A Research Agenda for Precision Medicine in Sepsis and Acute Respiratory Distress Syndrome: An Official American Thoracic Society Research Statement.

Background: Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. The recent success of precision medicine in non-critical care settings has resulted from the confluence of large clinical and biospecimen repositories, innovative bioinformatics, and novel trial designs. Similar advances for precision medicine in sepsis and in the acute respiratory distress syndrome (ARDS) are possible but will require further investigation and significant investment in infrastructure. Methods: This project was funded by the American Thoracic Society Board of Directors. A multidisciplinary and diverse working group reviewed the available literature, established a conceptual framework, and iteratively developed recommendations for the Precision Medicine Research Agenda for Sepsis and ARDS. Results: The following six priority recommendations were developed by the working group: 1) the creation of large richly phenotyped and harmonized knowledge networks of clinical, imaging, and multianalyte molecular data for sepsis and ARDS; 2) the implementation of novel trial designs, including adaptive designs, and embedding trial procedures in the electronic health record; 3) continued innovation in the data science and engineering methods required to identify heterogeneity of treatment effect; 4) further development of the tools necessary for the real-time application of precision medicine approaches; 5) work to ensure that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic, and demographic groups; and 6) the securement and maintenance of adequate and sustainable funding for precision medicine efforts. Conclusions: Precision medicine approaches that incorporate variability in genomic, biologic, and environmental factors may provide a path forward for better individualizing the delivery of therapies and improving care for patients with sepsis and ARDS.

Classification and diagnosis of pulmonary hypertension.

Pulmonary hypertension has been classified into five major subgroups in order to better understand and apply knowledge from the areas of molecular biology, pathophysiology and clinical science. Accurate classification of the patient not only optimizes diagnostic approach but also confers the best benefit, as therapeutic approaches are applied accurately. Current diagnostic strategies begin with a detailed history and physical, which are directed to elucidate symptoms that may increase the degree of suspicion. Subsequent application of a logical approach to progress through the diagnostic algorithm , with understanding of the complexity of this process, allows for best possible outcomes. Proper diagnosis and classification will eventually increase the potential for appropriate research and progress toward of a possible cure for this fatal disease.

The role of tyrosine kinase inhibitor "Lapatinib" in pulmonary hypertension.

INTRODUCTION: Pulmonary Arterial Hypertension (PAH) and cancer share growth factor and protein kinase signaling pathways that result in smooth muscle cell proliferation and vasculopathy. There is little known about the impact of Lapatinib on the pulmonary vasculature. After reporting a case of Lapatinib-induced PAH we investigated the association of Lapatinib with the development of PAH in our institution. METHODS: We reviewed charts for all patients treated with Lapatinib at our institution between 2008 and 2013. Patients who had undergone 2D-echocardiogram both prior to and after treatment were included in the analysis. Increase in Pulmonary artery systolic pressure (PASP) was assessed. Patients were also evaluated in terms of risk factors for non-Group 1 PAH. RESULTS: A total of 27 patients were found to have 2-D echo done before and after starting treatment with Lapatinib. Six patients were found to have significant increase in their PASP after starting treatment. Right heart catheterization before and after stopping the medication was available in three patient, confirming the diagnosis of PAH with complete resolution after stopping the medication. The median pre-treatment and post treatment PASP in those 6 patients was 29 mmHg and 65.5 mmHg respectively (N = 6; p = 0.027). CONCLUSION: Lapatinib might be associated with the development of PAH. PASP should be evaluated in patients who become short of breath while on treatment, and stopping the drug in cases where no other reasons are identified could be associated with reversibility of the elevated pulmonary artery pressure.

Development of a modified yoga program for pulmonary hypertension: a case series.

