CRTH2 Mediates Profibrotic Macrophage Differentiation and Promotes Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a particularly deadly form of pulmonary fibrosis of unknown cause. In patients with IPF, high serum and lung concentrations of CHI3L1 (chitinase 3 like 1) can be detected and are associated with poor survival. However, the roles of CHI3L1 in these diseases have not been fully elucidated. We hypothesize that CHI3L1 interacts with CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) to stimulate profibrotic macrophage differentiation and the development of pulmonary fibrosis and that circulating blood monocytes from patients with IPF are hyperresponsive to CHI3L1-CRTH2 signaling. We used murine pulmonary fibrosis models to investigate the role of CRTH2 in profibrotic macrophage differentiation and fibrosis development and primary human peripheral blood mononuclear cell culture to detect the difference of monocytes in the responses to CHI3L1 stimulation and CRTH2 inhibition between patients with IPF and normal control subjects. Our results showed that null mutation or small-molecule inhibition of CRTH2 prevents the development of pulmonary fibrosis in murine models. Furthermore, CHI3L1 stimulation induces a greater increase in CD206 expression in IPF monocytes than control monocytes. These results demonstrated that monocytes from patients with IPF appear to be hyperresponsive to CHI3L1 stimulation. These studies support targeting the CHI3L1-CRTH2 pathway as a promising therapeutic approach for IPF and that the sensitivity of blood monocytes to CHI3L1-induced profibrotic differentiation may serve as a biomarker that predicts responsiveness to CHI3L1- or CRTH2-based interventions.

Differences in Family Involvement in the Bedside Care of Patients in the ICU Based on Self-Identified Race.

OBJECTIVES: Being a caregiver for a patient in the ICU can place emotional burden on families and engaging families in caregiving can reduce psychological distress. Our goal was to observe support methods used by families in the ICU and identify differences between race/ethnicity. DESIGN: A secondary analysis of a multicenter before-and-after clinical trial. SETTING: Three hospitals in Chicago, Providence, and Florence, Italy. PARTICIPANTS: Family members of patients admitted to the ICU. INTERVENTIONS: In the primary study, an intervention was designed to engage families in seven domains that were based on the five physical senses (taste, touch, sight, smell, and sound), personal care, and spiritual care of the patient. During the control phase, nursing staff observed and recorded if they witnessed families participating in support methods unprompted. MEASUREMENTS AND MAIN RESULTS: We compared the use of support methods among families from different races, categorized by race as either White, Black, or other using generalized estimating equation population-averaged logistic regression analysis. A total of 133 patients and 226 family members were enrolled in the control arm of the primary study, with patients being 71.2% White, 17% Black, and 11.8% other. Compared with Whites, families who identified their race Black or other may be more likely to participate in support methods that included personal care, touch, or spiritual care. Families who identified as Black may also be more likely to incorporate audio or sound. There were no differences in the categories of sight, smell, or taste. CONCLUSIONS: Our study identifies racial differences in the use of bedside support methods in the ICU. Guiding families in a culturally congruent and open-minded manner may have the potential to decrease family distress and improve the experience for families in the ICU.

Family Care Rituals in the ICU to Reduce Symptoms of Post-Traumatic Stress Disorder in Family Members-A Multicenter, Multinational, Before-and-After Intervention Trial.

OBJECTIVES: To assess the feasibility and efficacy of implementing "Family Care Rituals" as a means of engaging family members in the care of patients admitted to the ICU with a high risk of ICU mortality on outcomes including stress-related symptoms in family members. DESIGN: Prospective, before-and-after intervention evaluation. SETTING: Two U.S. academic medical ICU's, and one Italian academic medical/surgical ICU. SUBJECTS: Family members of patients who had an attending predicted ICU mortality of greater than 30% within the first 24 hours of admission. INTERVENTIONS: A novel intervention titled "Family Care Rituals" during which, following a baseline observation period, family members enrolled in the intervention phase were given an informational booklet outlining opportunities for engagement in care of the patient during their ICU stay. MEASUREMENTS AND MAIN RESULTS: Primary outcome was symptoms of post-traumatic stress disorder in family members 90 days after patient death or ICU discharge. Secondary outcomes included symptoms of depression, anxiety, and family satisfaction. At 90-day follow-up, 131 of 226 family members (58.0%) responded preintervention and 129 of 226 family members (57.1%) responded postintervention. Symptoms of post-traumatic stress disorder were significantly higher preintervention than postintervention (39.2% vs 27.1%; unadjusted odds ratio, 0.58; p = 0.046). There was no significant difference in symptoms of depression (26.5% vs 25.2%; unadjusted odds ratio, 0.93; p = 0.818), anxiety (41.0% vs 45.5%; unadjusted odds ratio, 1.20; p = 0.234), or mean satisfaction scores (85.1 vs 89.0; unadjusted odds ratio, 3.85; p = 0.052) preintervention versus postintervention 90 days after patient death or ICU discharge. CONCLUSIONS: Offering opportunities such as family care rituals for family members to be involved with providing care for family members in the ICU was associated with reduced symptoms of post-traumatic stress disorder. This intervention may lessen the burden of stress-related symptoms in family members of ICU patients.

