Jørn Wetterslev

Background: The prevalence of occlusive lower extremity artery disease (LEAD) is rising worldwide while European epidemiology data are scarce. We report incidence and mortality of LEAD repair in Denmark from 1996 through 2018, stratified on open aorto-iliac, open peripheral, and endovascular repair. Methods: A nationwide cohort study of prospective data from population-based Danish registers covering 1996 to 2018. Comorbidity was assessed by Charlson’s Comorbidity Index (CCI). Incidence rate (IR) ratios and mortality rate ratios (MRR) were estimated by multivariable Poisson and Cox regression, respectively. Results: We identified 41,438 unique patients undergoing 46,236 incident first-time LEAD repairs by either aorto-iliac- (n=5213), peripheral surgery (n=18,665) or percutaneous transluminal angioplasty (PTA, n=22,358). From 1996 to 2018, the age- and sex-standardized IR for primary revascularization declined from 71.8 to 50.2 per 100,000 person-years (IRR, 0.70; 95% CI, 0.66– 0.75). Following a 2.5-fold IR increase of PTA from 1996 to 2010, all three repair techniques showed a declining trend after 2010. The declining IR was driven by decreasing LEAD repair due to claudication, and by persons aged below 80 years, while the IR increased in persons aged above 80 years (p interaction< 0.001). LEAD repair was more frequent in men (IRR_{female vs male}, 0.78; 95% CI, 0.77– 0.80), which was consistent over calendar time (p interaction=0.41). Crude mortality decreased following open/surgical repair, and increased following PTA, but all three techniques trended towards lower adjusted mortality comparing the start and the end of the study period (MRR_aorto-iliac, 0.71; 95% CI, 0.54– 0.93 vs MRR_peripheral, 0.76; 95% CI, 0.69– 0.83 vs MRR_PTA, 0.96; 95% CI, 0.86– 1.07). Increasing age and CCI, male sex, smoking, and care dependency associated with increased mortality. Conclusion: The incidence rate of LEAD repair decreased in Denmark from 1996 to 2018, especially in persons younger than 80 years, and primarily due to reduced revascularization for claudication. Adjusted mortality rates decreased following open surgery, but seemed unaltered following PTA.

Background: Significant changes in Western populations’ abdominal aortic aneurysm (AAA) epidemiology have been reported following the introduction of screening, endovascular AAA repair, and reduced tobacco consumption. We report incidence and mortality of AAA repair in Denmark from 1996 to 2018, where AAA screening was not implemented. Methods: Nationwide cohort study of prospective data from population-based Danish registries covering 1996 to 2018. We identified 15,395 patients undergoing first-time AAA repair using the Danish Vascular Registry. Comorbidity was assessed by Charlson’s Comorbidity Index (CCI). Incidence rate (IR) ratios and mortality rate ratios (MRR) were estimated by multivariable Poisson and Cox regression, respectively. Results: Overall AAA repair IR decreased by 24% from 1996 through 2018, mainly reflecting a 53% IR reduction in ruptured AAA repairs in men. Overall, the IR decreased 52– 63% in age groups below 70 years and increased 81% among octogenarians. The proportion of intact AAAs repaired endovascularly increased from 2% in 1996– 1999 to 42% in 2015– 2018. For both ruptured and intact AAAs the CCI score increased by 0.9% annually independently of age and sex. The adjusted five-year MRR in 2016– 2018 vs.1996– 2000 was 0.46 (95% confidence interval (CI): 0.39– 0.54) following ruptured and 0.51 (95% CI: 0.44– 0.59) following intact AAA repair. Conclusion: In Denmark, overall AAA repair incidence decreased between 1996 and 2018, primarily reflecting a reduction among males and a shift to an older population requiring intervention. These trends mirror changes in tobacco consumption in Denmark. Regardless of age and comorbidity, AAA repair mortality decreased markedly during the study period.

Background: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. Methods: This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life. Results: We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I² = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I² = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. Conclusions: Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. Trial registration: CRD42017081133, date of registration 28 November 2017.

