The risk of delirium after sedation with propofol or midazolam in intensive care unit patients.

AIM: Knowledge of risk factors may provide strategies to reduce the high burden of delirium in intensive care unit (ICU) patients. We aimed to compare the risk of delirium after deep sedation with propofol versus midazolam in ICU patients. METHODS: In this prospective cohort study, ICU patients who were in an unarousable state for ≥24 h due to continuous sedation with propofol and/or midazolam were included. Patients admitted ≤24 h, those with an acute neurological disorder and those receiving palliative sedation were excluded. ICU patients were assessed daily for delirium during the 7 days following an unarousable state due to continuous sedation. RESULTS: Among 950 included patients, 605 (64%) subjects were delirious during the 7 days after awaking. The proportion of subsequent delirium was higher after midazolam sedation (152/207 [73%] patients) and after both propofol and midazolam sedation (257/377 [68%] patients), compared to propofol sedation only (196/366 [54%] patients). Midazolam sedation (adjusted cause-specific hazard ratio [adj. cause-specific HR] 1.32, 95% confidence interval [CI] 1.05-1.66) and propofol and midazolam sedation (adj. cause-specific HR 1.29, 95% CI 1.06-1.56) were associated with a higher risk of subsequent delirium compared to propofol sedation only. CONCLUSION: This study among sedated ICU patients suggests that, compared to propofol sedation, midazolam sedation is associated with a higher risk of subsequent delirium. This risk seems more apparent in patients with high cumulative midazolam intravenous doses. Our findings underpin the recommendations of the Society of Critical Care Medicine Pain, Agitation/sedation, Delirium, Immobility (rehabilitation/mobilization), and Sleep (disruption) guidelines to use propofol over benzodiazepines for sedation in ICU patients.

A simple extemporaneous oral suspension of aprepitant yields sufficient pharmacokinetic exposure in children.

INTRODUCTION: Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment. The current pharmacokinetic study was developed to investigate whether this extemporaneous oral suspension offers an appropriate treatment option. METHODS: From 49 pediatric patients (0.7-17.9 years) 235 plasma concentrations were collected. Patients were either treated with our extemporaneous oral suspension (n = 26; 53%), commercially available capsules (n = 18; 37%), or the intravenous prodrug formulation of aprepitant (fosaprepitant, n = 5; 10%). Pharmacokinetic analyses were performed using nonlinear mixed effects modelling. RESULTS: A one-compartment model adequately described the pharmacokinetics of aprepitant in children. The bioavailability of the extemporaneous oral suspension was not significantly different to that of the capsules (P = 0.26). The observed bioavailability throughout the total population was 83% (95% CI 69%-97%). The absorption of the extemporaneous oral suspension was 39.4% (95%CI 19.5-57.4%) faster than that of capsules (mean absorption time of 1.78 h (95%CI 1.32-2.35), but was comparable to that of the commercial oral suspension. The median area under the curve after (fos)aprepitant was 22.2 mg/L*h (range 8.9-50.3 mg/L*h) on day 1. CONCLUSION: Our extemporaneous oral suspension is an adequate alternative for the commercially (un)available oral suspension in young children. An adequate exposure to aprepitant in children was yielded and the bioavailability of the extemporaneous suspension was comparable to capsules.

A Population Pharmacokinetic Modelling Approach to Unravel the Complex Pharmacokinetics of Vincristine in Children.

BACKGROUND: Vincristine, a chemotherapeutic agent that extensively binds to ß-tubulin, is commonly dosed at 1.4-2.0 mg/m2 capped at 2 mg. For infants, doses vary from 0.025-0.05 mg/kg or 50-80% of the mg/m2 dose. However, evidence for lower doses in infants compared to older children is lacking. This study was conducted to unravel the complex pharmacokinetics of vincristine, including the effects of age, to assist optimal dosing in this population. METHODS: 206 patients (0.04-33.9 years; 25 patients < 1 years), receiving vincristine, with 1297 plasma concentrations were included. Semi-mechanistic population pharmacokinetic analyses were performed using non-linear mixed effects modelling. RESULTS: A three-compartment model, with one saturable compartment resembling saturable binding to ß-tubulin and thus, saturable distribution, best described vincristine pharmacokinetics. Body weight and age were covariates significantly influencing the maximal binding capacity to ß-tubulin, which increased with increasing body weight and decreased with increasing age. Vincristine clearance (CL) was estimated as 30.6 L/h (95% confidence interval (CI) 27.6-33.0), intercompartmental CL (Q) as 63.2 L/h (95%CI 57.2-70.1), volume of distribution of the central compartment as 5.39 L (95%CI 4.23-6.46) and of the peripheral compartment as 400 L (95%CI 357-463) (all parameters correspond to a patient of 70 kg). The maximal binding capacity was 0.525 mg (95%CI 0.479-0.602) (for an 18 year old patient of 70 kg), with a high association rate constant, fixed at 1300 /h and a dissociation constant of 11.5 /h. INTERPRETATION: A decrease of vincristine ß-tubulin binding capacity with increasing age suggests that young children tolerate higher doses of vincristine.

