Thromboembolic and bleeding events in ICU patients with COVID-19: A nationwide, observational study.

BACKGROUND: Intensive care unit (ICU) patients with Coronavirus disease 2019 (COVID-19) have an increased risk of thromboembolic complications. We describe the occurrence of thromboembolic and bleeding events in all ICU patients with COVID-19 in Denmark during the first and second waves of the pandemic. METHODS: This was a sub-study of the Danish Intensive Care Covid database, in which all patients with SARS-CoV-2 admitted to Danish ICUs from 10th March 2020 to 30th June 2021 were included. We registered coagulation variables at admission, and all thromboembolic and bleeding events, and the use of heparins during ICU stay. Variables associated with thrombosis and bleeding and any association with 90-day mortality were estimated using Cox regression analyses. RESULTS: We included 1369 patients in this sub-study; 158 (12%, 95% confidence interval 10-13) had a thromboembolic event in ICU and 309 (23%, 20-25) had a bleeding event, among whom 81 patients (6%, 4.8-7.3) had major bleeding. We found that mechanical ventilation and increased D-dimer were associated with thrombosis and mechanical ventilation, low platelet count and presence of haematological malignancy were associated with bleeding. Most patients (76%) received increased doses of thromboprophylaxis during their ICU stay. Thromboembolic events were not associated with mortality in adjusted analysis (hazard ratio 1.35 [0.91-2.01, p = .14], whereas bleeding events were 1.55 [1.18-2.05, p = .002]). CONCLUSIONS: Both thromboembolic and bleeding events frequently occurred in ICU patients with COVID-19. Based on these data, it is not apparent that increased doses of thromboprophylaxis were beneficial.

Long-term outcomes in COVID-19 patients admitted to intensive care in Denmark: A nationwide observational study.

BACKGROUND: Among ICU patients with COVID-19, it is largely unknown how the overall outcome and resource use have changed with time, different genetic variants, and vaccination status. METHODS: For all Danish ICU patients with COVID-19 from March 10, 2020 to March 31, 2022, we manually retrieved data on demographics, comorbidities, vaccination status, use of life support, length of stay, and vital status from medical records. We compared patients based on the period of admittance and vaccination status and described changes in epidemiology related to the Omicron variant. RESULTS: Among all 2167 ICU patients with COVID-19, 327 were admitted during the first (March 10-19, 2020), 1053 during the second (May 20, 2020 to June 30, 2021) and 787 during the third wave (July 1, 2021 to March 31, 2022). We observed changes over the three waves in age (median 72 vs. 68 vs. 65 years), use of invasive mechanical ventilation (81% vs. 58% vs. 51%), renal replacement therapy (26% vs. 13% vs. 12%), extracorporeal membrane oxygenation (7% vs. 3% vs. 2%), duration of invasive mechanical ventilation (median 13 vs. 13 vs. 9 days) and ICU length of stay (median 13 vs. 10 vs. 7 days). Despite these changes, 90-day mortality remained constant (36% vs. 35% vs. 33%). Vaccination rates among ICU patients were 42% as compared to 80% in society. Unvaccinated versus vaccinated patients were younger (median 57 vs. 73 years), had less comorbidity (50% vs. 78%), and had lower 90-day mortality (29% vs. 51%). Patient characteristics changed significantly after the Omicron variant became dominant including a decrease in the use of COVID-specific pharmacological agents from 95% to 69%. CONCLUSIONS: In Danish ICUs, the use of life support declined, while mortality seemed unchanged throughout the three waves of COVID-19. Vaccination rates were lower among ICU patients than in society, but the selected group of vaccinated patients admitted to the ICU still had very severe disease courses. When the Omicron variant became dominant a lower fraction of SARS-CoV-2 positive patients received COVID treatment indicating other causes for ICU admission.

Long-term cognitive and functional status in Danish ICU patients with COVID-19.

