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Aims: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups.Methods: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors.Results: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant.Conclusion: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization. Aims: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups.Methods: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors.Results: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant.Conclusion: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization.

Poisonings contribute significantly to morbidity and mortality of patients. Some patients have numerous contacts to a poison information center, indicating repeated poisoning exposures. Information on the involved substances is necessary to explore methods to prevent self-harm and reduce mortality. The objective of this study was to characterize the patient population with repeated poison exposures in Denmark and identify the substances involved. This study was a retrospective cohort study of enquiries to the nationwide Danish Poison Information Centre and the Danish National Patient Registry. The databases were used to identify patients with more than five individual poisoning episodes within a 12-month-period between 1 January 2013, and 31 December 2017. One hundred and thirty-seven patients and 995 patients met the inclusion criteria in the Danish Poison Information Centre and the Danish National Patient Registry, respectively. The majority were women (82.5% and 66.3% for the Danish Poison Information Centre and the Danish National Patient Registry cohorts, respectively). The mean age was 24.7 and 29.5 years. Psychiatric comorbidities were frequent with 74.5% and 67.0% suffering from personality disorders and 70.1% and 54.5% from affective disorders in the Danish Poison Information Centre and the Danish National Patient Registry cohorts, respectively. One thousand seven hundred and fifty-two poisoning episodes were identified in the Danish Poison Information Centre database, and the most common types of substance were ‘pharmaceuticals’ (1,420 episodes). The most common medications ingested were quetiapine, paracetamol and cyclizine. Median number of contacts to the Danish Poison Information Centre was 10. Patients with one or more poisoning episodes involving cyclizine had on average 11.4 poisoning episodes involving cyclizine. In the Danish National Patient Registry cohort 80.9% were alive after 10 years compared to 97.7% in the background population. Most poisonings were intentional and occurred among younger women. Psychiatric comorbidity was frequent. Most often, pharmaceuticals were the toxic substance, mainly quetiapine, paracetamol and cyclizine. Changing the status of cyclizine from over the counter to prescription only medication, and implementing stricter rules for prescribing quetiapine, could limit future poisoning incidences.

The Danish Poison Information Centre (DPIC) regularly receives inquiries about nursing home residents who have been exposed to a medication error. The aim of this prospective cohort study was to describe and discuss the types and consequences of these errors. Data were collected from 1 March 2018 to 31 March 2019. Registered data included characteristics of caller and resident, data related to the suspected medication error, risk assessment and recommendation. Consequences and clinical outcomes were assessed by follow-up telephone calls. Over the study period, the DPIC was consulted about 145 medication errors occurring at Danish nursing homes. The median number of substances administered by error was two (interquartile range 1-5). Hospitalization was recommended in 21% of cases. In one-third of the cases where consultation with the DPIC was done with the resident either on his/her way to or in hospital, hospitalization was found unnecessary, and the resident could have stayed in accustomed surroundings for observation. Follow-up demonstrated that very few medication errors had a severe outcome. This prospective study illustrates that consulting with a poison information centre can qualify risk assessment and potentially reduce hospital admissions following medication errors in a nursing home setting.

Treatment guidelines for type 2 diabetes (T2D) recommend avoidance of hypoglycemia and less stringent glycemic control in older patients. We examined the relation of glycemic control to glucose-lowering medications use in a cohort of patients aged>80 years with a diagnosis of T2D and a hospital admission in the Capital Region of Denmark in 2012–2016. We extracted data on medication use, diagnoses, and biochemistry from the hospitals’ records. We identified 5,172 T2D patients with high degree of co-morbidity and where 17% had an HbA1c in the range recommended for frail, comorbid, older patients with type 2 diabetes (58–75 mmol/mol (7.5–9%)). Half of the patients (n = 2,575) had an HbA1c 1c-values 1c values 1c within the generally recommended glycemic targets. One third of patients did not meet the diagnostic criteria for T2D, and of the patients who were treated with glucose-lowering medications, one-fifth had HbA1c-values suggesting overtreatment.

Objective To investigate the association between mirtazapine exposure in pregnancy and risk of specific adverse pregnancy outcomes.Methods A register-based nationwide cohort study was conducted including all registered pregnancies in Denmark from 1997 to 2016. Mirtazapine-exposed pregnancies were compared with mirtazapine unexposed pregnancies in a 1:4 ratio matched according to propensity scores. Outcomes were major congenital malformations analyzed using log binomial models, and spontaneous abortion, stillbirth and neonatal death analyzed using Cox proportional hazard regression.Results From a source population of 1,650,649 pregnancies, the propensity score-matched cohort included 4475 pregnancies (895 mirtazapine exposed) in the analysis of major congenital malformations. The analyses of spontaneous abortion included 9 500 pregnancies (1900 mirtazapine exposed), and for the analyses of stillbirths and neonatal deaths 9725 (1 945 mirtazapine-exposed) and 4485 pregnancies (897 mirtazapine-exposed) were included, respectively. Thirty-one (3.5%) children were diagnosed with major congenital malformation among the mirtazapine exposed compared with 152 (4.3%) among the unexposed pregnancies (OR=0.81, 95% CI 0.55-1.20). Spontaneous abortion occurred in 237 (12.5%) of the mirtazapine exposed compared with 931 (12.3%) of the unexposed pregnancies (HR = 1.04%, 95% CI 0.91-1.20). The analyses revealed no increased risk of stillbirth (HR = 0.88%, 95% CI 0.34-2.29) or neonatal death (HR = 0.60%, 95% CI 0.18-2.02).Conclusions In this nationwide Danish register study, mirtazapine exposure in pregnancy was not associated with major congenital malformations, spontaneous abortion, stillbirth, or neonatal death. Clinicians and patients can be reassured that mirtazapine is safe in pregnancy.

