Toward Increased Understanding of the Steroid Controversy in Septic Shock No abstract available

Which Multicenter Randomized Controlled Trials in Critical Care Medicine Have Shown Reduced Mortality? A Systematic Review Objectives: To determine which multicenter randomized controlled trials in critically ill patients have shown that the study intervention was associated with a statistically significant reduction in mortality. Our analysis provides an update to a report published 10 years ago. Data Sources: MEDLINE database and PubMed interface from inception until April 30, 2019. Study Selection: All adult multicenter randomized controlled trials that evaluated the effects of any intervention or monitoring system in critically ill patients and reported mortality as a primary or secondary outcome were included. Data Extraction: Numbers of centers and patients, type of intervention, reported mortality outcome, and rate and level of significance were extracted into predefined tables. Included randomized controlled trials were classified as reporting reduced, increased, or no effect of the intervention on mortality. Methodologic quality of trials was evaluated using the updated Consolidated Standards of Reporting Trials statement. Data Synthesis: A total of 212 trials met the inclusion criteria: 27 (13%) reported a significant reduction in mortality, 16 (7%) an increase in mortality, and 170 (80%) no difference in mortality (one study was reported in 2 groups). Of the 27 trials reporting reduced mortality, six had assessed interventions likely to decrease ventilator-induced lung injury, including low tidal volume, prone position, and neuromuscular blockers, demonstrating the negative effects of mechanical ventilation strategies or improved process of care rather than positive effects of new therapies. Seven of the 27 trials reported beneficial effects of noninvasive ventilation. Results from some positive randomized controlled trials, for example, studies of recombinant activated protein C, talactoferrin, interleukin-1 receptor antagonist in sepsis, and muscle relaxants in severe acute respiratory distress syndrome were not replicated in subsequent randomized controlled trials. Other interventions, for example, gastric tonometry, have been abandoned. Conclusions: A systematic literature search provided no conclusive evidence of any pharmacologic intervention that has consistently reduced mortality in critically ill patients. Strategies associated with improved or noninvasive mechanical ventilation were associated with reduced mortality.

Promoting Family Engagement in the ICU: Experience From a National Collaborative of 63 ICUs* Objectives: As part of an improvement program targeting ICU, a national collaborative was launched to help hospitals implement patient- and family-centered care engagement initiatives. Design: Ten-month quality improvement collaborative. Setting: Guided by a national patient and family advisory group, participating teams implemented an individual project including open visitation; integrating families on rounds; establishing a patient and family advisory committee; using patient and family diaries, among others. Subjects: Sixty-three adult and PICU teams from both academic and community hospitals in 34 states participated. Interventions: Monthly team calls, quarterly webinars, newsletters, an online eCommunity, and team reporting assignments were used to facilitate project implementation. Measurements and Main Results: The Family Satisfaction with Care in the ICU 24 was used to assess family satisfaction. Clinician perceptions were assessed with the Institute for Patient- and Family-Centered Care Self-Assessment Inventory. Thematic analysis was used to explore narrative data captured from team reports of project barriers, facilitators, and the experience of participating in the collaborative. A total of 2,530 family member and 3,999 clinician surveys were completed. Postimplementation, family members reported statistically significant increases in overall family satisfaction, satisfaction with decision-making, and satisfaction with quality of care (Family Satisfaction with Care in the ICU mean score change range 0.83–1.24; p ≤ 0.027). Clinicians reported that opportunities for families to participate as members of the care team increased. Major barriers included lack of buy-in and ability to promote change in the clinical setting, managing the workload of implementation, and funding to support initiatives. Conclusions: A national collaborative format was useful to assist ICU teams to implement patient- and family-engagement initiatives. Enlisting stakeholder support, engaging unit-based champions, and highlighting benefits of family engagement can help ICU teams to promote family member involvement and engagement.

