Aksel Karl Georg Jensen

Antidepressant Use and Risk of Out-of-Hospital Cardiac Arrest: A Nationwide Case–Time–Control Study

Treatment with some types of antidepressants has been associated with sudden cardiac death. It is unknown whether the increased risk is due to a class effect or related to specific antidepressants within drug classes. All patients in Denmark with an out‐of‐hospital cardiac arrest (OHCA) were identified (2001–2007). Association between treatment with specific antidepressants and OHCA was examined by conditional logistic regression in case–time–control models. We identified 19,110 patients with an OHCA; 2,913 (15.2%) were receiving antidepressant treatment at the time of OHCA, with citalopram being the most frequently used type of antidepressant (50.8%). Tricyclic antidepressants (TCAs; odds ratio (OR) = 1.69, confidence interval (CI): 1.14–2.50) and selective serotonin reuptake inhibitors (SSRIs; OR = 1.21, CI: 1.00–1.47) were both associated with comparable increases in risk of OHCA, whereas no association was found for serotonin–norepinephrine reuptake inhibitors/noradrenergic and specific serotonergic antidepressants (SNRIs/NaSSAs; OR = 1.06, CI: 0.81–1.39). The increased risks were primarily driven by: citalopram (OR = 1.29, CI: 1.02–1.63) and nortriptyline (OR = 5.14, CI: 2.17–12.2). An association between cardiac arrest and antidepressant use could be documented in both the SSRI and TCA classes of drugs.

Antipsychotics and associated risk of out-of-hospital cardiac arrest

Antipsychotic drugs have been associated with sudden cardiac death, but differences in the risk of out–of–hospital cardiac arrest (OHCA) associated with different antipsychotic drug classes are not clear. We identified all OHCAs in Denmark (2001–2010). The risk of OHCA associated with antipsychotic drug use was evaluated by conditional logistic regression analysis in case–time–control models. In total, 2,205 (7.6%) of 28,947 OHCA patients received treatment with an antipsychotic drug at the time of the event. Overall, treatment with any antipsychotic drug was associated with OHCA (odds ratio (OR) = 1.53, 95% confidence interval (CI): 1.23–1.89), as was use with typical antipsychotics (OR = 1.66, CI: 1.27–2.17). By contrast, overall, atypical antipsychotic drug use was not (OR = 1.29, CI: 0.90–1.85). Two individual typical antipsychotic drugs, haloperidol (OR = 2.43, CI: 1.20–4.93) and levomepromazine (OR = 2.05, CI: 1.18–3.56), were associated with OHCA, as was one atypical antipsychotic drug, quetiapine (OR = 3.64, CI: 1.59–8.30).

Propofol-remifentanil or sevoflurane for children undergoing magnetic resonance imaging? A randomised study.

Magnetic resonance imaging (MRI) of children is generally performed under sedation or with general anaesthesia (GA), but the ideal regimen has not been found. The aim of this study was to see if propofol‐remifentanil would be a suitable alternative for the maintenance of anaesthesia in this category of patients.

On the validity of the case-time-control design for autocorrelated exposure histories

The case-time-control design is an extension of the case-crossover design capable of handling time trends in the exposure of the general population. Time-invariant confounders are controlled for by the design itself. The idea is to compare the exposure status of a person in one or several reference periods during which no event occurred with the exposure status of the same person in the index period where the event occurred. By comparing case-crossover results in cases to case-crossover results in controls, the exposure-outcome association can be estimated by conditional logistic regression. We review the mathematical assumptions underlying the case-time-control design and examine sensitivity to deviations from the assumed independence of within-individual exposure history. Results from simulating various scenarios suggest that the design is quite robust to deviations from this model assumption. In addition, we show that changes in exposure probability over time can be modeled in a flexible way using splines.

Effect of locally‐tailored labour management guidelines on intrahospital stillbirths and birth asphyxia at the referral hospital of Zanzibar: A quasi‐experimental pre‐post‐study (The PartoMa study)

To evaluate effect of locally tailored labour management guidelines (PartoMa guidelines) on intrahospital stillbirths and birth asphyxia.

Development and internal validation of the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU)

Intensive care unit (ICU) mortality prediction scores deteriorate over time, and their complexity decreases clinical applicability and commonly causes problems with missing data. We aimed to develop and internally validate a new and simple score that predicts 90‐day mortality in adults upon acute admission to the ICU: the Simplified Mortality Score for the Intensive Care Unit (SMS‐ICU).

Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life: A randomized clinical trial

Background: Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation. Objective: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. Methods: The Danish Calmette Study is a multicenter randomized trial conducted from 2012–2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no‐intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish‐speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician‐diagnosed and medically treated RW up to 13 months of age. Results: By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89–1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW. Conclusion: Neonatal BCG had no effect on the development of RW before 13 months of age.

Simplified Mortality Score for the Intensive Care Unit (SMS-ICU): protocol for the development and validation of a bedside clinical prediction rule

Introduction Mortality prediction scores are widely used in intensive care units (ICUs) and in research, but their predictive value deteriorates as scores age. Existing mortality prediction scores are imprecise and complex, which increases the risk of missing data and decreases the applicability bedside in daily clinical practice. We propose the development and validation of a new, simple and updated clinical prediction rule: the Simplified Mortality Score for use in the Intensive Care Unit (SMS-ICU). Methods and analysis During the first phase of the study, we will develop and internally validate a clinical prediction rule that predicts 90-day mortality on ICU admission. The development sample will comprise 4247 adult critically ill patients acutely admitted to the ICU, enrolled in 5 contemporary high-quality ICU studies/trials. The score will be developed using binary logistic regression analysis with backward stepwise elimination of candidate variables, and subsequently be converted into a point-based clinical prediction rule. The general performance, discrimination and calibration of the score will be evaluated, and the score will be internally validated using bootstrapping. During the second phase of the study, the score will be externally validated in a fully independent sample consisting of 3350 patients included in the ongoing Stress Ulcer Prophylaxis in the Intensive Care Unit trial. We will compare the performance of the SMS-ICU to that of existing scores. Ethics and dissemination We will use data from patients enrolled in studies/trials already approved by the relevant ethical committees and this study requires no further permissions. The results will be reported in accordance with the Transparent Reporting of multivariate prediction models for Individual Prognosis Or Diagnosis (TRIPOD) statement, and submitted to a peer-reviewed journal.

Neonatal BCG vaccination and atopic dermatitis before 13 months of age: A randomized clinical trial

Studies have suggested that Bacillus Calmette‐Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis.

Reply to the letter regarding our manuscript ‘Development and internal validation of the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU)’

We have read with interest the letter by Dr. Haniffa and colleagues regarding our recently published manuscript on the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU) clinical prediction rule. In general, we fully support the opinions and perspectives presented. We completely agree that prognostic models must be developed and validated, using appropriate methodology and reported in accordance with the TRIPOD statement. Also, we agree that appropriate reporting and handling of missing data is key, and we advocate for more widespread use of multiple imputation instead of complete case analysis or ‘normal’ imputation when data are not missing completely at random. Variables with high missingness in model development samples are likely to be missing when models are used in daily clinical practice. While statistical methods can account for this to a large extent in research, this is not possible in the clinical setting, and thus excluding these variables seems sound. Another important point is that all prognostic models should be externally validated, and if necessary, recalibrated (and subsequently externally validated) if used in markedly different settings. This improves predictions across settings, as for the different geographical equations for SAPS 3. Accordingly, clinical prediction rules developed in high-income countries – including the SMS-ICU should be externally validated, and recalibrated if necessary, in low-and-middle income countries prior to routine use in these countries and vice versa. Real-time automatic data capture from electronic healthcare information systems may decrease problems with missing data, however, sampling frequency affects model performance. Thus, automatic data capture may provide more extreme predictions due to few extreme or erroneous measurements. Consequently, it may be argued that data collection and verification, and handling of outliers by researchers is preferred. Prognostic models are useful tools, but with inherent limitations that must be acknowledged by users. No score will ever provide perfect predictions, and the use of severity scores to guide individual patient decisions has been recommended against. We are of the opinion that simpler scores are more valuable to clinicians than more complex scores, which are time-consuming and will often suffer from missing data. For clinicians, severity scores provide an objective extra piece of information to the puzzle, but never a definite answer. When used in research and to compare intensive care unit performances, we also believe that simpler scores with sufficient calibration has advantages over more complex scores, largely due to simpler data collection and handling and less missingness. Measuring the clinical usefulness and impact of prediction models has been recommended, and (cluster) randomised clinical trials can assess whether models that recommend certain actions (decision rules) improves patient-important outcomes. However, for severity scores that do not provide any treatment recommendations, the approach is less straightforward and research in this area is warranted. We perfectly agree that more research into better understanding the priorities of clinicians, researchers and administrators, when developing or advocating any prognostic model, as well as facilitators and barriers to clinical uptake is highly warranted.