OBJECTIVES To evaluate safety and effectiveness of prophylactic anticoagulation with low molecular weight heparin (LMWH) in individuals hospitalised for COVID-19. METHODS Using healthcare records from the capital region of Denmark (March 2020-February 2021) and Karolinska University Hospital in Sweden (February 2020-September 2021), we conducted an observational cohort study comparing clinical outcomes 30 days after admission among individuals hospitalised for COVID-19 starting prophylactic LMWH during the first 48 hours of hospitalisation with outcomes among those not receiving prophylactic anticoagulation. We used inverse probability weighting to adjust for confounders and bias due to missing information. Risk ratios, risk differences and robust 95% confidence intervals (CI) were estimated using binomial regression. Country-specific risk ratios were pooled using random-effects meta-analysis. RESULTS We included 1692 and 1868 individuals in the Danish and Swedish cohorts. Of these, 771 (46%) and 1167 (62%) received prophylactic LMWH up to 48 hours after admission. The combined mortality in Denmark and Sweden was 12% (N=432) and the pooled risk ratio was 0.89 (CI 0.61-1.29) comparing individuals who received LMWH to those who did not. The relative risk of ICU admission was 1.12 (CI 0.85-1.48), while we observed no increased risk of bleeding (RR 0.60, 0.14-2.59). The relative risk of venous thromboembolism was 0.68 (CI: 0.33-1.38) in Sweden. Less than 5 VTE events were observed among individuals receiving LMWH in Denmark, preventing a meaningful analysis. CONCLUSION We found no benefit on mortality with prophylactic LMWH and no increased risk of bleeding among COVID-19 patients receiving prophylactic LMWH. Objectives: To evaluate safety and effectiveness of prophylactic anticoagulation with low molecular weight heparin (LMWH) in individuals hospitalised for COVID-19. Methods: Using healthcare records from the Capital Region of Denmark (March 2020-February 2021) and Karolinska University Hospital in Sweden (February 2020-September 2021), we conducted an observational cohort study comparing clinical outcomes 30 days after admission among individuals hospitalised for COVID-19 starting prophylactic LMWH during the first 48 hours of hospitalisation with outcomes among those not receiving prophylactic anticoagulation. We used inverse probability weighting to adjust for confounders and bias due to missing information. Risk ratios, risk differences and robust 95% confidence intervals (CI) were estimated using binomial regression. Country-specific risk ratios were pooled using random-effects meta-analysis. Results: We included 1692 and 1868 individuals in the Danish and Swedish cohorts. Of these, 771 (46%) and 1167 (62%) received prophylactic LMWH up to 48 hours after admission. The combined mortality in Denmark and Sweden was 12% (N = 432) and the pooled risk ratio was 0.91 (CI 0.60-1.38) comparing individuals who received LMWH to those who did not. The relative risk of ICU admission was 1.12 (0.76-1.66), while we observed no increased risk of bleeding 0.63 (0.13-2.94). The relative risk of venous thromboembolism was 0.80 (0.43-1.47). Conclusion: We found no benefit on mortality with prophylactic LMWH and no increased risk of bleeding among COVID-19 patients receiving prophylactic LMWH.

Aim: To evaluate the prevalence of potentially hepatoxic paracetamol ingestion and associated N-acetylcysteine treatment in young children suspected of paracetamol poisoning. Methods: A retrospective cohort study of children aged 0–6 years suspected of paracetamol poisoning with a related plasma-paracetamol measurement in the Capital Region of Denmark in the period 2010–2017. Data from the clinical laboratory system were linked to data from electronic patient records via the unique identification number given to all Danish residents. Results: Of 297 children included, suspected single paracetamol overdoses were present in 281 (95%). Sixty-nine per cent were treated with N-acetylcysteine, and the mean treatment period was 20.3 h (SD 20.8). A maximum of 6 (2%) of the children suspected of single overdose had plasma-paracetamol concentrations that exceeded the recommended treatment thresholds. No cases of severe hepatotoxicity were registered. Adverse events to N-acetylcysteine-treatment were registered in 3 (2%) children including one anaphylactoid reaction (0.5%). Conclusion: This study shows that initiating N-acetylcysteine as a ‘one size fit all’ treatment regimen in all children aged 0–6 years with a suspected single paracetamol overdose leads to substantial overtreatment. The data support that it is feasible to initiate N-acetylcysteine within 10 h based on an early plasma-paracetamol test.

