Jørn Wetterslev

Tuborg Sundpark · Private Office

Background: Patch angioplasty in conventional carotid endarterectomy is suggested to reduce the risk of restenosis and recurrent ipsilateral stroke compared with primary closure. A systematic review of randomized clinical trials is needed to compare outcomes (benefits and harms) of both techniques. Methods: Searches (CENTRAL, PubMed/MEDLINE, EMB...

OBJECTIVES Liberal oxygen supplementation is often used in acute illness but has, in some studies, been associated with harm. We aimed to assess the benefits and harms of higher versus lower oxygenation strategies in acutely ill adults. METHODS We conducted an updated systematic review with meta-analysis and Trial Sequential Analysis (TSA) of rand...

Introduction Traditional carotid endarterectomy is considered to be the standard technique for prevention of a new stroke in patients with a symptomatic carotid stenosis. Use of plexus anesthesia or general anesthesia in traditional carotid endarterectomy is, to date, not unequivocally proven to be superior to one other. A systematic review was nee...

Objective : To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical diversity between trials in meta-analyses of interventions. Study design and setting : The development of CDIM was based on consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and valida...

Background Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher targ...

Objectives In this sub-study of the ‘Paracetamol and Ibuprofen in Combination’ (PANSAID) trial, in which participants were randomised to one of four different non-opioids analgesic regimen consisting of paracetamol, ibuprofen, or a combination of the two after planned primary total hip arthroplasty, our aims were to investigate the distribution of...

ABSTRACT Objectives: To summarise the evidence on benefits and harms of prompt closure versus gradual weaning of external ventricular drainage (EVD) in patients with hydrocephalus following aneurysmal subarachnoid haemorrhage (aSAH) based on randomised clinical trials (RCTs) in humans. Setting: RCTs comparing prompt closure versus gradual weaning o...

Background: During vascular surgery, restricted red-cell transfusion reduces frontal lobe oxygen (ScO2) saturation as determined by near-infrared spectroscopy. We evaluated whether an inadequate increase in cardiac output (CO) following haemodilution explains the reduction in ScO2. Methods: This is a posthoc analysis of data from the Transfusion...

Purpose: To describe the incidence of and risk factors for impaired cognitive function in ICU survivors. We hypothesized that age, severity of illness and days in coma, delirium, mechanical ventilation in the ICU would be associated with impaired cognitive function. Methods: We included all adults, alive 6-months after acute admission to one of...

Background The AID‐ICU trial aims to assess the benefits and harms of haloperidol for the treatment of delirium in acutely admitted, adult intensive care unit (ICU) patients. This paper describes the detailed statistical analysis plan for the primary publication of results from the AID‐ICU trial. Methods The AID‐ICU trial is a investigator‐initiat...

Background Patients undergoing emergency abdominal surgeryare at high risk of postoperative complications.Although postoperative treatment at an intermediate care unit may improveearly outcome, there is a lack of studies on the long‐term effects of such therapy. The aim of this study was to assess the long‐term effect of intermediate care versus st...

Background Limiting harm from postoperative pain treatment is important. However, long‐term follow‐up from acute pain trials are rare. The aim of the study is to provide long‐term follow‐up data regarding harm from the ‘Paracetamol and Ibuprofen in Combination’ (PANSAID) trial. Methods In this preplanned long‐term follow‐up study from the PANSAID...

Introduction Traditional carotid endarterectomy is considered to be the standard technique for prevention of a new stroke in patients with a symptomatic carotid stenosis. Use of patch angioplasty to restore the arterial wall after longitudinal endarterectomy is, to date, not unequivocally proven to be superior to eversion technique. A systematic re...

Background: No solid evidence exists on optimal oxygenation targets in intensive care patients. The Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial assesses the effects of a targeted arterial oxygen tension of 8 versus 12 kPa on 90-day mortality in acutely admitted adult patients with hypoxaemic respiratory failure. This ar...

Background: Acutely ill patients are at risk of stress-related gastrointestinal bleeding and prophylactic acid suppressants are frequently used. In this systematic review, we assessed the effects of stress ulcer prophylaxis (SUP) with proton pump inhibitors or histamine-2 receptor antagonists versus placebo or no prophylaxis in acutely ill hospita...