Overestimation of the effect of (fos)aprepitant on intravenous dexamethasone pharmacokinetics requires adaptation of the guidelines for children with chemotherapy-induced nausea and vomiting.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) are common side effects in pediatric oncology treatment. Besides 5-HT3-antagonists, both dexamethasone and aprepitant are cornerstone drugs in controlling these side effects. Based on results of adult studies, the dexamethasone dose is reduced by 50% when combined with aprepitant, because of a drug-drug interaction, even though data on the interaction in children is lacking. The current study was developed to investigate the effect of aprepitant on dexamethasone clearance (CL) in children, in order to assess if dexamethasone dose reduction for concomitant use of aprepitant is appropriate in the current antiemetic regimen. METHODS: In total, 65 children (0.6-17.9 years), receiving intravenous or oral antiemetic therapy (dexamethasone ± aprepitant) as standard of care, were included. 305 dexamethasone plasma concentrations were determined using LC-MS/MS. An integrated dexamethasone and aprepitant pharmacokinetic model was developed using non-linear mixed effects modelling in order to investigate the effect of aprepitant administration on dexamethasone CL. RESULTS: In this population, dexamethasone CL in patients with concomitant administration of aprepitant was reduced by approximately 30% of the uninhibited CL (23.3 L/h (95% confidence interval 20.4-26.0)). This result is not consistent with the results of adult studies (50% reduction). This difference was not age dependent, but might be related to the route of administration of dexamethasone. Future studies are needed to assess the difference in oral/intravenous dexamethasone. CONCLUSION: When dexamethasone is given intravenously as a component of triple therapy to prevent CINV in children, we advise to reduce the dexamethasone dose by 30% instead of 50%.

Mortality, causes of death and influence of medication use in patients with systemic lupus erythematosus vs matched controls.

OBJECTIVES: We wanted to estimate the magnitude of the risk from all-cause, cause-specific and sex-specific mortality in patients with SLE and relative risks compared with matched controls and to evaluate the influence of exposure to medication on risk of mortality in SLE. METHODS: We conducted a population-based cohort study using the Clinical Practice Research Datalink, Hospital Episode Statistics and national death certificates (from 1987 to 2012). Each SLE patient (n = 4343) was matched with up to six controls (n = 21 780) by age and sex. Cox proportional hazards models were used to estimate overall and cause-specific mortality rate ratios. RESULTS: Patients with SLE had a 1.8-fold increased mortality rate for all-cause mortality compared with age- and sex-matched subjects [adjusted hazard ratio (HR) = 1.80, 95% CI: 1.57, 2.08]. The HR was highest in patients aged 18-39 years (adjusted HR = 4.87, 95% CI: 1.93, 12.3). Mortality rates were not significantly different between male and female patients. Cumulative glucocorticoid use raised the mortality rate, whereas the HR was reduced by 45% with cumulative low-dose HCQ use. Patients with SLE had increased cause-specific mortality rates for cardiovascular disease, infections, non-infectious respiratory disease and for death attributable to accidents or suicide, whereas the mortality rate for cancer was reduced in comparison to controls. CONCLUSION: British patients with SLE had a 1.8-fold increased mortality rate compared with the general population. Glucocorticoid use and being diagnosed at a younger age were associated with an increased risk of mortality. HCQ use significantly reduced the mortality rate, but this association was found only in the lowest cumulative dosage exposure group.

