ARDS Review

AJRCCM Articles in Press. Published on 08-April-2019 as 10.1164/rccm.
201903-0550UP
Page 1 of 33
Update in Critical Care / ARDS 2018
Ivor S. Douglas, MD FRCP1, Joseph S Bednash, MD2, Daniel G. Fein, MD3, Rama K. Mallampalli, MD4,
Jason Mansoori, MD1 and Hayley B. Gershengorn, MD5.
1Pulmonary, Sleep and Critical Care Medicine, Denver Health Medical Center, Department of Medicine,
MC 4000, 601 Broadway Denver, CO 80204;

2Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC
Montefiore, NW 628, Pittsburgh, PA 15213.

3Montefiore Medical Center, Medical Arts Pavilion, 3400 Bainbridge Avenue , Room 5H Bronx, NY
10467
4Department of Medicine, The Ohio State University, 395 W. 12th Avenue, 3rd Floor Room 392,
Columbus, OH 43210;
5University of Miami, Miller School of Medicine, Division of Pulmonary, Allergy, Critical Care, and
Sleep Medicine Rosenstiel Medical Science Building, Rm. 7043B, 1600 NW 10th Avenue Miami, FL
33136;
Contributions: All authors contributed equally to the literature review, drafting and editing of the
manuscript.
Running Head: Critical Care and ARDS Update 2018
Body: 4990 words
References: 109
Copyright © 2019 by the American Thoracic Society

AJRCCM Articles in Press. Published on 08-April-2019 as 10.1164/rccm.201903-0550UP
Page 2 of 33
The vibrant and diverse spectrum of scientific output in the fields of Acute Lung Injury mechanisms,
clinical ARDS and the related fields of sepsis and non-pulmonary critical care are illustrated by
publications in ATS Journals during 2018. Efforts to translate basic mechanistic insights to clinical
diagnostics and therapeutics are a particular focus of this invited review.
Acute Respiratory Distress Syndrome and Experimental Acute Lung Injury
The acute respiratory distress syndrome (ARDS) has been studied in preclinical models of
experimental acute lung injury (ALI), a widespread alveolar-capillary insult resulting in significant
damage to normal functioning alveoli. A snapshot of injured alveoli reveals barrier membrane damage,
alveolar flooding with protein-rich edema, and activated inflammatory cells. This environment rich in
cytokines, cellular debris, proteinases, and reactive oxygen species leads to perturbation of molecular
signaling. Current therapy for ARDS is supportive care (1). Ongoing basic and translational research aims
to describe molecular pathways leading from insult to injury to identify novel therapies.
Experimental Methods
Reliable and reproducible disease models are central to fundamental discovery. In experimental
ALI mouse models, methods of euthanasia and lavage impact experimental results such as cell counts and
lavage protein levels but do not affect lung histology. In a mild injury model, euthanasia and lavage
methods limited the ability to detect differences in lung injury, lending evidence to the importance of
transparency in method reporting and thoughtful design (2).
Human distal airspace samples are invaluable to ARDS research. To determine if fluid from the
ventilator inline heat moisture exchanger (HME) is representative of the distal airspace in ARDS, samples
were collected from patients with ARDS and hydrostatic edema controls (3). Using liquid
chromatography–coupled tandem mass spectrometry, the protein composition and biomarker
quantification of HME fluid correlated strongly with fluid samples from deep airspaces (r2 = 0.849–

Page 3 of 33
0.951); there were distinct differences in the proteome of ARDS patients compared to controls, supporting
HME fluid as a valuable sampling source (4).
ARDS severity and treatment considerations are defined by the ratio of PaO2 to FiO2 (P/F).
Among 105 patients with moderate ARDS, those with more severe hypoxemia (P/F = 101-149 mmHg
vs.150-199 mmHg) demonstrated higher peak pressures, pH, PaCO2, heavier lungs, greater
heterogeneity, more non-inflated tissue, and greater lung recruitability (5). This study shows utility of
subdividing moderate ARDS using a P/F threshold of 150 mmHg, but the value of P/F alone in
identifying treatment responsive patients may be limited given the heterogeneity in ARDS (6).
Pathophysiology
To date, the search for pharmacological therapies for ARDS has been unsuccessful. Technology
allows for analysis of larger datasets to identify novel targets. Among subjects enrolled in ARDSNet
FACTT (Fluid and Catheter Treatment Trial), a single-nucleotide polymorphism (SNP) in mitogen-
activated protein kinase kinase kinase 1 (MAP3K1) was associated with decreased ventilator-free days
and greater inflammatory response (7). Study of diverse populations may identify novel targets as well. A
genome-wide association study was performed among 232 African American ARDS patients and 162 at-
risk controls (6). A nonsynonymous coding SNP (rs2228315) within the selectin P ligand gene, encoding
P-selectin glycoprotein ligand 1 (PSGL-1), was associated with increased ARDS susceptibility. In mouse
models, antibody neutralization of PSGL-1 attenuated endotoxin-induced lung inflammation (8). Another
gene implicated in ARDS pathogenesis is the non-muscle isoform of myosin light chain kinase
(nmMLCK) involved in vascular barrier maintenance and encoded by MYLK. Alternative splicing of
MYLK by hnRNPA1 led to increases in the pro-inflammatory isoform nmMLCK2, shown to be less
effective in vascular barrier restoration (9, 10).
Numerous previously identified candidate targets in experimental ALI are still being fully
characterized. The cytozyme nicotinamide phsphoribosyltransferase (NAMPT) is one such candidate.