The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study.

OBJECTIVES: It is unclear if a low- or high-volume IV fluid resuscitation strategy is better for patients with severe sepsis and septic shock. DESIGN: Prospective randomized controlled trial. SETTING: Two adult acute care hospitals within a single academic system. PATIENTS: Patients with severe sepsis and septic shock admitted from the emergency department to the ICU from November 2016 to February 2018. INTERVENTIONS: Patients were randomly assigned to a restrictive IV fluid resuscitation strategy (≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care. MEASUREMENTS AND MAIN RESULTS: We enrolled 109 patients, of whom 55 were assigned to the restrictive resuscitation group and 54 to the usual care group. The restrictive group received significantly less resuscitative IV fluid than the usual care group (47.1 vs 61.1 mL/kg; p = 0.01) over 72 hours. By 30 days, there were 12 deaths (21.8%) in the restrictive group and 12 deaths (22.2%) in the usual care group (odds ratio, 1.02; 95% CI, 0.41-2.53). There were no differences between groups in the rate of new organ failure, hospital or ICU length of stay, or serious adverse events. CONCLUSIONS: This pilot study demonstrates that a restrictive resuscitation strategy can successfully reduce the amount of IV fluid administered to patients with severe sepsis and septic shock compared with usual care. Although limited by the sample size, we observed no increase in mortality, organ failure, or adverse events. These findings further support that a restrictive IV fluid strategy should be explored in a larger multicenter trial.

Sexual health and health-related quality of life among women with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by progressive limitations in physical activity and health-related quality of life (HRQoL). HRQoL deficits may extend beyond the traditional domains of physical activity, psychological health, and emotional wellbeing to sexual health and function. Sexual HRQoL has not been studied in PAH, nor has the impact of PAH therapies themselves on sexual health and intimacy. In this initial investigation, we sought to explore HRQoL among women diagnosed with PAH and to determine if PAH treatment type (intravenous or subcutaneous prostanoids versus oral medications) was associated with levels of self-reported HRQoL assessed by validated measures for PAH-specific, general, and sexual HRQoL. We administered the emPHasis-10, Short Form (SF)-36, Female Sexual Dysfunction Scale-Revised (FSDS-R), and the Arizona Sexual Experience Scale (ASEX) to 35 women with self-reported World Health Organization Group 1 PAH at the 2016 Pulmonary Hypertension Association International Conference and Scientific Sessions. HRQoL instruments demonstrated excellent internal reliability. Women with PAH had high levels of sexual distress captured with the FSDS-R scale. The FSDS-R (but not ASEX) was significantly correlated to emPHasis-10 ( r = 0.64, p < 0.01) and most SF-36 domains ( r = - 0.36 to - 0.64, p < 0.05). Participants treated with intravenous or subcutaneous prostanoids had higher (worse) FSDS-R scores than those on oral therapies while ASEX, emPHasis-10, and SF-36 scores were similar across treatment types. Sexual HRQoL may impact overall quality of life in PAH and specific assessment of sexual health and functioning within intimate relationships may detect deficits in wellbeing not addressed by established HRQoL metrics. Further study to address all aspects of HRQoL in PAH is required.

The Modified Borg Dyspnea Scale does not predict hospitalization in pulmonary arterial hypertension.

