Perspectives of ICU Patients on Deferred Consent in the Context of Post-ICU Quality of Life: A Substudy of a Randomized Clinical Trial.

OBJECTIVES: Deferred consent enables research to be conducted in the ICU when patients are unable to provide consent themselves, and there is insufficient time to obtain consent from surrogates before commencing (trial) treatment. The aim of this study was to evaluate how former ICU patients reflect on their participation in a study with deferred consent and examine whether their opinions are influenced by the quality of life (QoL) following hospital discharge. DESIGN: Survey study by questionnaire. SETTING: Eight ICUs in The Netherlands. PATIENTS: Former ICU patients who participated in the ICONIC trial, a multicenter randomized clinical trial that evaluated oxygenation targets in mechanically ventilated ICU patients. INTERVENTIONS: Participants enrolled in the ICONIC trial in one of the eight participating centers in The Netherlands received a questionnaire 6 months after randomization. The questionnaire included 12 close-ended questions on their opinion about the deferred consent procedure. QoL was measured using the EQ-5D-5L questionnaire. By calculating the EQ-5D index, patients were divided into four QoL quartiles, where Q1 reflects the lowest and Q4 is the highest. MEASUREMENTS AND MAIN RESULTS: Of 362 participants who were contacted, 197 responded (54%). More than half of the respondents (59%) were unaware of their participation in the ICONIC study. In total 61% were content with the deferred consent procedure, 1% were not content, 25% neutral, 9% did not know, and 9% answered "other." Those with a higher QoL were more likely to be content ( p = 0.02). In all QoL groups, the legal representative was the most often preferred individual to provide consent. CONCLUSIONS: Former ICU patients who participated in the ICONIC study often did not remember their participation but were predominantly positive regarding the use of deferred consent. Those with a higher QoL were most likely to be content.

Conservative versus Liberal Oxygenation Targets in Intensive Care Unit Patients (ICONIC): A Randomized Clinical Trial.

Rationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear. Objectives: This study aimed to determine whether a low-oxygenation strategy would lower 28-day mortality compared with a high-oxygenation strategy. Methods: This randomized multicenter trial included mechanically ventilated ICU patients with an expected ventilation duration of at least 24 hours. Patients were randomized 1:1 to a low-oxygenation (PaO2, 55-80 mm Hg; or oxygen saturation as measured by pulse oximetry, 91-94%) or high-oxygenation (PaO2, 110-150 mm Hg; or oxygen saturation as measured by pulse oximetry, 96-100%) target until ICU discharge or 28 days after randomization, whichever came first. The primary outcome was 28-day mortality. The study was stopped prematurely because of the COVID-19 pandemic when 664 of the planned 1,512 patients were included. Measurements and Main Results: Between November 2018 and November 2021, a total of 664 patients were included in the trial: 335 in the low-oxygenation group and 329 in the high-oxygenation group. The median achieved PaO2 was 75 mm Hg (interquartile range, 70-84) and 115 mm Hg (interquartile range, 100-129) in the low- and high-oxygenation groups, respectively. At Day 28, 129 (38.5%) and 114 (34.7%) patients had died in the low- and high-oxygenation groups, respectively (risk ratio, 1.11; 95% confidence interval, 0.9-1.4; P = 0.30). At least one serious adverse event was reported in 12 (3.6%) and 17 (5.2%) patients in the low- and high-oxygenation groups, respectively. Conclusions: Among mechanically ventilated ICU patients with an expected mechanical ventilation duration of at least 24 hours, using a low-oxygenation strategy did not result in a reduction of 28-day mortality compared with a high-oxygenation strategy. Clinical trial registered with the National Trial Register and the International Clinical Trials Registry Platform (NTR7376).

The Impact of Thoracic Ultrasound on Clinical Management of Critically Ill Patients (UltraMan): An International Prospective Observational Study.