Incidence and Outcomes of Acute Laryngeal Injury After Prolonged Mechanical Ventilation* Objectives: Upper airway injury is a recognized complication of prolonged endotracheal intubation, yet little attention has been paid to the consequences of laryngeal injury and functional impact. The purpose of our study was to prospectively define the incidence of acute laryngeal injury and investigate the impact of injury on breathing and voice outcomes. Design: Prospective cohort study. Setting: Tertiary referral critical care center. Patients: Consecutive adult patients intubated greater than 12 hours in the medical ICU from August 2017 to May 2018 who underwent laryngoscopy within 36 hours of extubation. Interventions: Laryngoscopy following endotracheal intubation. Measurements and Main Results: One hundred consecutive patients (62% male; median age, 58.5 yr) underwent endoscopic examination after extubation. Acute laryngeal injury (i.e., mucosal ulceration or granulation tissue in the larynx) was present in 57 patients (57%). Patients with laryngeal injury had significantly worse patient-reported breathing (Clinical Chronic Obstructive Pulmonary Disease Questionnaire: median, 1.05; interquartile range, 0.48–2.10) and vocal symptoms (Voice Handicap Index-10: median, 2; interquartile range, 0–6) compared with patients without injury (Clinical Chronic Obstructive Pulmonary Disease Questionnaire: median, 0.20; interquartile range, 0–0.80; p < 0.001; and Voice Handicap Index-10: median, 0; interquartile range, 0–1; p = 0.005). Multivariable logistic regression independently associated diabetes, body habitus, and endotracheal tube size greater than 7.0 with the development of laryngeal injury. Conclusions: Acute laryngeal injury occurs in more than half of patients who receive mechanical ventilation and is associated with significantly worse breathing and voicing 10 weeks after extubation. An endotracheal tube greater than size 7.0, diabetes, and larger body habitus may predispose to injury. Our results suggest that acute laryngeal injury impacts functional recovery from critical illness.

Early Palliative Care Consultation in the Medical ICU: A Cluster Randomized Crossover Trial Objectives: To assess the impact of early triggered palliative care consultation on the outcomes of high-risk ICU patients. Design: Single-center cluster randomized crossover trial. Setting: Two medical ICUs at Barnes Jewish Hospital. Patients: Patients (n = 199) admitted to the medical ICUs from August 2017 to May 2018 with a positive palliative care screen indicating high risk for morbidity or mortality. Interventions: The medical ICUs were randomized to intervention or usual care followed by washout and crossover, with independent assignment of patients to each ICU at admission. Intervention arm patients received a palliative care consultation from an interprofessional team led by board-certified palliative care providers within 48 hours of ICU admission. Measurements and Main Results: Ninety-seven patients (48.7%) were assigned to the intervention and 102 (51.3%) to usual care. Transition to do-not-resuscitate/do-not-intubate occurred earlier and significantly more often in the intervention group than the control group (50.5% vs 23.4%; p < 0.0001). The intervention group had significantly more transfers to hospice care (18.6% vs 4.9%; p < 0.01) with fewer ventilator days (median 4 vs 6 d; p < 0.05), tracheostomies performed (1% vs 7.8%; p < 0.05), and postdischarge emergency department visits and/or readmissions (17.3% vs 38.9%; p < 0.01). Although total operating cost was not significantly different, medical ICU (p < 0.01) and pharmacy (p < 0.05) operating costs were significantly lower in the intervention group. There was no significant difference in ICU length of stay (median 5 vs 5.5 d), hospital length of stay (median 10 vs 11 d), in-hospital mortality (22.6% vs 29.4%), or 30-day mortality between groups (35.1% vs 36.3%) (p > 0.05). Conclusions: Early triggered palliative care consultation was associated with greater transition to do-not-resuscitate/do-not-intubate and to hospice care, as well as decreased ICU and post-ICU healthcare resource utilization. Our study suggests that routine palliative care consultation may positively impact the care of high risk, critically ill patients.

