Aalborg and Farsø, Denmark

The Ventilation During In-hospital Cardiac Arrest Study

Vaginal CO2 Laser Therapy for Genitourinary Syndrome in Breast Cancer Survivors

Fluid Administration and Fluid Accumulation in the Intensive Care Unit

Background: Fluid accumulation is associated with adverse outcome in ICU patients, however, assessment of fluid status is often difficult and no established definition and consistent detection method exists. Former research has primarily focused on the use of resuscitation fluid, but a substantial amount of fluid is administered throughout the entire ICU stay and this fluid may be a clinically relevant source of fluid accumulation. Objectives: To describe fluid administration practices during the entire ICU stay, and provide contemporary epidemiological data on fluid accumulation, fluid removal, risk factors and association with patient outcomes from a worldwide perspective. Study design: International inception cohort study. Patients will be included during a 14-day inception period to be chosen by each participating site. Population: Critically ill adult patients (≥ 18 years) with acute admission to the ICU. Intervention: None. Only routinely available data will be collected. Study duration: Patients are followed daily until ICU discharge or death for a maximum of 28 days. Follow-up is performed 90 days after ICU admission.

Bicarbonate for In-Hospital Cardiac Arrest

INfluenza VaccInation To Mitigate typE 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease in which T cells attack and destroy the insulin-producing β cells in the pancreatic islets. In theory, immunotherapies aimed at re-programming the immune system to avoid β cell destruction is a promising strategy to prevent T1D or delay onset of overt disease. In this trial we test the hypothesis that influenza vaccination is superior to no influenza vaccination in sustaining β cell function in early T1D. Secondary outcome measures include change in autoantibodies directed against antigens present in the pancreatic islets, measures of severity of disease, change in inflammatory markers, and antibody titers against the four viruses included in the vaccine. Despite improvements in care, T1D is a leading cause of debilitating complications and early death globally. Children with residual β cell function are at lower risk for severe hypoglycemia, have better diabetes regulation, and have lower insulin requirements compared to children without residual β cell function. Thus, a simple, cheap treatment to mitigate T1D is highly warranted.

Intraoperative Methadone for Postoperative Pain in Patients Undergoing Tonsillectomy

This study is an investigator-initiated, prospective, randomised controlled trial with two arms: an intervention arm (methadone) and a control arm (fentanyl). Patients scheduled for tonsillectomy at Randers Regional Hospital, Denmark, will be approached for study participation. Patients are randomised in a 1:1 ratio in blocks of varying sizes (between 4 and 8) to receive either intraoperative methadone or fentanyl. The randomisation assignment will be handled by the hospital pharmacy using a web-based central randomisation procedure (www.sealedenvelope.com). The study drug will be prepared by the hospital pharmacy at Aarhus University Hospital and delivered as kits with identical appearance, marked with the randomization number (1-130). On the day of surgery, a kit will be opened and a 10 ml syringe with study drug (methadone 2 mg/ml or fentanyl 30 microgram/ml or ) will prepared by a health care professional (nurse or medical doctor not involved in the study or the treatment of patients). Once prepared, the blinded study drug will be given to and handled by one of the research team members and administered after induction of anesthesia and prior to surgery The dose of the study drug will be administered as intravenous bolus dose in equipotent doses (0.2 mg/kg / 3 μg/kg) corresponding to 1 ml for every 10 kg of ideal body weight (women: height (cm) - 105. Men: height (cm) - 100)) after induction of anaesthesia and before the start of surgery. Postoperative data will be obtained by reviewing hospital records, by interview and electronic questionnaires sent by email.

