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The acute respiratory distress syndrome (ARDS) remains a common and highly morbid condition despite advances in the understanding and management of this complex critical illness. Recent work has illuminated the heterogeneity within ARDS and demonstrated the likely impact of heterogeneity on the identification of effective therapeutic interventions. Despite these challenges, new data have also informed the standard of care for ARDS and have resulted in the re-evaluation of previously established therapies, including ventilation strategies, pharmacologic interventions, and rescue therapies. As the field of ARDS continues to evolve, innovative approaches will be needed to further define phenotypes within ARDS and design targeted clinical trials.

In this Series paper, we review the current evidence for the use of high-flow oxygen therapy, inhaled gases, and aerosols in the care of critically ill patients. The available evidence supports the use of high-flow nasal cannulae for selected patients with acute hypoxaemic respiratory failure. Heliox might prevent intubation or improve gas flow in mechanically ventilated patients with severe asthma. Additionally, it might improve the delivery of aerosolised bronchodilators in obstructive lung disease in general. Inhaled nitric oxide might improve outcomes in a subset of patients with postoperative pulmonary hypertension who had cardiac surgery; however, it has not been shown to provide long-term benefit in patients with acute respiratory distress syndrome (ARDS). Inhaled prostacyclins, similar to inhaled nitric oxide, are not recommended for routine use in patients with ARDS, but can be used to improve oxygenation in patients who are not adequately stabilised with traditional therapies. Aerosolised bronchodilators are useful in mechanically ventilated patients with asthma and chronic obstructive pulmonary disease, but are not recommended for those with ARDS. Use of aerosolised antibiotics for ventilator-associated pneumonia and ventilator-associated tracheobronchitis shows promise, but the delivered dose can be highly variable if proper attention is not paid to the delivery method.

An 81-year-old man presented with fever, cough, and shortness of breath. Within a few hours after presentation, chest pain and respiratory distress developed. A chest radiograph showed bilateral patchy airspace opacities, with predominance in the peripheral lower lung zone and with relative sparing of the perihilar region. A diagnostic test was performed.

Background Interprofessional education (IPE), defined as when students from two or more professions learn about, from, and with each other, has been widely espoused as a way to promote collaborative and high-quality patient care. IPE initiatives are now commonplace in undergraduate medical education, but it is unclear whether the principles of IPE are reinforced during clinical rotations. Specifically, little is known about whether, when, and how interprofessional providers (IPPs), including nurses (RN), pharmacists (PharmD), and respiratory therapists (RT), participate in teaching medical students. This study aimed to elucidate the perspective of medical students about how IPPs impacted their education during clinical rotations in the intensive care unit (ICU). Methods Surveys were distributed to medical students who rotated in the medical ICUs at three academic medical centers over a 12-month period. Survey questions focused on three major domains: IPP roles during daily rounds, interprofessional teaching (IPT) outside of rounds, and students’ attitudes about IPT. Survey data were analyzed with descriptive and comparative statistics. Free text comments were analyzed using qualitative thematic analysis. Results Twenty five out of 53 medical students completed the survey (47%). Students reported that IPPs were commonly present on ICU rounds. Students’ reports of IPP teaching varied across professions. On a 5-point Likert scale, pharmacists were perceived to teach most frequently (mean 3.58, SD 0.81), compared to RTs (mean 2.88, SD 1.01) and nurses (mean 2.17, SD 0.80) (one-way ANOVA, F(2, 69) = [14.89], p  < 0.005). On a 7-point Likert scale, IPPs were described as teaching a moderate amount outside of rounds [RN (mean 3.46, SD 1.71), PharmD (mean 4.04, SD 1.49), RT (mean 4.00, SD 1.35)], with the majority of RN and RT teaching occurring at the bedside. Students reported generally positive attitudes about IPT, with most endorsing confidence in IPP knowledge base (92%) and teaching abilities (88%); 67% would have a positive reaction if attending physicians invited more IPT on rounds. Conclusions Medical students report variable levels of teaching from IPPs on ICU rounds, but similar levels of teaching outside of rounds. Students endorsed positive attitudes toward the idea of enhancing interprofessional teaching in the ICU.