BACKGROUND: Pulmonary hypertension (PH) is a hemodynamic condition in which the pressure in the bed of the pulmonary arteries is elevated. Although medications have improved both symptoms and mortality, PH remains a debilitating and devastating disease. Little is known about the effects of nonpharmacologic approaches, such as yoga and meditative breathing, in treatment of the disease. OBJECTIVE: Given the unique hemodynamic concerns of PH patients, the research team intended to describe the development and subsequent initiation of a therapeutic treatment plan that uses modified yoga and to evaluate its benefits and safety. DESIGN: This study was a case series with 3 PH patients of varying functional abilities. Each patient was provided with a DVD, access to YouTube video segments, and a download of the Yoga for PH application. The patients were asked to document their use of the home exercise regimen and journal around their subjective observations. They were also administered the Health Promoting Lifestyle Profile II (HPLPII) at the beginning and end of the 8 wk. SETTING: The study took place in a tertiary care, academic hospital in a large urban setting. PARTICIPANTS: In this case series, 3 patients with group 1 pulmonary arterial hypertension, with varying functional abilities, are described. INTERVENTION: Three discreet yoga programs were designed with modifications specific to PH patients: chair yoga, intermediate yoga with a chair assist, and experienced yoga. Patients were provided with a video, Yoga for PH, in the form of a DVD, a video on YouTube, and a downloadable application and were instructed to log activity and subjective markers of well-being. OUTCOME MEASURES: Subjective and objective effects on clinical, physical function, and psychological outcomes were measured. Subjective effects were identified through journaling as well as the self-administered questionnaire HPLPII. When available, 6-min walk distance (6MWD) testing and oxygen saturation were also used. RESULTS: The modified yoga program proved feasible, safe, and effective in the 3 described cases. Patients described decreases in anxiety and joint pain, with improvements in health-promoting behaviors as measured by the HPLPII. Overall mean scores for health-promoting lifestyle increased in each patient, though due to the small sample size, statistical significance cannot be measured. No patient experienced an adverse event associated with the practice. CONCLUSIONS: The modified yoga program for PH patients can provide a standardized, accessible starting point for further study on the feasibility, efficacy, and safety of such a program on a larger scale.

Maternal and Fetal Outcomes in Pulmonary Hypertension During Pregnancy: A Contemporary Nationwide Analysis.

Pulmonary hypertension (PH) disproportionately affects women, presenting challenges during pregnancy. Historically, patients with PH are advised to avoid pregnancy; however, recent reports have indicated that the incidence of adverse events in pregnant patients with PH may be lower than previously reported. We conducted a retrospective cohort study in pregnant patients with PH using the National Readmission Database from January 1, 2016, to December 31, 2020. PH was categorized according to the World Health Organization classification. Primary end points include maternal mortality and 30-day nonelective readmission rate. Other adverse short-term maternal (cardiovascular and obstetric) and fetal outcomes were also analyzed. Of 9,922,142 pregnant women, 3,532 (0.04%) had PH, with Group 1 PH noted in 1,833 (51.9%), Group 2 PH in 676 (19.1%), Group 3 PH in 604 (17.1%), Group 4 PH in 23 (0.7%), Group 5 PH in 98 (2.8%), and multifactorial PH in 298 (8.4%). PH patients exhibited higher rates of adverse cardiovascular events (15.7% vs 0.3% without PH, p <0.001) and mortality (0.9% vs 0.01% without PH, p <0.001). Mixed PH and Group 2 PH had the highest prevalence of adverse cardiovascular events in the World Health Organization PH groups. Patients with PH had a significantly higher nonelective 30-day readmission rate (10.4% vs 2.3%) and maternal adverse obstetric events (24.2% vs 9.1%) compared with those without PH (p <0.001) (Figure 1). In conclusion, pregnant women with PH had significantly higher adverse event rates, including in-hospital maternal mortality (85-fold), compared with those without PH.

Early initiation of prostacyclin in portopulmonary hypertension: 10 years of a transplant center's experience.