OBJECTIVES: To investigate the impact of thoracic ultrasound (TUS) examinations on clinical management in adult ICU patients. DESIGN: A prospective international observational study. SETTING: Four centers in The Netherlands and Italy. PATIENTS: Adult ICU patients (> 18 yr) that received a clinically indicated lung ultrasound examination. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinicians performing TUS completed a pre- and post-examination case report form. Patient characteristics, TUS, and resulting clinical effects were recorded. First, change of management, defined as a TUS-induced change in clinical impression leading to a change in treatment plan, was reported. Second, execution of intended management changes within 8 hours was verified. Third, change in fluid balance after 8 hours was calculated. A total of 725 TUS performed by 111 operators across 534 patients (mean age 63 ± 15.0, 70% male) were included. Almost half of TUS caused a change in clinical impression, which resulted in change of management in 39% of cases. The remainder of TUS confirmed the clinical impression, while a minority (4%) did not contribute. Eighty-nine percent of management changes indicated by TUS were executed within 8 hours. TUS examinations that led to a change in fluid management also led to distinct and appropriate changes in patient's fluid balance. CONCLUSIONS: In this international observational study in adult ICU patients, use of TUS had a major impact on clinical management. These results provide grounds for future randomized controlled trials to determine if TUS-induced changes in decision-making also lead to improved health outcomes.

Microglial cell response in α7 nicotinic acetylcholine receptor-deficient mice after systemic infection with Escherichia coli.

BACKGROUND: Development of neurodegeneration in older people has been associated with microglial cell activation triggered by systemic infection. We hypothesize that α7 nicotinic acetylcholine receptor (α7nAChR) plays an important role in regulation of this process. METHODS: 8- to 10-week-old male wild-type (WT) and α7nAChR knock-out (α7nAChR-/-) mice were intraperitoneally inoculated with live Escherichia (E.) coli or saline. After inoculation, all mice were treated with ceftriaxone (an antimicrobial drug) at 12 and 24 h and killed at 2 or 3 days. The microglial response was characterized by immunohistochemical staining with an ionized calcium-binding adaptor molecule 1 (Iba-1) antibody and flow cytometry. To quantify inflammatory response, mRNA expression of pro- and anti-inflammatory mediators was measured in brain and spleen. RESULTS: We observed no differences in Iba-1 positive cell number or morphology and flow cytometry (CD11b, CD45 and CD14) of microglial cells between WT and α7nAChR-/- mice after systemic infection. Infected α7nAChR-/- mice showed significantly higher mRNA expression in brain for tumor necrosis factor alpha (TNF-α) at day 2 and 3, interleukin 6 (IL-6) at day 2 and monocyte chemotactic protein 1 (MCP-1) and suppressor of cytokine signaling 1 (SOCS1) at day 3, there was significantly lower mRNA expression in brain for mitogen-activated protein kinase 1 (MAPK1) at day 2 and 3, high-mobility group 1 (HMGB-1) and CD11b at day 2, and deubiquitinase protein A20 (A20) at day 3 compared to infected WT mice. INTERPRETATION: Loss of function of α7nAChR during systemic infection led to an increased expression of TNF-α and IL-6 in brain after systemic infection with E. coli, but not to distinct differences in microglial cell number or morphological activation of microglia.

Long-Term Outcome of Patients With a Hematologic Malignancy and Multiple Organ Failure Admitted at the Intensive Care.

OBJECTIVES: Historically, patients with a hematologic malignancy have one of the highest mortality rates among cancer patients admitted to the ICU. Therefore, physicians are often reluctant to admit these patients to the ICU. The aim of our study was to examine the survival of patients who have a hematologic malignancy and multiple organ failure admitted to the ICU. DESIGN: This retrospective cohort study, part of the HEMA-ICU study group, was designed to study the survival of patients with a hematologic malignancy and organ failure after admission to the ICU. Patients were followed for at least 1 year. SETTING: Five university hospitals in the Netherlands. PATIENTS: One-thousand ninety-seven patients with a hematologic malignancy who were admitted at the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was 1-year survival. Organ failure was categorized as acute kidney injury, respiratory failure, hepatic failure, and hemodynamic failure; multiple organ failure was defined as failure of two or more organs. The World Health Organization performance score measured 3 months after discharge from the ICU was used as a measure of functional outcome. The 1-year survival rate among these patients was 38%. Multiple organ failure was inversely associated with long-term survival, and an absence of respiratory failure was the strongest predictor of 1-year survival. The survival rate among patients with 2, 3, and 4 failing organs was 27%, 22%, and 8%, respectively. Among all surviving patients for which World Health Organization scores were available, 39% had a World Health Organization performance score of 0-1 3 months after ICU discharge. Functional outcome was not associated with the number of failing organs. CONCLUSIONS: Our results suggest that multiple organ failure should not be used as a criterion for excluding a patient with a hematologic malignancy from admission to the ICU.

Time trend analysis of long term outcome of patients with haematological malignancies admitted at dutch intensive care units.