Page 4 of 33
Secreted eNAMPT (extracellular) engages Toll-like receptor (TLR)-4 in response to tumor necrosis factor
(TNF)- resulting in reduced endothelial cell apoptosis (11). Another candidate is gasdermin-D
(GSDMD), a cytoplasmic protein that induces inflammatory cell death or pyroptosis. Similar to NAMPT,
it leads to endothelial cell damage in experimental ALI and is released in microparticles from monocytes
in the setting of sepsis or inflammatory injury. This model provides a possible mechanism for indirect
pulmonary injury in sepsis (12, 13).
Numerous proteins contribute to alveolar-capillary barrier maintenance and may serve as targets
to preserve barrier integrity. Functioning in cell-cell adhesion, the erythropoietin-producing hepatoma
receptor tyrosine kinase A2 (EphA2) and its ligand, ephrinA1, can contribute to lung injury by increasing
barrier permeability. In a mouse model of ventilator induced lung injury (VILI), EphA2 antagonism had a
protective effect on mechanical lung injury (14). The SRY (sex-determining region on the Y
chromosome) – related high-mobility group box (Sox) group F family member, SOX18, increased the
expression of the tight junction protein CLDN5 involved in endothelial barrier maintenance. Gene
delivery of SOX18 to the mouse lung prevented endotoxin-induced lung injury and preserved lung
mechanics (15). Although not as well studied as vascular endothelium, alveolar epithelium contributes to
barrier function. Using immunofluorescence staining, the epithelial glycocalyx is rich in heparan and
chondroitin sulfate; heparan sulfate has importance in prevention of protein leak across the membrane
(16, 17).
A damage-associated molecular pattern (DAMP), CpG-containing cell-free mitochondrial DNA
(cf-mtDNA) is elevated in critically ill patients and is associated with increased morbidity and
mortality. Under basal conditions and after systemic infection, CpG-DNA binds to red blood cells
(RBCs) through Toll-like receptor 9 (TLR9), scavenging CpG-DNA and minimizing lung injury. These
findings provide a novel approach for developing new therapies leveraging natural homeostatic processes,
and suggest a role for RBCs in treatment of critical illness (18, 19).
Mechanisms of Lung Injury and Prevention in Humans

Page 5 of 33
In a preplanned ancillary substudy of the LIPS-A trial of aspirin for ARDS prevention, lipid
mediators, plasma thromboxane B2, aspirin-triggered lipoxin A4 (ATL), and peripheral blood leukocytes
were collected from 397 at-risk patients randomized to aspirin versus placebo (20). Baseline peripheral
blood monocyte counts, monocyte-platelet aggregates, and plasma ATL levels were associated with
development of ARDS. There was also a trend towards decreased incidence of ARDS with aspirin. While
conclusions are limited by the low incidence of ARDS (9.0%), these findings suggest a preventative role
for aspirin (21).
After severe blunt trauma, in a pilot study smoking status was associated with lung bacterial
community composition at ICU admission and at 48 hours (22). ARDS was associated with lung
community composition only at 48 hours and correlated with taxa that are relatively enriched in smokers
at ICU admission, suggesting that smoking-related changes in the microbiome could be related to ARDS
development after severe trauma (23).
Mechanical ventilation strategies in ARDS may propagate lung injury (24, 25). A challenge in
ARDS research is the heterogeneity of damage across the lung. In a bleomycin model of injury,
stereological modeling of lung architecture demonstrated correlation of heterogeneity of alveolar units
with injury. Injured alveoli required higher pressures to open and some units remain collapsed regardless
of pressure, similar to radiographic heterogeneity seen in humans with ARDS (26). Additionally,
uninjured lungs may be susceptible to VILI from heterogenous aeration. In a study assessing
mechanically ventilated sheep by computerized tomography, spatial heterogeneity of aeration and strain
increased only in supine lungs (27). Supine positioning associated with higher strains and atelectasis than
prone positioning at 24 hours, although absolute strains were below that considered globally injurious.
Prone positioning increased homogeneity of lung inflation without additional stretch induced by PEEP
(28).

Page 6 of 33
Optimizing PEEP during mechanical ventilation can help prevent lung overdistention and
biotrauma. Esophageal manometry has been proposed as a method for selection of optimal PEEP (29).
Esophageal pressures (Pes) accurately reflect local pleural pressures (Ppl) in dependent to middle lung
regions adjacent to the esophageal balloon in experimentally lung-injured pigs and human cadavers (30).
For nondependent lung, inspiratory transpulmonary pressure (Ptp) calculated from elastance ratio
corresponds to local Ptp. While these findings supports the use of esophageal manometry to minimize
atelectasis in nondependent lung regions(31) the recently published Phase II EPVent 2 clinical trial of
Pes-guided PEEP titration failed to reduce mortality or ventilator dependence among patients with
moderate to severe ARDS compared with an empirical high PEEP-Fio2 strategy(32). This rigorous
clinical trial is likely to curtail future enthusiasm for Ptp-guided PEEP selection.
Deflation-induced lung injury may also contribute to lung injury. Among ventilated rats
randomized to receive constant PEEP of 3 cmH20 (control) versus incrementally increasing PEEP from 3
to 11 cm H2O followed by abrupt deflation to zero PEEP, findings demonstrated deflation-induced lung
injury characterized by acute left ventricular decompensation, elevated pulmonary microvascular
pressures, edema, and resultant endothelial injury (33). Description of this novel form of lung injury
supports further studies to fully explain the mechanisms, pathologic consequences and potential clinical
relevance of abrupt lung deflation (34).
Potential Therapeutic Interventions in Pre-clinical Models
Preclinical therapeutic models in ARDS focus on restoring normal physiology and mitigating
alveolar damage. The tripartite motif family protein 72 (TRIM72), a protein with known functions in
membrane repair, was first described as contributing to skeletal muscle repair. In a mouse model of VILI,
inhaled TRIM72 enhanced repair of the lung epithelium and protected the lung from VILI if delivered
prior to insult (35, 36). Bronchopulmonary dysplasia (BPD) affects preterm infants exposed to
mechanical ventilation and oxygen. BPD is characterized by impaired lung alveolar epithelial and
vascular endothelial cell development. Elafin, an elastase-specific protease inhibitor, preserves