Aim: To investigate the effects of a comprehensive medication review intervention on health-related quality of life (HRQoL) and clinical outcomes in geriatric outpatients exposed to polypharmacy. Methods: Pragmatic, nonblinded, randomized clinical trial with follow-up after 4 and 13 months. Participants were geriatric outpatients taking ≥9 medicines. The intervention was an additional consultation with a physician focusing on reviewing medication, informing patients about their medicines and increasing cross-sectoral communication as supplement to and compared with usual care. The primary outcome was change in HRQoL after 4 months measured with the EuroQoL 5-dimension 5-level (EQ-5D-5L) questionnaire. Secondary outcomes were HRQoL after 13 months, mortality, admissions, falls and number of medicines after 4 and 13 months. Results: Of 785 eligible patients, 408 were included (age: mean 80.6 [standard deviation 7.22] years; number of medicines: median 12 [interquartile range 10–14]; females 71%). After 4 months, the adjusted between-group difference in EQ-5D-5L index score was 0.066 in favour of the medication consultation (95% confidence interval 0.01 to 0.12, P =.02). After 4 months, two (1%) participants had died in the medication-consultation group and nine (4%) in the usual-care group (log-rank test, P =.045). The medication consultation reduced the number of medicines by 2.0 (15.8%) after 4 months and 1.3 (10.7%) after 13 months. There were no statistically significant differences in mortality or HRQoL after 13 months, and no differences in falls or admissions. Conclusions: An additional consultation with medication review and increased communication as supplement to usual geriatric outpatient care improved HRQoL and reduced mortality after 4 months.

Tramadol is a commonly used opioid with a potential of addiction and abuse. Using Danish nationwide registers, we aimed to (1) characterise opioid poisonings; (2) assess the 30-day mortality following morphine, oxycodone, and mixed poisonings compared to tramadol poisonings; and (3) assess the development in tramadol poisonings during a 12-year period. Poisonings were identified from 2006 to 2017. A Cox proportional hazards regression model was used to estimate adjusted hazard ratios (aHRs) along with 95% confidence intervals (CIs) for 30-day mortality following morphine, oxycodone or mixed poisonings compared to tramadol poisonings. We identified 7718 opioid poisonings among 6365 patients. The patients with a tramadol poisoning were younger and had less comorbidities than the patients with a morphine, oxycodone or mixed poisoning. Within 30 days, a total of 205 patients died. The 30-day mortality risk was higher following morphine (aHR 3.2, 95% CI 2.0-5.1), oxycodone (aHR 2.1, 95% CI 1.2-3.6) and mixed poisonings (aHR 1.6, 95% CI 1.0-2.7) compared to tramadol poisonings. The annual number of tramadol poisonings increased from 233 in 2006 to 501 in 2013 and declined to 348 in 2017. In conclusion, despite a lower mortality risk compared to other opioid poisonings, physicians should consider the poisoning and abuse risks when prescribing tramadol.

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (eight with and eight without obesity) and matched control individuals (eight with and eight without obesity) were recruited. Each participant underwent a 1-h glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-h washout period. Plasma levels, metabolic clearance rate (MCR), half-life (T1/2), and volume of distribution of glucagon were evaluated, and a pharmacokinetic model was constructed. Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared with the control group, while no significant differences between the groups were found in glucagon T1/2. Individuals with obesity had neither a significantly decreased MCR, T1/2, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positivelywith fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes.

Introduction: The antipsychotic drug clozapine remains underutilized partly because of the risk of life-threatening adverse effects, such as neutropenia. Therefore, an extensive hematological monitoring program was set up to detect neutropenia. Methods: In this retrospective cohort study, we used registry-based data from the Capital Region of Denmark to investigate incidence rates of neutropenia among patients with a diagnosis of schizophrenia or other psychotic disorders and treated with clozapine for the first time. In a within-subject design, we compared rates of neutropenia in time periods where patients were exposed to clozapine versus time periods, where they were not exposed to clozapine. We also investigated whether the lengths of clozapine-associated neutropenia (CAN) were related to discontinuation of clozapine treatment. Results: Data from 520 clozapine users were included. The incidence rate of CAN was 3.2 cases per 100 person-years (95% confidence interval [CI]: 2.1–4.8) throughout the entire study. There was no significant difference in incidence rates of neutropenia during clozapine exposure and non-clozapine exposure, with an incidence rate ratio of 0.7 (95% CI: 0.4–1.3). One episode of severe neutropenia was detected. Episodes of CAN with only one sub-threshold neutrophil count were not associated with higher clozapine discontinuation (26%) than CAN episodes of more than one sub-threshold neutrophil count (28%). Conclusion: In the present study, we could not confirm that clozapine treatment was associated with neutropenia.

The COVID-19 pandemic has put massive strains on hospitals, and tools to guide hospital planners in resource allocation during the ebbs and flows of the pandemic are urgently needed. We investigate whether machine learning (ML) can be used for predictions of intensive care requirements a fixed number of days into the future. Retrospective design where health Records from 42,526 SARS-CoV-2 positive patients in Denmark was extracted. Random Forest (RF) models were trained to predict risk of ICU admission and use of mechanical ventilation after n days (n = 1, 2, …, 15). An extended analysis was provided for n = 5 and n = 10. Models predicted n-day risk of ICU admission with an area under the receiver operator characteristic curve (ROC-AUC) between 0.981 and 0.995, and n-day risk of use of ventilation with an ROC-AUC between 0.982 and 0.997. The corresponding n-day forecasting models predicted the needed ICU capacity with a coefficient of determination (R2) between 0.334 and 0.989 and use of ventilation with an R2 between 0.446 and 0.973. The forecasting models performed worst, when forecasting many days into the future (for large n). For n = 5, ICU capacity was predicted with ROC-AUC 0.990 and R2 0.928, and use of ventilator was predicted with ROC-AUC 0.994 and R2 0.854. Random Forest-based modelling can be used for accurate n-day forecasting predictions of ICU resource requirements, when n is not too large.

