Studying Continuous, Time-varying, and/or Complex Exposures Using Longitudinal Modified Treatment Policies.

This tutorial discusses a methodology for causal inference using longitudinal modified treatment policies. This method facilitates the mathematical formalization, identification, and estimation of many novel parameters and mathematically generalizes many commonly used parameters, such as the average treatment effect. Longitudinal modified treatment policies apply to a wide variety of exposures, including binary, multivariate, and continuous, and can accommodate time-varying treatments and confounders, competing risks, loss to follow-up, as well as survival, binary, or continuous outcomes. Longitudinal modified treatment policies can be seen as an extension of static and dynamic interventions to involve the natural value of treatment and, like dynamic interventions, can be used to define alternative estimands with a positivity assumption that is more likely to be satisfied than estimands corresponding to static interventions. This tutorial aims to illustrate several practical uses of the longitudinal modified treatment policy methodology, including describing different estimation strategies and their corresponding advantages and disadvantages. We provide numerous examples of types of research questions that can be answered using longitudinal modified treatment policies. We go into more depth with one of these examples, specifically, estimating the effect of delaying intubation on critically ill COVID-19 patients' mortality. We demonstrate the use of the open-source R package lmtp to estimate the effects, and we provide code on https://github.com/kathoffman/lmtp-tutorial.

Incidence of Enteral Nutrition-Related Diarrhea Among Critically Ill Patients in Intensive Care Units.

Enteral nutrition is a common nutritional modality in intensive care units. Despite its valuable benefits, it has many complications among which diarrhea is the most important. However, the incidence of enteral nutrition-related diarrhea is variable in the literature, with no established baseline in Jordan. The aim of this study was to investigate the incidence of enteral nutrition-related diarrhea in intensive care units of a major public hospital in Jordan. A prospective cohort design was adopted over 4 months. Using a consecutive sampling technique, 84 critically ill patients receiving enteral nutrition were recruited. King's Stool Chart was used. The incidence of enteral nutrition-related diarrhea calculated per patient and per feeding day was 63.1% and 13.2%, respectively. Significant positive associations were found between the incidence of diarrhea with feeding days (r = .356, p = .001) and intensive care unit length of stay (r = .254, p = .020). The same was found for the frequency of diarrhea (r = .633, p = .000; r = .439, p = .000, respectively). Conversely, a significant negative association was found between baseline serum albumin and frequency of diarrhea (r = -.250, p = .037). Enteral nutrition-related diarrhea is prevalent in Jordanian intensive care units, but it should not be a barrier to enteral nutrition delivery. It would be beneficial for intensive care unit nurses to improve their nutritional practices by following a nurse-led enteral nutrition protocol to guide the enteral nutrition practices utilizing multidisciplinary approaches.

Device associated complications in the intensive care unit.

Invasive devices are routinely used in the care of critically ill patients. Although they are often essential components of patient care, devices such as intravascular catheters, endotracheal tubes, and ventilators are a common source of complications in the intensive care unit. Critical care practitioners who use these devices need to use strategies for risk reduction and understand approaches to management when adverse events occur. This review discusses the identification, prevention, and management of complications of vascular, airway, and mechanical support devices commonly used in the intensive care unit.

Transthyretin and Nutritional Status in Critically Ill Adults on Parenteral Nutrition: A Prospective Cohort Study.

BACKGROUND AND AIMS: Correctly characterizing malnutrition is a challenge. Transthyretin (TTR) rapidly responds to adequate protein intake/infusion, which could be used as a marker to identify malnutrition. Nutritional therapy is used to prevent malnutrition. Parenteral nutrition (PN) requires daily monitoring to determine whether what is being offered is adequate. This article aims to investigate whether the practice of measuring TTR is justified. METHODS: Data from patients admitted to the ward or intensive care unit (ICU) were collected at three different times: within the first 72 h (T1) of PN use, on the 7th day (T2), and the 14th day (T3) after the initial assessment. RESULTS: 302 patients were included; the average age was 48.3 years old; the prevalence of death was 22.2%, and 61.6% of the sample were male. TTR values and the effectiveness of nutritional support in these patients were not associated with the outcome; however, meeting caloric needs was related to the outcome (p = 0.047). No association was found when TTR values were compared to the nutritional status. Thus, TTR was not a good indicator of nutritional risk or nutritional status in hospitalized patients. CONCLUSIONS: Undoubtedly, the TTR measurement was inversely proportional to CRP measurements. It was possible to conclude in this follow-up cohort of hospitalized patients that TTR values were not useful for determining whether the patient was malnourished, predicting death or effectiveness of nutritional support, yet based upon our analyses, a decrease in TTR greater than 0.024 units for every 1 unit increase in CRP might be due to ineffective nutritional supply.