Page 7 of 33
phosphorylated epidermal growth factor receptor (pEGFR) and Kruppel-like factor 4 (Klf4) signaling, a
pro-survival pathway in lung epithelium. Inhibition of elastases by elafin may have relevance in adults
with ARDS to combat alveolar-capillary barrier dysfunction (37, 38).
Sepsis and ARDS display profound cytokine dysregulation, with an initial burst in inflammatory
responses followed by relative immunosuppression. While numerous anti-inflammatory therapeutics have
been trialed, Rhesus -defensin (RTD)-1, an 18 amino acid peptide is unique; it displays both anti-
inflammatory and antimicrobial properties. In a mouse model of endotoxin-induced ARDS, RTD-1 was
protective in both pre- and post-treatment strategies (39, 40). Following the initial inflammatory phase,
post-septic patients are at a higher risk for secondary lower respiratory tract infection, thought to result
from “immune paralysis”. In a two-hit model of post-septic ARDS, administration of interferon (IFN)-,
a type I IFN, restored innate immune responsiveness with improvement in mortality. However, translation
to humans may prove difficult. IFN- therapy may worsen experimental lung injury in the acute phase
(41, 42) and in a recently completed clinical trial (NCT02622724), IFN--1a failed to reduce mortality or
increase ventilator free days in ARDS patients (43).
In the light of recent global events, study of ARDS from direct toxin inhalation (e.g., chlorine) is
an area of important study. A recent study evaluating oxygen supplementation in chlorine-exposed rats
resulted in significantly increased survival, but those surviving rats showed greater lung injury. Whether
this represents true morbidity caused by supplemental oxygen versus a survivor bias is unclear and raises
questions regarding oxygen delivery in other forms of ARDS (44, 45).
Therapeutic Role of Prone Positioning, Paralytics, and ECMO in Human ARDS
While prone positioning improves survival in ARDS (46), the causal association of well
characterized salutatory mechanisms of the prone position in ARDS (47) with mortality reduction remains
unclear. A prospective study using hydrochloric acid-induced lung injury in rats and pigs examined
whether prone positioning limits lung injury by minimizing “unstable” inflation (partial aeration with

Page 8 of 33
large tidal density swings, indicating increased local strain) (48). Findings demonstrated that radiologic
progression of early lung injury was limited by prone positioning with evidence of reduced unstable
inflation (49).
Neuromuscular blockade eliminates patient-ventilator interactions and reduces VILI (50). In a
retrospective study, there was no significant difference in mortality or hospital days between patients
receiving cisatracurium versus vecuronium (51). However, cisatracurium was associated with fewer
ventilator (-1.01 d; P=0.005) and ICU (-0.98 d; P=0.028) days. Although the observed effect is modest,
findings from this study support cisatracurium as the paralytic of choice in ARDS (51).
The recent Extracorporeal Membrane Oxygenation (ECMO) for Severe ARDS (EOLIA) trial
demonstrated inconclusive support for the benefit of ECMO (52). In a retrospective multicenter study
involving 203 immunocompromised patients with severe ECMO-treated ARDS, six-month survival was
30% (53). Outcomes were worse in patients with hematological malignancies, while 6-month mortality
was better in those with recently diagnosed (<30 days) immunodeficiency (odds ratio 0.32, P=0.002).
Lower platelet count, higher PCO2, age, and driving pressure were independent pre-ECMO predictors of
6-month mortality. This study affirms a call for personalized treatment strategies in critical care medicine
including ECMO (54).
Sepsis
The physiology, diagnosis and treatment of sepsis are areas of active investigation (55). To
evaluate if sepsis-associated brain dysfunction is related to sterile inflammatory mediators or bacterial
translocation to the central nervous system in a murine model gut-associated bacteria were shown to
disseminate to the brain of septic mice (56). Using human brain bank specimens the role of bacteria in
septic brain dysfunction was corroborated, as microbial communities in brain specimens from patients
who died from sepsis differed from those who died from non-sepsis causes.

Page 9 of 33
Tools to identify patients with sepsis or at risk for poorer outcomes remain a focus of
investigation. The performance of a multimarker gene expression assay (SeptiCyte LAB host response) in
447 patients across 8 sites (57) was compared to retrospective expert panel diagnosis. The SeptiCyte
LABtest distinguished sepsis from noninfectious systemic inflammation (AUROC 0.82 - 0.89, depending
on the degree of confidence in the clinical diagnosis) and outperformed both SIRS criteria and
procalcitonin levels. Clinical utility may be limited by the time delay for this assay and poor performance
in pneumonia patients.
Septic patients admitted to low case volume hospitals are known to have worse outcomes;
whether this risk extends to immunosuppressed patients was investigated using the Vizient administrative
database (58). The odds of hospital death were highest in hospitals with the lowest case volumes of
immunosuppressed septic patients (OR, 1.38; 95% CI, 1.27-1.5), consistent with observations in the
general sepsis population.
Skepticism remains regarding routine initial fluid resuscitation in early septic shock (59, 60). To
investigate the impact of early fluid administration, (61) anti-inflammatory cytokines and hemodynamic
parameters were measured following 40 ml/kg of 0.9% saline in sheep with endotoxemic, hyperdynamic
shock (61). Animals resuscitated with saline required more noradrenaline (335 ng/ml [95% CI, 256, 382]
vs. 233 ng/ml [95% CI, 144, 292]; P = 0.04) and had increased atrial natriuretic peptide release and
glycocalyx glycosaminoglycan hyaluron shedding. These findings suggestive of harm increase interest in
the ongoing CLOVERS (crystalloid liberal or vasopressor early resuscitation in sepsis) study in
humans(62).
Mesenchymal stem (stromal) cells (MSCs) may modify the pathophysiology of sepsis and
possibly alter outcomes. To examine the safety and tolerability of MSCs in septic shock, patients were
randomized within 24 hours of ICU admission to receive a single intravenous MSC dose of either
0.3, 1.0, or 3.0 × 106 cells/kg (63). With no serious adverse events or cytokine differences between
intervention and control cohorts, administration of freshly cultured MSCs appears safe at the studied