Background No standardized index exists to assess cardiovascular responsiveness to angiotensin-II. We hypothesized that a standardized index of initial blood pressure response to angiotensin-II treatment would be associated with clinical outcomes. Methods Using data from the Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we developed an Angiotensin-II Initial MAP Response Index of Treatment Effect (AIMRITE) defined as (MAP at hr1 – MAP at baseline)/study drug dose. We assessed AIMRITE continuously and, based on observed distributions, we additionally categorized patients as “responsive” or “resistant”, with responsiveness defined by an AIMRITE ≥ 0.90 mmHg/ng/kg/min. The primary clinical outcome was 28-day mortality. Secondary outcomes included days alive and vasopressor- or ventilator- or renal replacement therapy-free at day-7. Biological outcomes included baseline renin, angiotensin-II, and renin/angiotensin-II ratio, and their change at hr3. Results Of 158 placebo patients, as expected, 157 (99%) had AIMRITE < 0.90 mmHg/ng/kg/min (median AIMRITE 0.02; IQR − 0.03–0.10). In contrast, 163 patients assigned to angiotensin-II had a median AIMRITE of 1.43 mmHg/ng/kg/min (IQR 0.35–2.83). Of these, 97 (60%) were responsive (median AIMRITE 2.55; IQR 1.66–4.12) and 66 (40%) were resistant (median AIMRITE 0.24; IQR 0.10–0.52). Each 1.0-unit increase in AIMRITE was associated with a 16% lower hazard of death (HR: 0.84 per-mmHg/ng/kg/min [95% CI 0.74–0.95], p  = 0.0062). Responsive patients had half the mortality hazard than resistant patients (HR: 0.50 [95% CI 0.32–0.78], p  = 0.0026) and placebo patients (HR 0.58 [95% CI 0.40–0.86], p  = 0.0064). Resistant patients had a similar mortality hazard to placebo (HR 1.17 [95% CI 0.80–1.72], p  = 0.41). Compared to resistant patients, responsive patients had lower baseline renin and renin/angiotensin-II ratio, but a greater decrease in both at hr3. When stratified by baseline renin level, mortality was highest in placebo patients with high renin (69%) and angiotensin-II resistant patients with low renin (61%). Conclusions Among patients with catecholamine-refractory vasodilatory shock treated with angiotensin-II, the AIMRITE was associated with mortality at day-28. Responsive angiotensin-II patients had higher survival versus both angiotensin-II resistant patients and those treated with placebo plus standard vasopressors. This index may serve as a prognostic indicator and early identifier of patients most likely to benefit from angiotensin-II.

The contribution of aeration heterogeneity to lung injury during early mechanical ventilation of uninjured lungs is unknown. To test the hypotheses that a strategy consistent with clinical practice does not protect from worsening in lung strains during the first 24 hours of ventilation of initially normal lungs exposed to mild systemic endotoxemia in supine versus prone position, and that local neutrophilic inflammation is associated with local strain and blood volume at global strains below a proposed injurious threshold. Voxel-level aeration and tidal strain were assessed by computed tomography in sheep ventilated with low Vt and positive end-expiratory pressure while receiving intravenous endotoxin. Regional inflammation and blood volume were estimated from 2-deoxy-2-[(18)F]fluoro-d-glucose ( F-FDG) positron emission tomography. Spatial heterogeneity of aeration and strain increased only in supine lungs (P < 0.001), with higher strains and atelectasis than prone at 24 hours. Absolute strains were lower than those considered globally injurious. Strains redistributed to higher aeration areas as lung injury progressed in supine lungs. At 24 hours, tissue-normalized F-FDG uptake increased more in atelectatic and moderately high-aeration regions (>70%) than in normally aerated regions (P < 0.01), with differential mechanistically relevant regional gene expression. F-FDG phosphorylation rate was associated with strain and blood volume. Imaging findings were confirmed in ventilated patients with sepsis. Mechanical ventilation consistent with clinical practice did not generate excessive regional strain in heterogeneously aerated supine lungs. However, it allowed worsening of spatial strain distribution in these lungs, associated with increased inflammation. Our results support the implementation of early aeration homogenization in normal lungs.