A few decades ago, the chances of survival for patients with a haematological malignancy needing Intensive Care Unit (ICU) support were minimal. As a consequence, ICU admission policy was cautious. We hypothesized that the long-term outcome of patients with a haematological malignancy admitted to the ICU has improved in recent years. Furthermore, our objective was to evaluate the predictive value of the Acute Physiology and Chronic Health Evaluation (APACHE) II score. A total of 1095 patients from 5 Dutch university hospitals were included from 2003 until 2015. We studied the prevalence of patients' characteristics over time. By using annual odds ratios, we analysed which patients' characteristics could have had influenced possible trends in time. A approximated mortality rate was compared with the ICU mortality rate, to study the predictive value of the APACHE II score. Overall one-year mortality was 62%. The annual decrease in one-year mortality was 7%, whereas the APACHE II score increased over time. Decreased mortality rates were particularly observed in high-risk patients (acute myeloid leukaemia, old age, low platelet count, bleeding as admission reason and need for mechanical ventilation within 24 h of ICU admission). Furthermore, the APACHE II score overestimates mortality in this patient category.

Metrics of Arterial Hyperoxia and Associated Outcomes in Critical Care.

OBJECTIVE: Emerging evidence has shown the potential risks of arterial hyperoxia, but the lack of a clinical definition and methodologic limitations hamper the interpretation and clinical relevance of previous studies. Our purpose was to evaluate previously used and newly constructed metrics of arterial hyperoxia and systematically assess their association with clinical outcomes in different subgroups in the ICU. DESIGN: Observational cohort study. SETTING: Three large tertiary care ICUs in the Netherlands. PATIENTS: A total of 14,441 eligible ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 295,079 arterial blood gas analyses, including the PaO2, between July 2011 and July 2014 were extracted from the patient data management system database. Data from all admissions with more than one PaO2 measurement were supplemented with anonymous demographic and admission and discharge data from the Dutch National Intensive Care Evaluation registry. Mild hyperoxia was defined as PaO2 between 120 and 200 mm Hg; severe hyperoxia as PaO2 greater than 200 mm Hg. Characteristics of existing and newly constructed metrics for arterial hyperoxia were examined, and the associations with hospital mortality (primary outcome), ICU mortality, and ventilator-free days and alive at day 28 were retrospectively analyzed using regression models in different subgroups of patients. Severe hyperoxia was associated with higher mortality rates and fewer ventilator-free days in comparison to both mild hyperoxia and normoxia for all metrics except for the worst PaO2. Adjusted effect estimates for conditional mortality were larger for severe hyperoxia than for mild hyperoxia. This association was found both within and beyond the first 24 hours of admission and was consistent for large subgroups. The largest point estimates were found for the exposure identified by the average PaO2, closely followed by the median PaO2, and these estimates differed substantially between subsets. Time spent in hyperoxia showed a linear and positive relationship with hospital mortality. CONCLUSIONS: Our results suggest that we should limit the PaO2 levels of critically ill patients within a safe range, as we do with other physiologic variables. Analytical metrics of arterial hyperoxia should be judiciously considered when interpreting and comparing study results and future studies are needed to validate our findings in a randomized fashion design.

Effectiveness and Clinical Outcomes of a Two-Step Implementation of Conservative Oxygenation Targets in Critically Ill Patients: A Before and After Trial.

OBJECTIVES: Conservative oxygen therapy is aimed at the prevention of harm by iatrogenic hyperoxia while preserving adequate tissue oxygenation. Our aim was to study the effectiveness and clinical outcomes of a two-step implementation of conservative oxygenation targets in the ICU. DESIGN: This was a before and after stepwise implementation study of conservative oxygenation targets, between July 2011 and July 2014. The primary endpoint was the proportion of PaO2 values within the target range. Secondary outcomes included ventilator-free days at day 28, length of stay, and mortality. SETTING: Three closed-format ICUs in the Netherlands. PATIENTS: We analyzed data on 15,045 eligible admissions. INTERVENTIONS: The first implementation phase consisted of providing training and feedback on new guidelines instructing for explicit targets for arterial oxygen tension (PaO2, 55-86 mm Hg) and oxyhemoglobin saturation (SpO2, 92-95%). In the second phase, bedside clinicians were additionally assisted in guideline adherence by a computerized decision-support system. MEASUREMENTS AND MAIN RESULTS: The proportion of PaO2 in the target range increased from 47% at baseline to 63% in phase 1 and to 68% in phase 2 (p < 0.0001). Episodes of hyperoxia decreased (p < 0.0001), whereas hypoxic episodes remained unchanged (p = 0.06) during the study. Mechanical ventilation time was significantly lower (p < 0.01) during both study phases. After adjustment for potential confounders, ventilator-free days in phase 1 and phase 2 were higher than baseline: adjusted mean difference, 0.55 (95% CI, 0.25-0.84) and 0.48 (95% CI, 0.11-0.86), respectively. Adjusted ICU mortality and ICU-free days did not significantly differ between study phases. Hospital mortality decreased in reference to baseline: adjusted odds ratio, 0.84 (95% CI, 0.74-0.96) for phase 1 and 0.82 (95% CI, 0.69-0.96) for phase 2. CONCLUSIONS: Stepwise implementation of conservative oxygenation targets was feasible, effective, and seemed safe in critically ill patients. The implementation was associated with several changes in clinical outcomes, but the causal impact of conservative oxygenation is still to be determined.