Page 10 of 33
dosages. An additional recent phase 2 trial demonstrating the safety of 10.0 × 106 MSC/kg administration
(64)provides encouragement for future evaluations of optimal MSC dosing parameters and studies of
clinical efficacy.
Data from 185 hospitals in New York between April 1, 2014 and June 30 2016 (following a 2013
initiative to improve sepsis recognition) assessed 3-hour and 6-hour bundle compliance and associated
outcomes for septic patients (65). Bundle adherence increased and risk-adjusted mortality decreased
(28.8% to 24.4%, P<0.001); causality is unclear as these observations were uncontrolled for disease
severity and other temporal changes in care delivery.
Health system factors are increasingly being recognized to impact sepsis care. The impact of ICU
capacity strain on triage (to ICU vs ward) decisions for adults in the emergency department (ED) with
sepsis not requiring life support were evaluated (66). In adjusted analyses, only ICU occupancy was
independently associated with triage decision. For every 10% increase in ICU occupancy there was an
associated 13% decrease in the odds of ICU admission; and, for patients admitted to a medical ward, ICU
occupancy at the time of admission was associated with increased odds of hospital mortality (odds ratio,
1.61; 95% CI, 1.21 - 2.14). Other industries face similar challenges regarding occupancy and strain, yet
the end goal of care quality is unique to medicine (67). In a retrospective study of 361 community
dwelling adults presenting to a single academic ED with septic shock, arrival by advanced life support
(ALS) ambulance was associated with shorter door-to-antibiotic time than transport by basic life support
(BLS) ambulance or non-ambulance (ALS vs walk-in: 43 minutes faster, p=0.033; ALS vs BLS: 39
minutes faster, p=0.046) (68). This observation questions whether additional sepsis education for BLS
providers and the community versus expedited ED physician evaluation would improve time-to-
antibiotics.
Coping with Death and Chronic Critical Illness
10

Page 11 of 33
Several studies have investigated the psychological toll of death and chronic critical illness. In a
secondary analysis of 306 surrogates who participated in a multicenter RCT, 30% had evidence of PTSD
90-days after study enrollment (69). Surrogate anxiety, surrogate depression, and patient
unresponsiveness at hospital day 10 were independently associated with 90-day surrogate PTSD. In a
multicenter study in 28 French ICUs the impact of the organ donation process on grief was assessed (70).
Compared to relatives of donors, relatives of non-donors had more dissatisfaction with communication
(27% vs. 10%; P=0.021), feelings of shock by the donation request (65% vs. 19%; P<0.0001) and
struggles with the donation decision (53% vs. 27%; P=0.017). Understanding brain death was associated
with less grief (46.1% vs. 75%; P=0.026), yet grief did not differ between relatives of donors and non-
donors.
Programs and tools centered on improved end-of-life care may impact stakeholder experience.
Using data from >1 million ICU admissions across 151 New York State hospitals, a retrospective analysis
found having a palliative care program at the hospital to which patients were admitted was independently
associated with a 46% increased odds of discharge to hospice (unadjusted rates: 1.7% vs 1.4%) without
meaningful differences in inpatient resource use or hospital mortality (71). This work compels us to
consider how to deliver efficient and impactful palliative care (72). To address these issues, use of a web-
based, integrated palliative care planner to improve provider-family communication was evaluated (73).
Unmet palliative care needs were reduced, palliative care was delivered sooner, hospital length of stay
was shorter (20.5 (SD, 9.1) vs. 22.3 (SD, 16.0) days) and post-ICU hospice care increased (36% vs. 20%)
using the tool. A second study (74) found that a coping skills training program did not improve
psychological distress for all ICU survivors at 3 months; yet, it was effective among high-risk patients—
those with high baseline distress or ventilated >7 days. Together with the POPPI study of a nurse-led
intervention that was ineffective in reducing patient-reported PTSD symptoms (75) and the PARTNER
randomized trial which found no improvement in psychological burden with a family support intervention
11

Page 12 of 33
(76), future studies of structured communication and psychological support should identify patients and
families most likely to derive benefit.
ICU clinicians frequently care for dying patients. Structured interviews (n=100) revealed that the
perceived quality of death (OR 3.08; 95% CI, 1.75, 7.25), loss of dignity (OR, 2.95; 95% CI, 1.19, 7.29)
and patient suffering (OR, 2.34; CI, 1.03, 5.29) were associated with nursing emotional distress (77); yet,
patient symptoms and interventions (cardiac resuscitation or palliative care consultation) were not.
Because the emotional and existential components of the dying process are most distressing, nursing
empowerment and resilience may mitigate nursing distress. A qualitative study of 18 critical are
physicians was conducted to understand how conflict regarding end-of-life care with patient surrogates is
managed (78). A common technique was reciting a narrative of illness trajectory concluding with the
physician’s proposed plan of care. Physician use of persuasion varied and styles appeared to evolve over
time.
Risk-Stratification
Risk stratification for the critically ill is commonly used for outcome prediction. The validity of
existing risk scores is often low, particularly in under-resourced environments. A retrospective study of
450 patients in one Kenyan public sector national referral institution’s 6-bed ICU found 30-day mortality
to be 57.3% while MPM0-II predicted mortality was only 21.4% (AUROC 0.78, but poor calibration);
MPM0-II systematically underestimated mortality, but performed most poorly in less severely ill patients
(79), supporting development of illness severity indicators specific to resource-limited settings.
Several groups developed new tools to aid in risk-stratification. A machine-learning model was
developed and validated to predict risk for ICU readmission (80). The derived risk score was moderately
accurate (validation AUROC: 0.71, 95% CI, 0.70-0.72) and could be integrated into existing electronic
health records. Whether use in clinical practice would prevent ICU readmissions versus needlessly
delaying ICU discharge needs further study (81). The “AT-RISK” score for hypoxemia during emergent
tracheal intubation was developed from a secondary analysis of data from two RCTs of 426 adult ICU
12

