190) and malignant (n = 81) diagnoses. Resilience was equally high in women with benign and malignant diagnoses at both time points. Higher resilience associated with less pain, analgesic use, and better pain relief from the use of pain medication at 12 months after surgery. Pain intensity was similar in the two groups, but patients with benign diseases had less pain at 12 months than before surgery. Before surgery, patients' HRQoL was worse than that of the general population, but at 12 months the mean HRQoL of patients with benign diseases had improved to the same level as that in the general population but had decreased further in patients with malignant diseases. Anxiety was higher and life satisfaction was lower in patients with malignant diseases before surgery. At 12 months, anxiety had decreased in both groups, and life satisfaction had increased in patients with malignant diseases. Depression was similarly low in both groups and time points. CONCLUSIONS: Resilience correlated with less pain one year after surgery. After surgery, HRQoL improved in patients with benign diseases but deteriorated in patients with malignant diseases. Patients with low resilience should be identified during preoperative evaluation, and health care professionals should give these patients psychological support to enhance their resilience. Trial Registration ClinicalTrials.gov; registered October 29, 2019; identifier: NCT04142203; retrospectively registered.

Patient functional recovery after a 23-h surgery - a prospective, follow-up study.

PURPOSE: We evaluated patients' functional outcomes 2 weeks after a 23-h surgery model in a tertiary care hospital. METHODS: This prospective study comprised data on 993 consecutive adult patients who underwent a 23-h surgery. Patients were interviewed before surgery and at 14 days after surgery by telephone with a multidimensional structural survey including closed- and open-ended questions. Regarding functional outcomes, the patients were asked to assess their general wellbeing, energy levels and activities of daily living on a 5-point numeric rating scale (1 = poor to 5 = excellent). Data on patient characteristics, medical history, alcohol use, smoking status and pre-, peri- and postoperative pain and satisfaction with the care received were collected and analysed to determine whether these factors contributed to their recovery. The primary outcome measure was patient functional recovery at 14 days after surgery. RESULTS: Most patients reported moderate to excellent functional outcomes: 93.6% (95% CI, 92.1--95.1) of the patients showed a score ≥ 3 on the 5-point numeric scale. One out of four patients (23%) scored all three domains as excellent. A weak inverse correlation was noted between functional recovery and most pain in the 23-h postanaesthesia care unit as well as pain at 2 weeks after surgery. A weak positive correlation was noted between functional recovery and patient satisfaction with the instructions at discharge. CONCLUSIONS: Most patients showed ample functional recovery at 14 days after the 23-h surgery. Higher pain scores in the postanaesthesia care unit and 2 weeks after surgery predicted poor functional outcomes, and satisfaction with postoperative counselling predicted better outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04142203.

Psychiatric Symptoms, Posttraumatic Growth, and Life Satisfaction Among Parents of Seriously Ill Infants: A Prospective Case-Controlled Study.

We evaluated psychiatric symptoms, posttraumatic growth, and life satisfaction among the parents (n = 34) of newborns (n = 17) requiring therapeutic hypothermia or urgent surgery (interest group). Our control group included 60 parents of healthy newborns (n = 30). The first surveys were completed soon after diagnosis or delivery and the follow-up surveys 1 year later (participation rate 88% in the interest group and 70% in the control group). General stress was common in both groups but was more prevalent in the interest group as were depressive symptoms, too. Anxiety was more common in the interest group, although it showed a decrease from the baseline in both groups. Life satisfaction had an inverse correlation with all measures of psychiatric symptoms, and it was lower in the interest group in the early stage, but similar at 12 months due to the slight decline in the control group. Mothers in the interest group had more anxiety and depressive symptoms than fathers in the early stage. Mothers had more traumatic distress than fathers at both time points. Half of the parents experienced substantial posttraumatic growth at 12 months. In conclusion, the serious illness of an infant substantially affects the well-being of the parents in the early stages of illness and one year after the illness.

Resilience and health-related quality of life in patients with pulmonary diseases receiving ambulatory oxygen therapy.