Background Supplemental oxygen therapy is commonly required for respiratory failure requiring mechanical ventilation in the ICU. However, hyperoxaemia may be injurious and may increase mortality. We evaluated the relationship amongst the degree of hyperoxaemia and changes in fraction of inspired oxygen (Fio2) in response to hyperoxaemia, as well as...

When analysing and presenting results ofrandomised clinical trials, trialists rarely report if or how underlying statisticalassumptions were validated. To avoid data-driven biased trial results, it should be common practice to prospectively describe the assessments of underlying assumptions. In existing literature, there is no consensus onhow trial...

Purpose: Intravenous fluids are recommended during the initial management of sepsis, but the quality of evidence is low, and clinical equipoise exists. We aimed to assess patient-important benefits and harms of lower versus higher fluid volumes in adult patients with sepsis. Methods: We conducted a systematic review with meta-analysis and trial...

Introduction: Traditional carotid endarterectomy is considered to be the standard technique for prevention of a new stroke in patients with a symptomatic carotid stenosis. Use of plexus anesthesia or general anesthesia in traditional carotid endarterectomy is, to date, not unequivocally proven to be superior to one other. A systematic review is ne...

Purpose The Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial compared prophylactic pantoprazole with placebo in 3291 adult ICU patients at risk of clinically important gastrointestinal bleeding (CIB). As a predefined subgroup analysis suggested increased 90-day mortality with pantoprazole in the most severely ill patients, we aim...

Background: All clinical research benefits from transparency and validity. Transparency and validity of studies may increase by prospective registration of protocols and by publication of statistical analysis plans (SAPs) before data have been accessed to discern data-driven analyses from pre-planned analyses. Main message: Like clinical trials,...

Objective: Exposure to hyperoxemia and hypoxemia is common in out-of-hospital cardiac arrest (OHCA) patients following return of spontaneous circulation (ROSC), but its effects on neurological outcome are uncertain, and study results are inconsistent. Methods: Exploratory post hoc substudy of the Target Temperature Management (TTM) trial, includ...

Background: In patients with septic shock mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive versus (vs) standard-care intravenous (IV) fluid th...

Background: Myocardial injury after non-cardiac surgery occurs in a high number of patients, resulting in increased mortality in the postoperative period. The use of high inspiratory oxygen concentrations may cause hyperoxia, which is associated with impairment of coronary blood flow. Furthermore, the surgical stress response increases reactive ox...

International guidelines recommend low-molecular-weight heparin (LMWH) as first-line pharmacological option for the prevention of venous thromboembolism (VTE) in many patient categories. Guidance on the optimal prophylactic dose is lacking. We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized control...

Background: The mainstay treatment for hypoxaemia is oxygen therapy, which is given to the vast majority of adults admitted to the intensive care unit (ICU). The practice of oxygen administration has been liberal, which may result in hyperoxaemia. Some studies have indicated an association between hyperoxaemia and mortality, whilst other studies h...

Background: Haloperidol is the most frequently used drug to treat delirium in the critically ill patients. Yet, no systematic review has focussed on the effects of haloperidol in critically ill patients with delirium. Methods: We conducted a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials (RCTs) a...

Disease-related mortality (eg, cardiovascular mortality or breast-cancer mortality) is often used as an outcome in randomised clinical trials and systematic reviews. The rationale why disease-related mortality might be used in addition to, or instead of, all-cause mortality seems to be that disease-related mortality may more readily detect the expe...

Different doses of low-molecular-weight heparin (LMWH) are registered and used for thrombosis prophylaxis. We assessed benefits and harms of thrombosis prophylaxis with a predefined intermediate-dose LMWH compared with placebo or no treatment in patients at risk of venous thromboembolism (VTE). We performed a systematic review with meta-analyses an...

Introduction In Neuro Intensive Care Units (NICU) and neurosurgical units, patients with an external ventricular drain (EVD) due to hydrocephalus following aneurysmal subarachnoid haemorrhage (SAH) are commonly seen. Cessation of the EVD involves the dilemma of either closing the EVD directly, or gradually weaning it before removal. Development of...