Page 13 of 33
patients (82). Age, operator experience, patient race, indication for intubation, oxygen saturation at
induction, and body mass index were identified as predictors of severe hypoxemia (AUROC 0.71 (95%
CI, 0.65, 0.78)). Although this study used rigorous methodology, the score currently lacks external
validation (83). To assess risk for Pneumocystis jirovecii pneumonia (PjP) in patients with hematologic
malignancy and respiratory failure, a multivariable prediction model (development cohort: 1,092 patients;
validation cohort: 238 patients) was developed (84). Lymphoproliferative disease, no anti-PjP
prophylaxis, 3+ days between respiratory symptom onset and ICU admission and no radiographic
alveolar pattern were associated with higher PjP risk; age >50 and presence of shock or pleural effusion
made PjP less likely. A score of < 3 had excellent negative predictive value (97.9%) supporting
application in clinical practice.
Transitions of Care
Both patient and system factors may impact care transitions. A prospective cohort study of 754
older adults (age >70) admitted to the ICU established the role that pre-ICU cognitive status plays in
long-term outcomes (85). Any cognitive impairment (mini-mental status examination (MMSE) score <
28) was associated with increased post-ICU disability and, following multivariable analysis, moderate
impairment (MMSE<25) was independently associated with nursing home placement following discharge
(RR, 1.19; 95% CI, 1.04-1.36); cognitive impairment was not associated with 6-month mortality. A
qualitative study of 14 caregivers and 19 patients investigated modifiable processes that might optimize
transition to home-based MV (86). Facilitators of home MV were perceived improved health status while
receiving MV, attainment of knowledge and skills prior to home transition, social support and advanced
home preparation; barriers included conflict with health professionals regarding the feasibility home
ventilation, perceived lack of training and lack of skilled support at home. Professional support by
telephone, outreach, and further training would improve patient experiences with home MV.
Mechanical Ventilation
Variable Provider Practices
13

Page 14 of 33
To explore MV weaning practices, members of 6 regional intensive care societies were surveyed
(87). Among 1,144 respondents, there was geographic variability in the screening frequency for
spontaneous breathing trials (SBT), SBT techniques, ventilator modes, written protocols, use of non-
invasive ventilation and personnel involved in weaning. SBTs were most commonly performed with
pressure support and positive end-expiratory pressure (range, 56.5%-72.3%); use of T-piece was used
most in India (59.5%) and Europe (45.9%). An analysis of Medicare, fee-for-service data (11,268
patients, 345 physicians) found 30-day mortality for MV patients was associated with individual provider
(OR 0.72 to 1.64, median 0.99; IQR=0.92-1.09) (88). Neither years in practice nor annual volume of MV
patients drove this variability. Attributing outcomes to a specific administratively listed physician—when
multiple providers and care processes contribute to patient care—is challenging, however (89).
Inspiratory Muscle Impairment and PEEP
To examine the association of MV-induced diaphragmatic atrophy and prolonged MV, diaphragm
thickening fraction was measured by daily ultrasound (90). Decreasing thickness (>10%, diaphragm
atrophy) occurred in 41% of patients (median of day 4) and was associated with lower daily probability of
MV liberation (adjusted hazard ratio 0.69; 95% CI, 0.54-0.87; per 10% decrease) as well as prolonged
ICU admission. Increasing thickness (related to excessive effort) also predicted prolonged MV, while
patients with a thickening fraction similar to breathing at rest during the first 3 days had the shortest MV
duration. These findings support integration of diaphragm-protective strategies into clinical protocols
(91). The effect of MV with positive end-expiratory pressure (PEEP) as a contributor to diaphragm
dysfunction was assessed in a study of critically ill patients and rats (92). PEEP resulted in caudal
diaphragmatic movement, reduced muscle fiber length, and subsequent longitudinal atrophy (modulated
by the elasticity of titin, a giant sarcomeric protein). As longitudinal and cross-sectional atrophy may
contribute to failed SBTs, gradual reductions of PEEP before discontinuing MV could mitigate adverse
clinical consequences during weaning from MV (93).
14