BACKGROUND: Portopulmonary hypertension (PoPH) is a subgroup of Group 1 pulmonary arterial hypertension (PAH) with particularly poor prognosis. Delay in initiation of parenteral therapy may be the reason for poor outcome. METHODS: We conducted a prospective observational study of all patients with Group 1 PoPH evaluated at Henry Ford Hospital between January 2002 and July 2012. The cohort of the REVEAL Registry patients with PoPH was used as the comparator group. The patient survival rates at 5 years after diagnosis and 2 years after enrollment, treatment trends, and the freedom from all-cause hospitalization rates at 2 years after enrollment were compared using χ (2) analysis. RESULTS: Twenty-one patients were enrolled in the PH Clinic with PoPH from January 2002 through July 2012. Our patients were significantly more likely to be on prostacyclin IV at 90 days as compared to REVEAL PoPH patients (67 vs. 31 %; p = 0.002). Despite this, early outcomes were not significantly different between the groups: 2-year survival from enrollment (70 and 67 %, respectively; p = 0.77) and 2-year freedom from hospitalization (35 vs. 49 %, respectively; p = 0.29). However, 5-year survival from time of diagnosis was significantly higher in our cohort of PoPH patients (71 and 40 %, respectively; p = 0.02). CONCLUSIONS: Early initiation of parenteral prostacyclin therapy in PoPH patients at a single institution was associated with improved 5-year patient survival from diagnosis as compared to the REVEAL Registry of PoPH patients and allowed for clearance for transplant in 52 % of patients within 1 year.

A Way Forward in the COVID-19 Pandemic: Making the Case for Narrative Competence in Pulmonary and Critical Care Medicine.

Each surge of the coronavirus disease (COVID-19) pandemic presented new challenges to pulmonary and critical care practitioners. Although some of the initial challenges were somewhat less acute, clinicians now are left to face the physical, emotional, and mental toll of the past 2 years. The pandemic revealed a need for a more varied skillset, including space for reflection, tolerance of uncertainty, and humanism. These skills can assist clinicians who are left to heal from the difficulty of caring for patients in the absence of families who were excluded from the intensive care unit, public distrust of vaccines, and morgues overtaken by our patients. As pulmonary and critical care medicine practitioners and educators, we believe that cultivating practices, pedagogies, and institutional structures that foster narrative competence, "the ability to acknowledge, absorb, interpret, and act on the stories and plights of others," in our ourselves, our trainees, and our colleagues, may provide a productive way forward. In addition to fostering needed skills, this practice can promote necessary healing as well. This perspective introduces the practice of narrative competence, provides evidence of support for its implementation, and suggests opportunities for curricular integration.

Ultrasound-assisted catheter-directed thrombolysis versus anticoagulation alone for management of submassive pulmonary embolism.

BACKGROUND: Patients with submassive pulmonary embolism (PE) are vulnerable to sudden deterioration, recurrent PE, and progression to pulmonary hypertension and chronic right ventricular (RV) dysfunction. Previous studies have suggested a clinical benefit of using ultrasound-assisted catheter-directed thrombolysis (USCDT) to invasively manage patients with submassive PE. However, there is sparse data comparing the clinical outcomes of these patients when treated with USCDT versus anticoagulation (AC) alone. We sought to compare the outcomes of USCDT versus AC alone in the management of submassive PE. METHODS: 192 consecutive patients who underwent USCDT for submassive PE between January 2013 and February 2019 were identified. ICD9/ICD10 codes were used to detect 2554 patients diagnosed with PE who did not undergo thrombolysis. Propensity matching identified 192 patients with acute PE treated with AC alone. Clinical outcomes were compared between the two groups. Baseline demographics, laboratory values, and pulmonary embolism severity index scores were similar between the two cohorts. RESULTS: There was a significant reduction in mean systolic pulmonary artery pressure (sPAP) in the USCDT group compared to the AC group (∆11 vs ∆3.9 mmHg, p < 0.001). There was significant improvement in proportion of RV dysfunction in all patients, but the difference was larger in the USCDT group (∆43.3% vs ∆17.3%, p < 0.001). Patients who underwent USCDT had lower 30-day (4.3% vs 10.5%, p = 0.03), 90-day (5.5% vs 12.4%, p = 0.03), and 1-year mortality (6.2% vs 14.2%, p = 0.03). CONCLUSIONS: In patients with acute submassive PE, USCDT was associated with improved 30-day, 90-day, and 1 year mortality as compared to AC alone. USCDT also improved RV function and reduced sPAP to a greater degree than AC alone. Further studies are needed to verify these results in both short- and long-term outcomes.