Background Breathlessness is the most common symptom reported by patients with pulmonary arterial hypertension (PAH). The Modified Borg Dyspnea Scale (MBS) is routinely obtained during the six-minute walk test in the assessment of PAH patients, but it is not known whether the MBS predicts clinical outcomes such as hospitalizations in PAH. Methods We performed a retrospective study of World Health Organization (WHO) Group 1 PAH patients followed at our center. The dates of the first three MBS and hospitalizations that occurred within three months of a documented MBS were collected. Marginal Cox hazard regression modeling was used to assess for a relationship between MBS and all-cause as well as PAH-related hospitalization. Results A total of 50 patients were included; most (92%) were functional class III/IV, 44% and 65% were treatment-naïve prior to their first MBS and hospitalization, respectively. The first recorded MBS was inversely correlated with the first recorded six-minute walk distance (6MWD) (r = -0.41, P < 0.01) but did not track with WHO functional class (r = 0.07, P = 0.63). MBS did not predict all-cause (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.76-1.08; P = 0.28) or PAH-related hospitalization (HR, 1.04; 95% CI, 0.89-1.23; P = 0.61), though there was a strong relationship between 6MWD and PAH-related hospitalization ( P = 0.01). These findings persisted after multivariable adjustment. Conclusions Breathlessness as assessed by MBS does not predict all-cause or PAH-related hospitalization. Robust and validated patient-reported outcomes are needed in pulmonary vascular disease.

Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial.

RATIONALE: The aromatase inhibitor anastrozole blocks the conversion of androgens to estrogen and blunts pulmonary hypertension in animals, but its efficacy in treating patients with pulmonary arterial hypertension (PAH) is unknown. OBJECTIVES: We aimed to determine the safety and efficacy of anastrozole in PAH. METHODS: We performed a randomized, double-blind, placebo-controlled trial of anastrozole in patients with PAH who received background therapy at two centers. MEASUREMENTS AND MAIN RESULTS: A total of 18 patients with PAH were randomized to anastrozole 1 mg or matching placebo in a 2:1 ratio. The two co-primary outcomes were percent change from baseline in 17ß-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: -40%; interquartile range [IQR], -61 to -26% vs. -4%; IQR, -14 to +4%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = +26 m) compared with placebo (median change = -12 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo -2%; IQR, -7 to +1%; P = 0.042). Anastrozole had no effect on circulating biomarkers, functional class, or health-related quality of life. There was no difference in adverse events. CONCLUSIONS: Anastrozole significantly reduced E2 levels in patients with PAH but had no effect on TAPSE. Anastrozole was safe, well tolerated, and improved 6-minute-walk distance in this small "proof-of-principle" study. Larger and longer phase II clinical trials of anastrozole may be warranted in patients with PAH. Clinical trial registered with www.clinicaltrials.gov (NCT 1545336).

Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men.

RATIONALE: Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men. OBJECTIVES: We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men. METHODS: Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared with those from age- and body mass index-matched men without clinical cardiovascular disease. MEASUREMENTS AND MAIN RESULTS: There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH. CONCLUSIONS: Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease.

Visiting hours policies in New England intensive care units: strategies for improvement.

OBJECTIVE: Dying patients often feel isolated and alone, and restricted visiting hours in the intensive care unit (ICU) has been shown to increase anxiety and dissatisfaction in both critically ill patients and their families. Unrestricted visiting has been identified as a top-ten need by families of patients in the ICU. Because emotional distress experienced by patients and families may persist well beyond the ICU stay, an open visiting policy, by meeting the needs of patients and families, may improve the quality of end-of-life care in the ICU. This two-part study included a survey to determine the visiting hours policies of New England-area hospital ICUs, and nursing focus groups to describe challenges and barriers that nursing staff working in an open ICU have experienced and to provide solutions that will facilitate implementation of an open visiting hours policy. DESIGN: Two-part study: survey and focus groups. SETTING: ICUs in New England and one medical ICU in a tertiary care hospital. SUBJECTS: Registered nurses employed in medical ICUs. INTERVENTIONS: Adult ICUs in the six New England states were located using a library listing of all regional hospitals. A telephone questionnaire interview was used to ascertain visiting hours policies in each ICU. Six focus-group sessions were conducted with nursing staff who work in an urban, northeastern ICU with 8 yrs of experience with an unrestricted visiting hours policy. MEASUREMENTS AND MAIN RESULTS: A total of 171 hospitals completed the questionnaire (96%). From all ICUs surveyed, 62 (32%) had unrestricted, open visiting hours. Out of these, 57 (92%) were medical ICUs or mixed medical/surgical ICUs. Nursing staff identified three major areas of concern with an open visiting hours policy: space, conflict, and burden. Strategies for resolution that are either employed or advocated by nursing staff are described. CONCLUSIONS: The majority of ICUs in New England have restricted visiting hours. Only one third of ICUs have open visiting policies. Nursing concerns with an unrestricted ICU were identified and solutions were offered that may provide guidance for other ICUs considering adopting an open visiting hours policy.