Daily Sedation Interruption vs Continuous Sedation in Pediatric Patients Receiving Mechanical Ventilation: A Systematic Review and Meta-analysis.

Importance: The effectiveness of daily sedation interruption (DSI, defined as temporary interruption of sedation) has yet to be demonstrated in critically ill pediatric patients. Objective: To compare the clinical outcomes of DSI vs continuous intravenous (IV) sedation in patients receiving invasive mechanical ventilation (MV) support in the pediatric intensive care unit (PICU). Data Sources: A systematic search for studies was conducted using predefined keywords and Medical Subject Headings in 5 major databases (PubMed, Embase, Web of Science, CINAHL [Cumulated Index to Nursing and Allied Health Literature], and Cochrane Central Register of Controlled Trials) from database inception to October 31, 2023. Study Selection: Retrospective and prospective observational studies, randomized clinical trials (RCTs), and systematic reviews were assessed for inclusion. Studies were eligible if they compared DSI to continuous IV sedation in patients aged 18 years or younger requiring MV in the PICU. Data Extraction and Synthesis: Study characteristics, including the types of sedation, sedation protocols, and clinical outcomes, were extracted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed. A random-effects model was used to pool results from articles for the meta-analysis. Main Outcomes and Measures: The primary outcomes of interest were duration of MV and length of PICU stay. Secondary outcomes included total sedative dose requirement, adverse events (eg, complications associated with MV, withdrawal, and delirium), and mortality. Results: A total of 6 RCTs with 2810 pediatric patients (1569 males [55.8%]; mean age, 26.5 [95% CI, 15.0-37.9] months) were included in the final analysis; patients had a mean PRISM (Pediatric Risk of Mortality) score of 13.68 (95% CI, 10.75-16.61). Compared with continuous IV sedation, DSI was associated with a reduction in length of PICU stay (5 studies, n = 2770; mean difference [MD], -1.45 [95% CI, -2.75 to -0.15] days; P = .03]. There was no difference in MV duration (5 studies, n = 2750; MD, -0.93 [95% CI, -1.89 to 0.04] days; P = .06), total doses of midazolam (3 studies, n = 191; MD, -1.66 [95% CI, -3.95 to 0.63] mg/kg) and morphine used (2 studies, n = 189; MD, -2.63 [95% CI, -7.01 to 1.75] mg/kg), or adverse events (risk ratio [RR], 1.03 [95% CI, 0.74-1.42]; P = .88). There was no difference in mortality between patients exposed vs not exposed to DSI (RR, 0.89 [95% CI, 0.55-1.46]; P = .65). Conclusions and Relevance: This systematic review and meta-analysis found that use of DSI in pediatric patients was associated with reduced length of PICU stay with no increase in adverse events. Further research is needed to ascertain whether this strategy is associated with improved neurodevelopmental outcomes in PICU survivors.

Validation of a checklist to facilitate serious illness conversations in adult emergency in China: a single-centre pilot study.

BACKGROUND: Advances in emergency and critical care have improved outcomes, but gaps in communication and decision-making persist, especially in the emergency department (ED), prompting the development of a checklist to aid in serious illness conversations (SIC) in China. METHODS: This was a single-centre prospective interventional study on the quality improvement of SIC for life-sustaining treatment (LST). The study recruited patients consecutively for both its observational baseline and interventional stages until its conclusion. Eligible participants were adults over 18 years old admitted to the Emergency Intensive Care Unit (EICU) of a tertiary teaching hospital, possessing full decisional capacity or having a legal proxy. Exclusions were made for pregnant women, patients deceased upon arrival, those who refused participation, and individuals with incomplete data for analysis. First, a two-round Delphi process was organized to identify major elements and generate a standard process through a checklist. Subsequently, the efficacy of SIC in adult patients admitted to the EICU was compared using the Decisional Conflict Scale (DCS) score before (baseline group) and after (intervention group) implementing the checklist. RESULTS: The study participants presented with the most common comorbidities, such as diabetes, myocardial infarction, cerebrovascular disease, moderate-to-severe renal disease, congestive heart failure, and chronic pulmonary disease. The median Charlson Index did not differ between the baseline and intervention cohorts. The median length of hospital stay was 11.0 days, and 82.9% of patients survived until hospital discharge. The total DCS score was lower in the intervention group than in the baseline group. Three subscales, including the informed, values clarity, and support subscales, demonstrated significant differences between the intervention and baseline groups. Fewer intervention group patients agreed with and changed their minds about cardiopulmonary resuscitation (CPR) compared to the baseline group. CONCLUSION: The use of a SIC checklist in the EICU reduced the DCS score by increasing medical information disclosure, patient value awareness, and decision-making support.