PURPOSE: The IGF signaling cascade exerts important regulatory functions in human ovarian folliculogenesis. The scope of this study was to evaluate the transcription profile of insulin-like growth factor (IGF) genes during human ovarian follicle development and to analyze follicle fluid levels of key IGF proteins. METHODS: Gene expression profiling was performed with microarray gene analysis. The analysis was assessed from ovarian follicles and granulosa cells (GCs) obtained from isolated stage-specific human ovarian follicles, including preantral follicles, small antral follicles, and preovulatory follicles. Numerous genes involved in the IGF signaling pathway was evaluated and key genes were validated by qPCR from GCs. Protein levels of various IGF components of human follicular fluid (FF) were measured by ELISA and time-resolved immunofluorometric assays (TRIFMA). RESULTS: The gene expression levels of PAPPA, IGF2, IGF receptors and intracellular IGF-activated genes increased with increasing follicle size. This was especially prominent in the late preovulatory stage where IGF2 expression peaked. Protein levels of intact IGF binding protein-4 decreased significantly in FF from large preovulatory follicles compared with small antral follicles concomitant with higher protein levels of PAPP-A. The IGF modulators IGF-2 receptor, IGFBPs, stanniocalcins, and IGF-2 mRNA binding proteins were all observed to be expressed in the different follicle stages. CONCLUSIONS: This study confirms and highlights the importance of PAPP-A regulating bioactive IGF levels throughout folliculogenesis and especially for the high rate of granulosa cell proliferation and expression of key ovarian hormones important in the last part of the follicular phase of the menstrual cycle. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10815-019-01432-x) contains supplementary material, which is available to authorized users.

Background With increasing demand for total hip arthroplasty (THA) and total knee arthroplasty (TKA), a higher percentage of patients are identified with comorbidities that might increase the risk of complications. We aimed to elucidate the preoperative characteristics of patients with a fatal outcome or admission to the Intensive Care Unit (ICU) within 90 days after THA or TKA. We arbitrarily hypothesized that more than 50% of those patients would be frail. Methods This is a register based, explorative study including patients undergoing elective, unilateral, primary THA or TKA in the Capital Region of Denmark from 2010 to 2017, and who subsequently died or were admitted to the ICU within 90 days. The modified Frailty Index (mFI) was calculated from the medical records, and a score of ≥0.36 defined frailty. Results A total of 33,758 patients underwent THA or TKA, and 284 patients (0.8%) died or were admitted to the ICU within 90 days. Fifty-seven patients (20%) were frail (95% CI 16.2-25.7%). The most common comorbidities were hypertension (63%) and pulmonary diseases (32%), and 56% used walking aids. Two or more comorbidities were present in 65% of patients, and 14% had no comorbidities at all. Conclusion Only 20% of patients with a fatal outcome or ICU admission after elective THA or TKA could be categorized as frail based on the mFI. Further studies with a prospective design are needed to clarify the mFI as a risk stratification tool in elderly multimorbid patients undergoing elective arthroplasty surgery.

ImportanceThe COVID-19 pandemic has put massive strains on hospitals, and tools to guide hospital planners in resource allocation during the ebbs and flows of the pandemic are urgently needed.ObjectiveWe investigate whether Machine Learning (ML) can be used for predictions of intensive care requirements 5 and 10 days into the future.DesignRetrospective design where health Records from 34,012 SARS-CoV-2 positive patients was extracted. Random Forest (RF) models were trained to predict risk of ICU admission and use of mechanical ventilation after n days (n = 5, 10).SettingTwo Danish regions, encompassing approx. 2.5 million citizens.ParticipantsAll patients from the bi-regional area with a registered positive SARS-CoV-2 test from March 2020 to January 2021.Main outcomesPrediction of future 5- and 10-day requirements of ICU admission and ventilator use. Mortality was also predicted.ResultsModels predicted 5-day risk of ICU admission with an area under the receiver operator characteristic curve (ROC-AUC) of 0.986 and 5-day risk of use of ventilation with an ROC-AUC of 0.995. The corresponding 5-day forecasting models predicted the needed ICU capacity with a coefficient of determination (R2) of 0.930 and use of ventilation with an R2 of 0.934. Performance was comparable but slightly reduced for 10-day forecasting models.ConclusionsRandom Forest-based modelling can be used for accurate 5- and 10-day forecasting predictions of ICU resource requirements.FundingThe study was funded by grants from the Novo Nordisk Foundation to MS (#NNF20SA0062879 and #NNF19OC0055183) and MN (#NNF20SA0062879).The foundation took no part in project design, data handling and manuscript preparation.KEY POINTSQuestionCan machine learning models (ML) be used for predicting hospital and intensive care unit (ICU) resource requirements, and thus assist in logistics crisis management during the COVID-19 pandemic?FindingsRetrospective study of the resource use of 34.012 COVID-19 patients during the first and second COVID-19 wave in Denmark. ML models were trained for the purpose of predicting the number of patients needing ICU admission and ventilators 5 and 10 day after their first positive SARS-CoV-2 test. The study demonstrates that ML models can accurately predict intensive care admission requirements with 5-day area under the receiver operator characteristic curve (ROC-AUC) of 0.986 and need for ventilator support with a ROC-AUC of 0.995. 10-day predictions were comparable.MeaningThe study demonstrates that ML modelled could be a useful tool for hospital planners during crisis management, including the current COVID-19 pandemic.