Influence of allopurinol on thiopurine associated toxicity: A retrospective population-based cohort study.

AIMS: Thiopurines are important for treating inflammatory bowel disease, but are often discontinued due to adverse effects. Concomitant use of allopurinol might lower the risk of these unwanted effects, but large studies in the general population are lacking. The aims of this study were to evaluate rates of hepatotoxicity, myelotoxicity, pancreas toxicity and therapy persistence in adult thiopurine users with or without allopurinol. METHODS: A retrospective population-based cohort study was conducted within current thiopurine users (Clinical Practice Research Datalink). Among these patients, co-use of allopurinol was compared to non-use. Hazard ratios (HRs) for hepatotoxicity, myelotoxicity and pancreatitis were derived using time-dependent Cox proportional hazards models, and were adjusted for potential confounders. Persistence of thiopurine use was evaluated using Log-rank statistics. RESULTS: Patients using thiopurines (n = 37 360) were identified of which 1077 were concomitantly taking allopurinol. A 58% decreased risk of hepatotoxicity was observed in those concomitantly taking allopurinol (HR 0.42; 95% CI 0.30-0.60; NNT 46). Rate of myelotoxicity (HR 0.96; 95% CI 0.89-1.03) was not influenced. Risk of pancreatitis was increased (HR 3.00; 95% CI 1.01-8.93; NNH 337), but was only seen in those with active gout (suggesting confounding by indication). Finally, allopurinol co-users were able to maintain thiopurine therapy over twice as long as those not on allopurinol (3.9 years vs. 1.8 years, P < 0.0001). CONCLUSION: In thiopurine users, allopurinol is associated with a 58% reduced risk of hepatotoxicity. In addition, thiopurine persistence was prolonged by 2.1 years in allopurinol users. These data support the use of allopurinol in individuals requiring thiopurine therapy.

A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance.

AIM: To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing. METHODS: Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi-mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment. RESULTS: In both models, a similar clearance decrease of 7% (range -82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6-8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0-73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients. CONCLUSION: These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT.

Pattern of risks of systemic lupus erythematosus among statin users: a population-based cohort study.

OBJECTIVES: To examine the association between the use of statins and the risk of systemic lupus erythematosus (SLE) with focus on describing the patterns of risks over time. SETTING: A population-based cohort study using the UK Clinical Practice Research Datalink. PARTICIPANTS: All patients aged 40 years or older who had at least one prescription of statins during the period 1995-2009 were selected and matched by age, sex, practice and date of first prescription to non-users. The follow-up period of statin users was divided into periods of current, recent and past exposure, with patients moving among these three exposure categories over time. Current statin users were also stratified into ≤1 year or >1 year of use. MAIN OUTCOME MEASURES: Time-dependent Cox models were used to calculate HRs of SLE, adjusted for disease history and previous drug exposure. RESULTS: We included 1 039 694 patients, of whom 519 847 were statin users. Current statin users did not have an increased risk of developing SLE among patients aged ≥40 years (HRadjusted 0.75, 95% CI 0.53 to 1.07). Current statin users who continued the therapy for >1 year had a 38% lower risk of developing SLE (HRadjusted 0.62, 95% CI 0.42 to 0.93). When more specific definitions for SLE were used, this latter finding, however, was not observed. CONCLUSIONS: Our findings showed no effect of statins on the risk of developing SLE among patients aged ≥40 years. Further research is needed to study the long-term effects of statins on SLE.

Statins and Risk of Lower Limb Revision Surgery: The Influence of Differences in Study Design Using Electronic Health Records From the United Kingdom and Denmark.

Previous observational studies on statins have shown variable results based on the methodology used. Our objective was to study the association between statins and orthopedic implant failure and to explore the influence of methodological differences in study design. Our study base consisted of patients with a primary total joint replacement in Denmark and the United Kingdom (n = 189,286; 1987-2012). We used 4 study designs: 1) case-control (each patient with revision surgery matched to 4 controls), 2) time-dependent cohort (postoperative statin use as a time-varying exposure variable), 3) immortal time cohort (misclassifying the time postoperatively before statin use), and 4) time-exclusion cohort (excluding the time postoperatively before statin use). Cox proportional hazards models and logistic regression were used to estimate incidence rate ratios. In the time-dependent cohort design, statin use was associated with a decreased risk of revision surgery (adjusted incidence rate ratio (IRR) = 0.90, 95% confidence interval (CI): 0.85, 0.96), which was similar to our case-control results (IRR = 0.87, 95% CI: 0.81, 0.93). In contrast, both time-fixed cohort designs yielded substantially lower risk estimates (IRR = 0.36 (95% CI: 0.34, 0.38) and IRR = 0.65 (95% CI: 0.63, 0.68), respectively). We discourage the use of time-fixed cohort studies, which may falsely suggest protective effects. The simple choice of how to classify exposure can substantially change results from biologically plausible to implausible.

