Tramadol-paracetamol for postoperative pain after spine surgery - A randomized, double-blind, placebo-controlled study.

OBJECTIVES: Multimodal pain management is one component in enhanced recovery after surgery protocol. Here we evaluate the efficacy of tramadol-paracetamol in acute postoperative pain and pain outcome at 12 months after spine surgery in randomized, double-blind, placebo-controlled trial. METHODS: We randomized 120 patients undergoing spine surgery to receive, for add-on pain management, two tramadol-paracetamol 37.5 mg/325 mg (n = 61) or placebo tablets (n = 59) twice a day for 5 postoperative days. In the hospital, multimodal pain management consisted of dexketoprofen and oxycodone. After discharge, patients were prescribed ibuprofen 200 mg, maximum 1,200 mg/day. Pain, analgesic use, and satisfaction with pain medication were followed up with the Brief Pain Inventory questionnaire before surgery and at 1 and 52 weeks after surgery. The primary outcome was patients' satisfaction with pain medication 1 week after surgery. RESULTS: At 1 week after surgery, patients' satisfaction with pain medication was similarly high in the two groups, 75% [interquartile range, 30%] in the placebo group and 70% [40%] in the tramadol-paracetamol group (p = 0.949) on a scale: 0% = not satisfied, 100% = totally satisfied. At 1 week, ibuprofen dose was lower in the placebo group 200 mg [1,000] compared to the tramadol-paracetamol group, 800 mg [1,600] (p = 0.016). There was no difference in the need for rescue oxycodone. Patients in the tramadol-paracetamol group had more adverse events associated with analgesics during the first postoperative week (relative risk = 1.8, 95% confidence interval, 1.2-2.6). CONCLUSION: Add-on pain treatment with tramadol-paracetamol did not enhance patients' satisfaction with early pain management after back surgery.

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.

Non-obstetric surgery during pregnancy and the effects on maternal and fetal outcomes: A systematic review.

BACKGROUND AND OBJECTIVE: Non-obstetric surgery is fairly common in pregnant women. We performed a systematic review to update data on non-obstetric surgery in pregnant women. The aim of this review was to evaluate the effects of non-obstetric surgery during pregnancy on pregnancy, fetal and maternal outcomes. METHODS: A systematic literature search of MEDLINE and Scopus was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search span was from January 2000 to November 2022. Thirty-six studies matched the inclusion criteria, and 24 publications were identified through reference mining; 60 studies were included in this review. Outcome measures were miscarriage, stillbirth, preterm birth, low birth weight, low Apgar score, and infant and maternal morbidity and mortality rates. RESULTS: We obtained data for 80,205 women who underwent non-obstetric surgery and data for 16,655,486 women who did not undergo surgery during pregnancy. Prevalence of non-obstetric surgery was between 0.23% and 0.74% (median 0.37%). Appendectomy was the most common procedure with median prevalence of 0.10%. Near half (43%) of the procedures were performed during the second trimester, 32% during the first trimester, and 25% during the third trimester. Half of surgeries were scheduled, and half were emergent. Laparoscopic and open techniques were used equally for abdominal cavity. Women who underwent non-obstetric surgery during pregnancy had increased rate of stillbirth (odds ratio (OR) 2.0) and preterm birth (OR 2.1) compared to women without surgery. Surgery during pregnancy did not increase rate of miscarriage (OR 1.1), low 5 min Apgar scores (OR 1.1), the fetus being small for gestational age (OR 1.1) or congenital anomalies (OR 1.0). CONCLUSIONS: The prevalence of non-obstetric surgery has decreased during last decades, but still two out of 1000 pregnant women have scheduled surgery during pregnancy. Surgery during pregnancy increases the risk of stillbirth, and preterm birth. For abdominal cavity surgery, both laparoscopic and open approaches are feasible.

Cerebrospinal Fluid Diagnostics of Alzheimer's Disease in Patients with Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide and a frequent comorbidity in idiopathic normal pressure hydrocephalus (iNPH). The presence of AD pathology is associated with worse outcomes after a shunt procedure in iNPH. Preoperative diagnosis of AD is challenging in patients with iNPH, which involves reduced concentrations of the cerebrospinal fluid (CSF) AD biomarkers. OBJECTIVE: Our aim was to estimate the effect size of iNPH as a factor in CSF levels of AD biomarkers and to test if correction could be used to improve diagnostic value. METHODS: Our cohort included 222 iNPH patients with data in the Kuopio NPH registry and brain biopsy and CSF samples available. We divided the patients into groups according to AD pathology per brain biopsy. For control cohorts, we had CSF samples from cognitively healthy individuals (n = 33) and patients with diagnosed AD and no iNPH (n = 39).*-31ptResults:Levels of all investigated biomarkers differed significantly between groups, with the exception of t-Tau levels between healthy individuals and iNPH patients with AD pathology. Applying a correction factor for each biomarker (0.842*Aß1 - 42, 0.779*t-Tau, and 0.610*P-Tau181) for the effect of iNPH yielded a sensitivity of 2.4% and specificity of 100%. The ratio of P-Tau181 to Aß1 - 42 was moderately effective in aiding recognition of AD pathology in iNPH patients (sensitivity 0.79, specificity 0.76, area under the curve 0.824). CONCLUSION: Correcting for iNPH as a factor failed to improve diagnostic effectiveness, but the P-Tau181/Aß1 - 42 ratio showed some utility in the diagnosis of AD in iNPH patients.