BACKGROUND: Pulmonary diseases affect health-related quality of life (HRQoL), but there are few data on patients' adaptation to a serious illness. This study assessed resilience and its associations with HRQoL, life satisfaction, anxiety and depression in patients with pulmonary diseases receiving ambulatory oxygen therapy. METHODS: In this prospective cohort study, we enrolled 42 patients with pulmonary diseases receiving ambulatory oxygen therapy. The patients completed the following questionnaires at baseline and after one and three months; the Resilience Scale-25, the Life Satisfaction Scale-4, the 15D instrument of HRQoL, the Hospital Anxiety and Depression Scale (HADS) and the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST 2.0). To compare HRQoL, we recruited age- and gender-matched controls from the general population (n = 3574). The primary outcome was the proportion of patients with low resilience. RESULTS: Half (42-48%) of the patients had low resilience, which was correlated with low HRQoL, low levels of life satisfaction and higher levels of anxiety and depression. Patients had very low HRQoL compared to controls. Dissatisfaction with life increased during the 3-months follow-up, but only a few patients had anxiety or depression. Patient satisfaction with assistive technology was high; the median QUEST 2.0 score (scale 1-5) was 4.00 at baseline, 3.92 at one month and 3.88 at three months. CONCLUSIONS: Resilience was low in half of the patients with pulmonary diseases receiving ambulatory oxygen therapy. Higher resilience was positively correlated with HRQoL and life satisfaction and negatively correlated with anxiety and depression. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Record 507A023. Registered 17 September 2020-Retrospectively registered, https://clinicaltrials.gov/ct2/results?cond=&term=NCT04554225&cntry=&state=&city=&dist= .

Population pharmacokinetics of oxycodone: Premature neonates to adults.

BACKGROUND: Oxycodone is used in children and adults for the control of acute postoperative pain. Covariate influences such as age, size, and fat mass on oxycodone pharmacokinetic parameters over the human lifespan are poorly quantified. METHODS: Pooled oxycodone time-concentration profiles were available from preterm neonates to adults. Data from intravenous, intramuscular, buccal, and epidural formulations were analyzed using nonlinear mixed-effects models. Normal fat mass was used to determine the influence of fat on oxycodone pharmacokinetics. Theory-based allometry was used to scale pharmacokinetic parameters to a 70 kg individual. A maturation function described the increase in clearance in neonates and infants. RESULTS: There were 237 subjects (24 weeks postmenstrual age to 75 years; 0.44-110 kg) providing 1317 plasma concentrations. A three-compartment model with first-order elimination best described oxycodone disposition. Population parameter estimates were clearance (CL) 48.6 L.h-1 .70 kg-1 (CV 71%); intercompartmental clearances (Q2) 220 L.h-1 .70 kg-1 (CV 64%); Q3 1.45 L.h-1 .70 kg-1 ; volume of distribution in the central compartment (V1) 98.2 L.70 kg-1 (CV 76%); rapidly equilibrating peripheral compartment (V2) 90.1 L. 70 kg-1 (CV 76%); slow equilibrating peripheral compartment (V3) 28.9 L.70 kg-1 . Total body weight was the best size descriptor for clearances and volumes. Absorption halftimes (TABS ) were: 1.1 minutes for intramuscular, 70 minutes for epidural, 82 minutes for nasogastric, and 159.6 minutes for buccal administration routes. The relative bioavailability after nasogastric administration was 0.673 with a lag time of 8.7 minutes. CONCLUSIONS: Clearance matured with age; 8% of the typical adult value at 24 weeks postmenstrual age, 33% in a term neonate and reached 90% of the adult clearance value by the end of the first year of life. Allometric scaling using total body weight was the better size descriptor of oxycodone clearance than fat-free mass.

Oxycodone target concentration dosing for acute pain in children.

BACKGROUND: Oxycodone pharmacokinetics have been described in premature neonates through to obese adults. Covariate influences have been accounted for using allometry (size) and maturation of oxycodone clearance with age. The target concentration is dependent on pain intensity that may differ over pain duration or between individuals. METHODS: We assumed a target concentration of 35 mcg.L-1 (acceptable range ±20%) to be associated with adequate analgesia without increased risk of adverse effects from respiratory depression. Pharmacokinetic simulation was used to estimate dose in neonates through to obese adults given intravenous or parenteral oxycodone. RESULTS: There were 84% of simulated oxycodone concentrations within the acceptable range during maintenance dosing. Variability around the simulated target concentration decreased with age. The maturation of oxycodone clearance is reflected in changes to context-sensitive halftime where clearance is immature in neonates compared with older children and adults. The intravenous loading and maintenance doses for a typical 5-year-old child are 100 mcg.kg-1 and 33 mcg.kg-1 .h-1 . In a typical adult, the loading dose is 100 mcg.kg-1 and maintenance dose 23 mcg.kg-1 .h-1 . CONCLUSION: Simulation was used to suggest loading and maintenance doses to attain an oxycodone concentration of 35 mcg.L-1 predicted in adults. Although the covariates age and weight contribute 92% variability for clearance, there remains variability accounting for 16% of concentrations outside the target range. Duration of analgesic effect after ceasing infusion is anticipated to be longer in neonates where context-sensitive halftime is greater than older children and adults.