An expert panel Delphi consensus statement on the use of palliative care in the management of patients with pulmonary arterial hypertension.

Mortality in pulmonary arterial hypertension (PAH) remains high and referral to palliative or supportive care (P/SC) specialist services is recommended when appropriate. However, access to P/SC is frequently a challenge for patients with a noncancer diagnosis and few patients living with PAH report P/SC involvement in their care. A modified Delphi process of three questionnaires completed by a multidisciplinary panel (N = 15) was used to develop expert consensus statements regarding the use of P/SC to support patients with PAH. Panelists rated their agreement with each statement on a Likert scale. There was a strong consensus that patients should be referred to P/SC when disease symptoms become unmanageable or for end-of-life care. Services that achieved consensus were pain management techniques, end-of-life care, and psychosocial recommendations. Palliative or supportive care should be discussed with patients, preferably in-person, when disease symptoms become unmanageable, when starting treatment, when treatment-related adverse events occur or become refractory to initial intervention. Care partners and patient support groups were considered important in improving a patient's overall health outcomes, treatment adherence, and perception of care. Most patients with PAH experience cognitive and/or psychosocial changes and those who receive psychosocial management have better persistence and/or compliance with their treatment. These consensus statements provide guidance to healthcare providers on the "who and when" of referral to palliative care services, as well as the importance of focusing on the psychosocial aspects of patient care and quality of life.

Trust-Based Partnerships Are Essential - and Achievable - in Health Care Service.

When people think about trust in the context of health care, they typically focus on whether patients trust the competence of doctors and other health professionals. But for health care to reach its full potential as a service, trust must also include the notion of partnership, whereby patients see their clinicians as reliable, caring, shared decision-makers who provide ongoing "healing" in its broadest sense. Four interrelated service-quality concepts are central to fostering trust-based partnerships in health care: empathetic creativity, discretionary effort, seamless service, and fear mitigation. Health systems and institutions that prioritize trust-based partnerships with patients have put these concepts into practice using several concrete approaches: investing in organizational culture; hiring health professionals for their values, not just their skills; promoting continuous learning; attending to the power of language in all care interactions; offering patients "go-to" sources for timely assistance; and creating systems and structures that have trust built into their very design. It is in the real-world implementation of trust-based partnership that health care can reclaim its core mission.

Serious illness conversations in pulmonary hypertension.

Pulmonary arterial hypertension has evolved from a fatal disease with few treatment options to a chronic condition with improved survival. This improvement is possible through development of effective therapies as well as the expansion of risk stratification scores to assist clinical decision making. Despite improved disease control, quality of life, and overall prognosis, many challenges remain. The treatment itself is burdensome, with significant impact on quality of life. Many patients with pulmonary arterial hypertension still present with advanced, often end-stage disease. Increased use of mechanical circulatory support and catheter-based interventions have expanded use of extracorporeal life support and right ventricle assist devices. For these reasons as well as the long-term relationships pulmonary hypertension physicians have with patients and their families, navigating the course of the illness in a considered, proactive way is essential. Understanding individual goals and revisiting them as they change over time requires comfort with the conversation itself. There are many barriers and challenges to having effective, compassionate conversations in the clinical setting with time constraints being the most often cited. Compressed visits are necessarily focused on the clinical aspects, therapy and medication adherence and tolerance. Clinicians are sometimes wary of diminishing hope in the face of ongoing treatment. Having sufficient experience and comfort with these discussions can be empowering. In this paper, we discuss the challenges involved and propose a framework to assist in incorporating these discussions into clinical care.

Improving transitions of care for critically ill adult patients on pulmonary arterial hypertension medications.