Perceptions of Ethical Decision-Making Climate Among Clinicians Working in European and U.S. ICUs: Differences Between Nurses and Physicians* Objectives: To examine perceptions of nurses and physicians in regard to ethical decision-making climate in the ICU and to test the hypothesis that the worse the ethical decision-making climate, the greater the discordance between nurses’ and physicians’ rating of ethical decision-making climate with physicians hypothesized to rate the climate better than the nurses. Design: Prospective observational study. Setting: A total of 68 adult ICUs in 13 European countries and the United States. Subjects: ICU physicians and nurses. Interventions: None. Measurements and Main Results: Perceptions of ethical decision-making climate among clinicians were measured in April-May 2014, using a 35-items self-assessment questionnaire that evaluated seven factors (empowering leadership by physicians, interdisciplinary reflection, not avoiding end-of-life decisions, mutual respect within the interdisciplinary team, involvement of nurses in end-of-life care and decision-making, active decision-making by physicians, and ethical awareness). A total of 2,275 nurses and 717 physicians participated (response rate of 63%). Using cluster analysis, ICUs were categorized according to four ethical decision-making climates: good, average with nurses’ involvement at end-of-life, average without nurses’ involvement at end-of-life, and poor. Overall, physicians rated ethical decision-making climate more positively than nurses (p < 0.001 for all seven factors). Physicians had more positive perceptions of ethical decision-making climate than nurses in all 13 participating countries and in each individual participating ICU. Compared to ICUs with good or average ethical decision-making climates, ICUs with poor ethical decision-making climates had the greatest discordance between physicians and nurses. Although nurse/physician differences were found in all seven factors of ethical decision-making climate measurement, the factors with greatest discordance were regarding physician leadership, interdisciplinary reflection, and not avoiding end-of-life decisions. Conclusions: Physicians consistently perceived ICU ethical decision-making climate more positively than nurses. ICUs with poor ethical decision-making climates had the largest discrepancies.

Host-Response Subphenotypes Offer Prognostic Enrichment in Patients With or at Risk for Acute Respiratory Distress Syndrome* Objectives: Classification of patients with acute respiratory distress syndrome into hyper- and hypoinflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapy. We examined whether established subphenotypes are present not only in patients with acute respiratory distress syndrome but also in patients at risk for acute respiratory distress syndrome (ARFA) and then assessed the prognostic information of baseline subphenotyping on the evolution of host-response biomarkers and clinical outcomes. Design: Prospective, observational cohort study. Setting: Medical ICU at a tertiary academic medical center. Patients: Mechanically ventilated patients with acute respiratory distress syndrome or ARFA. Interventions: None. Measurements and Main Results: We performed longitudinal measurements of 10 plasma biomarkers of host injury and inflammation. We applied unsupervised latent class analysis methods utilizing baseline clinical and biomarker variables and demonstrated that two-class models (hyper- vs hypoinflammatory subphenotypes) offered improved fit compared with one-class models in both patients with acute respiratory distress syndrome and ARFA. Baseline assignment to the hyperinflammatory subphenotype (39/104 [38%] acute respiratory distress syndrome and 30/108 [28%] ARFA patients) was associated with higher severity of illness by Sequential Organ Failure Assessment scores and incidence of acute kidney injury in patients with acute respiratory distress syndrome, as well as higher 30-day mortality and longer duration of mechanical ventilation in ARFA patients (p < 0.0001). Hyperinflammatory patients exhibited persistent elevation of biomarkers of innate immunity for up to 2 weeks postintubation. Conclusions: Our results suggest that two distinct subphenotypes are present not only in patients with established acute respiratory distress syndrome but also in patients at risk for its development. Hyperinflammatory classification at baseline is associated with higher severity of illness, worse clinical outcomes, and trajectories of persistently elevated biomarkers of host injury and inflammation during acute critical illness compared with hypoinflammatory patients. Our findings provide strong rationale for examining treatment effect modifications by subphenotypes in randomized clinical trials to inform precision therapeutic approaches in critical care.