Page 15 of 33
To determine whether dependent lung injury is increased by spontaneous effort, regional lung
injury was compared in paralyzed vs. non-paralyzed animal models of severe ARDS (rabbit, pig) and 11
patients (94). Stronger effort (vs. muscle paralysis) caused local overstretch and greater tidal recruitment
in dependent lung and increased dependent lung injury. Such effort-dependent lung injury was reduced by
high PEEP by more uniformly distributing negative pleural pressure and lowering the magnitude of
spontaneous effort, suggesting that higher PEEP in patients with recruitable lungs may provide a
reasonable alternative to paralysis to limit the potentially damaging regional effects of strong, effortful
breathing (34).
A systematic review and meta-analysis evaluated the role of inspiratory muscle training (IMT;
i.e., inspiratory threshold loading and flow resistive loading) in critical illness (95) and found it feasible,
well tolerated, and associated with significant increases in maximal inspiratory and expiratory pressure.
IMT was additionally associated with reduced MV weaning duration (pooled mean difference 3.2 d; 95%
CI, 0.6-7.5.8 days; I2=95%). Clinicians may consider IMT to improve diaphragmatic strength for patients
who have difficulty being liberated from MV.
General and Non-pulmonary Critical Care
In-hospital cardiac arrest remains a highly lethal complication of critical illness. Intra-arrest acute
right ventricular dysfunction and pulmonary hypertension are well described and may contribute to low
rates of return of spontaneous circulation. The impact of addressing these physiologic abnormalities with
inhaled Nitric Oxide (iNO, 80 ppm) during hemodynamic-directed CPR was investigated in a swine
septic shock model after induction of ventricular fibrillation (96). All 10 animals receiving iNO survived
to 45 minutes compared to 27% with CPR alone (P<0.001). Mean coronary perfusion pressures were
significantly better at 2 and 10 minutes into CPR in the iNO group. This improvement in short term
outcomes requires validation and extension to longer-term survival rates; however, a potential benefit of
iNO is less vasopressor use during CPR, as high dose vasopressors are associated with worse neurologic
outcomes (97).
15

Page 16 of 33
The REDUCE (98) and MIND-USA (99) studies have questioned the role of the dopaminergic
pathway in the evolution of ICU delirium. To evaluate the role of low-dose nocturnal dexmedetomidine
(DEX; an alpha-2 receptor agonist) in the prevention of ICU delirium, a two center, double-blind
randomized (DEX at 0.2 μg/kg/h, titrated by 0.1 μg /kg/h to maximum of 0.7 μg/kg/h versus placebo)
controlled trial enrolled 100 delirium-free critically ill adults (100). Patients in the DEX group were less
likely to develop ICU-delirium (80% delirium free vs. placebo 54%, relative risk, 0.44; 95% CI, 0.23–
0.82), had more delirium- and coma-free ICU days, had less severe pain, received lower doses of other
sedatives, and were less likely to be deeply sedated. The limited generalizability of these findings to the
“sizable percentage of ICU patients who develop delirium quickly” provide justification for future study
of DEX in this population. (101)
In a post hoc analysis of the AKIKI (Artificial Kidney Initiation in Kidney Injury) trial (RCT in
31 French ICUs of RRT timing for patients requiring MV and/or catecholamine infusion), the association
of timing of renal support and outcomes stratified by illness severity was studied (102). Consistent with
the primary trial finding of no difference in 60 day survival, outcomes stratified by SAPS 3 score, SOFA
score, and presence or absence of sepsis or ARDS failed to find a difference between early vs delayed
RRT. Renal recovery occurred significantly earlier with the delayed RRT strategy in patients with septic
shock (adjusted HR for renal recovery: 1.90 (1.41-2.58); P<0.001) or ARDS (1.7 (1.1-2.5); P=0.009),
justifying a “wait and see” approach to RRT (103).
To explore the mechanisms of persistent injury associated anemia, bone marrow from 17 patients
undergoing operative fixation of a traumatic hip or femur fracture was compared with that from 22
elective hip repair patients and 8 healthy controls (104). Erythroid progenitor growth was decreased in
trauma patients compared to both healthy controls and elective hip fracture patients; trauma patients had
lower transferrin receptor expression than elective hip fracture patients. Bone marrow erythropoietin and
erythropoietin receptor expression was similar between groups. The authors propose a response of
“neuroendocrine activation and systemic inflammation propagat[ing] iron dysregulation, mobilization of
16

Page 17 of 33
hematopoietic progenitors to injured tissues, and suppression of erythroid progenitor growth” to explain
persistent anemia, and also suggest a role for Vitamin D in regulating hepcidin and proinflammatory
molecule expression (105) .
Middle East Respiratory Syndrome (MERS) is a coronavirus illness with significant morbidity
and mortality. In a retrospective study in 14 Saudi Arabian ICUs, 151 of 309 MERS patients received
corticosteroids, and those receiving corticosteroids were more likely to receive invasive MV (93.4% vs.
76.6%; P < 0.0001) and die by 90 days (74.2% vs. 57.6%; P = 0.002). Adjusting for baseline and time-
varying factors, corticosteroids were not associated with 90-day mortality but were associated with
delayed MERS RNA clearance (106). This finding is consistent with prior literature on harm from
corticosteroids in other coronavirus infections (e.g., severe acute respiratory syndrome). (107)
The subglottic space is rapidly colonized with potential pathogens in intubated critically ill
patients. Analysis of subglottic secretions from 24 intubated patients yielded abundant neutrophil
accumulation, MUC5B mucin hypersecretion, mucus hyperviscosity, reduced microbiological diversity,
and enrichment of known respiratory pathogenic bacteria (e.g., Pseudomonas, Enterococcus) (108),
arguing for increased focus on the subglottic space in the evolution of pulmonary infections in intubated
patients (109).
Conclusion
The wide spectrum of critical care publications in ATS Journals highlights the prevailing
challenge of translating highly novel mechanistic insights to effective patient-centered therapies. The
imperative for deriving and validating biologically robust disease definitions and endophenotypes linked
to high-precision biomarkers for outcome prediction and theranosis should continue to be a priority for
basic and clinical investigators in the fields of ARDS, respiratory failure, sepsis and other non-pulmonary
critical illnesses.
17