Vibrio cholerae non-O1 bacteraemia: description of three cases in the Netherlands and a literature review.

Vibrio cholerae non-O1 serogroup (VCNO) bacteraemia is a severe condition with a high case-fatality rate. We report three cases diagnosed in the Netherlands, identified during a national microbiological congress, and provide a literature review on VCNO bacteraemia. A search strategy including synonyms for 'VCNO' and 'bacteraemia' was applied to PubMed, Medline, Web of Science and Embase databases. The three cases were reported in elderly male patients after fish consumption and/or surface water contact. The literature search yielded 82 case reports on 90 cases and six case series. Thirty case reports were from Asia (30/90; 33%), concerned males (67/90; 74%), and around one third (38/90; 42%) involved a history of alcohol abuse and/or liver cirrhosis The presenting symptom often was gastroenteritis (47/90; 52%) which occurred after seafood consumption in 32% of the cases (15/47).Aside from the most frequent symptom being fever, results of case series concurred with these findings. Published cases also included rare presentations e.g. endophthalmitis and neonatal meningitis. Based on the limited data available, cephalosporins seemed the most effective treatment. Although mainly reported in Asia, VCNO bacteraemia occurs worldwide. While some risk factors for VCNO were identified in this study, the source of infection remains often unclear. Clinical presentation may vary greatly and therefore a quick microbiological diagnosis is indispensable.

Systemic inflammation and microglial activation: systematic review of animal experiments.

BACKGROUND: Animal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated delirium. We systematically reviewed animal experiments related to the effects of systemic inflammation on the microglial and inflammatory response in the brain. METHODS: We searched PubMed between January 1, 1950 and December 1, 2013 and Embase between January 1, 1988 and December 1, 2013 for animal studies on the influence of peripheral inflammatory stimuli on microglia and the brain. Identified studies were systematically scored on methodological quality. Two investigators extracted independently data on animal species, gender, age, and genetic background; number of animals; infectious stimulus; microglial cells; and other inflammatory parameters in the brain, including methods, time points after inoculation, and brain regions. RESULTS: Fifty-one studies were identified of which the majority was performed in mice (n = 30) or in rats (n = 19). Lipopolysaccharide (LPS) (dose ranging between 0.33 and 200 mg/kg) was used as a peripheral infectious stimulus in 39 studies (76 %), and live or heat-killed pathogens were used in 12 studies (24 %). Information about animal characteristics such as species, strain, sex, age, and weight were defined in 41 studies (80 %), and complete methods of the disease model were described in 35 studies (68 %). Studies were also heterogeneous with respect to methods used to assess microglial activation; markers used mostly were the ionized calcium binding adaptor molecule-1 (Iba-1), cluster of differentiation 68 (CD68), and CD11b. After LPS challenge microglial activation was seen 6 h after challenge and remained present for at least 3 days. Live Escherichia coli resulted in microglial activation after 2 days, and heat-killed bacteria after 2 weeks. Concomitant with microglial response, inflammatory parameters in the brain were reviewed in 23 of 51 studies (45 %). Microglial activation was associated with an increase in Toll-like receptor (TLR-2 and TLR-4), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1ß) messenger ribonucleic acid (mRNA) expression or protein levels. INTERPRETATION: Animal experiments robustly showed that peripheral inflammatory stimuli cause microglial activation. We observed distinct differences in microglial activation between systemic stimulation with (supranatural doses) LPS and live or heat-killed bacteria.