BACKGROUND Several studies in surgery and initial management of critical illness have indicated harmful effects of short-term exposure to hyperoxia. Exposure to and consequences of excessive oxygen administration in hospital wards are sparsely investigated. The aim of this study was to investigate the association between excessive oxygen administration in patients admitted to surgical or medical wards and 30-day mortality. METHODS We included patients in the Capital Region of Denmark who were admitted to hospital in 2014 for either myocardial infarction, acute exacerbation of chronic obstructive pulmonary disease (COPD), hip fracture or open abdominal surgery. We defined groups of inadequate, adequate or excessive oxygen administration based on peripheral oxygen saturation and oxygen administration values in the first 48 hours after admission. The primary outcome was mortality within 30 days, and data were analysed with multivariable logistic regression for age, gender and comorbidities. RESULTS We retrieved data from 11 196 patients, of which 81% had adequate, 18% had excessive and 1.8% inadequate oxygen administration. Mortality at 30 days was 4.2%, 7.6% and 27%, respectively, OR 1.46 (95%CI 1.16-1.84), P = .001 for patients with excessive compared to adequate oxygen administration. The association was significant in subgroups of patients admitted for acute exacerbation of COPD (OR 1.67, 95%CI 1.19-2.34) and myocardial infarction (OR 3.50, 95%CI 1.55-7.89). CONCLUSION Patients who received excessive oxygen administration in surgical and medical wards during the first 48 hours of admission had a higher mortality risk within 30 days compared to patients with adequate oxygen administration. However, inadequate oxygen therapy still renders highest mortality and should be avoided.

BackgroundPatients with severe COVID-19 have overwhelmed healthcare systems worldwide. We hypothesized that Machine Learning (ML) models could be used to predict risks at different stages of management (at diagnosis, hospital admission and ICU admission) and thereby provide insights into drivers and prognostic markers of disease progression and death.MethodsFrom a cohort of approx. 2.6 million citizens in the two regions of Denmark, SARS-CoV-2 PCR tests were performed on subjects suspected for COVID-19 disease; 3944 cases had at least one positive test and were subjected to further analysis. A cohort of SARS- CoV-2 positive cases from the United Kingdom Biobank was used for external validation.FindingsThe ML models predicted the risk of death (Receiver Operation Characteristics – Area Under the Curve, ROC-AUC) of 0.904 at diagnosis, 0.818, at hospital admission and 0.723 at Intensive Care Unit (ICU) admission. Similar metrics were achieved for predicted risks of hospital and ICU admission and use of mechanical ventilation. We identified some common risk factors, including age, body mass index (BMI) and hypertension as driving factors, although the top risk features shifted towards markers of shock and organ dysfunction in ICU patients. The external validation indicated fair predictive performance for mortality prediction, but suboptimal performance for predicting ICU admission.InterpretationML may be used to identify drivers of progression to more severe disease and for prognostication patients in patients with COVID-19. Prognostic features included age, BMI and hypertension, although markers of shock and organ dysfunction became more important in more severe cases.We provide access to an online risk calculator based on these findings.FundingThe study was funded by grants from the Novo Nordisk Foundation to MS (#NNF20SA0062879 and #NNF19OC0055183) and MN (#NNF20SA0062879). The foundation took no part in project design, data handling and manuscript preparation.

Introduction: Worldwide, the COVID-19 pandemic has put significant strains on hospital resources. Several studies have indicated that Machine Learning (ML) models can accurately predict adverse events (hospital and intensive care unit (ICU) admission, use of mechanical ventilation and death) on the individual patient level (micro prediction). We hypothesize that these micro predictions can be expanded to population wide (macro) forecasts for ICU resource planning. Methods: Electronic Health Record data from 34,012 SARS-CoV-2 positive patients from two Danish health care regions were extracted. Random Forest (RF) models were trained, using demographics, diagnoses code, laboratory tests and vital signs where available, to predict risk of ICU admission and use of mechanical ventilation after n days (n = 5, 10). These models were then used for a forecasting prognosis of the required hospital resources. Results: When using regular retraining on new data, RF models predicted 5-day risk of ICU admission with an area under the receiver operator characteristic curve (ROC-AUC) of 0∙986 and 5-day risk of use of ventilation with an ROC-AUC of 0∙995. The corresponding 5-day forecasting models predicted the needed ICU capacity with a coefficient of determination (R2) of 0∙930 and use of ventilation with an R2 of 0∙934. Performance was comparable but slightly reduced for 10-day forecasting models. Conclusions: Random Forest-based modelling of COVID-19 electronic health record data can be used for accurate 5- and 10-day forecasting predictions of ICU resource requirements. Funding Statement: The study was funded by grants from the Novo Nordisk Foundation to MS (#NNF20SA0062879 and #NNF19OC0055183) and MN (#NNF20SA0062879). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study was approved by the relevant legal boards: the Danish Patient Safety Authority (Styrelsen for Patientsikkerhed, approval #31-1521-257) and the Danish Data Protection Agency (Datatilsynet, approval #P-2020-320). Under Danish law, these agencies provide the required legal approval for the handling of sensitive patient data, including EHR data, without patient consent.