Background: The 'Paracetamol and Ibuprofen in Combination' (PANSAID) trial showed that combining paracetamol and ibuprofen resulted in lower opioid consumption than each drug alone and we did not findan increase in risk of harm when using ibuprofen versus paracetamol. The aim of this subgroup analysis was to investigate differences in benefits and...

Background: Intensive care unit (ICU) patients with acute kidney injury requiring renal replacement therapy (RRT) are considered at high risk of gastrointestinal (GI) bleeding and stress ulcer prophylaxis (SUP) is often prescribed. We aimed to assess the incidence of GI bleeding and effects of SUP in these patients. Methods: We assessed GI bleed...

Background: The aetiology and risk factors for clinically important gastrointestinal bleeding (CIB) in adult ICU patients may differ according to onset of CIB, which could affect the balance between benefits and harms of stress ulcer prophylaxis (SUP). Methods: We assessed the time to CIB in the Stress Ulcer Prophylaxis in the Intensive Care Uni...

Background: In the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, 3291 adult ICU patients at risk for gastrointestinal (GI) bleeding were randomly allocated to intravenous pantoprazole 40 mg or placebo once daily in the ICU. No difference was observed between the groups in the primary outcome 90-day mortality or the secondary...

Introduction: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the Conservative versus Liberal Approach to fluid therapy of Septic Shock in the Int...

Background: The long-term effects of stress ulcer prophylaxis with pantoprazole are unknown in ICU patients. We report one-year mortality outcome in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. Methods: In the SUP-ICU trial, acutely admitted adult ICU patients at risk of gastrointestinal bleeding were randomised to in...

Background: We aimed to describe the exposure to blood transfusions and mortality among patients with septic shock. Methods: We did a retrospective cohort study of two cohorts - patients with septic shock registered in a Danish ICU database (2008-2010) and patients from the Transfusion Requirements in Septic Shock (TRISS) trial (2011-2013). We e...

Background: Delirium among patients in the intensive care unit (ICU) is a common condition associated with increased morbidity and mortality. Haloperidol is the most frequently used pharmacologic intervention, but its use is not supported by firm evidence. Therefore, we are conducting Agents Intervening against Delirium in the Intensive Care Unit...

Objectives: Caregivers use clinical examination to timely recognize deterioration of a patient, yet data on the prognostic value of clinical examination are inconsistent. In the Simple Intensive Care Studies-I, we evaluated the association of clinical examination findings with 90-day mortality in critically ill patients. Design: Prospective sing...

Objective and methods: It is rare that trialists report power estimations of non-primary outcomes. In the present article, we will describe how to define a valid hierarchy of outcomes in a randomised clinical trial, to limit problems with Type I and Type II errors, using considerations on the clinical relevance of the outcomes and power estimation...

Objectives: Risks of random type I and II errors are associated with false positive and false negative findings. In conventional meta-analyses, the risks of random errors are insufficiently evaluated. Many meta-analyses, which appear conclusive, might, in fact, be inconclusive because of risks of random errors. We hypothesize that, for interventio...

Facemask ventilation is an essential part of airway management. Correctly predicting difficulties in facemask ventilation may reduce the risk of morbidity and mortality among patients at risk. We aimed to develop and evaluate a weighted risk score for predicting difficult facemask ventilation during anaesthesia. We analysed a cohort of 46,804 adult...

In order to ensure the validity of results of randomised clinical trials and under some circumstances to optimise statistical power, most statistical methods require validation of underlying statistical assumptions. The present paper describes how trialists in major medical journals report tests of underlying statistical assumptions when analysing...

Introduction Use of patch angioplasty in carotid endarterectomy (CEA) is suggested to reduce the risk of restenosis and recurrent ipsilateral stroke. The objective is to conduct a systematic review with meta-analysis and trial sequential analysis as well as Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments compar...

Background Acutely ill adults with hypoxaemic respiratory failure are at risk of life‐threatening hypoxia, and thus oxygen is often administered liberally. Excessive oxygen use may, however, increase the number of serious adverse events, including death. Establishing the optimal oxygenation level is important as existing evidence is of low quality...

