Evolving Management Practices for Early Sepsis-induced Hypoperfusion: A Narrative Review.

Sepsis causes significant morbidity and mortality worldwide. Resuscitation is a cornerstone of management. This review covers five areas of evolving practice in the management of early sepsis-induced hypoperfusion: fluid resuscitation volume, timing of vasopressor initiation, resuscitation targets, route of vasopressor administration, and use of invasive blood pressure monitoring. For each topic, we review the seminal evidence, discuss the evolution of practice over time, and highlight questions for additional research. Intravenous fluids are a core component of early sepsis resuscitation. However, with growing concerns about the harms of fluid, practice is evolving toward smaller-volume resuscitation, which is often paired with earlier vasopressor initiation. Large trials of fluid-restrictive, vasopressor-early strategies are providing more information about the safety and potential benefit of these approaches. Lowering blood pressure targets is a means to prevent fluid overload and reduce exposure to vasopressors; mean arterial pressure targets of 60-65 mm Hg appear to be safe, at least in older patients. With the trend toward earlier vasopressor initiation, the need for central administration of vasopressors has been questioned, and peripheral vasopressor use is increasing, although it is not universally accepted. Similarly, although guidelines suggest the use of invasive blood pressure monitoring with arterial catheters in patients receiving vasopressors, blood pressure cuffs are less invasive and often sufficient. Overall, the management of early sepsis-induced hypoperfusion is evolving toward fluid-sparing and less-invasive strategies. However, many questions remain, and additional data are needed to further optimize our approach to resuscitation.

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.

Electric impedance tomography-guided PEEP titration reduces mechanical power in ARDS: a randomized crossover pilot trial.

BACKGROUND: In patients with acute respiratory distress syndrome undergoing mechanical ventilation, positive end-expiratory pressure (PEEP) can lead to recruitment or overdistension. Current strategies utilized for PEEP titration do not permit the distinction. Electric impedance tomography (EIT) detects and quantifies the presence of both collapse and overdistension. We investigated whether using EIT-guided PEEP titration leads to decreased mechanical power compared to high-PEEP/FiO2 tables. METHODS: A single-center, randomized crossover pilot trial comparing EIT-guided PEEP selection versus PEEP selection using the High-PEEP/FiO2 table in patients with moderate-severe acute respiratory distress syndrome. The primary outcome was the change in mechanical power after each PEEP selection strategy. Secondary outcomes included changes in the 4 × driving pressure + respiratory rate (4 ΔP, + RR index) index, driving pressure, plateau pressure, PaO2/FiO2 ratio, and static compliance. RESULTS: EIT was consistently associated with a decrease in mechanical power compared to PEEP/FiO2 tables (mean difference - 4.36 J/min, 95% CI - 6.7, - 1.95, p = 0.002) and led to lower values in the 4ΔP + RR index (- 11.42 J/min, 95% CI - 19.01, - 3.82, p = 0.007) mainly driven by a decrease in the elastic-dynamic power (- 1.61 J/min, - 2.99, - 0.22, p = 0.027). The elastic-static and resistive powers were unchanged. Similarly, EIT led to a statistically significant change in set PEEP (- 2 cmH2O, p = 0.046), driving pressure, (- 2.92 cmH2O, p = 0.003), peak pressure (- 6.25 cmH2O, p = 0.003), plateau pressure (- 4.53 cmH2O, p = 0.006), and static respiratory system compliance (+ 7.93 ml/cmH2O, p = 0.008). CONCLUSIONS: In patients with moderate-severe acute respiratory distress syndrome, EIT-guided PEEP titration reduces mechanical power mainly through a reduction in elastic-dynamic power. Trial registration This trial was prospectively registered on Clinicaltrials.gov (NCT03793842) on January 4th, 2019.

Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients.

BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality. RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality. CONCLUSIONS: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

Electrical Impedance Tomography in Acute Respiratory Distress Syndrome Management.