Association Between Arterial Hyperoxia and Outcome in Subsets of Critical Illness: A Systematic Review, Meta-Analysis, and Meta-Regression of Cohort Studies.

OBJECTIVE: Oxygen is vital during critical illness, but hyperoxia may harm patients. Our aim was to systematically evaluate the methodology and findings of cohort studies investigating the effects of hyperoxia in critically ill adults. DATA SOURCE: A meta-analysis and meta-regression analysis of cohort studies published between 2008 and 2015 was conducted. Electronic databases of MEDLINE, EMBASE, and Web of Science were systematically searched for the keywords hyperoxia and mortality or outcome. STUDY SELECTION: Publications assessing the effect of arterial hyperoxia on outcome in critically ill adults (≥ 18 yr) admitted to critical care units were eligible. We excluded studies in patients with chronic obstructive pulmonary disease, extracorporeal life support or hyperbaric oxygen therapy, and animal studies. Due to a lack of data, no studies dedicated to patients with acute lung injury, sepsis, shock, or multiple trauma could be included. DATA EXTRACTION: Studies were included independent of admission diagnosis and definition of hyperoxia. The primary outcome measure was in-hospital mortality, and results were stratified for relevant subgroups (cardiac arrest, traumatic brain injury, stroke, post-cardiac surgery, and any mechanical ventilation). The effects of arterial oxygenation on functional outcome, long-term mortality, and discharge variables were studied as secondary outcomes. DATA SYNTHESIS: Twenty-four studies were included of which five studies were only for a subset of the analyses. Nineteen studies were pooled for meta-analyses and showed that arterial hyperoxia during admission increases hospital mortality: adjusted odds ratio, 1.21 (95% CI, 1.08-1.37) (p = 0.001). Functional outcome measures were diverse and generally showed a more favorable outcome for normoxia. CONCLUSIONS: In various subsets of critically ill patients, arterial hyperoxia was associated with poor hospital outcome. Considering the substantial heterogeneity of included studies and the lack of a clinical definition, more evidence is needed to provide optimal oxygen targets to critical care physicians.

Critical care management of systemic mastocytosis: when every wasp is a killer bee.

Since the critical care physician will most likely be involved in a life-threatening expression of systemic mastocytosis, recognition of this disease is of utmost importance in the critical care management of these patients. Mastocytosis is a severely under-recognized disease because it typically occurs secondary to another condition and thus may occur more frequently than assumed. In this article, we will review the current knowledge on the treatment of mastocytosis crises with an emphasis on critical care management. Mastocytosis is characterized by the clonal proliferation and accumulation of mast cells in different tissues. Mast cell mediators contain a wide range of biologically active substances that may lead to itching and hives but may ultimately lead to anaphylactic shock caused by the release of histamine and other mediators from mast cells. The mainstay of therapy is the avoidance of potential triggers of mast cell degranulation and, if unsuccessful, blocking the cascade of mast cell mediators. The critical care physician should be well aware of the special precautions which should be kept in mind throughout the management of a mastocytosis crisis to avoid massive mast cell degranulation. Histamine-releasing drugs and certain physical triggers like temperature change should be avoided.

Associations of arterial carbon dioxide and arterial oxygen concentrations with hospital mortality after resuscitation from cardiac arrest.

INTRODUCTION: Arterial concentrations of carbon dioxide (PaCO2) and oxygen (PaO2) during admission to the intensive care unit (ICU) may substantially affect organ perfusion and outcome after cardiac arrest. Our aim was to investigate the independent and synergistic effects of both parameters on hospital mortality. METHODS: This was a cohort study using data from mechanically ventilated cardiac arrest patients in the Dutch National Intensive Care Evaluation (NICE) registry between 2007 and 2012. PaCO2 and PaO2 levels from arterial blood gas analyses corresponding to the worst oxygenation in the first 24 h of ICU stay were retrieved for analyses. Logistic regression analyses were performed to assess the relationship between hospital mortality and both categorized groups and a spline-based transformation of the continuous values of PaCO2 and PaO2. RESULTS: In total, 5,258 cardiac arrest patients admitted to 82 ICUs in the Netherlands were included. In the first 24 h of ICU admission, hypocapnia was encountered in 22 %, and hypercapnia in 35 % of included cases. Hypoxia and hyperoxia were observed in 8 % and 3 % of the patients, respectively. Both PaCO2 and PaO2 had an independent U-shaped relationship with hospital mortality and after adjustment for confounders, hypocapnia and hypoxia were significant predictors of hospital mortality: OR 1.37 (95 % CI 1.17-1.61) and OR 1.34 (95 % CI 1.08-1.66). A synergistic effect of concurrent derangements of PaCO2 and PaO2 was not observed (P = 0.75). CONCLUSIONS: The effects of aberrant arterial carbon dioxide and arterial oxygen concentrations were independently but not synergistically associated with hospital mortality after cardiac arrest.