Improving Diagnostics in Cervical Dysplasia

Cervical cancer is the fourth most common cancer in women worldwide, and comprises approximately 7% of all new cancers in women. To reduce the disease burden, accurate and timely diagnosis of cervical precancerous lesions are crucial. Aim: The aim of this study is to evaluate whether optimizing present procedures can improve diagnosis of precancerous cervical lesions. The study aims to: 1. Initiate a double blind study to investigate, if the diagnosis of cervical precancerous lesions can be improved among elderly women aged ≥ 50 years, by providing pretreatment with vaginal estrogen prior to the colposcopic examination. Background: In Denmark, about 400 women are diagnosed with cervical cancer annually, and around 15.000 women are diagnosed and treated with cervical precancerous lesions. Cervical cancer is preventable through HPV vaccination and screening, yet the incidence rates have stagnated. Cervical cancer is caused by an infection with a high-risk human papillomavirus (HPV), which is a common sexually transmitted disease, with a life-time risk of >80%. In 10-15% of the infected women, the infection becomes persistent, and may cause precancerous lesions (Cervical Intraepithelial Neoplasia, CIN). CIN is graded according to severity (CIN1, CIN2, and CIN3), and can progress and develop into cancer if left untreated. The classification of CIN dictates the treatment course, and surgical treatment (cone biopsy) is recommended in most cases of CIN2 or worse (CIN2+). To identify precancerous lesions, all 23-64-year-old women in Denmark are invited for screening with a cervical cytology sample or an HPV test every third or five years. The cervical cytology sample is classified as mild (low-grade squamous intraepithelial lesion, LSIL) or moderate to severe (high-grade squamous intraepithelial lesion, HSIL). ASCUS is a term used to describe atypical cervical squamous cells of undetermined significance. An abnormal screening sample results in a referral for further examination by colposcopy. It allows close visualization of the cervix in order to detect suspicious lesions, and collection of cervical biopsies. Diagnostic of cervical precancerous lesions: Colposcopy is the most important diagnostic tools to detect cervical precancerous lesions and thereby prevention of cervical cancer. The area on the cervix where precancerous lesions and cancer develops is called the transformation zone (TZ), and the squamocolumnar junction (SCJ) refers to the internal margin of the TZ. The TZ is classified as type 1, 2 or 3 according to the visibility of all or part of the upper limit of the SCJ, that is either found completely visible (TZ1), partly visible (TZ2) or not visible (TZ3). To perform optimal examination and obtain a correct diagnosis, it is essential for the physician to identify the TZ. However, the colposcopy procedure may be challenging and performs poorly, especially among elderly women due to natural age-related changes of the cervix. After menopause, the TZ will retract into the cervical canal, which makes visualization of the SCJ and TZ difficult, rendering the colposcopy examination inadequate. Previous studies revealed inadequate colposcopy in up to 30-97%, increasing with age. Consequently, this increases the risk of developing cancer due to diagnostic delay, but also the risk of undergoing several colposcopy examinations or overtreatment by a cone biopsy (thereby also the risks related to surgery), causing adverse psychological outcomes, before a final diagnosis is achieved. Evidence-based practice is lacking on how, especially elderly women should be examined and followed-up in case of inadequate colposcopic examinations. This is a noteworthy public health concern, as elderly women are more likely to be diagnosed with advanced cervical cancer with higher mortality, due to late prognosis and faster disease progression. Furthermore, this group of elderly women is expected to increase in the future, due to the increasing female life expectancy, and due to the extensions of the cervical cancer screening programs in some countries, including Denmark. Optimizing the colposcopic performance: A few studies with limited sample sizes (ranging between 35 to 50 participants) suggested that pretreatment with estrogen prior to colposcopy may improve visualization of TZ and consequently improve diagnostics in elderly women. However, the quality of the previous studies is far from adequate and comparable. Furthermore, apart from age, there is also no risk factors described (e.g. previous dysplasia) with respect to the type of TZ as 1, 2 or 3. Hypotheses for this study: • Treatment with vaginal estrogen prior to colposcopy will improve the colposcopy performance in women aged ≥ 50 years as compared to standard procedure which is no treatment. Material and methods: The study will be designed as a randomized controlled double-blinded multicenter study. Enrollment will be performed at the Departments of Gynecology in Denmark (cities: Randers, Herning, Horsens and Odense). Eligible women will be booked for colposcopy as usual. By using the Danish National Patient registry, the investigators will be able to identify women referred for colposcopy, and collect relevant patient data. This will be combined with data from the nationwide Danish Pathology Data Bank, which will provide the histopathological results of the biopsies. The colposcopic examination will be performed by nurses and physicians who routinely perform colposcopies. Stata version 16 will be used for data analysis, and data will be stored in the RedCap database. A study protocol will be prepared in details. The report of the trial will conform to the CONSORT guidelines, and be reported according to the STARD 2015 guidelines. Eligible women will be randomized 1:1 prior to examination with either: A) Pretreatment with vaginal application of estrogen 30 microgram once a day every night for 14 days. B) Placebo with vaginal application without estrogen once a day every night for 14 days. Study medication will be mailed to the women after receiving written and telephone informed consent. The colposcopy examination will be performed according to current procedures and the Danish national guidelines (DSOG). All biopsies will be collected in one tube for histopathological evaluation. Patients will after examination be asked to score possible side-effects of the pretreatment. Statistical consideration: Assuming that the TZ will be visible in 54% of women aged ≥ 50 years in the group receiving placebo, and 81% in the estrogen pre-treatment group, the investigators will be able to detect an improvement in visibility of TZ of 50% or above. This improvement estimate was based on previous research, and also with reference to a clinically relevant threshold. Thus, with a power of 90% and an alpha value of 5%, a sample size of 62 women in each group will be required. To allow for a protocol violation of 20%, 75 women will be included in each group. After enrollment of approximately 30 women in each group, an inter-rim analysis will be performed. Feasibility and ethics: The chosen gynecological departments receive a large number of referrals for this patient group, which will ensure a large enrollment. The study will be reported to the Danish Data Protection Agency, the Central Denmark Region Committee on Biomedical Research Ethics and The Danish Health Authority (Danish Medicine Agency), and also registered as a clinical trial (www.clinicaltrials.gov). The GCP unit will supervise the project. Project information will be given to the women orally and written, and they must understand Danish to accept given information before participation. All information will be anonymized prior to analysis. Participation in the study will not have any consequence for the treatment of the women. The dose of estrogen is within the well-known standard recommendation, with a minimum of side effect. It is widely used and recommended by gynecologists to women aged ≥50 years.