Use of thiazolidinediones and the risk of elective hip or knee replacement: a population based case-control study.

AIMS: Osteoarthritis (OA) is the most common musculoskeletal condition in the elderly population. However, no disease modifying drug exists for this disease. In vivo animal studies have suggested that thiazolidinediones (TZD) may be used as disease modifying osteoarthritis drugs (DMOADs). To our knowledge, this has not yet been examined in humans before. The aim was to determine the risk of total joint replacement (TJR) in patients using TZDs compared with diabetic patients using other antidiabetic drugs. METHODS: A population based case-control study was performed using the Clinical Practice Research Datalink (CPRD). Cases (n = 94 609) were defined as patients >18 years of age who had undergone total knee (TKR) or hip replacement (THR) between 2000 and 2012. Controls were matched by age, gender and practice/surgery. Conditional logistic regression analyses were used to estimate the risk of TKR and THR with the use of TZDs in patients currently using one or more antidiabetic drugs. In order to determine effect with prolonged use, we also stratified TZD users by total number of prescriptions prior to surgery. We statistically adjusted our analyses for lifestyle factory, comorbidities and concomitant drug use. RESULTS: There was no difference in risk of TKR (OR 1.09, 95% CI 0.93, 1.27) and THR (OR 0.92, 95% CI 0.76, 1.10) when TZD users were compared with other AD users. Furthermore, we did not find an association with prolonged use of TZDs and TJR. CONCLUSION: Despite promising results from animal in vivo studies, this study did not find any evidence for a disease modifying osteoarthritic effect of TZDs.

Safety and efficacy of new oral anticoagulants and low-molecular-weight heparins compared with aspirin in patients undergoing total knee and hip replacements.

BACKGROUND: There has been much debate recently on the best type of thromboprophylaxis following elective total joint replacement surgery. OBJECTIVE: This study aims to compare rates of venous thromboembolism (VTE), gastro-intestinal (GI) bleeding and mortality events, with use of new oral anticoagulants (NOAC) or low-molecular-weight heparins (LMWHs) compared with aspirin in patients undergoing total joint replacement. METHODS: A population-based retrospective cohort study was performed using the Clinical Practice Research Datalink. Patients ≥18 years of age who had undergone total knee (n = 3261) or hip replacement (THR (n = 4016)) between 2008 and 2012 were included. Within this population, three cohorts were selected, based on their first prescription within the 35-day period after surgery: use of NOACs only, LMWHs only and aspirin only. Incidence rates were calculated, and Cox proportional hazard models were fitted to estimate the risk of VTE, GI bleeding and all-cause mortality with the use of NOACs and LMWHs compared with aspirin use after total knee replacement and THR. We statistically adjusted our analyses for lifestyle factors, comorbidities and concomitant drug use. RESULTS: Total knee replacement and THR patients currently on LMWHs had higher risk of VTE (HR = 17.2 (6.9-43.0) and HR = 39.5 (18.0-87.0), respectively), GI bleeding (HR = 20.9 (1.9-232.3) and HR = 2.0 (0.2-17.2), respectively) and all-cause mortality (HR = 4.3 (1.7-12.4) and HR = 4.0 (2.4-6.7), respectively). NOAC use was associated with an increased risk of GI bleeding in patients undergoing THR surgery. CONCLUSIONS: In contrast to previous studies, we found an increased risk of VTE, GI bleeding and all-cause mortality with the use of LMWHs compared with aspirin. Risk of GI bleeding was increased with the use of NOACs compared with aspirin use after THR surgery. Copyright © 2016 John Wiley & Sons, Ltd.

Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor agonists: a population-based cohort analysis.

Glucagon-like Peptide-1 receptor agonists (GLP1-ra) are a relatively new class of anti-hyperglycemic drugs which may positively affect bone metabolism and thereby decrease (osteoporotic) bone fracture risk. Data on the effect of GLP1-ra on fracture risk are scarce and limited to clinical trial data only. The aim of this study was to investigate, in a population-based cohort, the association between the use of GLP1-ra and bone fracture risk. We conducted a population-based cohort study, with the use of data from the Clinical Practice Research Datalink (CPRD) database (2007-2012). The study population (N = 216,816) consisted of all individuals with type 2 diabetes patients with at least one prescription for a non-insulin anti-diabetic drug and were over 18 years of age. Cox proportional hazards models were used to estimate the hazard ratio of fracture in GLP1-ra users versus never-GLP1-ra users. Time-dependent adjustments were made for age, sex, lifestyle, comorbidity and the use of other drugs. There was no decreased risk of fracture with current use of GLP1-ra compared to never-GLP1-ra use (adjusted HR 0.99, 95 % CI 0.82-1.19). Osteoporotic fracture risk was also not decreased by current GLP1-ra use (adjusted HR 0.97; 95 % CI 0.72-1.32). In addition, stratification according to cumulative dose did not show a decreased bone fracture risk with increasing cumulative GLP1-ra dose. We showed in a population-based cohort study that GLP1-ra use is not associated with a decreased bone fracture risk compared to users of other anti-hyperglycemic drugs. Future research is needed to elucidate the potential working mechanisms of GLP1-ra on bone.

Influence of a strict glucose protocol on serum potassium and glucose concentrations and their association with mortality in intensive care patients.

INTRODUCTION: Tight glucose control therapy (TGC) has been implemented to control hyperglycemia in ICU patients. TGC may also influence serum potassium concentrations. We therefore investigated the influence of TGC on both serum glucose and serum potassium concentrations and associated mortality. METHOD: We performed a retrospective analysis including all patients admitted to the ICU of a tertiary hospital for 24 hours or more and with at least three serum glucose and serum potassium concentrations between 1999-2001 (conventional period), 2002-2006 (implementation period) or 2007-2009 (TGC period). Segmented regression analysis was used to estimate changes in outcomes that occurred after the intervention controlling for pre-intervention trends. Means and standard deviations (SDs) of serum glucose and serum potassium concentrations, and rate of severe hypoglycemia (≤ 2.2 mmol/L) and hypokalemia (≤ 3 mmol/L), were compared between the TGC and conventional period. RESULTS: Although mean serum glucose concentrations dropped 2.1 mmol/L (95% CI =-1.8 to -2.3 mmol/L, p<0.002), mean serum potassium concentrations did not change (absolute increase 0.02 mmol/L; 95% CI = -0.06 to 0.09 mmol/L, p=0.64). The rate of severe hypoglycemia increased with 5.9% (95% CI=-3.0 to -8.9, p<0.002), but the rate of hypokalemia remained equal (absolute reduction 4.8%; 95% CI = -11.1% to 1.5%, p=0.13). The SD of serum glucose concentrations within a patient did not change, while the SD of serum potassium concentrations even decreased 0.04 mmol/L (95% CI = -0.01 to -0.07, p = 0.01). ICU mortality decreased but this decrease was not significant (absolute difference -3.63%; 95% CI = -9.33 to 2.09, p = 0.20). Mean serum glucose concentrations, mean serum potassium concentrations and SDs of both serum glucose and serum potassium concentrations were all independently associated with ICU mortality. Highest mortality rates were seen at both the lowest and highest mean values (U/J-shaped association) and mortality rates increased with increasing variability (SDs) for both serum glucose and serum potassium concentrations. CONCLUSION: Our study shows that a TGC was not associated with an increased risk of serum potassium related events. Low and high mean values and high variability of both serum glucose and serum potassium concentrations are predictors for high ICU mortality.

No detrimental association between antibiotic use and immune checkpoint inhibitor therapy: an observational cohort study comparing patients with ICI-treated and TKI-treated melanoma and NSCLC.