Bench-to-bedside review: the effects of hyperoxia during critical illness.

Oxygen administration is uniformly used in emergency and intensive care medicine and has life-saving potential in critical conditions. However, excessive oxygenation also has deleterious properties in various pathophysiological processes and consequently both clinical and translational studies investigating hyperoxia during critical illness have gained increasing interest. Reactive oxygen species are notorious by-products of hyperoxia and play a pivotal role in cell signaling pathways. The effects are diverse, but when the homeostatic balance is disturbed, reactive oxygen species typically conserve a vicious cycle of tissue injury, characterized by cell damage, cell death, and inflammation. The most prominent symptoms in the abundantly exposed lungs include tracheobronchitis, pulmonary edema, and respiratory failure. In addition, absorptive atelectasis results as a physiological phenomenon with increasing levels of inspiratory oxygen. Hyperoxia-induced vasoconstriction can be beneficial during vasodilatory shock, but hemodynamic changes may also impose risk when organ perfusion is impaired. In this context, oxygen may be recognized as a multifaceted agent, a modifiable risk factor, and a feasible target for intervention. Although most clinical outcomes are still under extensive investigation, careful titration of oxygen supply is warranted in order to secure adequate tissue oxygenation while preventing hyperoxic harm.

Daily variation in blood glucose levels during continuous enteral nutrition in patients on the intensive care unit: a retrospective observational study.

BACKGROUND: The circadian timing system coordinates daily cycles in physiological functions, including glucose metabolism and insulin sensitivity. Here, the aim was to characterise the 24-h variation in glucose levels in critically ill patients during continuous enteral nutrition after controlling for potential sources of bias. METHODS: Time-stamped clinical data from adult patients who stayed in the Intensive Care Unit (ICU) for at least 4 days and received enteral nutrition were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Linear mixed-effects and XGBoost modelling were used to determine the effect of time of day on blood glucose values. FINDINGS: In total, 207,647 glucose measurements collected during enteral nutrition were available from 6,929 ICU patients (3,948 males and 2,981 females). Using linear mixed-effects modelling, time of day had a significant effect on blood glucose levels (p < 0.001), with a peak of 9.6 [9.5-9.6; estimated marginal means, 95% CI] mmol/L at 10:00 in the morning and a trough of 8.6 [8.5-8.6] mmol/L at 02:00 at night. A similar impact of time of day on glucose levels was found with the XGBoost regression model. INTERPRETATION: These results revealed marked 24-h variation in glucose levels in ICU patients even during continuous enteral nutrition. This 24-h pattern persists after adjustment for potential sources of bias, suggesting it may be the result of endogenous biological rhythmicity. FUNDING: This work was supported by a VENI grant from the Netherlands Organisation for Health Research and Development (ZonMw), an institutional project grant, and by the Dutch Research Council (NWO).

Sleep in the intensive and intermediate care units: Exploring related factors of delirium, benzodiazepine use and mortality.

AIM OF THE STUDY: The primary purpose was to examine sleep difficulties and delirium in the Intensive and Intermediate Care Unit. Secondarily, factors impacting night-time sleep duration and quality, mortality, and the impact of benzodiazepine use on sleep outcomes were investigated. MATERIALS AND METHODS: This retrospective study encompassed data from 323 intensive and intermediate care unit admissions collected in the Netherlands, spanning from November 2018 to May 2020. Sleep quality was measured using the Richards-Campbell Sleep Questionnaire. Night-time sleep duration was nurse-reported. We investigated associations of these sleep outcomes with age, sex, length-of-stay, natural daylight, disease severity, mechanical ventilation, benzodiazepine use, and delirium using Generalized Estimating Equations models. Associations with one-year post-discharge mortality were analyzed using Cox regression. RESULTS: Night-time sleep duration was short (median 4.5 hours) and sleep quality poor (mean score 4.9/10). Benzodiazepine use was common (24 % of included nights) and was negatively associated with night-time sleep duration and quality (B = -0.558 and -0.533, p <.001). Delirium and overnight transfers were negatively associated with sleep quality (B = -0.716 and -1.831, p <.05). The day-to-night sleep ratio was higher in the three days before delirium onset than in non-delirious individuals (p <.05). Age, disease severity and female sex were associated with increased one-year mortality. Sleep quality was negatively, but not-significantly, associated with mortality (p =.070). CONCLUSIONS: Night-time sleep in the critical care environment has a short duration and poor quality. Benzodiazepine use was not associated with improved sleep. Sleep patterns change ahead of delirium onset. IMPLICATIONS FOR CLINICAL PRACTICE: Consistent sleep monitoring should be part of routine nursing practice, using a validated instrument like the Richards-Campbell Sleep Questionnaire. Given the lack of proven efficacy of benzodiazepines in promoting sleep in critical care settings, it is vital to develop more effective sleep treatments that include non-benzodiazepine medication and sleep hygiene strategies.