A Study of Population and Sex-specific Troponin Cutoffs for Ruling Out Acute Myocardial Infarction

The present use of non-sex specific diagnostic cut-off levels of troponins in the diagnosis of acute myocardial infarction (MI) leads to under-diagnostication of acute MI in women and over-diagnostication in men. The purpose of this study is to document this through a randomized nationwide clinical implementation of population and sex-specific cut-off levels. Coronary artery disease (CAD) is globally the leading cause of mortality for men and women. The latest consensus statement defines myocardial infarction as 1) a rise and/or fall in cardiac troponins with 2) at least one value above the 99th percentile upper reference limit (URL) in the context of 3) symptoms or clinical evidence of myocardial ischemia. Thus, levels of cardiac troponins play a key role in the diagnostic work-up in general. Currently, uniform manufacturer-provided URLs, defined by the 99th percentile of cardiac troponins in a healthy reference population, is applied in Danish hospitals as a diagnostic cut-off for acute MI for both men and women. Lower levels of cardiac troponins are seen in healthy women as compared to healthy men, i.e. twice as high levels are seen in men. On this basis the clinical use of one uniform 99th percentile URL for cardiac troponins - i.e. applying the same diagnostic levels for men and women - may lead to a systematic under-diagnostication of acute MI in women and potentially an over-diagnostication of acute MI in men. Accordingly, the use of sex-specific 99th percentile URL of cardiac troponins are now recommended in recent guidelines by international cardiological societies, but this remains to be introduced in clinical practice. The 99th percentile URLs for cardiac troponins currently used in Danish Hospitals are provided by the manufacturer of each specific assay based on blood samples from a healthy reference population collected by the manufacturer. Studies have shown that the 99th percentile value is dependent on patient sex as well as on the reference population selected and the definition for "healthy" used in these studies. It is well known that the 99th percentile URL should stem from a local reference population. This recommendation has never been implemented in Denmark. The overall purpose of the study is to evaluate the clinical effect of implementing population and sex-specific 99th percentile URL for cardiac troponins in Denmark. To determine the sex-specific 99th percentile URLs of troponins based on a healthy Danish reference population, blood samples from healthy Danish blood donors, were analyzed using one troponin T assay and four troponin I assays. Second, the DANSPOT study is a nationwide cluster-randomized trial with "stepped-wedge" design with participation of all 22 Danish hospital laboratories and associated departments of cardiology. With one-month intervals, each of 22 centers are randomized to shift from the presently applied uniform 99th percentile URL of troponin to our newly determined population and sex-specific 99th percentiles URLs. Each patient is followed in Danish registries for 12 months after first admission. The clinical significance of sex-specific 99th percentile URLs of troponin is poorly investigated and for the same reason not yet implemented in Denmark or many other countries. The basic hypothesis of the DANSPOT study is that the implementation of population and sex-specific 99th URLs for troponin, will ensure that the right patients receive the right treatment. The investigators expect to detect significantly more women with acute MI, theoretically resulting in a more accurate diagnosis and treatment of women and men with acute MI. This would be guideline-defining for implementing sex-specific cutoffs for cardiac troponin in Denmark as well as internationally as recommended in guidelines by professional cardiological societies.

The Effect of Hypnotherapeutic Sound-files on the Sleep of Parents in the Neonatal Unit.