Allergic Immune Diseases and the Risk of Mortality Among Patients Hospitalized for Acute Infection* Objectives: The immune response during sepsis remains poorly understood and is likely influenced by the host’s preexisting immunologic comorbidities. Although more than 20% of the U.S. population has an allergic-atopic disease, the type 2 immune response that is overactive in these diseases can also mediate beneficial pro-resolving, tissue-repair functions. Thus, the presence of allergic immunologic comorbidities may be advantageous for patients suffering from sepsis. The objective of this study was to test the hypothesis that comorbid type 2 immune diseases confer protection against morbidity and mortality due to acute infection. Design: Retrospective cohort study of patients hospitalized with an acute infection between November 2008 and January 2016 using electronic health record data. Setting: Single tertiary-care academic medical center. Patients: Admissions to the hospital through the emergency department with likely infection at the time of admission who may or may not have had a type 2 immune-mediated disease, defined as asthma, allergic rhinitis, atopic dermatitis, or food allergy, as determined by International Classification of Diseases, 9th Revision, Clinical Modification codes. Interventions: None. Measurements and Main Results: Of 10,789 admissions for infection, 2,578 (24%) had a type 2 disease; these patients were more likely to be female, black, and younger than patients without type 2 diseases. In unadjusted analyses, type 2 patients had decreased odds of dying during the hospitalization (0.47; 95% CI, 0.38–0.59, p < 0.001), while having more than one type 2 disease conferred a dose-dependent reduction in the risk of mortality (p < 0.001). When adjusting for demographics, medications, types of infection, and illness severity, the presence of a type 2 disease remained protective (odds ratio, 0.55; 95% CI, 0.43–0.70; p < 0.001). Similar results were found using a propensity score analysis (odds ratio, 0.57; 95% CI, 0.45–0.71; p < 0.001). Conclusions: Patients with type 2 diseases admitted with acute infections have reduced mortality, implying that the type 2 immune response is protective in sepsis.

Vasopressin Versus Norepinephrine for the Management of Septic Shock in Cancer Patients: The VANCS II Randomized Clinical Trial* Objectives: Previous trials suggest that vasopressin may improve outcomes in patients with vasodilatory shock. The aim of this study was to evaluate whether vasopressin could be superior to norepinephrine to improve outcomes in cancer patients with septic shock. Design: Single-center, randomized, double-blind clinical trial, and meta-analysis of randomized trials. Setting: ICU of a tertiary care hospital. Patients: Two-hundred fifty patients 18 years old or older with cancer and septic shock. Interventions: Patients were assigned to either vasopressin or norepinephrine as first-line vasopressor therapy. An updated meta-analysis was also conducted including randomized trials published until October 2018. Measurements and Main Results: The primary outcome was all-cause mortality at 28 days after randomization. Prespecified secondary outcomes included 90-days all-cause mortality rate; number of days alive and free of advanced organ support at day 28; and Sequential Organ Failure Assessment score 24 hours and 96 hours after randomization. We also measure the prevalence of adverse effects in 28 days. A total of 250 patients were randomized. The primary outcome was observed in 71 patients (56.8%) in the vasopressin group and 66 patients (52.8%) in the norepinephrine group (p = 0.52). There were no significant differences in 90-day mortality (90 patients [72.0%] and 94 patients [75.2%], respectively; p = 0.56), number of days alive and free of advanced organ support, adverse events, or Sequential Organ Failure Assessment score. Conclusions: In cancer patients with septic shock, vasopressin as first-line vasopressor therapy was not superior to norepinephrine in reducing 28-day mortality rate.

Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy* Objectives: To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting. Design: Parallel-arm, randomized, double-blinded, placebo-controlled trial. Setting: Academic medical center in La Jolla, California. Patients: Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy. Interventions: Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU. Measurements and Main Results: Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5–1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2–3 d] vs ramelteon 3 d [2–5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1–3 d] vs ramelteon 3 d [2–4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3–5 d] vs 4 d [3–6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2–3.2; p = 0.717), all placebo versus ramelteon, respectively. Conclusions: Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.