Merja Kokki

Objectives: This retrospective study aimed to estimate vancomycin area under the curve over 24 h (AUC₂₄) at steady state for pediatric patients from 1 month to 18 years to update the dose recommendations in a tertiary hospital. Methods: A total of 46 vancomycin treatments from 42 patients in the years 2014–2024 were analyzed. AUC₂₄ was estimated for the initial dose regimen using Bayesian forecasting and a trough concentration (n = 32) or first-order pharmacokinetic (PK) equations and a pair of practical peak and trough concentrations at steady state (n = 14). Three published population PK models (Colin, Kloprogge, and Le models) were compared using typical parameter values (a priori predictions) to find a suitable model for Bayesian estimation. For the Le model, the effect of converting plasma creatinine (PCr) measured with IDMS-traceable enzymatic assay to Jaffe method value was evaluated using published equations. Results: Le model without enzymatic-to-Jaffe PCr conversion and the Colin model were suitable for Bayesian forecasting. These models gave similar Bayesian AUC₂₄ estimates (a posteriori). In all 46 treatments, estimated AUC₂₄ was within the currently recommended range of 400–600 mg·h/L in 8 (17%) treatments, below this range in 36 (78%) treatments, and above this range in 2 (4%) treatments, respectively. Estimated AUC₂₄ was below 300 mg·h/L in 46% of treatments. Conclusions: Le and Colin models were suitable for our pediatric patients for Bayesian forecasting. AUC₂₄ estimates for the initial dose regimen were lower than commonly recommended. A more uniform dosing policy is needed in our hospital, and higher initial doses should be considered.

Background: Epidural oxycodone is a highly effective analgesic. However, oxycodone's distribution in the spinal cord after epidural injection is not known. In this experimental study, we evaluated the segmental spinal cord, brain, cerebrospinal fluid and plasma distribution and foetal exposure of epidurally administered oxycodone in a pregnant sheep model. Methods: Twenty‐eight pregnant ewes were given a single 0.1 mg/kg ( n = 23) or 0.2 mg/kg ( n = 5) epidural oxycodone bolus through a lumbar catheter. Tissue samples were collected from the spinal cord at the epidural catheter tip area, 10 cm caudal and 10, 20 and 30 cm cranial to that, brain tissue, cerebrospinal fluid and plasma after euthanasia from ewes and foetuses. The concentrations of oxycodone and its metabolites oxymorphone and noroxycodone were analysed with ultra‐performance liquid chromatography mass spectrometry. Results: During autopsy, 23 ewes had catheters in the epidural space. The median oxycodone concentrations in the ewes' spinal cord were 9820 (IQR: 1001, 11,600) ng/g at the epidural catheter tip area, and similar at 10 cm caudal and at 10 and 20 cm cranial to that. At 30 cm cranial to the tip site, the concentration was significantly lower, 2910 (600, 8895) ng/g. Oxycodone concentrations in the ewes' brain tissues were substantially lower, IQR 53–155 ng/g, as were the plasma concentrations (IQR: 8.4–16 ng/mL) and CSF concentrations (IQR 6.1–34 ng/mL). Foetal exposure to oxycodone was negligible. Conclusions: This experimental study suggests that after epidural administration, oxycodone distributes into the spinal cord in high concentrations over a relatively long area. Editorial Comment: In this large animal experimental model involving pregnant ewes, oxycodone kinetics after epidural injection were examined for different doses. Concentrations of the test drug were measured in tissues at different times throughout the central nervous systems, after ending the experiment.

Background: Plasma phosphorylated tau isoforms 181 (pTau181) and 217 (pTau217) are promising Alzheimer's disease (AD) biomarkers. Objective: We evaluated the performance of pTau181 and pTau217 in the differential diagnostics between AD, other neurodegenerative diseases and non-neurodegenerative participants. Methods: We included 104 patients with neurodegenerative diseases (37 with AD, 21 with synucleinopathies [SYNU], 24 with frontotemporal dementia [FTD] and 22 with idiopathic normal-pressure hydrocephalus [iNPH]) and 50 participants without neurodegenerative disorders (33 individuals undergoing knee arthroplasty and 17 with psychiatric diagnoses). pTau181 and pTau217 were measured via single-molecule array. Results: pTau181 differentiated AD patients from psychiatric patients with an area under the curve (AUC) of 0.879 and AD patients from all other participants with an AUC of 0.685. pTau181 was higher in patients with AD compared to FTD, iNPH, and non-neurodegenerative (ND) patients. pTau217 differentiated AD patients from psychiatric patients, with an AUC of 0.998, and AD patients from all other groups, with an AUC of 0.835. pTau217 was higher in AD patients compared to ND, FTD, and SYNU patients, but it did not differ between AD and iNPH patients without adjustment for age as a covariate. Conclusions: Our prospective cohort data indicate that pTau217 differentiates AD patients from psychiatric patients, with an excellent AUC value in receiver operating characteristic analysis. Our study supports the use of pTau217 rather than pTau181 as a minimally invasive tool to differentiate AD from non-neurodegenerative diseases (e.g., psychiatric disorders). Further studies are needed to determine the nature of pTau217 in iNPH.