Rapid Use of High-sensitive Cardiac Troponin I for ruling-in and Ruling-out of Acute Myocardial Infarction

Background: Chest pain is a key symptom of acute coronary syndrome (ACS), but can also represent other cardiac and non-cardiac diseases. Rapid identification of ACS in terms of 'rule-in' or 'rule-out' is essential in order to minimize treatment delay and time to discharge. In the absence of ST-segment elevation myocardial infarction (STEMI) at initial ACS evaluation, the European Society of Cardiology guidelines recommend repeated measurements of high-sensitive cardiac troponin (hs-cTn) at presentation (0h) and 3 hours (3h) after presentation to rule-in and rule-out myocardial infarction (MI). An accelerated algorithm for ruling-in and ruling-out MI after 1h (0h/1h algorithm) has recently been suggested by the European Society of Cardiology as a valid alternative to the standard approach. The novel 0h/1h algorithm has only been validated for certain hs-cTn assays. However, routine use of the 0h/1h algorithm is still not widely implemented, as further data on algorithm performance are warranted. A study of patients undergoing transcoronary ablation of septal hypertrophy, a clinical model of MI, shows that troponin concentrations measured by a hs-cTn assay significantly increase already after 15 minutes. This indicates that it may be possible to evaluate troponin dynamics even earlier than suggested by the 0h/1h algorithm. So far, no large-scale studies have included measurements of hs-cTn at 30m, and no 0h/30m algorithm has been derived. Therefore it is unknown if rule-in and rule-out of MI can be done safely using a 0h/30m algorithm. Aim: To investigate if a high-sensitive Troponin Assay can rule-in or rule-out MI, when using a 0h/30m and a 0h/1h algorithm. Patients and methods: This prospective cohort study will include patients presenting to the Emergency Department with chest pain suggestive of ACS. The study is designed to enroll 1.000 patients with complete blood samples (0h, 30m, 1h and 3h). The expected incidence of MI in our population is inevitably low due to pre-hospital risk-stratification based on point-of-care troponin and electrocardiogram evaluation in the ambulance. Thus, patients with a very high pre-test probability of MI will be admitted to tertiary care centers with cardiac catheterization facilities rather than a regional hospital as in present study. Pilot study calculations estimate an expected prevalence of MI in our study cohort of approximately 7.4%. Assuming a negative predictive value of 99.7% in the rule-out group, a distribution with 7% patients in the rule-in group and 20% assigned to the observational zone (patients who can't be stratified to either the rule-out or the rule-in group), enrolment of at least 500 patients for derivation of the algorithms and at least 500 for the validation of the respective algorithms will provide an acceptable lower boundary of 98.2% of the two-sided 95% confidence interval. All patients aged ≥18 years referred to the emergency department at Randers Regional Hospital, Randers, Denmark with chest pain and admitted on the suspicion of ACS will be eligible for the study. Patients will be recruited after initial contact with an emergency department nurse when results of an electrocardiogram as well as vital sign parameters (blood pressure, heart rate, peripheral oxygen saturation, respiratory rate and temperature) are available. Patients <18 years of age, with STEMI at admission, in dialysis treatment or pregnant will be excluded. The study is conducted in accordance with the Declaration of Helsinki. Oral and written consent will be obtained. Patients will be asked for informed consent to have information passed on from the electronic patient journal regarding gender, age, medicine, previous MI and co-morbidity for use in this study only. Patients declining to participate will receive standard treatment. Serial blood samples will be drawn at 0h (admission), 30m, 1h and 3h. The blood samples will be analyzed using high-sensitive troponin assays. Additional blood will be stored for each time point to establish a research biobank. Troponin values and troponin dynamics will be paired with final diagnosis for each patient. Two independent physicians will adjudicate the patients' final diagnosis based on data from the electronic patient journal (including physical examination, patient history, laboratory results, electrocardiogram, and other examinations). In cases of disagreement, a consensus decision will be reached after a case review. The treating physician will be blinded to test results at 30m and 1h, with the final therapeutic decision being left to the discretion of the attending physician and relying on troponin measurements at 0h and 3h only. All patients will be asked to complete a questionnaire on, e.g., time of chest pain onset and peak, chest pain characteristics (localization, radiation, sensation), additional symptoms at presentation (diaphoresis, nausea, abdominal pain, syncope, dyspnoea, palpitations), height and weight, smoking status and family history of coronary artery disease. Significance: This study challenges existing time limits for ACS evaluation by investigating the diagnostic value of hs-cTnI measurements at 30m. If our study shows that rule-out of MI can be performed safely at 30m, ACS evaluation can potentially be accelerated even further. Furthermore, our study will provide data on the performance of the 0h/1h algorithm in a Danish patient cohort. If this study demonstrates that the 0h/1h diagnostic algorithm can be used to safely rule-out MI in a patient cohort with a different risk profile, it can contribute to the acceptance of novel accelerated diagnostic approaches and favor global implementation of the 0h/1h algorithm.