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.

Psychiatric symptoms and couple satisfaction in parents of newborns before and during the COVID-19 pandemic-A comparison of two prospective studies.

AIMS: To assess anxiety, depression, perceived stress, couple satisfaction and life satisfaction of parents of healthy newborns in two cohorts in 2015 and in 2020 during the COVID-19 pandemic. DESIGN: A prospective follow-up study. METHODS: We enrolled 60 parents of healthy newborns (n = 30 dyads) in 2015 and 60 parents (n = 30 dyads) in 2020. Both parents completed six valid and reliable questionnaires independently 1-2 days and 12 months after delivery: Beck Anxiety Inventory, Beck Depression Inventory-II, Edinburgh Postnatal Depression Scale, Perceived Stress Scale, Couple Satisfaction Index and Life Satisfaction Scale-4. RESULTS: Anxiety was more common but couple satisfaction better in both parents during the COVID-19 pandemic than in 2015. Depressive symptoms and perceived stress were similarly low, and life satisfaction was similarly high in both cohorts, indicating ample parental resilience. There was a moderate positive association between previous mental health disorders and parental anxiety after delivery during the COVID-19 pandemic.

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.

Central nervous system distribution of buprenorphine in pregnant sheep, fetuses and newborn lambs after continuous transdermal and single subcutaneous extended-release dosing.

Buprenorphine is used during pregnancy for the treatment of opioid use disorder. Limited data exist on the central nervous system (CNS) permeation and distribution, and on the fetal exposure to buprenorphine. The aim of our study was to determine the extent of buprenorphine distribution to CNS in the pregnant sheep, and their fetus at steady-state, and their newborn lambs postdelivery, using three different dosing regimens. Twenty-eight pregnant ewes in late gestation received buprenorphine via 7-day transdermal patch releasing buprenorphine 20 µg/h (n=9) or 40 µg/h (n=11), or an extended-release 8 mg/week subcutaneous injection (n=8). Plasma, cerebrospinal fluid, and CNS tissue samples were collected at steady-state from ewes and fetuses, and from lambs 0.33 - 45 hours after delivery. High accumulation of buprenorphine was observed in all CNS tissues. The median CNS/plasma concentration -ratios of buprenorphine in different CNS areas ranged between 13 and 50 in the ewes, and between 26 and 198 in the fetuses. In the ewes the CNS/plasma -ratios were similar after the three dosing regimens, but higher in the fetuses in the 40 µg/h dosing group, medians 65 - 122, than in the 20 µg/h group, medians 26 - 54. The subcutaneous injection (theoretical release rate 47.6 µg/h) produced higher concentrations than observed after 40 µg/h transdermal patch dosing. The median fetal/maternal concentration -ratios in different dosing groups ranged between 0.21 and 0.54 in plasma, and between 0.38 and 1.3 in CNS tissues, respectively, with the highest ratios observed in the spinal cord. Buprenorphine concentrations in the cerebrospinal fluid were 8 - 13 % of the concurrent plasma concentration in the ewes and 28 % in the fetuses. Buprenorphine was quantifiable in the newborn lambs' plasma and CNS tissues two days postdelivery. Norbuprenorphine was analyzed from all plasma, cerebrospinal fluid, and CNS tissue samples but was nondetectable or below the LLOQ in most. The current study demonstrates that buprenorphine accumulates into CNS tissues at much higher concentrations than in plasma in pregnant sheep, fetuses, and their newborn lambs even 45 hours after delivery.

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.

In utero deposition of trace elements and metals in tissues.

INTRODUCTION: All animals, including humans, are exposed to heavy metals which are known to accumulate in different tissues, especially in bone. During pregnancy, the maternal bone turnover is increased and the metals in the mother's body can be mobilized into the bloodstream. Heavy metals in maternal blood are known to pass through the placenta to the fetal blood and finally, deposited to bone tissue. However, there are no studies on the concentration of metals in the fetal solid tissues and until now, the rate of metal transfer from mother to fetus is not exactly known. MATERIALS AND METHODS: Samples of the blood, liver, placenta, and three different bones were collected from 17 pregnant ewes and their 27 fetuses. The animals had no known exposure to heavy metals. The concentrations of Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, P, Pb, Rb, Sb, Sn, Sr, Te, Ti, Tl, V, and Zn were analyzed using ICP-MS. RESULTS AND DISCUSSION: The concentration of Sb, Sn, Te, and Tl were under the detection limit in all the samples. The other metals were found in all maternal and fetal tissues, suggesting that all detectable metals cross the placenta. Blood concentrations were low compared to solid tissue concentrations. The concentrations of essential elements varied between maternal and fetal tissues, which could be explained by biological differences. The differences in concentrations of non-essential elements between the ewe and fetuses were smaller. The most significant differences were between maternal and fetal concentrations of Ba and Sr, which is at least partly explained by the mineralization degree of the bone. CONCLUSION: Heavy metals accumulate in fetal solid tissues in sheep that are not directly exposed to heavy metals. Because of the differences in anatomy between human and sheep placenta, the accumulation in the tissue of human fetuses should be extrapolated cautiously. However, there might be some clinical relevance for fertile aged women who are exposed to heavy metals, such as women who work in the metal industry or who have undergone joint replacement surgery.