INTRODUCTION: This study describes the types and health consequences of medication errors in residential facilities for which the Danish Poison Information Center (DPIC) was contacted.METHODS: This study is based on all inquiries made by residential facilities to the DPIC during a 13-month period. Information about inquirers and residents, data related to the medication error, symptoms, risk assessments and recommendations was collected, and a follow-up phone call was made to evaluate the clinical outcomes, preferably within one week.RESULTS: During the study period, the DPIC received 146 inquiries concerning medication errors in residential facilities. Nearly all inquiries concerned excess administration of medication (96%) and often involved medications targeting the nervous system (65%). In 9% of cases, the DPIC recommended hospitalisation. Most medication errors (92%) were considered of & ldquo;no or minor risk & rdquo;. Administration of medication to the wrong resident is a frequent reason for consulting the DPIC (45%) in cases with medication errors.CONCLUSIONS: In this study, we inventoried the inquiries made to the DPIC about medication errors in residential facilities in Denmark. Most medication errors did not carry a risk of serious health consequences, but continued monitoring is warranted to minimise risk in this vulnerable population. FUNDING: Copenhagen Center for Health Technology (5001105002), Department of Clinical Pharmacology (Bispebjerg Hospital, The Capital Region) (1152871001).TRIAL REGISTRATION: not relevant.

Local anaesthetic systemic toxicity (LAST) gives rise to symptoms from the central nervous and cardiovascular systems. Knowledge about symptoms and risk factors is crucial in preventing LAST. Treatment of severe symptoms should often include vasopressors and sodium bicarbonate. In cardiac arrest the guidelines for advance life support including high-quality cardiopulmonary resuscitation (CPR) should be followed - emphasising prolonged CPR and extracorporeal life support (ECLS) in case of LAST. The conclusion of this review is that intravenous lipid emulsion should only be considered, when other interventions fail, and ECLS is unavailable.

Background Intravenous high‐dose glucagon is a recommended antidote against beta‐blocker poisonings, but clinical effects are unclear. We therefore investigated hemodynamic effects and safety of high‐dose glucagon with and without concomitant beta‐blockade. Methods and Results In a randomized crossover study, 10 healthy men received combinations of esmolol (1.25 mg/kg bolus+0.75 mg/kg/min infusion), glucagon (50 µg/kg), and identical volumes of saline placebo on 5 separate days in random order (saline+saline; esmolol+saline; esmolol+glucagon bolus; saline+glucagon infusion; saline+glucagon bolus). On individual days, esmolol/saline was infused from −15 to 30 minutes. Glucagon/saline was administered from 0 minutes as a 2‐minute intravenous bolus or as a 30‐minute infusion (same total glucagon dose). End points were hemodynamic and adverse effects of glucagon compared with saline. Compared with saline, glucagon bolus increased mean heart rate by 13.0 beats per minute (95% CI, 8.0–18.0; P P =0.002), diastolic blood pressure by 9.4 mm Hg (95% CI, 6.3–12.6; P P =0.003) at the 5‐minute time point on days without beta‐blockade. Similar effects of glucagon bolus occurred on days with beta‐blockade and between 15 and 30 minutes during infusion. Hemodynamic effects of glucagon thus reflected pharmacologic glucagon plasma concentrations. Glucagon‐induced nausea occurred in 80% of participants despite ondansetron pretreatment. Conclusions High‐dose glucagon boluses had significant hemodynamic effects regardless of beta‐blockade. A glucagon infusion had comparable and apparently longer‐lasting effects compared with bolus, indicating that infusion may be preferable to bolus injections. Registration Information URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03533179.

Loperamide is an over-the-counter anti-diarrhoeal agent. In supratherapeutic doses, loperamide penetrates the blood-brain barrier, exceeds the efflux capacity of P-glycoprotein and binds to central opioid receptors. We report a case of a 33-year-old woman with a history of opioid abuse, who had a long-term excessive daily intake of loperamide in order to achieve a euphoric effect. Cardiac arrhythmias, respiratory depression and death have been reported in relation to excessive loperamide use.

IntroductionCurrent pharmacological treatment options for hyperemesis gravidarum have been introduced based on scarce evidence and are often not sufficiently effective. Several case reports suggest that mirtazapine, an antidepressant, may be an effective treatment for hyperemesis gravidarum, but so far there are no controlled trials investigating the potential effect of mirtazapine on hyperemesis gravidarum. The antiemetic ondansetron is currently widely used to treat hyperemesis gravidarum despite sparse evidence of effect in pregnant women. This study aims to investigate the effect of mirtazapine on hyperemesis gravidarum while also providing data on the effect of ondansetron.Methods and analysisThis randomised double-blind placebo-controlled multicentre trial will be conducted in eight Danish hospitals. One hundred and eighty pregnant women referred to secondary care for hyperemesis gravidarum will be randomly allocated to 14-day treatment with either mirtazapine, ondansetron or placebo. Main inclusion criterion will be Pregnancy Unique Quantification of Emesis (PUQE-24) score ≥13 or PUQE-24 score ≥7 if accompanied by weight loss >5% of pre-pregnancy weight or hospitalisation. Participants are eligible regardless of whether other antiemetics, including ondansetron, have been tried. The coprimary outcomes are effects of mirtazapine and ondansetron, respectively, on PUQE-24 score tested hierarchically on day 2 and day 14. Secondary outcomes include, but are not limited to, differences between the three groups in number of daily vomiting episodes, dropout due to treatment failure, use of rescue medication, weight change and side effects.Ethics and disseminationThe trial has been approved by the Regional Committees on Health Research Ethics in the Capital Region of Denmark, the Danish Medicines Agency and the Danish Data Protection Agency. Results will be published in peer-reviewed journals and submitted to relevant conferences.Trial registration numberNCT03785691