Normobaric hypoxia training in military aviation and subsequent hypoxia symptom recognition.

Altitude hypoxia episodes are increasingly common in military aviation. Hypoxia training is mandatory for fighter pilots, but evidence-based data on the effects of training are scarce. The purpose of this study was to validate the normobaric hypoxia (NH) training effect. Data were collected from 89 pilots from the Finnish Air Force (FINAF). This survey was conducted in a tactical F/A-18C Hornet simulator in two sessions under normobaric conditions, in which the pilots performed flight missions and breathed 21% oxygen (O2) in nitrogen (N2), and blinded to the pilot, the breathing gas was changed to a hypoxic mixture containing either 8, 7 or 6% O2 in N2. The time taken to notice hypoxia symptoms and peripheral capillary O2 saturation was measured. A mean of 2.4 years after the initial training, pilots recognised their hypoxic symptoms 18 s quicker with 8% O2 mixture, 20 s quicker with 7% O2 and 10 s quicker with 6% O2. Our data indicate that NH training in a flight simulator helps pilots to recognise hypoxia symptoms earlier, and may, thus, enhance flight safety.Practitioner Summary: We show that hypoxia training enhances pilots' ability to recognise symptoms of acute normobaric hypoxic exposure up to 2.4 years after an initial NH training session. Based on these data, refreshment NH training is nowadays mandatory every 3 years in the FINAF as opposed to the North Atlantic Treaty Organisation (NATO) Standardisation Agreement (STANAG) requirement of 5-year intervals between hypoxia trainings.Abbreviations: O2: oxygen; TUC; time of usefull consciousness; SpO2: peripheral capillary oxygen saturation; NATO: North Atlantic Treaty Organization; STANAG: stanrdization agreement; HH: hypobaric hypoxia; NH: normobaric hypoxia; FINAF: finnish air force; N2: nitrogen; ECG: electrocardiogram; CI: confidence interval; SD: standard deviation.

Oxycodone for pain management in the latent phase of labour - A pragmatic trial.

BACKGROUND: Parenteral opioids are used for pain relief in labour but there are little data for oxycodone in this context. The aim of this study was to evaluate the efficacy, foetal exposure and safety of subcutaneous oxycodone in the latent phase of labour. METHODS: This pragmatic trial included 76 parturients, who received subcutaneous oxycodone for pain relief in the latent phase of labour according to the hospital protocol: an initial dose 0.1 mg/kg, and a second dose, 0.05 mg/kg, could be administered four hours later. Pain intensity and pain relief were assessed using a numerical rating scale of 0-10. After delivery, blood samples from the maternal and umbilical veins were collected, and plasma concentrations of oxycodone and its main metabolites were quantified using UPLC-MS/MS. The Apgar scores and maternal and neonatal adverse effects were recorded. RESULTS: The foetal exposure at birth was low, the median oxycodone and oxymorphone umbilical vein plasma concentrations were 1.2 ng/mL (range 0.21-7.8) and 0.14 ng/mL (0-0.26), respectively. Pain scores decreased substantially, from a median pain score of 7/10 before oxycodone to median scores of 5/10 at 30 minutes after administration, 5/10 at 60 minutes and 6/10 at 120 minutes. The median Apgar score was 9 (range 2-10) at 1 minute and 9 (6-10) at 5 minutes. Maternal adverse effects were mild, and there were no oxycodone-related neonatal adverse effects. CONCLUSION: Subcutaneous oxycodone provided effective analgesia during the latent phase of labour. Newborn exposure at birth was low, and oxycodone was well-tolerated.

NRF2 regulates endothelial glycolysis and proliferation with miR-93 and mediates the effects of oxidized phospholipids on endothelial activation.