BACKGROUND: ICU admission due to COVID-19 may result in cognitive and physical impairment. We investigated the long-term cognitive and physical status of Danish ICU patients with COVID-19. METHODS: We included all patients with COVID-19 admitted to Danish ICUs between March 10 and May 19, 2020. Patients were the contacted prospectively at 6 and 12 months for follow-up. Our primary outcomes were cognitive function and frailty at 6 and 12 months after ICU admission, estimated by the Mini Montreal Cognitive Assessment, and the Clinical Frailty Scale. Secondary outcomes were 6- and 12-month mortality, health-related quality of life (HRQoL) assessed by EQ-5D-5L, functional status (Barthel activities of daily living and Lawton-Brody instrumental activities of daily living), and fatigue (Fatigue Assessment Scale). The study had no information on pre-ICU admission status for the participants. RESULTS: A total of 326 patients were included. The 6- and 12-month mortality was 37% and 38%, respectively. Among the 204 six-month survivors, 105 (51%) participated in the 6-month follow-up; among the 202 twelve-month survivors, 95 (47%) participated in the 12-month follow-up. At 6 months, cognitive scores indicated impairment for 26% (95% confidence interval [CI], 11.4-12.4) and at 12 months for 17% (95% CI, 12.0-12.8) of participants. Frailty was indicated in 20% (95% CI, 3.4-3.9) at 6 months, and for 18% (95% CI, 3.3-3.8) at 12 months. Fatigue was reported by 52% at 6 months, and by 47% at 12 months. For HRQoL, moderate, severe, or extreme health problems were reported by 28% at 6 months, and by 25% at 12 months. CONCLUSION: Long-term cognitive, functional impairment was found in up to one in four of patients surviving intensive care for COVID-19. Fatigue was present in nearly half the survivors at both 6 and 12 months. However, pre-ICU admission status of the patients was unknown.

Changes over time in characteristics, resource use and outcomes among ICU patients with COVID-19-A nationwide, observational study in Denmark.

BACKGROUND: Characteristics and care of intensive care unit (ICU) patients with COVID-19 may have changed during the pandemic, but longitudinal data assessing this are limited. We compared patients with COVID-19 admitted to Danish ICUs in the first wave with those admitted later. METHODS: Among all Danish ICU patients with COVID-19, we compared demographics, chronic comorbidities, use of organ support, length of stay and vital status of those admitted 10 March to 19 May 2020 (first wave) versus 20 May 2020 to 30 June 2021. We analysed risk factors for death by adjusted logistic regression analysis. RESULTS: Among all hospitalised patients with COVID-19, a lower proportion was admitted to ICU after the first wave (13% vs. 8%). Among all 1374 ICU patients with COVID-19, 326 were admitted during the first wave. There were no major differences in patient's characteristics or mortality between the two periods, but use of invasive mechanical ventilation (81% vs. 58% of patients), renal replacement therapy (26% vs. 13%) and ECMO (8% vs. 3%) and median length of stay in ICU (13 vs. 10 days) and in hospital (20 vs. 17 days) were all significantly lower after the first wave. Risk factors for death were higher age, larger burden of comorbidities (heart failure, pulmonary disease and kidney disease) and active cancer, but not admission during or after the first wave. CONCLUSIONS: After the first wave of COVID-19 in Denmark, a lower proportion of hospitalised patients with COVID-19 were admitted to ICU. Among ICU patients, use of organ support was lower and length of stay was reduced, but mortality rates remained at a relatively high level.

Characteristics, interventions, and longer term outcomes of COVID-19 ICU patients in Denmark-A nationwide, observational study.

BACKGROUND: Most data on intensive care unit (ICU) patients with COVID-19 originate in selected populations from stressed healthcare systems with shorter term follow-up. We present characteristics, interventions and longer term outcomes of the entire, unselected cohort of all ICU patients with COVID-19 in Denmark where the ICU capacity was not exceeded. METHODS: We identified all patients with SARS-CoV-2 admitted to any Danish ICU from 10 March to 19 May 2020 and registered demographics, chronic comorbidities, use of organ support, length of stay, and vital status from patient files. Risk factors for death were analyzed using adjusted Cox regression analysis. RESULTS: There were 323 ICU patients with confirmed COVID-19. Median age was 68 years, 74% were men, 50% had hypertension, 21% diabetes, and 20% chronic pulmonary disease; 29% had no chronic comorbidity. Invasive mechanical ventilation was used in 82%, vasopressors in 83%, renal replacement therapy in 26%, and extra corporeal membrane oxygenation in 8%. ICU stay was median 13 days (IQR 6-22) and hospital stay 19 days (11-30). Median follow-up was 79 days. At end of follow-up, 118 had died (37%), 15 (4%) were still in hospital hereof 4 in ICU as of 16 June 2020. Risk factors for mortality included male gender, age, chronic pulmonary disease, active cancer, and number of co-morbidities. CONCLUSIONS: In this nationwide, population-based cohort of ICU patients with COVID-19, longer term survival was high despite high age and substantial use of organ support. Male gender, age, and chronic co-morbidities, in particular chronic pulmonary disease, were associated with increased risk of death.

