Physiologic Determinants of Near-Infrared Spectroscopy-Derived Cerebral and Tissue Oxygen Saturation Measurements in Critically Ill Patients.

OBJECTIVES: Near-infrared spectroscopy (NIRS) is a potentially valuable modality to monitor the adequacy of oxygen delivery to the brain and other tissues in critically ill patients, but little is known about the physiologic determinants of NIRS-derived tissue oxygen saturations. The purpose of this study was to assess the contribution of routinely measured physiologic parameters to tissue oxygen saturation measured by NIRS. DESIGN: An observational sub-study of patients enrolled in the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomized feasibility trial. SETTING: Two ICUs in the United Kingdom. PATIENTS: Patients were recruited for the RADAR-2 study, which compared a conservative approach to fluid therapy and deresuscitation with usual care. Those included in this sub-study underwent continuous NIRS monitoring of cerebral oxygen saturations (SctO2) and quadriceps muscle tissue saturations (SmtO2). INTERVENTION: Synchronized and continuous mean arterial pressure (MAP), heart rate (HR), and pulse oximetry (oxygen saturation, Spo2) measurements were recorded alongside NIRS data. Arterial Paco2, Pao2, and hemoglobin concentration were recorded 12 hourly. Linear mixed effect models were used to investigate the association between these physiologic variables and cerebral and muscle tissue oxygen saturations. MEASUREMENTS AND MAIN RESULTS: Sixty-six patients were included in the analysis. Linear mixed models demonstrated that Paco2, Spo2, MAP, and HR were weakly associated with SctO2 but only explained 7.1% of the total variation. Spo2 and MAP were associated with SmtO2, but together only explained 0.8% of its total variation. The remaining variability was predominantly accounted for by between-subject differences. CONCLUSIONS: Our findings demonstrated that only a small proportion of variability in NIRS-derived cerebral and tissue oximetry measurements could be explained by routinely measured physiologic variables. We conclude that for NIRS to be a useful monitoring modality in critical care, considerable further research is required to understand physiologic determinants and prognostic significance.

Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects.

Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue damage and loss of tissue function. Historically, the neutrophil serine proteases (NSPs) have been the main subject of neutrophil protease research. Despite highly promising cell-based and animal model work, clinical trials involving the inhibition of NSPs have shown mixed results in lung disease patients. As such, the cutting edge of neutrophil-derived protease research has shifted to proteases that have had little-to-no research in neutrophils to date. These include the cysteine and serine cathepsins, the metzincins and the calpains, among others. This review aims to outline the previous work carried out on NSPs, including the shortcomings of some of the inhibitor-orientated clinical trials. Our growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation will then be discussed. Additionally, the potential of targeting these more obscure neutrophil proteases will be highlighted, as they may represent new targets for inhibitor-based treatments of neutrophil-mediated lung inflammation.

TRPV2 modulates mechanically Induced ATP Release from Human bronchial epithelial cells.

Repetitive bouts of coughing expose the large airways to significant cycles of shear stress. This leads to the release of alarmins and the tussive agent adenosine triphosphate (ATP) which may be modulated by the activity of ion channels present in the human airway. This study aimed to investigate the role of the transient receptor potential subfamily vanilloid member 2 (TRPV2) channel in mechanically induced ATP release from primary bronchial epithelial cells (PBECs).PBECs were obtained from individuals undergoing bronchoscopy. They were cultured in vitro and exposed to mechanical stress in the form of compressive and fluid shear stress (CFSS) or fluid shear stress (FSS) alone at various intensities. ATP release was measured using a luciferin-luciferase assay. Functional TRPV2 protein expression in human PBECs was investigated by confocal calcium imaging. The role of TRPV2 inhibition on FSS-induced ATP release was investigated using the TRPV2 inhibitor tranilast or siRNA knockdown of TRPV2. TRPV2 protein expression in human lung tissue was also determined by immunohistochemistry.ATP release was significantly increased in PBECs subjected to CFSS compared with control (unstimulated) PBECs (N = 3, ***P < 0.001). PBECs expressed functional TRPV2 channels. TRPV2 protein was also detected in fixed human lung tissue. ATP release from FFS stimulated PBECs was decreased by the TRPV2 inhibitor tranilast (N = 3, **P < 0.01) (vehicle: 159 ± 17.49 nM, tranilast: 25.08 ± 5.1 nM) or by TRPV2 siRNA knockdown (N = 3, *P < 0.05) (vehicle: 197 ± 24.52 nM, siRNA: 119 ± 26.85 nM).In conclusion, TRPV2 is expressed in the human airway and modulates ATP release from mechanically stimulated PBECs.