In a double-blinded, randomized, crossover trial, we investigated the hemodynamic effects of high-dose intravenous lipid emulsion (ILE) with/without metoprolol. Ten healthy volunteers each completed 4 trial days (placebo + ILE; metoprolol + placebo; metoprolol + ILE; placebo + placebo) in random order. Metoprolol was administered as an initial bolus (10 mg), followed by an infusion (50 mg) from 5 to 30 minutes. ILE was administered as a bolus at 12.5 minutes (2.5 mL/kg), followed by a 15-minute infusion (0.25 mL/kg per minute). On metoprolol + ILE days (compared with metoprolol + placebo) after 120 minutes, mean heart rates were significantly higher (difference, 5.5 beats per minute (bpm); 95% confidence interval (CI), 3.0-8.1 bpm; P < 0.001), and average relative cardiac output was higher (difference, 10 percentage points; 95% CI, 5-15 percentage points; P < 0.001). The hemodynamic effect of ILE developed gradually. ILE had no effect on plasma metoprolol or major adverse events. In conclusion, high-dose ILE has relatively marginal and delayed hemodynamic effects that may have limited clinical relevance in the short-term clinical toxicological setting.

BACKGROUND: Calcium channel blockers (CCBs) are widely used drugs that have a narrow therapeutic index. Even minor overdoses must be treated in-hospital due to the risk of severe hypotension and bradycardia. We aimed to describe trends in CCB use and overdoses in Denmark.METHODS: Data on enquiries concerning CCBs reported to the Danish Poisons Information Center (DPIC) from January 2009 to January 2015 was coupled with data on hospitalization and mortality obtained from Danish National Registers. We obtained data on the general use of CCBs in Denmark and retrieved medical charts on fatal cases.RESULTS: From a total of 126,987 enquiries to the DPIC in 2009-2014 we identified 339 CCB unique exposures (3‰ of all). Children CONCLUSION: Four fifths of enquiries to the DPIC result in hospitalization and one fifth concern small children. Mortality were infrequent and occurred only in adults with suicidal exposures and with and an overrepresentation of verapamil exposures.

Objective Extended release (ER) tablets/capsules in massive ingestion overdoses are prone to form pharmacobezoars potentially increasing the risk of late-appearing toxic effects and prolonged symptoms. Oral activated charcoal is often sufficient to prevent drug absorption, but in a recent massive ingestion of highly toxic substances, prior orogastric lavage might be considered. The disintegration characteristics of ER preparations in overdose situations is valuable to understand if the time line and course of the intoxication might be prolonged, but information on these characteristics are unavailable. Slow disintegration and/or pharmacobezoar formation, and the large size makes ER preparation impossible to evacuate using a 30F orogastric lavage tube. This study evaluates the disintegration and pharmacobezoar formation of a simulated massive ER tablet ingestion in an in vitro model, using a selection of extended release tablets, with different disintegrating characteristics when present in therapeutic numbers. Furthermore, the sizes of the formed pharmacobezoars were compared with the dimensions of a 30F orogastric lavage tube. Method A standardized model mimicking the physical effects on pharmaceutical preparations in simulated gastric fluid (SGF) was developed and tested on three mono-depot ER tablets (quetiapine/Seroquel®XR 50 mg, paracetamol/Pinex®Retard 500 mg, verapamil/Isoptin®Retard 240 mg), one poly-depot ER tablet (carbamazepine/Tegretol®Retard 200 mg), and one immediate-release tablet (paracetamol/Panodil® 500mg). Thirty tablets were placed in polyamide mesh bags, either together in one bag or in separate bags, immersed in 1 L SGF, and incubated at 37 °C for 48 h. Released drugs were quantified at 0.5-48 h. Results Visual inspection showed that Seroquel®XR, Pinex®Retard, and Isoptin®Retard tablets formed firm pharmacobezoars stable for more than 4 h and intact fractions remained for up to 24 h. Drug releases were reduced by 53%, 40%, and 31%, respectively, for up to 8 h compared to separated tablets. Light microscopy showed that contact with SGF transformed the coating of Seroquel®XR and Pinex®Retard to a diffusion-controlled swelled gel-layer, and the Isoptin®Retard tablets into a rigid and slow-releasing matrix. Tegretol®Retard disintegrated into microspheres within 30 min, and Panodil® disintegrated within minutes. Discussion The developed pharmacobezoars of mono-depot ER tablets demonstrated prolonged drug release. Neither the formed pharmacobezoars, nor the single tablets of the tested mono-depot ER preparations, would pass through the lumen of a standard orogastric lavage tube, rendering this modality ineffective for tablet removal in gastrointestinal decontamination.

AIMS To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P

Context: The intravenous (IV) N-acetylcysteine (NAC) regimen used worldwide in paracetamol overdose is complex with three separate weight-based doses and is associated with a high incidence of adverse events including non-allergic anaphylactoid reactions (NAARs). In 2012, Denmark adopted the two-bag IV NAC regimen which combined the first two infusions of the three-bag regimen and kept the third infusion unchanged. We compared the safety and efficacy of the two-bag IV NAC regimen with the traditional Danish three-bag regimen. Methods: A medical chart review was conducted in three Danish medical centers from January 2012 through December 2014. Safety and efficacy data were compared for patients who received the traditional infusion protocol in Denmark or the 20-h two-bag IV regimen. Results: Four hundred and ninety-three cases received the two-bag regimen and 274 received the three-bag regimen. The overall incidence of NAARs was 9% with all being mild to moderate in intensity. Fewer subjects in the two-bag group (4%) developed NAARs compared to 17% in the three-bag group (p Conclusions: The incidence of NAARs was lower in patients receiving acetylcysteine in a two-bag regimen compared to the traditional Danish three-bag regimen without an apparent reduction in efficacy.