Epidural Oxycodone for Acute Pain.

Epidural analgesia is commonly used in labour analgesia and in postoperative pain after major surgery. It is highly effective in severe acute pain, has minimal effects on foetus and newborn, may reduce postoperative complications, and enhance patient satisfaction. In epidural analgesia, low concentrations of local anaesthetics are combined with opioids. Two opioids, morphine and sufentanil, have been approved for epidural use, but there is an interest in evaluating other opioids as well. Oxycodone is one of the most commonly used opioids in acute pain management. However, data on its use in epidural analgesia are sparse. In this narrative review, we describe the preclinical and clinical data on epidural oxycodone. Early data from the 1990s suggested that the epidural administration of oxycodone may not offer any meaningful benefits over intravenous administration, but more recent clinical data show that oxycodone has advantageous pharmacokinetics after epidural administration and that epidural administration is more efficacious than intravenous administration. Further studies are needed on the safety and efficacy of continuous epidural oxycodone administration and its use in epidural admixture.

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.

Peripheral chemoreflex activation and cardiac function during hypoxemia in near-term fetal sheep without placental compromise.

A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheral vasoconstriction and redistribution of blood flow to protect the brain, myocardium, and adrenal glands. By using a chronically instrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship between peripheral chemoreflex activation induced by hypoxemia and central hemodynamics. A total of 17 Åland landrace sheep fetuses at 115-128/145 gestational days were instrumented. Carotid artery was catheterized in 10 fetuses and descending aorta in 7 fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascular hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane anesthesia. Comparable data to baseline were collected 10 min (acute hypoxemia) and 60 min (prolonged hypoxemia) after maternal hypo-oxygenation to saturation level of 70%-80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower and lactate levels were higher in the descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aorta increased, whereas in the carotid artery, MAP decreased. In addition, right pulmonary artery pulsatility index values increased, and the diastolic component in the aortic isthmus blood flow velocity waveform became more retrograde, thus decreasing the aortic isthmus antegrade/retrograde blood flow (AoI Net Flow) ratio. Both fetal ventricular cardiac outputs were maintained even during prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hypoxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed left ventricular cardiac output (LVCO) or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.NEW & NOTEWORTHY During fetal hypoxemia with intact placental circulation, peripheral chemoreflex was activated, as demonstrated by an increase in the descending aorta blood pressure, pulmonary vasoconstriction, and an increase in retrograde diastolic AoI blood flow, while both ventricular cardiac outputs remained stable. However, perfusion pressure in the cerebral circulation decreased. These changes were seen even during prolonged hypoxemia when significant metabolic acidosis developed. Weight-indexed LVCO or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.

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.

MATERNAL AND FETAL BUPRENORPHINE PHARMACOKINETICS IN PREGNANT SHEEP DURING TRANSDERMAL PATCH DOSING: Buprenorphine pharmacokinetics in pregnant sheep.

BACKGROUND: Buprenorphine is used in the opioid maintenance treatment for opioid dependent patients, including pregnant women. Despite the wide use, limited data exists on buprenorphine pharmacokinetics and fetal exposure during pregnancy. The aim of our study was to determine the buprenorphine pharmacokinetics during transdermal patch dosing to pregnant sheep and, to determine the extent of transplacental transfer of buprenorphine to the fetus. METHODS: Pregnant sheep in late gestation (n=50) received 20, 25 or 40 µg/h of buprenorphine as a 7-day extended-release transdermal patch. Plasma samples were collected from the ewe and the fetus on days 1 - 6, and buprenorphine and norbuprenorphine concentrations were determined. During the exposure period the sheep had a surgical procedure on the second day, a recovery phase, and an experimental procedure on the sixth day. In the experiment, hypoxia was induced under anesthesia for 18 sheep to investigate if decreased fetal pH would cause ion-trapping of buprenorphine in the fetus. The fetal/maternal plasma concentration ratio was determined on the second and on the sixth exposure day at baseline and during hypoxia. Maternal pharmacokinetics were modelled with a population pharmacokinetic method using the data from this study and our previous intravenous administration study. RESULTS: The transdermal patch provided an extended release of buprenorphine throughout the exposure period, but the release rate declined approximately 20 h after patch placement. The median fetal/maternal plasma concentration ratio was 13 - 27 % throughout the exposure period at baseline. A ratio over 100 % was observed for four sheep on the sixth exposure day (102 - 269 %). A minor increase was seen in the median fetal/maternal-ratios during maternal hypoxia. Norbuprenorphine was undetected in all plasma samples. CONCLUSIONS: The low transplacental passage of less than one fourth of the ewe's exposure supports buprenorphine as an alternative to methadone in opioid maintenance therapy during pregnancy.

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= .