Communication in critical care tracheostomy patients dependent upon cuff inflation: A scoping review.

OBJECTIVES: The aim of this study was to synthesise the evidence concerning communication in critically ill tracheostomy patients dependent on cuff inflation. The aim was to identify the psychological impact on patients awake and alert with tracheostomies but unable to speak; strategies utilised to enable communication and facilitators and barriers for the success of these strategies. REVIEW METHOD USED: This scoping review was conducted using the Joanna Briggs Institute framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. DATA SOURCES: CINAHL, Embase, Medline, and Web of Science were searched from 1st January 2000 to 30th September 2023 and supplemented with hand searching of references from included studies. REVIEW METHODS: Studies were eligible if they addressed the psychological impact of voicelessness and/or the structure, process, and outcomes of augmentative and alternative communication (AAC) systems, in addition to facilitators and barriers to effectiveness. The population of interest included critically ill tracheostomy patients dependent on cuff inflation, their families, and healthcare workers. Screening and data extraction were undertaken by two reviewers independently. Data analysis involved descriptive statistics and content analysis. RESULTS: A total of 23 studies met the inclusion criteria: 11 were qualitative, nine were quantitative, and three were mixed-methods studies. Voicelessness elicited negative emotions, predominantly frustration. AAC systems, encompassing unaided and aided (low-tech and high-tech) methods, presented both advantages and drawbacks. High-tech strategies held promise for patients with physical limitations. Patients equally appreciated the support offered through unaided strategies, including eye contact and touch. Facilitating factors included speech therapy involvement and assessment. Patient-related challenges were the most frequent barriers. CONCLUSION: Facilitating meaningful communication for critically ill tracheostomy patients dependent on cuff inflation is of paramount psychological significance. Whilst AAC systems are practicable, they are not without limitations, implying the absence of a universally applicable solution. This underscores the importance of continuous evaluation, reinforced by a multidisciplinary team. REVIEW PROTOCOL REGISTERED: 27 July 2022. REVIEW REGISTRATION: Open Science Framework Registries: https://osf.io/kbrjn/.

Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes.

RATIONALE: Heterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating biomarkers have defined hyper-inflammatory and hypo-inflammatory subphenotypes in ARDS associated with differential treatment response. It is unknown if similar subphenotypes exist in sepsis populations where leucocyte transcriptomic-defined subphenotypes have been reported. OBJECTIVES: We investigated whether inflammatory clusters based on cytokine protein abundance were seen in sepsis, and the relationships with previously described transcriptomic subphenotypes. METHODS: Hierarchical cluster and latent class analysis were applied to an observational study (UK Genomic Advances in Sepsis (GAinS)) (n=124 patients) and two clinical trial datasets (VANISH, n=155 and LeoPARDS, n=484) in which the plasma protein abundance of 65, 21, 11 circulating cytokines, cytokine receptors and regulators were quantified. Clinical features, outcomes, response to trial treatments and assignment to transcriptomic subphenotypes were compared between inflammatory clusters. MEASUREMENTS AND MAIN RESULTS: We identified two (UK GAinS, VANISH) or three (LeoPARDS) inflammatory clusters. A group with high levels of pro-inflammatory and anti-inflammatory cytokines was seen that was associated with worse organ dysfunction and survival. No interaction between inflammatory clusters and trial treatment response was found. We found variable overlap of inflammatory clusters and leucocyte transcriptomic subphenotypes. CONCLUSIONS: These findings demonstrate that differences in response at the level of cytokine biology show clustering related to severity, but not treatment response, and may provide complementary information to transcriptomic sepsis subphenotypes. TRIAL REGISTRATION NUMBER: ISRCTN20769191, ISRCTN12776039.

Vascular leak in sepsis: physiological basis and potential therapeutic advances.