Page 18 of 33
References:
1. Yadav H, Thompson BT, Gajic O. Fifty Years of Research in ARDS. Is Acute Respiratory Distress
Syndrome a Preventable Disease? American journal of respiratory and critical care medicine
2017; 195: 725-736.
2. Tighe RM, Birukova A, Yaeger MJ, Reece SW, Gowdy KM. Euthanasia- and Lavage-mediated Effects
on Bronchoalveolar Measures of Lung Injury and Inflammation. Am J Respir Cell Mol Biol 2018;
59: 257-266.
3. McNeil JB, Shaver CM, Kerchberger VE, Russell DW, Grove BS, Warren MA, Wickersham NE, Ware
LB, McDonald WH, Bastarache JA. Novel Method for Noninvasive Sampling of the Distal
Airspace in Acute Respiratory Distress Syndrome. American journal of respiratory and critical
care medicine 2018; 197: 1027-1035.
4. Bain W, Lee JS. Ventilator Circuit Trash May Be a Research Treasure. American journal of respiratory
and critical care medicine 2018; 197: 979-980.
5. Maiolo G, Collino F, Vasques F, Rapetti F, Tonetti T, Romitti F, Cressoni M, Chiumello D, Moerer O,
Herrmann P, Friede T, Quintel M, Gattinoni L. Reclassifying Acute Respiratory Distress
Syndrome. American journal of respiratory and critical care medicine 2018; 197: 1586-1595.
6. Del Sorbo L, Nava S, Rubenfeld G, Thompson T, Ranieri VM. Assessing Risk and Treatment
Responsiveness in ARDS. Beyond Physiology. American journal of respiratory and critical care
medicine 2018; 197: 1516-1518.
7. Morrell ED, O’Mahony DS, Glavan BJ, Harju-Baker S, Nguyen C, Gunderson S, Abrahamson A,
Radella F, Rona G, Black RA, Wurfel MM. Genetic Variation in MAP3K1 Associates with
Ventilator-Free Days in Acute Respiratory Distress Syndrome. American Journal of Respiratory
Cell and Molecular Biology 2018; 58: 117-125.
18

Page 19 of 33
8. Rogers AJ. Genome-Wide Association Study in Acute Respiratory Distress Syndrome. Finding the
Needle in the Haystack to Advance Our Understanding of Acute Respiratory Distress Syndrome.
American journal of respiratory and critical care medicine 2018; 197: 1373-1374.
9. Mascarenhas JB, Tchourbanov AY, Danilov SM, Zhou T, Wang T, Garcia JGN. The Splicing Factor
hnRNPA1 Regulates Alternate Splicing of the MYLK Gene. Am J Respir Cell Mol Biol 2018; 58:
604-613.
10. Brazee PL, Dada LA. Splice Wars: The Role of MLCK Isoforms in Ventilation-induced Lung Injury.
Am J Respir Cell Mol Biol 2018; 58: 549-550.
11. Oita RC, Camp SM, Ma W, Ceco E, Harbeck M, Singleton P, Messana J, Sun X, Wang T, Garcia
JGN. Novel Mechanism for Nicotinamide Phosphoribosyltransferase Inhibition of TNF-alpha-
mediated Apoptosis in Human Lung Endothelial Cells. Am J Respir Cell Mol Biol 2018; 59: 36-
44.
12. Mitra S, Exline M, Habyarimana F, Gavrilin MA, Baker PJ, Masters SL, Wewers MD, Sarkar A.
Microparticulate Caspase 1 Regulates Gasdermin D and Pulmonary Vascular Endothelial Cell
Injury. Am J Respir Cell Mol Biol 2018; 59: 56-64.
13. Singla S, Machado RF. Death of the Endothelium in Sepsis: Understanding the Crime Scene. Am J
Respir Cell Mol Biol 2018; 59: 3-4.
14. Park BH, Shin MH, Douglas IS, Chung KS, Song JH, Kim SY, Kim EY, Jung JY, Kang YA, Chang J,
Kim YS, Park MS. Erythropoietin-Producing Hepatoma Receptor Tyrosine Kinase A2
Modulation Associates with Protective Effect of Prone Position in Ventilator-induced Lung
Injury. Am J Respir Cell Mol Biol 2018; 58: 519-529.
15. Gross CM, Kellner M, Wang T, Lu Q, Sun X, Zemskov EA, Noonepalle S, Kangath A, Kumar S,
Gonzalez-Garay M, Desai AA, Aggarwal S, Gorshkov B, Klinger C, Verin AD, Catravas JD,
Jacobson JR, Yuan JX, Rafikov R, Garcia JGN, Black SM. LPS-induced Acute Lung Injury
Involves NF-kappaB-mediated Downregulation of SOX18. Am J Respir Cell Mol Biol 2018; 58:
614-624.
19

