Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Neurology, Peri-Transplant Medicine, Infectious Disease, and Gastroenterology Considerations.

OBJECTIVES: To develop evidence-based recommendations for clinicians caring for adults with acute liver failure (ALF) or acute on chronic liver failure (ACLF) in the ICU. DESIGN: The guideline panel comprised 27 members with expertise in aspects of care of the critically ill patient with liver failure or methodology. We adhered to the Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development. INTERVENTIONS: In part 2 of this guideline, the panel was divided into four subgroups: neurology, peri-transplant, infectious diseases, and gastrointestinal groups. We developed and selected Population, Intervention, Comparison, and Outcomes (PICO) questions according to importance to patients and practicing clinicians. For each PICO question, we conducted a systematic review and meta-analysis where applicable. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements. MEASUREMENTS AND MAIN RESULTS: We report 28 recommendations (from 31 PICO questions) on the management ALF and ACLF in the ICU. Overall, five were strong recommendations, 21 were conditional recommendations, two were best-practice statements, and we were unable to issue a recommendation for five questions due to insufficient evidence. CONCLUSIONS: Multidisciplinary, international experts formulated evidence-based recommendations for the management ALF and ACLF patients in the ICU, acknowledging that most recommendations were based on low quality and indirect evidence.

The cuff leak test in critically ill patients: An international survey of intensivists.

BACKGROUND: The cuff leak test (CLT) is used to assess laryngeal edema prior to extubation. There is limited evidence for its diagnostic accuracy and conflicting guidelines surrounding its use in critically ill patients who do not have risk factors for laryngeal edema. The primary study aim was to describe intensivists' beliefs, attitudes, and practice regarding the use of the CLT. METHODS: A 13-item survey was developed, pilot-tested, and subjected to clinical sensibility testing. The survey was distributed electronically through MetaClinician®. Descriptive statistics and multivariable regression analysis were performed to examine associations between participant demographics and survey responses. RESULTS: 1184 practicing intensivists from 17 countries in North and South America, Europe, Oceania, and Asia participated. The majority (59%) of respondents reported rarely or never perform the CLT prior to extubating patients not at high risk of laryngeal edema, which correlated with 54% of respondents reporting they believed a failed CLT did not predict reintubation. Intensivists from the Middle East were 2.4 times more likely to request a CLT compared to those from North America. Intensivists with base training in medicine or emergency medicine were more likely to request a CLT prior to extubation compared to those with base training in anesthesiology. CONCLUSION: Use of the CLT prior to extubating patients not at high risk of laryngeal edema in the intensive care unit is highly variable. Practice appears to be influenced by country of practice and base specialty training.

Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Cardiovascular, Endocrine, Hematologic, Pulmonary, and Renal Considerations.

OBJECTIVES: To develop evidence-based recommendations for clinicians caring for adults with acute or acute on chronic liver failure in the ICU. DESIGN: The guideline panel comprised 29 members with expertise in aspects of care of the critically ill patient with liver failure and/or methodology. The Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy were followed throughout. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development. SETTING: The panel was divided into nine subgroups: cardiovascular, hematology, pulmonary, renal, endocrine and nutrition, gastrointestinal, infection, perioperative, and neurology. INTERVENTIONS: We developed and selected population, intervention, comparison, and outcomes questions according to importance to patients and practicing clinicians. For each population, intervention, comparison, and outcomes question, we conducted a systematic review aiming to identify the best available evidence, statistically summarized the evidence whenever applicable, and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements. MEASUREMENTS AND MAIN RESULTS: In this article, we report 29 recommendations (from 30 population, intervention, comparison, and outcomes questions) on the management acute or acute on chronic liver failure in the ICU, related to five groups (cardiovascular, hematology, pulmonary, renal, and endocrine). Overall, six were strong recommendations, 19 were conditional recommendations, four were best-practice statements, and in two instances, the panel did not issue a recommendation due to insufficient evidence. CONCLUSIONS: Multidisciplinary international experts were able to formulate evidence-based recommendations for the management acute or acute on chronic liver failure in the ICU, acknowledging that most recommendations were based on low-quality indirect evidence.

Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial.

Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 µg/mL; difference, 7.94 µg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

An Official American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults. Rehabilitation Protocols, Ventilator Liberation Protocols, and Cuff Leak Tests.

BACKGROUND: Interventions that lead to earlier liberation from mechanical ventilation can improve patient outcomes. This guideline, a collaborative effort between the American Thoracic Society and the American College of Chest Physicians, provides evidence-based recommendations to optimize liberation from mechanical ventilation in critically ill adults. METHODS: Two methodologists performed evidence syntheses to summarize available evidence relevant to key questions about liberation from mechanical ventilation. The methodologists appraised the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach and summarized the results in evidence profiles. The guideline panel then formulated recommendations after considering the balance of desirable consequences (benefits) versus undesirable consequences (burdens, adverse effects, and costs), the certainty in the evidence, and the feasibility and acceptability of various interventions. Recommendations were rated as strong or conditional. RESULTS: The guideline panel made four conditional recommendations related to rehabilitation protocols, ventilator liberation protocols, and cuff leak tests. The recommendations were for acutely hospitalized adults mechanically ventilated for more than 24 hours to receive protocolized rehabilitation directed toward early mobilization, be managed with a ventilator liberation protocol, be assessed with a cuff leak test if they meet extubation criteria but are deemed high risk for postextubation stridor, and be administered systemic steroids for at least 4 hours before extubation if they fail the cuff leak test. CONCLUSIONS: The American Thoracic Society/American College of Chest Physicians recommendations are intended to support healthcare professionals in their decisions related to liberating critically ill adults from mechanical ventilation.

Official Executive Summary of an American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults.

BACKGROUND: This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society and the American College of Chest Physicians. METHODS: A multidisciplinary panel posed six clinical questions in a Population, Intervention, Comparator, and Outcomes format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, the confidence in the evidence, the certainty about how much the public values the main outcomes, the magnitude and balance of desirable and undesirable outcomes, the resources and costs associated with the intervention, the impact on health disparities, and the acceptability and feasibility of the intervention. RESULTS: Evidence-based recommendations were formulated and graded initially by subcommittees and then modified after full-panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation. CONCLUSIONS: The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and Chest.

Rosuvastatin for sepsis-associated acute respiratory distress syndrome.

BACKGROUND: In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS. METHODS: We conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a double-blind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure-free days to day 14. RESULTS: The study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P=0.21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P=0.96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was associated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P=0.01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P=0.003). Rosuvastatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range. CONCLUSIONS: Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.).

Pediatric calfactant in acute respiratory distress syndrome trial.

RATIONALE: Our previous studies in children with acute lung injury/acute respiratory distress syndrome demonstrated improved outcomes with exogenous surfactant (calfactant) administration. Sample sizes in those studies were small, however, and the subject populations heterogeneous, thus making recommendations tenuous. OBJECTIVE: To investigate the efficacy of surfactant administration in a larger, more homogenous population of children with lung injury/acute respiratory distress syndrome due to direct lung injury. DESIGN AND SETTING: Masked, randomized, placebo-controlled trial in 24 children's hospitals in six different countries. PATIENTS AND METHODS: Children 37 weeks postconception to 18 years old with lung injury/acute respiratory distress syndrome due to direct lung injury were randomized to receive up to three doses of 30 mg/cm height of surfactant (calfactant) versus placebo (air) within 48 hours of intubation and initiation of mechanical ventilation. The primary outcome was mortality at 90 days. Ventilator-free days, changes in oxygenation, and adverse events were also assessed. RESULTS: The study was stopped at the sponsor's request after the second interim analysis for presumed futility. A total of 110 subjects were enrolled, with consent withdrawn from one whose data are unavailable. There were no significant differences between groups except in hospital-free days (10.4 ± 7.8 placebo vs 6.4 ± 7.8 surfactant; p = 0.01). Overall 90-day mortality was 11% (seven surfactant, five placebo). No immediate improvement in oxygenation was associated with surfactant administration. CONCLUSIONS: Surfactant did not improve outcomes relative to placebo in this trial of children with direct lung injury/acute respiratory distress syndrome. Differences in concentration of the surfactant, failure to recruit the lung during surfactant administration, or using two rather than four position changes during administration are possible explanations for the difference from previous studies. Exogenous surfactant cannot be recommended at this time for children with direct lung injury/acute respiratory distress syndrome.