Mortality among male forensic and non-forensic psychiatric patients: matched cohort study of rates, predictors and causes-of-death.

Background: The mortality of forensic psychiatric (FP) patients compared to non-forensic psychiatric (non-FP) patients has been sparsely examined.Methods: We conducted a matched cohort study and compared Danish male FP patients (n = 490) who underwent pre-trial forensic psychiatric assessment (FPA) 1980-1992 and were subsequently sentenced to psychiatric treatment with matched (on year of birth, marital status, and municipality of residence) male non-FP patients (n = 490) and male general population controls (n = 1716). FP and non-FP patients were also matched on major psychiatric diagnostic categories. To determine mortality and identify potential predictors of mortality, we linked nationwide register data (demographics, education, employment, psychiatric admission pattern and diagnoses, cause of death) to study cohorts. Average follow-up time was 19 years from FPA assessment/sampling until death/censoring or 31 December 2010 and risk factors were studied/controlled with Cox proportional hazard analysis.Results: Overall, psychiatric patients had significantly higher mortality compared to matched general population controls (medium to large effects). Among patients, 44% (213) of FP vs. 36% (178) of matched non-FP patients died during follow-up (p = 0.02). When we used Cox regression modeling to control for potential risk factors; age, education, immigrant background, employed/studying at index, length of psychiatric inpatient stay/year, and ever being diagnosed with substance use disorder (SUD), FP patient status was no longer significantly associated with increased mortality, whereas SUD and longer inpatient time per year were independently associated with increased mortality.Discussion: This study suggests that SUD and longer inpatient time per year are independent risk factors for increased mortality in psychiatric patients.

Lower short-term mortality in ICU patients on chronic dialysis than in those requiring acute dialysis.

BACKGROUND: In ICU patients, we aimed to describe the outcomes of those with end-stage renal disease (ESRD) as compared to those requiring acute renal replacement therapy (RRT). METHODS: Retrospective analysis of all adult patients admitted to a general, university hospital ICU from 2005 to 2012. ESRD was defined as use of chronic RRT >90 days prior to admission. RESULTS: We included 5927 patients of whom 1004 (17%) received acute RRT and 161 (3%) had pre-existing ESRD requiring RRT. Thirty-day mortality was 42% vs 28% for acute RRT vs ESRD patients (adjusted hazard ratio (aHR) 0.90 (0.61-1.34)), and 16% for those not requiring RRT (aHR 0.91 (0.60-1.38) compared to ESRD patients). Ninety-day mortality was 55% vs 45% for acute RRT vs ESRD patients (aHR 0.96 (0.70-1.31)), and 22% for those not requiring RRT (aHR 1.19 (0.84-1.67) compared to ESRD patients). Ninety-day ESRD survivors were younger, less severely ill and needed less vasopressor treatment than 90-day ESRD non-survivors. Five-year mortality was 68% vs 69% for acute RRT vs ESRD patients (aHR 1.06 (0.81-1.39)), and 38% for those not requiring RRT (aHR 1.31 (0.99-1.74) compared to ESRD patients). CONCLUSIONS: The crude mortality for patients with pre-existing ESRD was high. Short-term mortality was within range of those not receiving RRT when adjusted for confounders. The severity of acute illness and the burden of comorbidities may be more important than the lack of kidney function per se for the short-term prognosis of RRT patients in the ICU.

Prevention of rhabdomyolysis-induced acute kidney injury - A DASAIM/DSIT clinical practice guideline.