OBJECTIVE: To describe, through a narrative review, the physiologic principles underlying electrical impedance tomography, and its potential applications in managing acute respiratory distress syndrome (ARDS). To address the current evidence supporting its use in different clinical scenarios along the ARDS management continuum. DATA SOURCES: We performed an online search in Pubmed to review articles. We searched MEDLINE, Cochrane Central Register, and clinicaltrials.gov for controlled trials databases. STUDY SELECTION: Selected publications included case series, pilot-physiologic studies, observational cohorts, and randomized controlled trials. To describe the rationale underlying physiologic principles, we included experimental studies. DATA EXTRACTION: Data from relevant publications were reviewed, analyzed, and its content summarized. DATA SYNTHESIS: Electrical impedance tomography is an imaging technique that has aided in understanding the mechanisms underlying multiple interventions used in ARDS management. It has the potential to monitor and predict the response to prone positioning, aid in the dosage of flow rate in high-flow nasal cannula, and guide the titration of positive-end expiratory pressure during invasive mechanical ventilation. The latter has been demonstrated to improve physiologic and mechanical parameters correlating with lung recruitment. Similarly, its use in detecting pneumothorax and harmful patient-ventilator interactions such as pendelluft has been proven effective. Nonetheless, its impact on clinically meaningful outcomes remains to be determined. CONCLUSIONS: Electrical impedance tomography is a potential tool for the individualized management of ARDS throughout its different stages. Clinical trials should aim to determine whether a specific approach can improve clinical outcomes in ARDS management.

Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

Importance: Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19. Objective: To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19. Design, Setting, and Participants: An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021. Interventions: Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = 293) or a therapeutic dose of heparin only (usual care) (n = 269) in a 1:1 ratio for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures: The composite primary outcome was organ support-free days evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, -1 to 21 days; higher scores indicate less organ support and better outcomes). The primary safety outcome was major bleeding by 28 days as defined by the International Society on Thrombosis and Hemostasis. Results: Enrollment of non-critically ill patients was discontinued when the prespecified criterion for futility was met. All 562 patients who were randomized (mean age, 52.7 [SD, 13.5] years; 41.5% women) completed the trial and 87% received a therapeutic dose of heparin by the end of study day 1. In the P2Y12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37%. The median number of organ support-free days was 21 days (IQR, 20-21 days) among patients in the P2Y12 inhibitor group and was 21 days (IQR, 21-21 days) in the usual care group (adjusted odds ratio, 0.83 [95% credible interval, 0.55-1.25]; posterior probability of futility [defined as an odds ratio <1.2], 96%). Major bleeding occurred in 6 patients (2.0%) in the P2Y12 inhibitor group and in 2 patients (0.7%) in the usual care group (adjusted odds ratio, 3.31 [95% CI, 0.64-17.2]; P = .15). Conclusions and Relevance: Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y12 inhibitor in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in an increased odds of improvement in organ support-free days within 21 days during hospitalization. Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.

BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).

Bronchopleural Fistula in the Mechanically Ventilated Patient: A Concise Review.

OBJECTIVE: To describe the physiology of air leak in bronchopleural fistula in mechanically ventilated patients and how understanding of its physiology drives management of positive-pressure ventilation. To provide guidance of lung isolation, mechanical ventilator, pleural catheter, and endobronchial strategies for the management of bronchopleural fistula on mechanical ventilation. DATA SOURCES: Online search of PubMed and manual review of articles (laboratory and patient studies) was performed. STUDY SELECTION: Articles relevant to bronchopleural fistula, mechanical ventilation in patients with bronchopleural fistula, independent lung ventilation, high-flow ventilatory modes, physiology of persistent air leak, extracorporeal membrane oxygenation, fluid dynamics of bronchopleural fistula airflow, and intrapleural catheter management were selected. Randomized trials, observational studies, case reports, and physiologic studies were included. DATA EXTRACTION: Data from selected studies were qualitatively evaluated for this review. We included data illustrating the physiology of driving pressure across a bronchopleural fistula as well as data, largely from case reports, demonstrating management and outcomes with various ventilator modes, intrapleural catheter techniques, endoscopic placement of occlusion and valve devices, and extracorporeal membrane oxygenation. Themes related to managing persistent air leak with mechanical ventilation were reviewed and extracted. DATA SYNTHESIS: In case reports that demonstrate different approaches to managing patients with bronchopleural fistula requiring mechanical ventilation, common themes emerge. Strategies aimed at decreasing peak inspiratory pressure, using lower tidal volumes, lowering positive end-expiratory pressure, decreasing the inspiratory time, and decreasing the respiratory rate, while minimizing negative intrapleural pressure decreases airflow across the bronchopleural fistula. CONCLUSIONS: Mechanical ventilation and intrapleural catheter management must be individualized and aimed at reducing air leak. Clinicians should emphasize reducing peak inspiratory pressures, reducing positive end-expiratory pressure, and limiting negative intrapleural pressure. In refractory cases, clinicians can consider lung isolation, independent lung ventilation, or extracorporeal membrane oxygenation in appropriate patients as well as definitive management with advanced bronchoscopic placement of valves or occlusion devices.