PURPOSE: The purpose of this report is to describe the activities of critical care and ambulatory care pharmacists in a multidisciplinary transitions-of-care (TOC) service for critically ill patients with pulmonary arterial hypertension (PAH) receiving PAH medications. SUMMARY: Initiation of medications for treatment of PAH involves complex medication access steps. In the ambulatory care setting, multidisciplinary teams often have a process for completing these steps to ensure access to PAH medications. Patients with PAH are frequently admitted to an intensive care unit (ICU), and their home PAH medications are continued and/or new medications are initiated in the ICU setting. Inpatient multidisciplinary teams are often unfamiliar with the medication access steps unique to PAH medications. The coordination and completion of medication access steps in the inpatient setting is critical to ensure access to medications at discharge and prevent delays in care. A PAH-specific TOC bundle for patients prescribed a PAH medication who are admitted to the ICU was developed by a multidisciplinary team at an academic teaching hospital. The service involves a critical care pharmacist completing a PAH medication history, assessing for PAH medication access barriers, and referring patients to an ambulatory care pharmacist for postdischarge telephone follow-up. In collaboration with the PAH multidisciplinary team, a standardized workflow to be initiated by the critical care pharmacist was developed to streamline completion of PAH medication access steps. Within 3 days of hospital discharge, the ambulatory care pharmacist calls referred patients to ensure access to PAH medications, provide disease state and medication education, and request that the patient schedule a follow-up office visit to take place within 14 days of discharge. CONCLUSION: Collaboration by a PAH multidisciplinary team, critical care pharmacist, and ambulatory care pharmacist can improve TOC related to PAH medication access for patients with PAH. The PAH TOC bundle serves as a model that may be transferable to other health centers.

Transitioning Parenteral or Inhaled Treprostinil to Oral Treprostinil Diolamine: Case Series and Review of the Literature.

Treprostinil diolamine is the first oral dosage preparation of a prostacyclin analogue for use in treatment naive pulmonary arterial hypertension (PAH). This case series and review of the available literature describes the experience of patients with PAH receiving treprostinil by intravenous (IV), subcutaneous (SQ), or inhalation route who were transitioned to treprostinil diolamine. At our institution, 3 patients were transitioned to treprostinil diolamine who received treprostinil administered by each of the alternative routes: IV, SQ, and inhalation. All patients tolerated the transition without significant worsening of disease end points. In the literature, 5 additional reports representing 48 patients were transitioned to treprostinil diolamine from an alternate route of administration. A majority (92%) of patients were hospitalized during the cross-titration phase and tolerated the transition without changes in disease markers or significant adverse effect. Six (13%) patients required reinitiation of parenteral therapy due to clinical decline. The most common dosing frequency utilized for treprostinil diolamine was 3 times per day. In patients with stable PAH receiving parenteral or inhaled treprostinil, a transition to treprostinil diolamine was a safe approach in a highly select population meeting clinical end points. Additional studies are required to further describe this clinical strategy before accepted in clinical practice.

Finding Hope and Healing When Cure Is Not Possible.

Traditional medical training focused on curing disease may not prepare clinicians to provide comfort and solace to their patients facing life-limiting illness. But dying patients and their families still need healing, and clinicians can actively facilitate it. We explore the clinician's role in the healing journey through the lens of pediatric brain cancer. Specifically, we examine how clinicians can help affected families find their way from "focused hope" (which centers on cure) to "intrinsic hope," which offers a more realistic and resilient emotional foundation as the child's death approaches and letting go becomes essential. Drawing on their clinical experience and medical knowledge, clinicians can help families comprehend the lessons that their seriously ill child's body has to teach, highlighting the importance of cherishing the present and creating new memories that outlast the disease. Clinicians can avoid the mindset of "nothing more can be done," emphasizing that there is plenty to do in providing physical, emotional, and spiritual comfort. Clinicians can learn how to be "unconditionally present" for patients and families without immersing themselves in anguish and, eventually, how to help the family find freedom from despair and a full life that still honors the child's memory.