Phospholipids, such as 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC), are the major components of cell membranes. Their exposure to reactive oxygen species creates oxidized phospholipids, which predispose to the development of chronic inflammatory diseases and metabolic disorders through endothelial activation and dysfunction. Although the effects of oxidized PAPC (oxPAPC) on endothelial cells have been previously studied, the underlying molecular mechanisms evoking biological responses remain largely unknown. Here, we investigated the molecular mechanisms of oxPAPC function with a special emphasis on NRF2-regulated microRNAs (miRNAs) in human umbilical vein endothelial cells (HUVECs) utilizing miRNA profiling, global run-on sequencing (GRO-seq), genome-wide NRF2 binding model, and RNA sequencing (RNA-seq) with miRNA overexpression and silencing. We report that the central regulators of endothelial activity, KLF2 for quiescence, PFKFB3 for glycolysis, and VEGFA, FOXO1 and MYC for growth and proliferation, are regulated by transcription factor NRF2 and the NRF2-regulated miR-106b∼25 cluster member, miR-93, in HUVECs. Mechanistically, oxPAPC was found to induce glycolysis and proliferation NRF2-dependently, and oxPAPC-dependent induction of the miR-106b∼25 cluster was mediated by NRF2. Additionally, several regulatory loops were established between NRF2, miR-93 and the essential regulators of healthy endothelium, collectively implying that NRF2 controls the switch between the quiescent and the proliferative endothelial states together with miR-93.

Physiologically based pharmacokinetic modelling of oxycodone drug-drug interactions.

Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug-drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3-4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4-4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.

Nurses´ perceptions of automated dispensing cabinets - an observational study and an online survey.

BACKGROUND: Thirty-two automated dispensing cabinets (ADCs) were introduced in May 2015 in Kuopio University Hospital, Finland. These medication distribution systems represent relatively new technology in Europe and are aimed at rationalising the medication process and improving patient safety. Nurses are the end-users of ADCs, and it is therefore important to survey their perceptions of ADCs. Our aim was to investigate nurses' perceptions of ADCs and the impacts of ADCs on nurses' work. METHODS: The study was conducted in the Anaesthesia and Surgical Unit (OR) and Intensive Care Unit (ICU), of a tertiary care hospital, in Finland. We used two different research methods: observation and a survey. The observational study consisted of two 5-day observation periods in both units, one before (2014) and the other after (2016) the introduction of ADCs. An online questionnaire was distributed to 346 nurses in April 2017. The data were analysed using descriptive statistics including frequencies and percentages and the Chi-Square test. RESULTS: The majority (n = 68) of the 81 respondents were satisfied with ADCs. Attitudes to ADCs were more positive in the ICU than in the OR. Nearly 80% of the nurses in the ICU and 42% in the OR found that ADCs make their work easier. The observational study revealed that in the OR, time spent on dispensing and preparing medications decreased on average by 32 min per 8-h shift and more time was spent on direct patient care activities. The need to collect medicines from outside the operating theatre during an operation was less after the introduction of ADCs than before that. Some resistance to change was observed in the OR in the form of non-compliance with some instructions; nurses took medicines from ADCs when someone else was logged in and the barcode was not always used. The results of the survey support these findings. CONCLUSIONS: Overall, nurses were satisfied with ADCs and stated that they make their work easier. In the ICU, nurses were more satisfied with ADCs and complied with the instructions better than the nurses in the OR. One reason for that can be the more extensive pilot period in the ICU.

Analgesic efficacy and pharmacokinetics of epidural oxycodone in pain management after gynaecological laparoscopy-A randomised, double blind, active control, double-dummy clinical comparison with intravenous administration.

AIMS: Early pain after laparoscopy is often severe. Oxycodone is a feasible analgesic option after laparoscopy, but there are sparse data on epidural administration. The aim was to evaluate the analgesic efficacy and pharmacokinetics of a single dose of epidural oxycodone as a part of multimodal analgesia after gynaecological laparoscopy. METHODS: Women (n = 60), aged 23-71 years, undergoing elective gynaecological laparoscopy, were administrated either epidural oxycodone 0.1 mg kg-1 and intravenous (i.v.) saline (EPI-group n = 31), or epidural saline and i.v. oxycodone 0.1 mg kg-1 (IV-group = 29) in a randomised, double blind, active control, double dummy clinical trial. A pharmacokinetic model was developed using population modelling of plasma and cerebrospinal fluid (CSF) concentrations obtained in these patients and data of 2 published studies. The primary outcome was the amount of i.v. fentanyl for rescue analgesia during the first 4 hours. RESULTS: Twenty of the 31 patients in the EPI-group and 26 of the 29 patients in the IV-group needed i.v. fentanyl for rescue analgesia, P = .021. The median (interquartile range) number of fentanyl doses were 1.0 (1.0-3.0) in the EPI-group and 2.5 (1.0-4.0) doses in the IV-group, P = .008. Plasma concentrations were similar, but CSF concentrations were 100-fold higher in the EPI-group. The population model indicated that 60% of oxycodone injected into the epidural space enters into CSF and 40% is absorbed into the systemic circulation. CONCLUSIONS: The data support superiority of epidural administration of oxycodone compared to i.v. administration during the first hours after laparoscopic surgery. This is likely to be based on enhanced permeation into the central nervous system after epidural administration.