BACKGROUND: Rhabdomyolysis-induced acute kidney injury (AKI) is a common and serious condition. We aimed to summarise the available evidence on this topic and provide recommendations according to current standards for trustworthy guidelines. METHODS: This guideline was developed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). The following preventive interventions were assessed: (a) fluids, (b) diuretics, (c) alkalinisation, (d) antioxidants, and (e) renal replacement therapy. Exclusively patient-important outcomes were assessed. RESULTS: We suggest using early rather than late fluid resuscitation (weak recommendation, very low quality of evidence). We suggest using crystalloids rather than colloids (weak recommendation, low quality of evidence). We suggest against routine use of loop diuretics as compared to none (weak recommendation, very low quality of evidence). We suggest against use of mannitol as compared to none (weak recommendation, very low quality of evidence). We suggest against routine use of any diuretic as compared to none (weak recommendation, very low quality of evidence). We suggest against routine use of alkalinisation with sodium bicarbonate as compared to none (weak recommendation, low quality of evidence). We suggest against the routine use of any alkalinisation as compared to none (weak recommendation, low quality of evidence). We suggest against routine use of renal replacement therapy as compared to none (weak recommendation, low quality of evidence). For the remaining PICO questions, no recommendations were issued. CONCLUSION: The quantity and quality of evidence supporting preventive interventions for rhabdomyolysis-induced AKI is low/very low. We were able to issue eight weak recommendations and no strong recommendations.

Prevalence of antibiotic resistance genes in bacterial communities associated with Cladophora glomerata mats along the nearshore of Lake Ontario.

The alga Cladophora glomerata can erupt in nuisance blooms throughout the lower Great Lakes. Since bacterial abundance increases with the emergence and decay of Cladophora, we investigated the prevalence of antibiotic resistance (ABR) in Cladophora-associated bacterial communities up-gradient and down-gradient from a large sewage treatment plant (STP) on Lake Ontario. Although STPs are well-known sources of ABR, we also expected detectable ABR from up-gradient wetland communities, since they receive surface run-off from urban and agricultural sources. Statistically significant differences in aquatic bacterial abundance and ABR were found between down-gradient beach samples and up-gradient coastal wetland samples (ANOVA, Holm-Sidak test, p < 0.05). Decaying and free-floating Cladophora sampled near the STP had the highest bacterial densities overall, including on ampicillin- and vancomycin-treated plates. However, quantitative polymerase chain reaction analysis of the ABR genes ampC, tetA, tetB, and vanA from environmental communities showed a different pattern. Some of the highest ABR gene levels occurred at the 2 coastal wetland sites (vanA). Overall, bacterial ABR profiles from environmental samples were distinguishable between living and decaying Cladophora, inferring that Cladophora may control bacterial ABR depending on its life-cycle stage. Our results also show how spatially and temporally dynamic ABR is in nearshore aquatic bacteria, which warrants further research.

Perioperative treatment of patients with sepsis.

PURPOSE OF REVIEW: Key elements in the initial resuscitation and stabilization of the patient with sepsis are fluid therapy, vasopressor or inotropic support, administration of adequate antibiotics and source control. This review will primarily discuss fluid, vasopressor and antibiotic therapy because these have been the subject of the recent large clinical trials. RECENT FINDINGS: On the basis of the recent large randomized clinical trials, starch solutions should be avoided in patients with sepsis because there is no evidence of benefit and clear signals of harm including adverse effects on kidney and haemostatic function and increased mortality in one trial. Ongoing trials are investigating the efficacy and safety of albumin and red blood cell transfusion in patients with sepsis. Norepinephrine should be the first-line vasopressor agent because accumulating evidence shows more adverse events with the use of dopamine. Early initiation of adequate antibiotic therapy is recommended and etomidate should not be used in patients with sepsis. SUMMARY: Recent high-quality trials in the intensive care setting have provided data to improve the treatment and thereby the outcome of patients with sepsis. These findings may be used in the perioperative setting to minimize the harmful effects of specific interventions.

Attitudes to drug trials among relatives of unconscious intensive care patients.