Preoperative cerebrospinal fluid cytokine levels and the risk of postoperative delirium in elderly hip fracture patients.

BACKGROUND: Aging and neurodegenerative disease predispose to delirium and are both associated with increased activity of the innate immune system resulting in an imbalance between pro- and anti-inflammatory mediators in the brain. We examined whether hip fracture patients who develop postoperative delirium have altered levels of inflammatory mediators in cerebrospinal fluid (CSF) prior to surgery. METHODS: Patients were 75 years and older and admitted for surgical repair of an acute hip fracture. CSF samples were collected preoperatively. In an exploratory study, we measured 42 cytokines and chemokines by multiplex analysis. We compared CSF levels between patients with and without postoperative delirium and examined the association between CSF cytokine levels and delirium severity. Delirium was diagnosed with the Confusion Assessment Method; severity of delirium was measured with the Delirium Rating Scale Revised-98. Mann-Whitney U tests or Student t-tests were used for between-group comparisons and the Spearman correlation coefficient was used for correlation analyses. RESULTS: Sixty-one patients were included, of whom 23 patients (37.7%) developed postsurgical delirium. Concentrations of Fms-like tyrosine kinase-3 (P=0.021), Interleukin-1 receptor antagonist (P=0.032) and Interleukin-6 (P=0.005) were significantly lower in patients who developed delirium postoperatively. CONCLUSIONS: Our findings fit the hypothesis that delirium after surgery results from a dysfunctional neuroinflammatory response: stressing the role of reduced levels of anti-inflammatory mediators in this process. TRIAL REGISTRATION: The Effect of Taurine on Morbidity and Mortality in the Elderly Hip Fracture Patient. REGISTRATION NUMBER: NCT00497978. Local ethical protocol number: NL16222.094.07.

Effect of lung ultrasound-guided fluid deresuscitation on duration of ventilation in intensive care unit patients (CONFIDENCE): protocol for a multicentre randomised controlled trial.

BACKGROUND: Fluid therapy is a common intervention in critically ill patients. It is increasingly recognised that deresuscitation is an essential part of fluid therapy and delayed deresuscitation is associated with longer invasive ventilation and length of intensive care unit (ICU) stay. However, optimal timing and rate of deresuscitation remain unclear. Lung ultrasound (LUS) may be used to identify fluid overload. We hypothesise that daily LUS-guided deresuscitation is superior to deresuscitation without LUS in critically ill patients expected to undergo invasive ventilation for more than 24 h in terms of ventilator free-days and being alive at day 28. METHODS: The "effect of lung ultrasound-guided fluid deresuscitation on duration of ventilation in intensive care unit patients" (CONFIDENCE) is a national, multicentre, open-label, randomised controlled trial (RCT) in adult critically ill patients that are expected to be invasively ventilated for at least 24 h. Patients with conditions that preclude a negative fluid balance or LUS examination are excluded. CONFIDENCE will operate in 10 ICUs in the Netherlands and enrol 1000 patients. After hemodynamic stabilisation, patients assigned to the intervention will receive daily LUS with fluid balance recommendations. Subjects in the control arm are deresuscitated at the physician's discretion without the use of LUS. The primary endpoint is the number of ventilator-free days and being alive at day 28. Secondary endpoints include the duration of invasive ventilation; 28-day mortality; 90-day mortality; ICU, in hospital and total length of stay; cumulative fluid balance on days 1-7 after randomisation and on days 1-7 after start of LUS examination; mean serum lactate on days 1-7; the incidence of reintubations, chest drain placement, atrial fibrillation, kidney injury (KDIGO stadium ≥ 2) and hypernatremia; the use of invasive hemodynamic monitoring, and chest-X-ray; and quality of life at day 28. DISCUSSION: The CONFIDENCE trial is the first RCT comparing the effect of LUS-guided deresuscitation to routine care in invasively ventilated ICU patients. If proven effective, LUS-guided deresuscitation could improve outcomes in some of the most vulnerable and resource-intensive patients in a manner that is non-invasive, easy to perform, and well-implementable. TRIAL REGISTRATION: ClinicalTrials.gov NCT05188092. Registered since January 12, 2022.