The kidney: the critical organ system for guiding nutrition therapy in the ICU-patient?

Most randomized controlled studies on nutrition in intensive care patients did not yield conclusive results or were neutral or negative concerning the primary endpoints but also in most secondary endpoints. However, there is a consistent observation that in several of these studies there was a negative effect of the nutrition intervention on the kidneys in one of the study arms. During the early phase and in unstable periods during further course of disease an inadequate clinical nutrition can damage the kidneys, can elicit or aggravate acute kidney injury and/ or increase requirements of renal replacement therapy (RRT). This relates to total energy intake, glucose intake/hyperglycemia and protein/ amino acid intake at various stages of renal dysfunction. The kidney could present a critical organ system for guiding nutrition therapy, a close monitoring of kidney function should be observed and nutrition therapy may need to be adapted accordingly. The long-held dogma of performing full nutrition and accept an otherwise not necessary RRT is definitely to be refuted.

The role of lipid emulsions containing omega-3 fatty acids for medical and surgical critical care patients.

In critical illness the regulation of inflammation and oxidative stress can improve patient outcomes, and thus omega-3 polyunsaturated fatty acids (PUFAs) have been used as part of parenteral nutrition (PN) owing to their potential anti-inflammatory effects. The international lipids in PN Summit, encompassed discussions and the production of consensus guidelines concerning PN intravenous lipid emulsion (ILE) use in critical care. The Lipid Summit participants agreed that the inclusion of fish oil in ILEs is associated with meaningful clinical benefits without signals of harm, based on a strong biological rationale and current clinical evidence. Decisions concerning ILE choice should be made based on current evidence, thus addressing clinical requirements for guidance, particularly as further definitive evidence seems unlikely to occur. In addition, a future of individualized ICU care is envisioned, yielding better clinical outcomes. This approach will require the greater use of intelligent study designs incorporating the use of biomarkers of omega-3 derivatives, inflammatory-resolving processes, and/or muscle protein breakdown.

[Positioning therapy for intensive care patients]. / Lagerungstherapie bei Intensivpatienten.

The current S3 guideline, "Positioning Therapy and Mobilization of Critically Ill Patients in Intensive Care Units", introduces methodological changes and substantive updates compared to the previous version. Additionally, new evidence-based insights with specified PICO questions have been integrated, aiming for a more precise application of recommendations in clinical practice and thus enhancing the care of critically ill patients.A notable aspect is the more nuanced approach to early mobilization, which is recommended to commence within the first 72 hours of ICU admission. A staged concept and score-based mobilization schema facilitate improved patient rehabilitation. Mobilization should be standard of care, i.e., immobilization should be ordered by the physician. The guideline provides suggestions for the duration and additional mobilization measures to ensure patients stand, transfer actively from bed to chair, or walk as frequently as possible. These recommendations apply even during ECMO therapy, highlighting the importance of early mobilization.Further updates include semi-recumbent positions of at least 40° in intubated patients, with careful consideration of potential side effects. Continuous lateral rotation therapy (CLRT) is not advised due to the progress in intensive care therapy, shifting from deep sedation toward responsive patient management.Prone positioning (PP) involves rotating the patient 180° onto the ventral side. It is recommended as a therapeutic option for invasively ventilated patients with ARDS and impaired arterial oxygenation (PaO2/FiO2 <150mmHg), with a recommended minimum duration of 12 hours, ideally 16 hours. Special recommendations apply, for example, to COVID-19 patients with acute hypoxemic respiratory failure, where awake proning should be considered.Additionally, new chapters have been introduced focusing on assistive devices and neuromuscular electrical stimulation.

Study protocol for ADAPT-TDM: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring.

INTRODUCTION: Critically ill patients are at risk of suboptimal beta-lactam antibiotic (beta-lactam) exposure due to the impact of altered physiology on pharmacokinetics. Suboptimal concentrations can lead to treatment failure or toxicity. Therapeutic drug monitoring (TDM) involves adjusting doses based on measured plasma concentrations and individualising dosing to improve the likelihood of improving exposure. Despite its potential benefits, its adoption has been slow, and data on implementation, dose adaptation and safety are sparse. The aim of this trial is to assess the feasibility and fidelity of implementing beta-lactam TDM-guided dosing in the intensive care unit setting. METHODS AND ANALYSIS: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring (ADAPT-TDM) is a single-centre, unblinded, feasibility randomised controlled trial aiming to enroll up to 60 critically ill adult participants (≥18 years). TDM and dose adjustment will be performed daily in the intervention group; the standard of care group will undergo plasma sampling, but no dose adjustment. The main outcomes include: (1) feasibility of recruitment, defined as the number of participants who are recruited from a pool of eligible participants, and (2) fidelity of TDM, defined as the degree to which TDM as a test is delivered as intended, from accurate sample collection, sample processing to result availability. Secondary outcomes include target attainment, uptake of TDM-guided dosing and incidence of neurotoxicity, hepatotoxicity and nephrotoxicity. ETHICS AND DISSEMINATION: This study has been approved by the Alfred Hospital human research ethics committee, Office of Ethics and Research Governance (reference: Project No. 565/22; date of approval: 22/11/2022). Prospective consent will be obtained and the study will be conducted in accordance with the Declaration of Helsinki. The finalised manuscript, including aggregate data, will be submitted for publication in a peer reviewed journal. ADAPT-TDM will determine whether beta-lactam TDM-guided dose adaptation is reproducible and feasible and provide important information required to implement this intervention in a phase III trial. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12623000032651.