Purpose In the subgroup of patients with Simplified Acute Physiology Score (SAPS) II > 53 in the Stress Ulcer Prophylaxis in Intensive Care Unit (SUP-ICU) trial, there was interaction (P = 0.049) suggesting increased mortality in patients allocated to pantoprazole as compared with placebo. We aimed to explore this further. Methods The SUP-ICU tria...

Current guidelines advocate to limit red-cell transfusion during surgery, but the feasibility and safety of such strategy remains unclear as the majority of evidence is based on postoperative stable patients. We assessed the effects of a protocol aiming to restrict red-cell transfusion throughout hospitalization for vascular surgery. Fifty-eight pa...

Importance Multimodal postoperative analgesia is widely used but lacks evidence of benefit. Objective Investigate beneficial and harmful effects of 4 nonopioid analgesics regimens. Design, Setting, and Participants Randomized, blinded, placebo-controlled, 4-group trial in 6 Danish hospitals with 90-day follow-up that included 556 patients undergo...

Objectives We assessed the evidence from reviews and meta-analyses of randomised clinical trials on the effects of pharmacological prevention and management of delirium in intensive care unit (ICU) patients. Methods We searched for reviews in July 2017 in: Cochrane Library, MEDLINE, Embase, Science Citation Index, BIOSIS Previews, CINAHL and LILAC...

Background: Delirium is a common complication in critically ill patients and carries an increased risk of mortality and morbidity. Dexmedetomidine can potentially treat delirium by diminishing predisposing factors. The evidence regarding the use of dexmedetomidine in the management of delirium is conflicting. This protocol aims to identify the ben...

Purpose: Clinical examination is often the first step to diagnose shock and estimate cardiac index. In the Simple Intensive Care Studies-I, we assessed the association and diagnostic performance of clinical signs for estimation of cardiac index in critically ill patients. Methods: In this prospective, single-centre cohort study, we included all a...

Purpose Most intensive care unit (ICU) patients receive stress ulcer prophylaxis. We present updated evidence on the effects of prophylactic proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) versus placebo/no prophylaxis on patient-important outcomes in adult ICU patients. Methods We conducted a systematic review with meta-...

Background Delirium is a common complication in critically ill patients and carries an increased risk of mortality and morbidity. Dexmedetomidine can potentially prevent delirium by diminishing predisposing factors. The evidence regarding the use of dexmedetomidine in preventing delirium is conflicting. This protocol aims to identify the beneficial...

Background Dopamine has been used in patients with cardiac dysfunction for more than five decades. Yet, no systematic review has assessed the effects of dopamine in critically ill patients with cardiac dysfunction. Methods This systematic review was conducted following The Cochrane Handbook for Systematic Reviews of Interventions. We searched for...

Importance Prognostication of neurologic outcome after cardiac arrest is an important but challenging aspect of patient therapy management in critical care units. Objective To determine whether serum neurofilament light chain (NFL) levels can be used for prognostication of neurologic outcome after cardiac arrest. Design, Setting and Participants...

Background Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear. Methods In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admissi...

Introduction Central sensitization plays a pivotal role in maintenance of pain and is believed to be intricately involved in several chronic pain conditions. One clinical manifestation of central sensitization is secondary hyperalgesia. The degree of secondary hyperalgesia presumably reflects individual levels of central sensitization. The objectiv...

CONSORT 2010 checklist. (DOC)

Background: Use of supplemental oxygen during surgery to reduce the incidence of SSI was investigated in the PROXI trial, which found no reduced frequency of SSI. Subsequently, it has been suggested that a restrictive fluid regimen and hypothermia in some patients could explain why no beneficial effect of supplemental oxygen was found. We evaluated...

Background Oxygen is liberally administered in intensive care units (ICUs). Nevertheless, ICU doctors’ preferences for supplementing oxygen are inadequately described. The aim was to identify ICU doctors’ preferences for arterial oxygenation levels in mechanically ventilated adult ICU patients. Methods In April to August 2016, an online multiple‐c...