Sepsis is a life-threatening condition characterised by endothelial barrier dysfunction and impairment of normal microcirculatory function, resulting in a state of hypoperfusion and tissue oedema. No specific pharmacological therapies are currently used to attenuate microvascular injury. Given the prominent role of endothelial breakdown and microcirculatory dysfunction in sepsis, there is a need for effective strategies to protect the endothelium. In this review we will discuss key mechanisms and putative therapeutic agents relevant to endothelial barrier function.

An International Survey of the Management of Atrial Fibrillation in Critically Unwell Patients.

OBJECTIVES: To evaluate the current management of new-onset atrial fibrillation and compare differences in practice regionally. DESIGN: Cross-sectional survey. SETTING: United States, Canada, United Kingdom, Europe, Australia, and New Zealand. SUBJECTS: Critical care attending physicians/consultants and fellows. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 386 surveys were included in our analysis. Rate control was the preferred treatment approach for hemodynamically stable patients (69.1%), and amiodarone was the most used antiarrhythmic medication (70.9%). For hemodynamically unstable patients, a strategy of electrolyte supplementation and antiarrhythmic therapy was most common (54.7%). Physicians responding to the survey distributed by the Society of Critical Care Medicine were more likely to prescribe beta-blockers as a first-line antiarrhythmic medication (38.4%), use more transthoracic echocardiography than respondents from other regions (82.4%), and more likely to refer patients who survive their ICU stay for cardiology follow-up if they had new-onset atrial fibrillation (57.2%). The majority of survey respondents (83.0%) were interested in participating in future studies of atrial fibrillation in critically ill patients. CONCLUSIONS: Significant variation exists in the management of new-onset atrial fibrillation in critically ill patients, as well as geographic variation. Further research is necessary to inform guidelines in this population and establish if differences in practice impact long-term outcomes.

Whole blood thiamine, intravenous thiamine supplementation and delirium occurrence in the intensive care unit: retrospective cohort analyses.

BACKGROUND: Thiamine di-phosphate is an essential cofactor in glucose metabolism, glutamate transformation and acetylcholinesterase activity, pathways associated with delirium occurrence. We hypothesised that a deficiency in whole blood thiamine and intravenous thiamine supplementation could impact delirium occurrence. AIM: To establish whether a deficiency in whole blood thiamine and/or intravenous thiamine supplementation within 72 h of intensive care admission is associated with delirium occurrence. METHOD: The first dataset was secondary analysis of a previous study in an intensive care unit in the Netherlands, reported in 2017. The second dataset contained consecutive intensive care admissions 2 years before (period 1: October 2014 to October 2016) and after (period 2: April 2017 to April 2019) routine thiamine supplementation was introduced within 72 h of admission. Delirium was defined as a positive Confusion Assessment Method-Intensive Care Unit score(s) in 24 h. RESULTS: Analysis of the first dataset (n = 57) using logistic regression showed no relationship between delirium and sepsis or whole blood thiamine, but a significant association with age (p = 0.014). In the second dataset (n = 3074), 15.1% received IV thiamine in period 1 and 62.6% during period 2. Hierarchical regression analysis reported reduction in delirium occurrence in the second period; this did not reach statistical significance, OR = 0.81 (95% CI 0.652-1.002); p = 0.052. CONCLUSION: No relationship was detected between whole blood thiamine and delirium occurrence on admission, at 24 and 48 h. It remains unclear whether routine intravenous thiamine supplementation during intensive care admission impacts delirium occurrence. Further prospective randomised clinical trials are needed.

Cell-based Therapies for Acute Respiratory Distress Syndrome: Where Are We Now?

There is considerable interest in the potential for cell-based therapies, particularly mesenchymal stromal cells (MSCs) and their products, as a therapy for acute respiratory distress syndrome (ARDS). MSCs exert effects via diverse mechanisms including reducing excessive inflammation by modulating neutrophil, macrophage and T-cell function, decreasing pulmonary permeability and lung edema, and promoting tissue repair. Clinical studies indicate that MSCs are safe and well tolerated, with promising therapeutic benefits in specific clinical settings, leading to regulatory approvals of MSCs for specific indications in some countries.This perspective reassesses the therapeutic potential of MSC-based therapies for ARDS given insights from recent cell therapy trials in both COVID-19 and in 'classic' ARDS, and discusses studies in graft-vs.-host disease, one of the few licensed indications for MSC therapies. We identify important unknowns in the current literature, address challenges to clinical translation, and propose an approach to facilitate assessment of the therapeutic promise of MSC-based therapies for ARDS.

The Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal Compared With Conventional Lung Protective Ventilation on Cardiac Function.

OBJECTIVES: Lower tidal volume ventilation (targeting 3 mL/kg predicted body weight, PBW) facilitated by extracorporeal carbon dioxide removal (ECCO2R) has been investigated as a potential therapy for acute hypoxemic respiratory failure (AHRF) in the pRotective vEntilation with veno-venouS lung assisT in respiratory failure (REST) trial. We investigated the effect of this strategy on cardiac function, and in particular the right ventricle. DESIGN: Substudy of the REST trial. SETTING: Nine U.K. ICUs. PATIENTS: Patients with AHRF (Pao2/Fio2 < 150 mm Hg [20 kPa]). INTERVENTION: Transthoracic echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements were collected at baseline and postrandomization in patients randomized to ECCO2R or usual care. MEASUREMENTS: The primary outcome measures were a difference in tricuspid annular plane systolic excursion (TAPSE) on postrandomization echocardiogram and difference in NT-proBNP postrandomization. RESULTS: There were 21 patients included in the echocardiography cohort (ECCO2R, n = 13; usual care, n = 8). Patient characteristics were similar in both groups at baseline. Median (interquartile range) tidal volumes were lower in the ECCO2R group compared with the usual care group postrandomization; 3.6 (3.1-4.2) mL/kg PBW versus 5.2 (4.9-5.7) mL/kg PBW, respectively (p = 0.01). There was no difference in the primary outcome measure of mean (sd) TAPSE in the ECCO2R and usual care groups postrandomization; 21.3 (5.4) mm versus 20.1 (3.2) mm, respectively (p = 0.60). There were 75 patients included in the NT-proBNP cohort (ECCO2R, n = 36; usual care, n = 39). Patient characteristics were similar in both groups at baseline. Median (interquartile range [IQR]) tidal volumes were lower in the ECCO2R group than the usual care group postrandomization; 3.8 (3.3-4.2) mL/kg PBW versus 6.7 (5.8-8.1) mL/kg PBW, respectively (p < 0.0001). There was no difference in median (IQR) NT-proBNP postrandomization; 1121 (241-5370) pg/mL versus 1393 (723-4332) pg/mL in the ECCO2R and usual care groups, respectively (p = 0.30). CONCLUSIONS: In patients with AHRF, a reduction in tidal volume facilitated by ECCO2R, did not modify cardiac function.

Advancing specificity in delirium: The delirium subtyping initiative.

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. HIGHLIGHTS: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS).

BACKGROUND: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. METHODS: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. RESULTS: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. CONCLUSIONS: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS.

Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK.

INTRODUCTION: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care. METHODS AND ANALYSIS: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs. ETHICS AND DISSEMINATION: The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03653832.

Inhibition of bradykinin in SARS-CoV-2 infection: a randomised, double-blind trial of icatibant compared with placebo (ICASARS).

SARS-CoV-2 binds to ACE2 receptors and enters cells. The symptoms are cough, breathlessness, loss of taste/smell and X-ray evidence of infiltrates on chest imaging initially caused by oedema, and subsequently by a lymphocytic pneumonitis. Coagulopathy, thrombosis and hypotension occur. Worse disease occurs with age, obesity, ischaemic heart disease, hypertension and diabetes.These features may be due to abnormal activation of the contact system. This triggers coagulation and the kallikrein-kinin system, leading to accumulation of bradykinin and its derivatives, which act on receptors B1R and B2R. Receptor activation causes cough, hypotension, oedema and release of the cytokine interleukin-6 (IL-6) which recruits lymphocytes. These effects are core features seen in early SARS CoV-2 infection. METHODS AND ANALYSIS: In this study, hypoxic patients with COVID-19 with symptom onset ≤7 days will be randomised to either a bradykinin inhibitor (icatibant) or placebo. Patients and investigators will be blinded. The primary outcome will be blood oxygenation, measured by arterial blood sampling. The secondary outcome will be cardiovascular status. Retinal imaging will be performed to assess vessel size. Blood samples will be taken for measurement of inflammatory analyses including IL-6. As a separate substudy, we will also take comparator blood inflammatory samples from a COVID-19-negative cohort. ETHICS AND DISSEMINATION: The study has received the following approvals: West Midlands-Edgbaston Research Ethics Committee. Medicines and Healthcare products Regulatory Agency has issued a clinical trial authorisation. Belfast Health and Social Care Trust is the study sponsor. Results will be made available to participants upon request and findings will be presented and published. TRIAL REGISTRATION NUMBER: NCT05407597.