Resilience in children and their parents enduring pediatric medical traumatic stress.

Due to the general lack of familiarity with the concept in the medical field, resilience is rarely considered in pediatric medical traumas. Resilience is an ability that enables recovery after adversities such as traumas, surgeries, serious health problems, or social issues. Stress from medical traumas encompasses both the psychological and physical responses of children and their families. Lack of resilience in children with medical traumatic stress may contribute to poor adjustment, slow recovery, disruptive behaviors, and psychiatric disorders. Furthermore, persistent parental distress increases the child's risk of low resilience. Consequently, these patients and their parents require early identification. This is achievable using a common stress measure such as the Perceived Stress Scale. Moreover, health care providers can screen patients' risks for low resilience, which include few social contacts, poor family functioning, and low cohesion among family members. Findings from the stress scale and screened risks could indicate the need for additional psychosocial support at the time of diagnosis of a serious illness, soon after injuries, and before and after operations. Such interventions can include decreasing distress, counseling children and their parents, and enabling strong connections to health care providers. Health care providers can help parents to minimize distress and adjust to their child's illness, thereby supporting the child's resilience, adjustment, and recovery.

The analgesic efficacy and pharmacokinetics of epidural oxycodone after gynaecological laparotomy: a randomized, double-blind, double-dummy comparison with intravenous administration.

AIM: The aim of the present study was to compare the analgesic efficacy of epidural and intravenous (i.v.) oxycodone at the same dose. METHODS: In this randomized, double-blind, double-dummy clinical trial, 30 women, aged 24-67 years, undergoing elective gynaecological laparotomy, were administrated either i.v. saline and epidural oxycodone 0.1 mg·kg-1 (EPI group; n = 15) or i.v. oxycodone 0.1 mg·kg-1 and epidural saline (IV group; n = 15). For multimodal analgesia, patients received i.v. paracetamol and dexketoprofen, and a triple-mixture epidural infusion after the first 4 h postoperatively. The primary outcome was the total dose of i.v. fentanyl for rescue analgesia during the first 4 h postoperatively. RESULTS: All patients required fentanyl during the first 4 h. The median number of fentanyl doses were three (quartiles 1, 8) in the EPI group and seven (6, 9) in the IV group (mean difference 3.1; 95% confidence interval 0.9, 5.2; P = 0.01). After the first 4 h, the two groups needed a similar total dose of epidural infusion. Patient satisfaction was similarly high in both groups, and both administration routes were well tolerated. CONCLUSIONS: The data support the superiority of epidural oxycodone compared with that of i.v. administration in pain management after laparotomy.

How do different extracorporeal circulation systems affect metoprolol bioavailability in coronary artery bypass surgery patients.

PURPOSE: Cardiac surgery and conventional extracorporeal circulation (CECC) impair the bioavailability of drugs administered by mouth. It is not known whether miniaturized ECC (MECC) or off-pump surgery (OPCAB) affect the bioavailability in similar manner. We evaluated the metoprolol bioavailability in patients undergoing CABG surgery with CECC, MECC, or having OPCAB. METHODS: Thirty patients, ten in each group, aged 44-79 years, scheduled for CABG surgery were administered 50 mg metoprolol by mouth on the preoperative day at 8-10 a.m. and 8 p.m., 2 h before surgery, and thereafter daily at 8 a.m. and 8 p.m. Blood samples were collected up to 12 h after the morning dose on the preoperative day and on first and third postoperative days. Metoprolol concentration in plasma was analyzed using liquid chromatography-mass spectrometry. RESULTS: The absorption of metoprolol was markedly reduced on the first postoperative day in all three groups, but recovered to the preoperative level on the third postoperative day. The geometric means (90% confidence interval) of AUC0-12 on the first and third postoperative days versus the preoperative day were 44 (26-74)% and 109 (86-139)% in the CECC-group, 28 (16-50)% and 79 (59-105)% in the MECC-group, and 26 (12-56)% and 96 (77-119)% in the OPCAB-group, respectively. Two patients in the CECC-group and two in the MECC-group developed atrial fibrillation (AF). The bioavailability and the drug concentrations of metoprolol in patients developing AF did not differ from those who remained in sinus rhythm. CONCLUSION: The bioavailability of metoprolol by mouth was markedly reduced in the early phase after CABG with no difference between the CECC-, MECC-, and OPCAB-groups.