Purpose To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial. Methods We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1 year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function. Results Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points [99% confidence interval (CI) − 4.8 to 7.8]. Mean differences were 0.00 (99% CI − 0.06 to 0.05) for EQ-5D-5L index values, − 0.65 for EQ VAS (− 5.40 to 4.08), and − 0.14 for Mini MoCA (− 1.59 to 1.14) for the restrictive-fluid group versus the standard-fluid group. The results for survivors only were similar in both groups. Conclusions Among adult ICU patients with septic shock, restrictive versus standard IV fluid therapy resulted in similar survival, HRQoL, and cognitive function at 1 year, but clinically important differences could not be ruled out.

Objectives: To assess any benefit or harm, we conducted a systematic review of randomised clinical trials (RCTs) allocating adults to dexmedetomidine versus placebo/no intervention for the prevention of delirium in intensive care or post‐operative care units.Data Sources: We searched Medline, Embase, CENTRAL and other databases. The last search was 9 April 2022.Data Extraction: Literature screening, data extraction and risk of bias volume 2 assessments were performed independently and in duplicate. Primary outcomes were occurrences of serious adverse events (SAEs), delirium and all‐cause mortality. We used meta‐analysis, Trial Sequential Analysis, and GRADE (Grading Recommendations Assessment, Development and Evaluation).Data Synthesis: Eighty‐one RCTs (15,745 patients) provided data for our primary outcomes. Results from trials at low risk of bias showed that dexmedetomidine may reduce the occurrence of the most frequently reported SAEs (relative risk [RR] 0.69; 95% CI 0.43–1.09), cumulated SAEs (RR 0.70; 95% CI 0.52–0.95) and the occurrence of delirium (RR 0.62; 95% CI 0.43–0.89). The certainty of evidence was very low for delirium. Mortality was very low in trials at low risk of bias (0.4% in the dexmedetomidine groups and 1.0% in the control groups) and meta‐analysis did not provide conclusive evidence that dexmedetomidine may result in lower or higher all‐cause mortality (RR 0.47; 95% CI 0.18–1.21). There was a lack of information from trial results at low risk of bias for all primary outcomes.Conclusions: Trial results at low risk of bias showed that dexmedetomidine might reduce occurrences of SAEs and delirium, while no conclusive evidence was found for effects on all‐cause mortality. The certainty of evidence ranged from very low for occurrence of delirium to low for the remaining outcomes.

Purpose We assessed outcomes after 1 year of lower versus higher oxygenation targets in intensive care unit (ICU) patients with severe hypoxaemia. Methods Pre-planned analyses evaluating 1-year mortality and health-related quality-of-life (HRQoL) outcomes in the previously published Handling Oxygenation Targets in the ICU trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygen of 8 kPa or 12 kPa throughout the ICU stay up to 90 days. One-year all-cause mortality was assessed in the intention-to-treat population. HRQoL was assessed using EuroQol 5 dimensions 5 levels (EQ-5D-5L) questionnaire and EQ visual analogue scale score (EQ-VAS), and analyses were conducted in both survivors only and the intention-to-treat population with assignment of the worst scores to deceased patients. Results We obtained 1-year vital status for 2887/2928 (98.6%), and HRQoL for 2600/2928 (88.8%) of the trial population. One year after randomisation, 707/1442 patients (49%) in the lower oxygenation group vs. 704/1445 (48.7%) in the higher oxygenation group had died (adjusted risk ratio 1.00; 95% confidence interval 0.93–1.08, p = 0.92). In total, 1189/1476 (80.4%) 1-year survivors participated in HRQoL interviews: median EQ-VAS scores were 65 (interquartile range 50–80) in the lower oxygenation group versus 67 (50–80) in the higher oxygenation group (p = 0.98). None of the five EQ-5D-5L dimensions differed between groups. Conclusion Among adult ICU patients with severe hypoxaemia, a lower oxygenation target (8 kPa) did not improve survival or HRQoL at 1 year as compared to a higher oxygenation target (12 kPa).