BACKGROUND: In many countries relatives are asked to consent on behalf of ICU patients prior to inclusion in clinical trials. However, the attitudes to drug trials among relatives of unconscious ICU patients are largely unknown. METHODS: We performed a prospective questionnaire survey at two university hospital ICUs of the next-of-kin to 50 unconscious adult patients. They were asked to complete a questionnaire within 48 hours of the patients' acute ICU admission. RESULTS: Forty-two relatives returned the questionnaire of which 41 were completed by direct family members and in one case by a friend to the patient.The majority of relatives (36/42) were positive/positive with some scepticism towards performing drug trials in unconscious ICU patients and 30/42 would most likely accept trial-participation by their relative. The majority (30/42) agreed that they should decide if their relative was to participate in a drug trial and 24 of these found that the treating clinician/ICU consultant should also consent. The majority (27/42) found that deferred consent would be acceptable if there was a limited time frame for initiation of treatment, however 8 respondents found this unacceptable when the intervention was a new drug.The majority of relatives stipulated that adherence to legislation, treatment benefit for the study patient and for future patients, no patient-risk or -discomfort and development of new drugs were important factors if their relative was to participate in an ICU drug trial. When questioned about doctors' motives for performing drug trials the wish for drug development and better patient care were highly rated among relatives. CONCLUSIONS: In general, relatives to unconscious ICU patients expressed positive attitudes to drug trials in the ICU and the inclusion of their relative in drug trials. Consent by next-of-kin and deferred consent was acceptable to the majority of relatives.

Long-Term Violent Reoffending Following Forensic Psychiatric Treatment: Comparing Forensic Psychiatric Examinees and General Offender Controls.

Background: Long-term violent re-offending in forensic psychiatric (FP) patients vs. non-FP offenders is largely unknown. Methods: We studied rates and facets of long-term violent reoffending among 1,062 violent forensic psychiatric examinees (FPE) consecutively undergoing pre-trial, forensic psychiatric examination (FPE) in Denmark during 1980-1992. Altogether, 392 were sentenced to FP treatment (FPE+T); the remaining 670 examinees received ordinary non-FP sanctions (FPE-T). FPE+T were compared to 392 contemporary matched violent general offenders (GEN) without FPE or other psychiatric contacts and sentenced to ordinary non-FP sanctions. FPE data were linked to population-based registers with sociodemographic, psychiatric, and crime information, and we estimated relative risks controlling for birth year, sex, educational and marital status, and previous violent crime. Results: During follow-up (mean = 18.0-19.5 years), FPE+T and GEN had any violent recidivism rates of 43% vs. 29% [adjusted hazard ratio (aHR) = 1.5; 95% CI, 1.1-1.9], respectively. Corresponding findings for severe violence (21% vs. 14%; aHR = 1.3; 95% CI, 0.9-1.9) and recurrent violence (3+ violent convictions; 16% vs. 6%; adjusted odds ratio [aOR] = 2.5; 95% CI, 1.5-4.4) also suggested weakly to moderately increased risks in FPE+T, albeit non-significantly for the former. Comparing FPE+T to FPE-T suggested decreased risk of any violence (43% vs. 51%; aHR = 0.8; 95% CI, 0.6-1.1), severe (21% vs. 34%; aHR = 0.6; 95% CI, 0.4-0.8), and recurrent violence [16% vs. 22%; adjusted odds ratio (aOR) = 0.7; 95% CI, 0.5-1.0] in FP patients, though non-significantly for any violence and recurrent violence. Among all FPE examinees, violent reoffending was independently predicted by male sex, younger age, pre-index violent crime, personality disorder (vs. schizophrenia spectrum and other psychiatric disorder), substance use disorder, and 5+ hospital admissions. Conclusion: FPE examinees, untreated followed by treated, reoffend violently more often than GENs. Similar trends are suggested also for severe and recurrent violence suggesting a need for continua of services for FPE examinees, independently of medico-legal status (i.e., sentencing to treatment or not).

Forced fluid removal versus usual care in intensive care patients with high-risk acute kidney injury and severe fluid overload (FFAKI): study protocol for a randomised controlled pilot trial.