Purpose: We assessed the prevalence and variables associated with haloperidol use for delirium in ICU patients and explored any associations of haloperidol use with 90-day mortality. Methods: All acutely admitted, adult ICU patients were screened during a 2-week inception period. We followed the patient throughout their ICU stay and assessed 90-...

Background In critically ill patients, hypoxaemia is a common clinical manifestation of inadequate gas exchange in the lungs. Supplemental oxygen is therefore given to all critically ill patients. This can result in hyperoxaemia, and some observational studies have identified harms with hyperoxia. The objective of this systematic review is to criti...

Background Oxygen therapy is used liberally for all patients undergoing anaesthesia. Recent studies have raised concerns that it may not be without complications when arterial oxygen concentrations reach supranormal concentrations (hyperoxia). Studies of oxygen therapy have raised concerns that the risk of myocardial injury and infarction is elevat...

Cohort studies have indicated that avoidance of neuromuscular blocking agents (NMBA) is a risk factor for difficult tracheal intubation. However, the impact of avoiding NMBA on tracheal intubation, possible adverse effects, and postoperative discomfort has not been evaluated in a systematic review of randomised trials. We searched several databases...

Background In the intensive care unit (ICU), stress ulcer prophylaxis with proton pump inhibitors or histamine‐2‐receptor antagonists is standard of care although gastrointestinal bleeding remains uncommon. It remains unknown whether its use is associated with benefits or harms and the quality of evidence supporting the use of stress ulcer prophyla...

Background Critically ill patients are at risk of gastrointestinal bleeding, but clinically important gastrointestinal bleeding is rare. The majority of intensive care unit (ICU) patients receive stress ulcer prophylaxis (SUP), despite uncertainty concerning the balance between benefit and harm. For approximately half of ICU patients with gastroint...

Background: In the intensive care unit, the prevalence of delirium is high. Delirium has been associated with morbidity and mortality including more ventilator days, longer intensive care unit stay, increased long-term mortality, and cognitive impairment. Thus, the burden of delirium for patients, relatives, and societies is considerable. The obje...

Background: Available evidence has been inconclusive on whether pulmonary artery perfusion during cardiopulmonary bypass (CPB) is associated with decreased or increased mortality, pulmonary events, and serious adverse events (SAEs) after open heart surgery. To our knowledge, no previous systematic reviews have included meta-analyses of these inter...

Background: Surgical site infection (SSI) and other postoperative complications are associated with high costs, morbidity, secondary surgery, and mortality. Many studies have identified factors that may prevent SSI and pulmonary complications, but it is important to know when they in fact occur. The aim of this study was to investigate the diagnos...

Rationale Meta‐analysed intervention effect estimates are perceived to represent the highest level of evidence. However, such effects and the randomized clinical trials which are included in them need critical appraisal before the effects can be trusted. Objective Critical appraisal of a predefined set of all meta‐analyses on interventions in inte...

PurposePatients in the intensive care unit (ICU) are often transfused with red blood cells (RBC). During storage, the RBCs and storage medium undergo changes, which may have clinical consequences. Several trials now have assessed these consequences, and we reviewed the present evidence on the effects of shorter versus longer storage time of transfu...

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of interventions to increase exercise and all types of physical activity, versus no intervention (exercise and physical activity as usual) for people with congenital heart disease. © 2018 The Cochrane Collaboration. Published by John Wiley...

Background: Proton pump inhibitors are often used in critically ill patients to prevent gastrointestinal bleeding despite limited evidence for benefit. Patients with acute kidney injury requiring renal replacement therapy (RRT) are at high risk of gastrointestinal bleeding as (pre-)uremia induces coagulopathy through effects on platelets and coagu...

Background Missing data may seriously compromise inferences from randomised clinical trials, especially if missing data are not handled appropriately. The potential bias due to missing data depends on the mechanism causing the data to be missing, and the analytical methods applied to amend the missingness. Therefore, the analysis of trial data with...

Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with perso...

Background Evidence-based clinical practice is challenging in all fields, but poses special barriers in the field of rare diseases. The present paper summarises the main barriers faced by clinical research in rare diseases, and highlights opportunities for improvement. Methods Systematic literature searches without meta-analyses and internal Europ...