BACKGROUND: The role of antibiotics in malignancies treated with immune checkpoint inhibitors (ICI) remains unclear. Several studies suggested a detrimental impact of antibiotic use on the response to ICI, but were susceptible to confounding by indication. Our objective was therefore to assess whether the relationship between antibiotic use and ICI response is causative or merely associative. METHODS: A large, single-center observational cohort study was performed with individuals treated for either non-small cell lung carcinoma (NSCLC) or metastatic melanoma. An effect modification approach was used, aiming to estimate the association between antibiotic use and overall survival (OS) and compare these estimates between individuals receiving first-line ICI treatment versus those receiving first-line tyrosine kinase inhibitors (TKIs). Exposure of interest was antibiotic use within 30 days before the start of anticancer treatment. HRs for OS were estimated for antibiotics versus no antibiotics in each cohort using multivariable propensity adjusted analysis. The "true antibiotic effect" within the ICI versus TKI cohort was modeled using an interaction term. RESULTS: A total of 4534 patients were included, of which 1908 in the ICI cohort and 817 in the TKI cohort. Approximately 10% of patients in each cohort used antibiotics within 30 days before the start of anticancer treatment. Our results demonstrate a lack of synergistic interaction between current antibiotic use and ICI therapy in relation to OS: although antibiotic use was significantly associated with OS decline in the ICI cohort (HR=1.26 (95% CI 1.04 to 1.51)), a similar magnitude in OS decline was found within the TKI cohort (HR=1.24 (95% CI 0.95 to 1.62)). This was reflected by the synergy index (HR=0.96 (95% CI 0.70 to 1.31)), which implied no synergistic interaction between current antibiotic use and ICI. CONCLUSION: This study strongly suggests that there is no causal detrimental association between antibiotic use and ICI therapy outcome when looking at OS in individuals with malignant melanoma or NSCLC. The frequently observed inverse association between antibiotics and ICI response in previous studies is most likely driven by confounding by indication, which was confirmed by the findings in our reference TKI cohort.

Within-episode repeat antibiotic prescriptions in patients with respiratory tract infections: A population-based cohort study.

BACKGROUND: Antimicrobial stewardship interventions mainly focus on initial antibiotic prescriptions, with few considering within-episode repeat prescriptions. We aimed to describe the magnitude, type and determinants of within-episode repeat antibiotic prescriptions in patients presenting to primary care with respiratory tract infections (RTIs). METHODS: We conducted a population-based cohort study among 530 sampled English general practices within the Clinical Practice Research Datalink (CPRD). All individuals with a primary care RTI consultation for which an antibiotic was prescribed between March 2018 and February 2022. Main outcome measurement was repeat antibiotic prescriptions within 28 days of a RTI visit stratified by age (children vs. adults) and RTI type (lower vs. upper RTI). Multivariable logistic regression and principal components analyses were used to identify risk factors and patient clusters at risk for within-episode repeat prescriptions. FINDINGS: 905,964 RTI episodes with at least one antibiotic prescription were identified. In adults, 19.9% (95% CI 19.3-20.5%) had at least one within-episode repeat prescription for a lower RTI, compared to 10.5% (95% CI 10.3-10.8%) for an upper RTI. In children, this was around 10% irrespective of RTI type. The majority of repeat prescriptions occurred a median of 10 days after the initial prescription and was the same antibiotic class in 48.3% of cases. Frequent RTI related GP visits and prior within-RTI-episode repeat antibiotic prescriptions were main factors associated with repeat prescriptions in both adults and children irrespective of RTI type. Young (<2 years) and older (65+) age were associated with repeat prescriptions. Among those aged 2-64 years, allergic rhinitis, COPD and oral corticosteroids were associated with repeat prescriptions. INTERPRETATIONS: Repeat within-episode antibiotic use accounts for a significant proportion of all antibiotics prescribed for RTIs, with same class antibiotics unlikely to confer clinical benefit and is therefore a prime target for future antimicrobial stewardship interventions.

Association of Busulfan Exposure and Outcomes after HCT for Patients with an Inborn Error of Immunity.