There are scarce data on the development of health-related quality of life (HRQoL) over time and how psychological factors affect patients’ adaptation to severe pulmonary diseases. This prospective 24-month follow-up study assessed HRQoL and its associations with anxiety, depression, resilience, and life satisfaction in pulmonary disease patients receiving ambulatory oxygen therapy. We enrolled 47 patients who were prescribed ambulatory oxygen therapy for severe pulmonary diseases, and 3 months of data have been published previously. Patients completed five questionnaires at baseline and at 3, 6, 12 and 24 months: the 15D HRQoL instrument, the Hospital Anxiety and Depression Scale (HADS), the Life Satisfaction Scale-4, the Resilience Scale-25, and the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST 2.0). The primary outcome was the HRQoL at 24 months. At 24 months, data were available for 19 patients (response rate 40%). Patients had very low HRQoL at baseline, which decreased substantially during the 24-month follow-up. There was a strong inverse correlation between HRQoL and anxiety, depression and life satisfaction and a strong positive correlation with resilience. However, half of the patients with severe pulmonary diseases receiving ambulatory oxygen therapy who had better psychological functioning were happy with life and did not feel lonely at all. Patient satisfaction with assistive technology and services was high. A low HRQoL in patients with severe pulmonary disease is strongly associated with poor psychological functioning. As anxiety, depression and resilience are modifiable factors, these factors should be evaluated in patients prescribed ambulatory oxygen therapy. ClinicalTrials.gov Protocol Record 507A023. Registered 17 September 2020 - Registered, https://clinicaltrials.gov/ct2/results?cond=&term=NCT04554225&cntry=&state=&city=&dist= .

Background: Idiopathic normal pressure hydrocephalus (iNPH) is a common disorder in aging populations. Alzheimer's disease (AD) is a significant comorbidity in iNPH patients, and the presence of AD pathology is associated with worse shunting outcomes. Cerebrospinal fluid (CSF) concentrations of AD-associated biomarkers in iNPH patients are universally reduced and the exact mechanism related to this is unknown. Objective: Our aim was to study the effects of ventricular volume on CSF AD-associated biomarker levels in iNPH patients, to determine whether a dilution effect occurs and to assess if brain AD pathology contributes to this effect. Methods: A total of 153 iNPH patients had lumbar CSF samples available for analysis, along with brain MRIs of sufficient quality. Automated image analysis software was used to determine the volume of different brain segments. Volumes normalized for age, sex and head size were used for analysis. Brain biopsy data on AD pathology was also available. Results: None of the intracerebral ventricular volumes correlated with CSF levels of AD-associated biomarkers, indicating no dilution effect was present in this context. However, in iNPH patients positive for amyloid-β pathology in the biopsy, the volume of the fourth ventricle correlated inversely with all investigated biomarkers. Conclusions: Intracerebral ventricular volumes do not correlate with AD biomarker levels in CSF, arguing against a dilution effect. However, in patients with AD pathology, the volume of the fourth ventricle is inversely correlated with CSF T-Tau and P-Tau ₁₈₁ levels, suggesting a complex relationship between brain AD pathology, CSF flow and CSF volume in iNPH patients.

Background/Objectives: Psychological factors impact patient-reported outcome measures (PROMs). This study assessed the influence of preoperative anxiety, depression, and resilience on postoperative pain interference and life satisfaction one year after spine surgery. Methods: This study was a secondary analysis of a study involving 120 patients who underwent elective spine surgery and were randomly assigned to receive either tramadol–paracetamol (37.5 mg/325 mg; two tablets; n = 61) or placebo (n = 59) twice per day for pain management during the first five postoperative days. Patients completed the Life Satisfaction Scale-4, Brief Pain Inventory, Hospital Anxiety and Depression Scale, and Resilience Scale-14 questionnaires before surgery and at 28 days and 52 weeks post surgery. The primary outcomes were life satisfaction and pain interference at 12 months after spine surgery and their associations with preoperative anxiety, depression, and resilience. Results: Data from 113 patients (94% response rate) were collected at 52 weeks postoperatively. The number of patients reporting satisfaction with their life increased from three (5%) and two (3%) before surgery to 23 (41%) and 19 (34%), while pain interference decreased from a median of 4.1 to 1.2 and from 4.4 to 1.9 on a scale of 0–10 at 12 months in the placebo and tramadol–paracetamol groups, respectively. The linear regression analysis revealed no statistically significant predictive value for preoperative anxiety, depression, or resilience score for life satisfaction and pain interference at 12 months after spine surgery. Conclusions: These results highlight that psychological factors, anxiety, depression, and resilience did not have an impact on postoperative pain outcomes and life satisfaction in patients undergoing spine surgery.

Background and Objective For neonates and infants receiving intermittent vancomycin infusions, the area under the concentration-time curve during 24 h (AUC24) is often estimated with Bayesian forecasting using one or more measured vancomycin concentrations. When practical peak and trough concentrations are measured at steady state, AUC24 can also be calculated with first-order steady-state equations for a one-compartment model (Sawchuk–Zaske method), but previously this method has been applied only for adults. The objective of this study was to compare AUC24 values obtained with the Sawchuk–Zaske method and two Bayesian models. Methods AUC24 values were estimated retrospectively for 18 neonates and infants with steady-state peak and trough concentrations using traditional compartmental analysis with a one-compartment model (reference method), the Sawchuk–Zaske method, and Bayesian forecasting with two previously published models. In Bayesian forecasting, both original and modified residual error models were used. In the modified models, the residual error was reduced by setting the additive residual error to zero and the proportional error to 15%. Results AUC24 estimates obtained with the Sawchuk–Zaske method differed − 2.7 to 0.9% from the reference method. When both peak and trough concentrations were used in Bayesian forecasting, 61% and 33% of AUC24 estimates obtained with two original models differed less than 15% from the reference method, and these fractions increased to 83% and 72% with the modified models, respectively. Conclusion When practical peak and trough concentrations are measured at steady state, the simple Sawchuk–Zaske method is very useful for AUC24 estimation in neonates and infants. In Bayesian forecasting, the reduced residual error model can be used to improve the model fit.

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.

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.