Effect of an emergency department intensive care unit on medical intensive unit admissions and care: A retrospective cohort study.

OBJECTIVE: Evaluate the impact of an emergency critical care center (EC3) on the admissions of critically ill patients to a critical care medicine unit (CCMU) and their outcomes. METHODS: This was a retrospective before/after cohort study in a tertiary university teaching hospital. To improve the care of critically ill patients in the emergency department (ED), a 9-bed EC3 was opened in the ED in February 2015. All critically ill patients in the emergency department must receive intensive support in EC3 before being considered for admission to the CCMU for further treatment. Patients from the emergency department account for a significant proportion of the patients admitted to the CCMU. The proportions of patients admitted to the CCMU from the ED were analyzed 1 year before and 1 year after the opening of the EC3. We also compared the admission data, demographic data, APACHE III scores and patient outcomes among patients admitted from ED to the CCMU in the year before and the year after the opening of the EC3. RESULT: The establishment of the EC3 was associated with a decreased proportion of patients admitted to the CCMU from the ED (OR 0.73 95% CI 0.63-0.84, p < 0.01), a decrease in the proportion of patients with sepsis admitted from the ED (OR 0.68, 95% CI, 0.54-0.87, p < 0.01) and a decrease in the proportion of patients with gastrointestinal bleeding admitted from the ED (OR 0.49, 95% CI 0.28-0.84, p < 0.05). Following the establishment of the EC3, patients admitted to the CCMU had a higher APACHE III score in 2015 (74.85 ± 30.42 vs 72.39 ± 29.64, p = 0.015). Fewer low-risk patients were admitted to the CCMU for monitoring following the opening of the EC3 (112 [6.8%] vs. 181 [9.3%], p < 0.01). Propensity score matching analysis showed that the opening of the EC3 was associated with improved 60-day survival (HR 0.84, 95% CI 0.70-0.99, p = 0.046). CONCLUSION: Following the opening of the EC3, the proportion of CCMU admissions from the ED decreased. The EC3 may be most effective at reducing the admission of lower-acuity patients with GI bleeding and possibly sepsis. The EC3 may be associated with improved survival in ED patients.

Coronavirus Disease 2019 (COVID-19) Clinical Trial Oversight at a Major Academic Medical Center: Approach of Michigan Medicine.

Clinicians, eager to offer the best care in the absence of guiding data, have provided patients with coronavirus disease 2019 (COVID-19) diverse clinical interventions. This usage has led to perceptions of efficacy of some interventions that, while receiving media coverage, lack robust evidence. Moving forward, randomized controlled clinical trials are necessary to ensure that clinicians can treat patients effectively during this outbreak and the next. To do so, academic medical centers must address 2 key research issues: (1) how to effectively and efficiently determine which trials have the best chance of benefiting current and future patients and (2) how to establish a transparent and ethical process for subject recruitment while maintaining research integrity and without overburdening patients or staff. We share here the current methods used by Michigan Medicine to address these issues.

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.

Deadoption of low-value practices in the ICU.