The relationship of fluid administration to outcome in the pediatric calfactant in acute respiratory distress syndrome trial.

OBJECTIVES: Adult studies have demonstrated the relationship between fluid overload and poor outcomes in acute lung injury/acute respiratory distress syndrome. The approach of pediatric intensivists to fluid management in acute lung injury/acute respiratory distress syndrome and its effect on outcomes is less clear. In a post hoc analysis of our Calfactant in Acute Respiratory Distress Syndrome trial, we examined the relationship of fluid balance to in-hospital outcomes in subjects with acute lung injury/acute respiratory distress syndrome. DESIGN: Calfactant in Acute Respiratory Distress Syndrome was a masked randomized controlled trial of calfactant surfactant versus placebo in pediatric patients with acute lung injury/acute respiratory distress syndrome due to direct lung injury. Caregivers were encouraged to follow a conservative fluid management guideline based on the adult Fluid and Catheter Treatment Trial. Daily fluid balance was collected for the first 7 days after trial enrollment and correlated with clinical outcomes. PATIENTS AND SETTING: Children admitted to PICUs with acute lung injury/acute respiratory distress syndrome from 24 children's hospitals in six different countries. INTERVENTION: Post hoc analysis of daily fluid balance in subjects from the Pediatric Calfactant in Acute Respiratory Distress Syndrome trial. MEASUREMENTS AND MAIN RESULTS: Despite the conservative fluid guideline, fluid management was more consistent with a "liberal" approach. On average, study subjects accumulated 1.96 ± 4.2 L/m over the first 7 days of the trial. Subjects who died accumulated on average 8.7 ± 9.5 L/m versus 1.2 ± 2.4 L/m in survivors. Increasing fluid accumulation was associated with fewer ventilator-free days and worsening oxygenation. Multivariable regression models that included age, gender, Pediatric Risk of Mortality score, initial oxygen saturation index and PaO2/FIO2 ratio, injury category, and treatment arm failed to account for the differences in fluid management. CONCLUSIONS: Pediatric intensivists generally follow a "liberal" approach to fluid management in children with acute lung injury/acute respiratory distress syndrome. Illness severity or oxygenation disturbance did not explain differences in fluid accumulation but such accumulation was associated with worsening oxygenation, a longer ventilator course, and increased mortality. A more conservative approach to fluid management may improve outcomes in children with acute lung injury/acute respiratory distress syndrome.

Commercial air travel after pneumothorax: a review of the literature.

Because of the physiological stresses of commercial air travel, the presence of a pneumothorax has long been felt to be an absolute contraindication to flight. Additionally, most medical societies recommend that patients wait at least 2 weeks after radiographic resolution of the pneumothorax before they attempt to travel in a nonurgent fashion via commercial air transport. This review sought to survey the current body of literature on this topic to determine if a medical consensus exists; furthermore, this review considered the scientific support, if any, supporting these recommendations. In this review, we found a paucity of data on the issue and noted only a handful of prospective and retrospective studies; thus, true evidence-based recommendations are difficult to develop at this time. We have made recommendations, when possible, addressing the nonurgent commercial air travel for the patient with a recent pneumothorax. However, more scientific research is necessary in order to reach an evidence-based conclusion on pneumothoraces and flying.

Optimizing Respiratory Therapy Resources by De-Implementing Low-Value Care.