Higher versus lower oxygenation strategies in the general intensive care unit population: A systematic review, meta-analysis and meta-regression of randomized controlled trials.

PURPOSE: Oxygen therapy is vital in adult intensive care unit (ICU) patients, but it is indistinct whether higher or lower oxygen targets are favorable. Our aim was to update the findings of randomized controlled trials (RTCs) comparing higher and lower oxygen strategies. MATERIALS AND METHODS: MEDLINE, EMBASE, and Web of Science were searched. RCTs comparing higher (liberal, hyperoxia) and lower (conservative, normoxia) oxygen in adult mechanically ventilated ICU patients were included. The main outcome was 90-day mortality; other outcomes include serious adverse events (SAE), support free days and length of stay (LOS). RESULTS: No significant difference was observed for 90-day mortality. A lower incidence was found for SAEs, favoring lower oxygenation (OR, 0.86; 95%CI, 0.77-0.96; I 2 13%). No differences were observed in either support free days at day 28 or ICU and hospital LOS. CONCLUSIONS: No difference was found for 90-day mortality, support free days and ICU and hospital LOS. However, a lower incidence of SAEs was found for lower oxygenation. These findings may have clinical implications for practice guidelines, yet it remains of paramount importance to continue conducting clinical trials, comparing groups with a clinically relevant contrast and focusing on the impact of important side effects.

Towards Fixed Dosing of Tocilizumab in ICU-Admitted COVID-19 Patients: Results of an Observational Population Pharmacokinetic and Descriptive Pharmacodynamic Study.

BACKGROUND AND OBJECTIVE: In the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including survival in intensive care unit (ICU)-admitted coronavirus disease 2019 (COVID)-19 patients. Therefore tocilizumab has been added to many COVID-19 treatment guidelines. Because obesity is a risk factor for the development of severe COVID-19, concerns have been raised about overtreatment, as well as undertreatment, through weight-based dosing of tocilizumab. The currently applied dose of 8 mg/kg is based on the use of this drug for other indications, however it has not formally been investigated for COVID-19. In this study, the pharmacokinetics and pharmacodynamics of tocilizumab were investigated in ICU-admitted COVID-19 patients. METHODS: This was an open-label, single-centre, observational population pharmacokinetic and descriptive pharmacodynamic evaluation study. Enrolled patients, with polymerase chain reaction-confirmed COVID-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received intravenous tocilizumab 8 mg/kg (maximum 800 mg) within 24 h after admission to the ICU and received dexamethasone 6 mg daily as concomitant therapy. For evaluation of the pharmacokinetics and pharmacodynamics of tocilizumab, all time points from day 0 to 20 days after dose administration were eligible for collection. A nonlinear mixed-effects model was developed to characterize the population pharmacokinetic parameters of tocilizumab in ICU-admitted COVID-19 patients. Covariate analysis was performed to identify potential covariates for dose individualization. For the development of alternative dosing schedules, Monte Carlo simulations using the final model were performed. RESULTS: Overall, 29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and nonlinear clearance (CL) was developed and validated. Average CL was estimated to be 0.725 L/day, average volume of distribution (Vd) was 4.34 L, maximum elimination rate (Vmax) was 4.19 µg/day, and concentration at which the elimination pathway is half saturated (Km) was 0.22 µg/mL. Interindividual variability was identified for CL (18.9%) and Vd (21%). Average area under the concentration versus time curve from time zero to infinity of the first dose (AUCinf 1st DOSE) was 938 [±190] µg/mL*days. All patients had tocilizumab exposure above 1 µg/mL for at least 15 days. Bodyweight-based dosing increases variability in exposure compared with fixed dosing. CONCLUSIONS: This study provides evidence to support a fixed dose of tocilizumab 600 mg in COVID-19 patients. Fixed dosing is a safe, logistically attractive, and drug expenses saving alternative compared with the current 8 mg/kg recommendation.