Drug-drug interactions (DDIs) occur commonly and may lead to severe adverse drug reactions if not handled appropriately. Considerable information to support clinical decision making regarding potential DDIs is available in the literature and through various systems providing electronic decision support for healthcare providers. The challenge for the prescribing physician lies in sorting out the evidence and identifying those drugs for which potential interactions are likely to become clinically manifest. P-glycoprotein (P-gp) is a drug transporting protein that is found in the plasma membranes in cells of barrier and elimination organs, and plays a role in drug absorption and excretion. Increasingly, P-gp has been acknowledged as an important player in potential DDIs and a growing body of information on the role of this transporter in DDIs has become available from research and from the drug approval process. This has led to a clear need for a comprehensive review of P-gp-mediated DDIs with a focus on highlighting the drugs that are likely to lead to clinically relevant DDIs. The objective of this review is to provide information for identifying and interpreting evidence of P-gp-mediated DDIs and to suggest a classification for individual drugs based on both in vitro and in vivo evidence (substrates, inhibitors and inducers). Further, various ways of handling potential DDIs in clinical practice are described and exemplified in relation to drugs interfering with P-gp.

Context: N-acetylcysteine (NAC) is used worldwide to prevent liver injury after paracetamol overdoses. Anaphylactoid reactions to NAC occur frequently and often lead to treatment interruptions or d...

INTRODUCTION Hyperoxia after cardiac arrest may be associated with higher mortality, and trials have found that excess oxygen administration in patients with myocardial infarction is associated with increased infarct size. The effect of hyperoxia before cardiac arrest is sparsely investigated. Our aim was to assess the association between excessive oxygen administration before cardiac arrest and the extent of subsequent myocardial injury. METHODS We performed a retrospective study including patients who had in-hospital cardiac arrest during 2014 in the Capital Region of Denmark. We excluded patients without peripheral oxygen saturation measurements within 48 hours before cardiac arrest. Patients were divided in three groups of pre-arrest oxygen exposure, based on average peripheral oxygen saturation and supplemental oxygen. Primary outcome was peak troponin concentration within 30 days. Secondary outcomes included 30-day mortality. Data were analyzed using multiple logistic regression and Wilcoxon rank sum test. RESULTS Of 163 patients with cardiac arrest, 28 had excessive oxygen administration (17%), 105 had normal oxygen administration (64%) and 30 had insufficient oxygen administration (18%) before cardiac arrest. Peak troponin was median 224 ng/L in the excessive oxygen administration group vs 365 ng/L in the normal oxygen administration group (P = .54); 20 of 28 (71%) in the excessive oxygen administration group died within 30 days compared to 54 of 105 (51%) in the normal oxygen administration group. (OR 1.87, 95% CI 0.56-6.19) CONCLUSIONS: Excessive oxygen administration within 48 hours before in-hospital cardiac arrest was not statistically associated with significantly higher peak troponin or mortality.

IV iron is indicated in clinical conditions, where rapid anaemia alleviation and repletion of iron stores are required. The acute toxicity of IV iron is ascribed to the presence of labile iron in plasma. Thus, shorter plasma residence time might improve the safety profile, even for compounds holding‐on the iron tightly. In this single‐centre, open‐label, single‐dose escalation study, we evaluated the elimination kinetics of ferric bepectate (FBP) compared to those of ferric carboxymaltose (FCM). Thirty‐three iron‐depleted anaemic patients who had undergone cardiac surgery were included and received 200, 500 or 1500 mg FBP or 500 mg FCM. Plasma drug curves were subjected to model‐free analysis. Because saturation kinetics was found, a compartmental model with limited elimination capacity was applied. Urinary iron excretion was also analysed. The initial non‐compartmental analysis revealed an increasing AUC/dose ratio for FBP. For both drugs, the central distribution compartment corresponded to plasma volume, and elimination followed Michaelis‐Menten saturation kinetics. Maximal elimination rates (V max) were 224 mg/h and 81 mg/h for FBP 500 mg and FCM 500 mg, respectively; drug concentrations at half V max (K m), 99 mg/L and 212 mg/L, respectively; and terminal plasma half‐life (T½), 3.05 h and 8.96 h, respectively. Both drugs were equally effective in eliciting an early ferritin rise. Urinary iron excretion was measurable in all patients receiving FCM but not in those receiving FBP, which was well tolerated. Intravenous iron drugs are subject to capacity‐limited elimination with different saturation thresholds. Urinary iron excretion can be used as a surrogate for labile plasma iron.

Propranolol is often prescribed to younger people with exam-related performance anxiety. Evidence for effect as well as safety is, however, sparse for this non-approved indication. Furthermore, only relatively large pack sizes are available in Denmark. This may spur an unnecessary, permanent overuse and increase the risk of overdosing and poisoning. The aim of this review is to examine the evidence for the effect as well as safety of propranolol for exam-related performance anxiety and to discuss, whether the use of this drug for this unapproved indication is rational.

Orogastric aspiration (OA) without orogastric lavage has been the traditional gastric emptying method of choice in Denmark; this being based on national historic studies on poisoned patients. The treatment is still observed to be initiated prior to consultations with the Danish poisons information centre. In this review, we present relevant knowledge in the field of OA. The procedure should only be considered in very limited cases and never routinely. Also, an algorithm is presented for its rare use in relation to other more effective gastrointestinal decontamination methods.