PURPOSE OF REVIEW: Change of practice in the ICU, particularly the discontinuation of approaches, which are no longer felt to be beneficial, can be challenging. This review will examine this issue and outline current thinking regarding how to best approach it. RECENT FINDINGS: Practices in medicine that do not provide patients benefit and possibly cause harm exist throughout medicine and are called low-value practices. Some low-value practices have successfully been removed from the ICU whereas others remain. The process of removing these practices from established care is often called deadoption. Low-value practices that are simply ineffective but produce comparatively less harm or cost, may represent a significant challenge to deadoption. Additionally, although no single intervention has been identified as the preferred method of deadoption of a low-value practice, we advocate for a multimodal approach. SUMMARY: Deadoption in the intensive care unit of practices that either cause harm or are significantly costly relative to their benefit remains an elusive goal. Attempts at deadoption should target local ICU circumstances, while still encompassing the spectrum of care outside the ICU, engage nursing more fully, promote the use of local champions, especially peers, and recognize the requirement to seek sustainability.

Rapid breath analysis for acute respiratory distress syndrome diagnostics using a portable two-dimensional gas chromatography device.

Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury, responsible for high mortality and long-term morbidity. As a dynamic syndrome with multiple etiologies, its timely diagnosis is difficult as is tracking the course of the syndrome. Therefore, there is a significant need for early, rapid detection and diagnosis as well as clinical trajectory monitoring of ARDS. Here, we report our work on using human breath to differentiate ARDS and non-ARDS causes of respiratory failure. A fully automated portable 2-dimensional gas chromatography device with high peak capacity (> 200 at the resolution of 1), high sensitivity (sub-ppb), and rapid analysis capability (~ 30 min) was designed and made in-house for on-site analysis of patients' breath. A total of 85 breath samples from 48 ARDS patients and controls were collected. Ninety-seven elution peaks were separated and detected in 13 min. An algorithm based on machine learning, principal component analysis (PCA), and linear discriminant analysis (LDA) was developed. As compared to the adjudications done by physicians based on the Berlin criteria, our device and algorithm achieved an overall accuracy of 87.1% with 94.1% positive predictive value and 82.4% negative predictive value. The high overall accuracy and high positive predicative value suggest that the breath analysis method can accurately diagnose ARDS. The ability to continuously and non-invasively monitor exhaled breath for early diagnosis, disease trajectory tracking, and outcome prediction monitoring of ARDS may have a significant impact on changing practice and improving patient outcomes. Graphical abstract.

An Official American Thoracic Society Research Statement: Implementation Science in Pulmonary, Critical Care, and Sleep Medicine.

BACKGROUND: Many advances in health care fail to reach patients. Implementation science is the study of novel approaches to mitigate this evidence-to-practice gap. METHODS: The American Thoracic Society (ATS) created a multidisciplinary ad hoc committee to develop a research statement on implementation science in pulmonary, critical care, and sleep medicine. The committee used an iterative consensus process to define implementation science and review the use of conceptual frameworks to guide implementation science for the pulmonary, critical care, and sleep community and to explore how professional medical societies such as the ATS can promote implementation science. RESULTS: The committee defined implementation science as the study of the mechanisms by which effective health care interventions are either adopted or not adopted in clinical and community settings. The committee also distinguished implementation science from the act of implementation. Ideally, implementation science should include early and continuous stakeholder involvement and the use of conceptual frameworks (i.e., models to systematize the conduct of studies and standardize the communication of findings). Multiple conceptual frameworks are available, and we suggest the selection of one or more frameworks on the basis of the specific research question and setting. Professional medical societies such as the ATS can have an important role in promoting implementation science. Recommendations for professional societies to consider include: unifying implementation science activities through a single organizational structure, linking front-line clinicians with implementation scientists, seeking collaborations to prioritize and conduct implementation science studies, supporting implementation science projects through funding opportunities, working with research funding bodies to set the research agenda in the field, collaborating with external bodies responsible for health care delivery, disseminating results of implementation science through scientific journals and conferences, and teaching the next generation about implementation science through courses and other media. CONCLUSIONS: Implementation science plays an increasingly important role in health care. Through support of implementation science, the ATS and other professional medical societies can work with other stakeholders to lead this effort.

Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial.

Importance: The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown. Objective: To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States. Interventions: Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76). Main Outcomes and Measures: The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days. Results: Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54). Conclusions and Relevance: Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting. Trial Registration: clinicaltrials.gov Identifier: NCT01335932.