Allogeneic HCT is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). Objective of this study was to assess the optimal busulfan exposure prior to allogeneic HCT for patients with an IEI who received an intravenous busulfan-based conditioning regimen between 2000 and 2023. Patients from 17 international centers were included. Main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined-immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (AUCCENTER) and was re-estimated using a validated model (AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) CID, 154 (27.4%) SCID, 101 (18.0%) HLH-related disorders, and 134 (23.8%) neutrophil disorders. Median busulfan AUCNONMEM was 69.0 mg×h/L and correlated poorly with AUCCENTER (r2=0.54). Patients with SCID, HLH-related, and neutrophil disorders were analyzed together (n=389), because CID disease subtype was an effect modifier (p=0.03). Estimated 2-year EFS was 78.5%. In patients with the found optimal busulfan AUCNONMEM of 70-90 mg×h/L, 2-year EFS was superior to <70 mg×h/L (adj-HR 1.97, 95% CI 1.11-3.49, p=0.02), and >90 mg×h/L (adj-HR 5.05, 95% CI 2.43-10.49, p<0.0001). Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg×h/L. For CID patients, optimal AUCNONMEM for donor chimerism was found to be >70 mg×h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg×h/L (range 70-90). Our study stresses the importance to uniformly using a validated population PK-model to estimate the AUCNONMEM.

Risk of gastrointestinal bleeding in patients undergoing total hip or knee replacement compared with matched controls: a nationwide cohort study.

OBJECTIVES: Gastrointestinal (GI) bleeding may impose a serious threat in patients undergoing total hip or knee replacement (THR/TKR). The objectives of this study are to evaluate the timing of GI bleeding following THR/TKR and to determine the effect modification by proton pump inhibitor (PPI) use. METHODS: In a nationwide Danish cohort study, we selected all patients with a primary THR/TKR between 1998 and 2007 (n=95,115). Three control subjects without THR/TKR were matched by age, sex, and region. We calculated disease and medication adjusted (adj.) Hazard ratios (HRs) for GI bleeding with THR/TKR vs. controls. PPI use was assessed in the previous 3 months (in a time-dependent manner). RESULTS: We identified a 6-fold increased risk of GI bleeding during the first 2 weeks following THR (adj. HR, 6.02; 95% confidence interval (CI), 4.06-8.92) and a 2.3-fold increased risk for TKR patients (adj. HR, 2.30; 95% CI, 1.17-4.54), both vs. matched controls. The elevated risk lasted longer in THR patients (12 weeks) as compared with TKR patients (6 weeks). PPI use lowered the HR for GI bleeding by 74% during the first 6 weeks following THR, but not TKR. CONCLUSIONS: This study demonstrated an increased risk of GI bleeding during the first 2 weeks following THR (6-fold) and TKR (2.3-fold), and remained increased for up to 6 (TKR) to 12 weeks (THR) after surgery. PPI use substantially lowered this elevated risk in THR patients, but not in TKR patients.

Drug waste of ready-to-administer syringes in the intensive care unit: Aseptically prepared syringes versus prefilled sterilized syringes.

BACKGROUND: The availability of ready-to-administer (RTA) syringes for intravenous (IV) drugs facilitates rapid and safe administration in emergency and intensive care situations. Hospital pharmacies can prepare RTA syringes through aseptic batchwise filling. Due to excess production of these RTA syringes for sufficient availability for patient care and their limited (microbiological) shelf-life, waste is unavoidable, which contributes to environmental pollution. RTA prefilled sterilized syringes (PFSSs) have much longer shelf-lives than aseptically prepared RTA syringes and might contribute to reducing drug waste. AIM: This study aimed to evaluate the difference in drug waste between RTA syringes that were prepared through aseptic batchwise filling and RTA PFSSs in the Intensive Care Unit (ICU). METHODS: We measured drug waste of RTA syringes over an 8-year time period from August 2015 to May 2023 in the 32-bed ICU of the University Medical Center Utrecht. We distinguished between RTA syringes prepared through aseptic batchwise filling by our hospital pharmacy ("RTA aseptic syringes", shelf-life of 31 days) and RTA PFSSs (shelf-life of 18 months). An intervention group of three drug products that were replaced by PFSSs was compared to a control group of five drug products that were not replaced by PFSSs during the study period. We then defined four different periods within the total study period, based on quarantine time of the RTA aseptic syringes and time of PFSS introduction: 1) no quarantine, 2) 3-day quarantine, 3) 7-day quarantine and 4) PFSS introduction. Our primary endpoint was the number of RTA syringes that was wasted, expressed as the percentage of the total number of syringes dispensed to the ICU in each of these four periods. We used a Kruskall-Wallis test to test if waste percentages differed between time periods in the control and intervention groups, with a post-hoc Dunn's test for pairwise comparisons. Furthermore, we applied two interrupted time series (ITS) analyses to visualize and test the effect of introducing different quarantine times and the PFSSs on waste percentage. RESULTS: Introduction of PFSSs significantly decreased drug waste of RTA syringes irrespective of drug type in the intervention group, from 31% during the 7-day quarantine period to 5% after introduction of the PFSS (p<0.001). The control group showed no significant decrease in drug waste over the same time periods (from 20% to 16%; p=0.726). We observed a significant difference in the total drug waste of RTA aseptic syringes between time periods, which may be attributed to the implementation of different quality control quarantine procedures. The ITS model of the intervention group showed a direct decrease of 17.7% in waste percentage after the introduction of PFSSs (p=0.083). CONCLUSION: Drug waste of RTA syringes for the ICU can be significantly decreased by introducing PFSSs, supporting hospitals to enhance environmental sustainability. Furthermore, the waste percentage of RTA syringes prepared through aseptic batchwise filling is significantly impacted by duration of quarantine time.