Best Practices in Caring for Seriously Ill Patients.

Palliative care (PC) is the art and science of providing goal-concordant care, skillfully managing complex and refractory pain and nonpain symptoms, mitigating suffering, and augmenting quality of life for seriously ill patients throughout the course of the illness trajectory. The primary team should provide generalist PC for all seriously ill patients and know when to refer patients to specialist PC. Specialty-level PC services should be reserved for complex problems beyond the scope of primary PC. This article reviews principles and best practices to support patient-centered PC.

Resilience after severe critical illness: a prospective, multicentre, observational study (RESIREA).

BACKGROUND: Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience. METHODS: This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ). RESULTS: Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience (p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008-1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950-0.996; p = 0.02). CONCLUSIONS: Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes.

From Traditional Typing to Intelligent Insights: A Narrative Review of Directions Toward Targeted Therapies in Delirium.

Delirium is a heterogeneous syndrome characterized by an acute change in level of consciousness that is associated with inattention and disorganized thinking. Delirium affects most critically ill patients and is associated with poor patient-oriented outcomes such as increased mortality, longer ICU and hospital length of stay, and worse long-term cognitive outcomes. The concept of delirium and its subtypes has existed since nearly the beginning of recorded medical literature, yet robust therapies have yet to be identified. Analogous to other critical illness syndromes, we suspect the lack of identified therapies stems from patient heterogeneity and prior subtyping efforts that do not capture the underlying etiology of delirium. The time has come to leverage machine learning approaches, such as supervised and unsupervised clustering, to identify clinical and pathophysiological distinct clusters of delirium that will likely respond differently to various interventions. We use sedation in the ICU as an example of how precision therapies can be applied to critically ill patients, highlighting the fact that while for some patients a sedative drug may cause delirium, in another cohort sedation is the specific treatment. Finally, we conclude with a proposition to move away from the term delirium, and rather focus on the treatable traits that may allow precision therapies to be tested.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

Vitamin K: a potential missing link in critical illness-a scoping review.

BACKGROUND: Vitamin K is essential for numerous physiological processes, including coagulation, bone metabolism, tissue calcification, and antioxidant activity. Deficiency, prevalent in critically ill ICU patients, impacts coagulation and increases the risk of bleeding and other complications. This review aims to elucidate the metabolism of vitamin K in the context of critical illness and identify a potential therapeutic approach. METHODS: In December 2023, a scoping review was conducted using the PRISMA Extension for Scoping Reviews. Literature was searched in PubMed, Embase, and Cochrane databases without restrictions. Inclusion criteria were studies on adult ICU patients discussing vitamin K deficiency and/or supplementation. RESULTS: A total of 1712 articles were screened, and 13 met the inclusion criteria. Vitamin K deficiency in ICU patients is linked to malnutrition, impaired absorption, antibiotic use, increased turnover, and genetic factors. Observational studies show higher PIVKA-II levels in ICU patients, indicating reduced vitamin K status. Risk factors include inadequate intake, disrupted absorption, and increased physiological demands. Supplementation studies suggest vitamin K can improve status but not normalize it completely. Vitamin K deficiency may correlate with prolonged ICU stays, mechanical ventilation, and increased mortality. Factors such as genetic polymorphisms and disrupted microbiomes also contribute to deficiency, underscoring the need for individualized nutritional strategies and further research on optimal supplementation dosages and administration routes. CONCLUSIONS: Addressing vitamin K deficiency in ICU patients is crucial for mitigating risks associated with critical illness, yet optimal management strategies require further investigation. IMPACT RESEARCH: To the best of our knowledge, this review is the first to address the prevalence and progression of vitamin K deficiency in critically ill patients. It guides clinicians in diagnosing and managing vitamin K deficiency in intensive care and suggests practical strategies for supplementing vitamin K in critically ill patients. This review provides a comprehensive overview of the existing literature, and serves as a valuable resource for clinicians, researchers, and policymakers in critical care medicine.