BACKGROUND: Our institution was experiencing a respiratory therapy staffing crisis during the COVID-19 pandemic, in part due to excessive workload. We identified an opportunity to reduce burden by limiting use of 3% hypertonic saline and/or N-acetylcysteine nebulizer therapies (3%HTS/NAC). METHODS: Leveraging the science of de-implementation, we established a policy empowering respiratory therapists to discontinue 3%HTS/NAC not meeting the American Association for Respiratory Care (AARC) Clinical Practice Guideline: Effectiveness of Pharmacologic Airway Clearance Therapies in Hospitalized Patients. After a 3-month period of educating physicians and advanced practice practitioners the policy went to into effect. Outcomes measured included monthly number of treatments, orders, and full-time employees associated with administering nebulized 3%HTS/NAC. RESULTS: Post policy activation, the monthly mean 3%HTS/NAC treatments were significantly reduced to 547.5 ± 284.3 from 3,565.2 ± 596.4 (P < .001) as were the associated monthly mean of full-time employees, 0.8 ± 0.41 from 5.1 ± 0.86 (P < .001). The monthly mean 3%HTS/NAC orders also fell to 93.8 ± 31.5 from 370.0 ± 46.9 (P < .001). Monthly mean non-3%HTS/NAC treatments remained stable; post policy was 3,089.4 ± 611.4 and baseline 3,279.6 ± 695.0 (P = 1.0). CONCLUSIONS: Implementing a policy that empowers respiratory therapists to promote adherence to AARC Clinical Guidelines reduced low-value therapies, costs, and staffing needs.

The evolution of eProtocols that enable reproducible clinical research and care methods.

Unnecessary variation in clinical care and clinical research reduces our ability to determine what healthcare interventions are effective. Reducing this unnecessary variation could lead to further healthcare quality improvement and more effective clinical research. We have developed and used electronic decision support tools (eProtocols) to reduce unnecessary variation. Our eProtocols have progressed from a locally developed mainframe computer application in one clinical site (LDS Hospital) to web-based applications available in multiple languages and used internationally. We use eProtocol-insulin as an example to illustrate this evolution. We initially developed eProtocol-insulin as a local quality improvement effort to manage stress hyperglycemia in the adult intensive care unit (ICU). We extended eProtocol-insulin use to translate our quality improvement results into usual clinical care at Intermountain Healthcare ICUs. We exported eProtocol-insulin to support research in other US and international institutions, and extended our work to the pediatric ICU. We iteratively refined eProtocol-insulin throughout these transitions, and incorporated new knowledge about managing stress hyperglycemia in the ICU. Based on our experience in the development and clinical use of eProtocols, we outline remaining challenges to eProtocol development, widespread distribution and use, and suggest a process for eProtocol development. Technical and regulatory issues, as well as standardization of protocol development, validation and maintenance, need to be addressed. Resolution of these issues should facilitate general use of eProtocols to improve patient care.

Biological Effects of Intravenous Vitamin C on Neutrophil Extracellular Traps and the Endothelial Glycocalyx in Patients with Sepsis-Induced ARDS.

(1) Background: The disease-modifying mechanisms of high-dose intravenous vitamin C (HDIVC) in sepsis induced acute respiratory distress syndrome (ARDS) is unclear. (2) Methods: We performed a post hoc study of plasma biomarkers from subjects enrolled in the randomized placebo-controlled trial CITRIS-ALI. We explored the effects of HDIVC on cell-free DNA (cfDNA) and syndecan-1, surrogates for neutrophil extracellular trap (NET) formation and degradation of the endothelial glycocalyx, respectively. (3) Results: In 167 study subjects, baseline cfDNA levels in HDIVC (84 subjects) and placebo (83 subjects) were 2.18 ng/µL (SD 4.20 ng/µL) and 2.65 ng/µL (SD 3.87 ng/µL), respectively, p = 0.45. At 48-h, the cfDNA reduction was 1.02 ng/µL greater in HDIVC than placebo, p = 0.05. Mean baseline syndecan-1 levels in HDIVC and placebo were 9.49 ng/mL (SD 5.57 ng/mL) and 10.83 ng/mL (SD 5.95 ng/mL), respectively, p = 0.14. At 48 h, placebo subjects exhibited a 1.53 ng/mL (95% CI, 0.96 to 2.11) increase in syndecan-1 vs. 0.75 ng/mL (95% CI, 0.21 to 1.29, p = 0.05), in HDIVC subjects. (4) Conclusions: HDIVC infusion attenuated cell-free DNA and syndecan-1, biomarkers associated with sepsis-induced ARDS. Improvement of these biomarkers suggests amelioration of NETosis and shedding of the vascular endothelial glycocalyx, respectively.