Initiation of continuous renal replacement therapy versus intermittent hemodialysis in critically ill patients with severe acute kidney injury: a secondary analysis of STARRT-AKI trial.

BACKGROUND: There is controversy regarding the optimal renal-replacement therapy (RRT) modality for critically ill patients with acute kidney injury (AKI). METHODS: We conducted a secondary analysis of the STandard versus Accelerated Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial to compare outcomes among patients who initiated RRT with either continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD). We generated a propensity score for the likelihood of receiving CRRT and used inverse probability of treatment with overlap-weighting to address baseline inter-group differences. The primary outcome was a composite of death or RRT dependence at 90-days after randomization. RESULTS: We identified 1590 trial participants who initially received CRRT and 606 who initially received IHD. The composite outcome of death or RRT dependence at 90-days occurred in 823 (51.8%) patients who commenced CRRT and 329 (54.3%) patients who commenced IHD (unadjusted odds ratio (OR) 0.90; 95% confidence interval (CI) 0.75-1.09). After balancing baseline characteristics with overlap weighting, initial receipt of CRRT was associated with a lower risk of death or RRT dependence at 90-days compared with initial receipt of IHD (OR 0.81; 95% CI 0.66-0.99). This association was predominantly driven by a lower risk of RRT dependence at 90-days (OR 0.61; 95% CI 0.39-0.94). CONCLUSIONS: In critically ill patients with severe AKI, initiation of CRRT, as compared to IHD, was associated with a significant reduction in the composite outcome of death or RRT dependence at 90-days.

Elevated Plasma Interleukin-18 Identifies High-Risk Acute Respiratory Distress Syndrome Patients not Distinguished by Prior Latent Class Analyses Using Traditional Inflammatory Cytokines: A Retrospective Analysis of Two Randomized Clinical Trials.

OBJECTIVES: Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct "high-risk" patients not captured by prior LCA classifications. DESIGN: Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar's test and then tested the correlation between IL-18 and LCA biomarkers using Pearson's exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup. SETTING: Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients. SUBJECTS: Six hundred eighty-three patients in SAILS and 511 patients in HARP-2. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17-0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8-6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2-3.8; p = 0.009). CONCLUSIONS: Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts.

Opioid, sedative, preadmission medication and iatrogenic withdrawal risk in UK adult critically ill patients: a point prevalence study.

BACKGROUND: Iatrogenic withdrawal syndrome, after exposure medication known to cause withdrawal is recognised, yet under described in adult intensive care. AIM: To investigate, opioid, sedation, and preadmission medication practice in critically ill adults with focus on aspects associated with iatrogenic withdrawal syndrome. METHOD: One-day point prevalence study in UK intensive care units (ICUs). We collected ICU admission medication and/or substances with withdrawal potential, sedation policy, opioid and sedative use, dose, and duration. RESULTS: Thirty-seven from 39 participating ICUs contributed data from 386 patients. The prevalence rate for parenteral opioid and sedative medication was 56.1% (212 patients). Twenty-three ICUs (59%) had no sedation/analgesia policy, and no ICUs screened for iatrogenic withdrawal. Patient admission medications with withdrawal-potential included antidepressants or antipsychotics (43, 20.3%) and nicotine (41, 19.3%). Of 212 patients, 202 (95.3%) received opioids, 163 (76.9%) sedatives and 153 (72.2%) both. Two hundred and two (95.3%) patients received opioids: 167 (82.7%) by continuous infusions and 90 (44.6%) patients for longer than 96-h. One hundred and sixty-three (76.9%) patients received sedatives: 157 (77.7%) by continuous infusions and 74 (45.4%) patients for longer than 96-h. CONCLUSION: Opioid sedative and admission medication with iatrogenic withdrawal syndrome potential prevalence rates were high, and a high proportion of ICUs had no sedative/analgesic policies. Nearly half of patients received continuous opioids and sedatives for longer than 96-h placing them at high risk of iatrogenic withdrawal. No participating unit reported using a validated tool for iatrogenic withdrawal assessment.