BACKGROUND: Intravenous administration of fluids is an essential part of critical care. While some fluid administration is likely beneficial, there is increasing observational evidence that the development of fluid overload is associated with increased mortality. There are no randomised trials to confirm this association in patients with acute kidney injury. We aim to perform a pilot trial to test the feasibility of forced fluid removal compared to standard care in patients with acute kidney injury and severe fluid overload, the FFAKI trial. METHODS: Then FFAKI trial is a pilot, multicentre, randomised clinical trial recruiting adult intensive care patients with acute kidney injury and fluid overload, defined as more than 10% of ideal bodyweight. Patients are randomised with concealed allocation to either standard care or forced fluid removal with a therapeutic target of negative net fluid balance ≥1 mL/kg/h. The safety of fluid removal is continually evaluated according to predefined criteria of hypoperfusion: lactate ≥4 mmol/L, mean arterial pressure <50 mmHg or mottling beyond the edge of the kneecaps. If patients fulfil one of these criteria, fluid removal is suspended until hypoperfusion has resolved. The primary outcome measure is fluid balance at 5 days after randomisation and secondary outcomes include mean daily fluid balance, fluid balance at discharge from the intensive care unit, time to neutral fluid balance, number of serious adverse reactions and number of protocol violations. All patients are followed for 90 days. DISCUSSION: The FFAKI trial started in October 2015 and, when completed, will provide data to evaluate whether a large trial of forced fluid removal in critically ill patients is feasible. Our primary outcome will show if the experimental intervention leads to a clinically relevant difference in fluid balance, which could prove beneficial in intensive care patients with acute kidney injury. TRIAL REGISTRATION: EudraCT, identifier: 2015-001701-13. Registered on 19 September 2015; ClinicalTrials.gov, identifier: NCT02458157 . Registered on 21 May 2015; Danish Ethics Committee, identifier: H-15009589H. Registered on 22 September 2015; Danish Health and Medicines Authority, identifier: 2015070013. Registered on 11 August 2015.

Consecutive thrombelastography clot strength profiles in patients with severe sepsis and their association with 28-day mortality: a prospective study.

PURPOSE: The aim of this study was to assess associations between consecutive thrombelastography (TEG) profiles and standard coagulation tests and disease severity and mortality in patients with severe sepsis. MATERIALS AND METHODS: This was a prospective observational study of adults with severe sepsis admitted to the intensive care unit (ICU). Clinical scores/variables, infection, TEG, biochemistry, therapy, and overall mortality were recorded. RESULTS: Fifty patients (60% men, median age 62 years, 28-day mortality 24%) were included. At admission, 22%, 48%, and 30% had a hypocoagulable, normocoagulable, and hypercoagulable TEG clot strength (maximum amplitude [MA]), respectively. Hypocoagulable patients had higher Sequential Organ Failure Assessment and disseminated intravascular coagulation scores compared with hypercoagulable patients and higher 28-day mortality compared with normocoagulable patients (all P < .05). Most patients (73%-91%) displayed a TEG MA comparable with the admission profile during the initial 4 ICU days or until death/discharge. Patients progressing to hypocoagulable MA had a high early mortality (80%) and hypocoagulable MA independently predicted 28-day mortality (adjusted odds ratio, 4.29 [95% confidence interval, 1.35-13.65], P = .014). In hypocoagulable and hypercoagulable patients, only fibrinogen (P = .041 and P < .001, respectively) contributed independently to clot strength, whereas both platelets (P < .001) and fibrinogen (P < .001) contributed independently to clot strength in normocoagulable patients. CONCLUSIONS: The ICU admission TEG MA remained constant for several days in patients with severe sepsis and hypocoagulable MA independently predicted 28-day mortality.

Consecutive daily measurements of luminal concentrations of lactate in the rectum in septic shock patients.

In a recent study we found no difference in the concentrations of luminal lactate in the rectum between nonsurvivors and survivors in early septic shock (<24 h). This study was initiated to investigate if there are any changes in the concentrations of luminal lactate in the rectum during the first 3 days of septic shock and possible differences between nonsurvivors and survivors. Methods. We studied 22 patients with septic shock in this observational study. Six to 24 h after the onset of septic shock the concentration of lactate in the rectal lumen was estimated by 4 h equilibrium dialysis (day 1). The rectal dialysis was repeated on day 2 and day 3. Results. The concentration of lactate in the rectal lumen did not change over the 3 days in neither nonsurvivors nor survivors. Rectal luminal and arterial lactate concentrations were not different. Conclusion. There was no change in the concentration of lactate in the rectal lumen over time in patients with septic shock. Also, there was no difference between nonsurvivors and survivors.