Timing of stroke in patients undergoing total hip replacement and matched controls: a nationwide cohort study.

BACKGROUND AND PURPOSE: Stroke is a potentially fatal complication of total hip replacements (THR). However, timing of stroke in THR patients compared with matched controls and influence of drug use remain unknown. The objective of this study was to determine timing of stroke in patients with THR compared with matched control subjects. METHODS: A nationwide cohort study was conducted within the Danish registers (1998-2007). Included patients were those with a primary THR in the study period (n=66,583) and were matched by age, sex, and region to three referent subjects without THR or total knee replacements. Time-dependent Cox models were used to derive hazard ratios and were adjusted for disease history and drug use. RESULTS: A 4.7-fold increased risk of ischemic stroke (adjusted hazard ratio, 4.69; 95% CI, 3.12-7.06), and a 4.4-fold increased risk of hemorrhagic stroke (adjusted hazard ratio, 4.40; 95% CI, 2.01-9.62) were found within 2 weeks following THR, compared with matched controls. The risk remained elevated during the first 6 postoperative weeks for ischemic stroke, and the first 12 weeks for hemorrhagic stroke. Outpatient antiplatelet drug use lowered the 6-week hazard ratios for ischemic stroke by 70%, although not affecting risk of hemorrhagic stroke. CONCLUSIONS: This study shows, that THR patients have a 4.7-fold increased risk of ischemic stroke, and a 4.4-fold increased risk of hemorrhagic stroke during the first 2 weeks postsurgery. Risk assessment of stroke in individual patients undergoing THR (ie, evaluate other risk factors for stroke) should be considered during the first 6 to 12 weeks.

Knee arthroplasty and risk of hip fracture: a population-based, case-control study.

The majority of knee arthroplasties (KAs) are performed in patients with osteoarthritis (OA). Although bone mass may be increased in these patients, subjects with knee OA may have an increased risk of hip fracture, possibly due to an increased severity of falls. However, in patients with KAs, risk of hip fracture has not been studied extensively. We evaluated the association between KAs and hip fracture risk in a population-based case-control study using the Dutch PHARMO Record Linkage System (1991-2002, n = 33,104). Cases were patients with a first admission for hip fracture; controls were matched by age, gender, and geographic location. Neither group had a previous history of fracture. Time since first KA was calculated. Analyses were adjusted for disease and drug history. A 54% increased hip fracture risk was found in patients who underwent KA (adjusted [adj.] OR = 1.54, 95% CI 1.19-2.00). We found a strong effect modification by age in these patients: the youngest patients (aged 18-70 years) were at more increased risk for hip fracture (adj. OR = 2.76, 95% CI 1.16-6.59), while we could not detect a statistical increase in patients aged >80 years. Furthermore, the association tended to be greater during the first few years after surgery, although it did not reach statistical significance. We found that KAs are associated with a 54% increased risk of hip fracture, in particular among adult patients aged <71 years old. Fracture risk assessment could be considered in patients who are about to undergo a KA.