Outcomes and risk factors associated with new-onset atrial fibrillation (AF) during acute respiratory distress syndrome (ARDS) are unclear. We investigated mortality and risk factors associated with new-onset AF during ARDS. We obtained data from the ARDS Network Albuterol for Treatment of Acute Lung Injury trial, which prospectively identified new-onset AF among patients with ARDS as an adverse event. We determined Acute Physiology and Chronic Health Evaluation III–adjusted associations between new-onset AF and 90-day mortality. We also examined associations between new-onset AF and markers of inflammation (interleukin 6 and interleukin 8), myocardial injury (troponin I), autonomic activation (epinephrine), and atrial stretch (central venous pressure) as well as other clinical characteristics. Of 282 patients (mean age, 51.6 years; 45% women; 77% white) enrolled in Albuterol for Treatment of Acute Lung Injury, 28 (10%) developed new-onset AF during the study. We did not identify associations between new-onset AF and baseline central venous pressure, plasma levels of troponin I, epinephrine, interleukin 6, or interleukin 8. New-onset AF during ARDS was associated with increased 90-day mortality (new-onset AF, 43% vs no new-onset AF, 19%; Acute Physiology and Chronic Health Evaluation–adjusted odds ratio, 3.09 [95% confidence interval, 1.24-7.72]; P = .02). New-onset AF during ARDS is associated with increased mortality; however, its mechanisms require further study.

IntroductionSepsis is a highly morbid condition characterized by multi-organ dysfunction resulting from dysregulated inflammation in response to acute infection. Mitochondrial dysfunction may contribute to sepsis pathogenesis, but quantifying mitochondrial dysfunction remains challenging.ObjectiveTo assess the extent to which circulating markers of mitochondrial dysfunction are increased in septic shock, and their relationship to severity and mortality.MethodsWe performed both full-scan and targeted (known markers of genetic mitochondrial disease) metabolomics on plasma to determine markers of mitochondrial dysfunction which distinguish subjects with septic shock (n = 42) from cardiogenic shock without infection (n = 19), bacteremia without sepsis (n = 18), and ambulatory controls (n = 19) – the latter three being conditions in which mitochondrial function, proxied by peripheral oxygen consumption, is presumed intact.ResultsNine metabolites were significantly increased in septic shock compared to all three comparator groups. This list includes N-formyl-l-methionine (f-Met), a marker of dysregulated mitochondrial protein translation, and N-lactoyl-phenylalanine (lac-Phe), representative of the N-lactoyl-amino acids (lac-AAs), which are elevated in plasma of patients with monogenic mitochondrial disease. Compared to lactate, the clinical biomarker used to define septic shock, there was greater separation between survivors and non-survivors of septic shock for both f-Met and the lac-AAs measured within 24 h of ICU admission. Additionally, tryptophan was the one metabolite significantly decreased in septic shock compared to all other groups, while its breakdown product kynurenate was one of the 9 significantly increased.ConclusionFuture studies which validate the measurement of lac-AAs and f-Met in conjunction with lactate could define a sepsis subtype characterized by mitochondrial dysfunction.

Background Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient’s response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects. Methods We studied 5 controls and 4 subjects with PAH using HRCT and 13 NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV 2 Qtotal ) and its components in the vertical (CV 2 Qvgrad ) and cranio-caudal (CV 2 Qzgrad ) directions, and the residual heterogeneity (CV 2 Qr ), were assessed at baseline and while breathing oxygen and nitric oxide (O 2  + iNO). The length scale spectrum of CV 2 Qr was determined from 10 to 110 mm, and the response of regional perfusion to O 2  + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Q vgrad ) were derived from perfusion images, and ventilation-perfusion distributions from images of 13 NN washout kinetics. Results O 2  + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O 2  + iNO, CV 2 Qvgrad was significantly higher in controls than in PAH (0.08 (0.055–0.10) vs. 6.7 × 10 –3 (2 × 10 –4 –0.02), p < 0.001) with a considerable gap between groups. Q vgrad and CV 2 Qtotal showed smaller differences: − 7.3 vs. − 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV 2 Qvgrad had the largest effect size among the primary parameters during O 2  + iNO. CV 2 Qr , and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant. Conclusions Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.