Background: During vascular surgery, restricted red‐cell transfusion reduces frontal lobe oxygen (ScO₂) saturation as determined by near‐infrared spectroscopy. We evaluated whether inadequate increase in cardiac output (CO) following haemodilution explains reduction in ScO₂.Methods: This is a post‐hoc analysis of data from the Transfusion in Vascular surgery (TV) Trial where patients were randomized on haemoglobin drop below 9.7 g/dL to red‐cell transfusion at haemoglobin below 8.0 (low‐trigger) vs 9.7 g/dL (high‐trigger). Fluid administration was guided by optimizing stroke volume. We compared mean intraoperative levels of CO, haemoglobin, oxygen delivery, and CO at nadir ScO₂ with linear regression adjusted for age, operation type and baseline. Data for 46 patients randomized before end of surgery were included for analysis.Results: The low‐trigger resulted in a 7.1% lower mean intraoperative haemoglobin level (mean difference, −0.74 g/dL; P < .001) and reduced volume of red‐cell transfused (median [inter‐quartile range], 0 [0‐300] vs 450 mL [300‐675]; P < .001) compared with the high‐trigger group. Mean CO during surgery was numerically 7.3% higher in the low‐trigger compared with the high‐trigger group (mean difference, 0.36 L/min; 95% confidence interval (CI.95), −0.05 to 0.78; P = .092; n = 42). At the nadir ScO₂‐level, CO was 11.9% higher in the low‐trigger group (mean difference, 0.58 L/min; CI.95, 0.10‐1.07; P = .024). No difference in oxygen delivery was detected between trial groups (MD, 1.39 dL_O2/min; CI.95, −6.16 to 8.93; P = .721).Conclusion: Vascular surgical patients exposed to restrictive RBC transfusion elicit the expected increase in CO making it unlikely that their potentially limited cardiac capacity explains the associated ScO₂ decrease.

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 an investigator‐initiated, pragmatic, international, multicentre, randomized, blinded, parallel‐group trial allocating 1000 adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. The primary outcome measure is days alive and out of hospital within 90 days post‐randomization. Secondary outcome measures are days alive without delirium or coma, serious adverse reactions (SARs) to haloperidol, use of escape medicine, days alive without mechanical ventilation, and mortality, health‐related quality‐of‐life measures and cognitive function 1‐year post‐randomization. Statistical analysis will be conducted in accordance with the current pre‐specified statistical analysis plan. One formal interim analysis will be performed. The primary outcome will be adjusted for stratification variables (site and delirium motor subtype) and compared between treatment groups using a likelihood ratio test described by Jensen et al A secondary analysis will be conducted with additional adjustment of the primary outcome for prognostic variables at baseline. The primary conclusion of the trial will be based on the intention‐to‐treat analysis of the primary outcome adjusted for stratification variables.Conclusion: The AID‐ICU trial will provide important, high‐quality data on the benefits and harms of treatment with haloperidol in acutely admitted, adult patients with manifest delirium in the ICU.

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 review is needed for evaluation of benefits and harms of the eversion technique versus the traditional endarterectomy with patch angioplasty in patients with symptomatic carotid stenosis. Methods and outcomes The review will be conducted according to this protocol following the recommendations of the ‘Cochrane Handbook for Systematic Reviews’ and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Randomised clinical trials comparing eversion technique versus endarterectomy with patch angioplasty in patients with a symptomatic stenosis of the internal carotid artery will be included. Primary outcomes are all-cause mortality rate, health-related quality of life and serious adverse events. Secondary outcomes are 30-day stroke and mortality rate, symptomatic arterial restenosis or occlusion and non-serious adverse events. The databases Cochrane Central Register of Controlled Trials, PubMed/MEDLINE and EMBASE will be searched (November 2019). We will primarily base our conclusions on meta-analyses of trials with overall low-risk of bias. We will use trial sequential analysis to assist the evaluation of imprecision in Grading of Recommendations, Assessment, Development and Evaluation. However, if pooled point estimates of all trials are similar to pooled point estimates of trials with overall low risk of bias and there is lack of a statistical significant interaction between estimates from trials with overall high risk of bias and trials with overall low risk of bias we will consider the trial sequential analysis adjusted precision of the estimate achieved in all trials as the result of our meta-analyses. Ethics and dissemination The proposed systematic review will collect and analyse data from published studies, therefore, ethical approval is not required. The results of the review will be disseminated by publication in a peer-review journal and submitted for presentation at conferences. PROSPERO registration number CRD42019119361.