Page 20 of 33
16. Haeger SM, Liu X, Han X, McNeil JB, Oshima K, McMurtry SA, Yang Y, Ouyang Y, Zhang F,
Nozik-Grayck E, Zemans RL, Tuder RM, Bastarache JA, Linhardt RJ, Schmidt EP. Epithelial
Heparan Sulfate Contributes to Alveolar Barrier Function and Is Shed during Lung Injury. Am J
17. Weidenfeld S, Kuebler WM. Shedding First Light on the Alveolar Epithelial Glycocalyx. Am J Respir
Cell Mol Biol 2018; 59: 283-284.
18. Hotz MJ, Qing D, Shashaty MGS, Zhang P, Faust H, Sondheimer N, Rivella S, Worthen GS,
Mangalmurti NS. Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to
Maintain Quiescence and to Prevent Lung Injury. American journal of respiratory and critical
care medicine 2018; 197: 470-480.
19. Hippensteel JA, Schmidt EP. Sequestering Damage-associated Molecular Patterns in Critical Illness.
A Novel Homeostatic Role for the Erythrocyte. American journal of respiratory and critical care
medicine 2018; 197: 416-418.
20. Abdulnour RE, Gunderson T, Barkas I, Timmons JY, Barnig C, Gong M, Kor DJ, Gajic O, Talmor D,
Carter RE, Levy BD. Early Intravascular Events Are Associated with Development of Acute
Respiratory Distress Syndrome. A Substudy of the LIPS-A Clinical Trial. American journal of
respiratory and critical care medicine 2018; 197: 1575-1585.
21. Middleton EA, Zimmerman GA. Early Returns in Vascular Inflammation in ARDS. American journal
of respiratory and critical care medicine 2018; 197: 1514-1516.
22. Panzer AR, Lynch SV, Langelier C, Christie JD, McCauley K, Nelson M, Cheung CK, Benowitz NL,
Cohen MJ, Calfee CS. Lung Microbiota Is Related to Smoking Status and to Development of
Acute Respiratory Distress Syndrome in Critically Ill Trauma Patients. American journal of
23. Dickson RP. The Lung Microbiome and ARDS. It Is Time to Broaden the Model. American journal
of respiratory and critical care medicine 2018; 197: 549-551.
20

Page 21 of 33
24. Acute Respiratory Distress Syndrome N, Brower RG, Matthay MA, Morris A, Schoenfeld D,
Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional
tidal volumes for acute lung injury and the acute respiratory distress syndrome. The New England
journal of medicine 2000; 342: 1301-1308.
25. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. The New England journal of medicine 2013;
369: 2126-2136.
26. Knudsen L, Lopez-Rodriguez E, Berndt L, Steffen L, Ruppert C, Bates JHT, Ochs M, Smith BJ.
Alveolar Micromechanics in Bleomycin-induced Lung Injury. Am J Respir Cell Mol Biol 2018;
59: 757-769.
27. Motta-Ribeiro GC, Hashimoto S, Winkler T, Baron RM, Grogg K, Paula L, Santos A, Zeng C,
Hibbert K, Harris RS, Bajwa E, Vidal Melo MF. Deterioration of Regional Lung Strain and
Inflammation during Early Lung Injury. American journal of respiratory and critical care
medicine 2018; 198: 891-902.
28. Cereda M, Xin Y, Rizi RR. Acute Respiratory Distress Syndrome: Can Data from the Sick Guide
Care for the Healthy? American journal of respiratory and critical care medicine 2018; 198: 830-
832.
29. Talmor D, Sarge T, Malhotra A, O'Donnell CR, Ritz R, Lisbon A, Novack V, Loring SH. Mechanical
ventilation guided by esophageal pressure in acute lung injury. The New England journal of
medicine 2008; 359: 2095-2104.
30. Yoshida T, Amato MBP, Grieco DL, Chen L, Lima CAS, Roldan R, Morais CCA, Gomes S, Costa
ELV, Cardoso PFG, Charbonney E, Richard JM, Brochard L, Kavanagh BP. Esophageal
Manometry and Regional Transpulmonary Pressure in Lung Injury. American journal of
31. Grasso S, Stripoli T. Transpulmonary Pressure-based Mechanical Ventilation in Acute Respiratory
Distress Syndrome. From Theory to Practice? American journal of respiratory and critical care
medicine 2018; 197: 977-978.
21

Page 22 of 33
32. Beitler JR, Sarge T, Banner-Goodspeed VM, Gong MN, Cook D, Novack V, Loring SH, Talmor D,
Group ftE-S. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal
Pressure–Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free
From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A
Randomized Clinical TrialEffect of an Esophageal Pressure–Guided PEEP Titration Strategy vs
an Empirical High PEEP-Fio2 Strategy in ARDSEffect of an Esophageal Pressure–Guided PEEP
Titration Strategy vs an Empirical High PEEP-Fio2 Strategy in ARDS. JAMA : the journal of the
American Medical Association 2019; 321: 846-857.
33. Katira BH, Engelberts D, Otulakowski G, Giesinger RE, Yoshida T, Post M, Kuebler WM, Connelly
KA, Kavanagh BP. Abrupt Deflation after Sustained Inflation Causes Lung Injury. American
journal of respiratory and critical care medicine 2018; 198: 1165-1176.
34. Marini JJ, Gattinoni L. Protecting the Ventilated Lung: Vascular Surge and Deflation Energetics.
35. Hardin CC. TRIMming Ventilator-induced Lung Injury by Enhancing Cell Membrane Repair. Am J
36. Nagre N, Cong X, Ji HL, Schreiber JM, Fu H, Pepper I, Warren S, Sill JM, Hubmayr RD, Zhao X.
Inhaled TRIM72 Protein Protects Ventilation Injury to the Lung through Injury-guided Cell
Repair. Am J Respir Cell Mol Biol 2018; 59: 635-647.
37. Alejandre Alcazar MA, Kaschwich M, Ertsey R, Preuss S, Milla C, Mujahid S, Masumi J, Khan S,
Mokres LM, Tian L, Mohr J, Hirani DV, Rabinovitch M, Bland RD. Elafin Treatment Rescues
EGFR-Klf4 Signaling and Lung Cell Survival in Ventilated Newborn Mice. Am J Respir Cell
Mol Biol 2018; 59: 623-634.
38. Lal CV, Ambalavanan N. Mechanisms of Ventilator-induced Lung Injury: Is the Elafin in the Room?
Am J Respir Cell Mol Biol 2018; 59: 531-532.
39. Jayne JG, Bensman TJ, Schaal JB, Park AYJ, Kimura E, Tran D, Selsted ME, Beringer PM. Rhesus
θ-Defensin-1 Attenuates Endotoxin-induced Acute Lung Injury by Inhibiting Proinflammatory
22

Page 23 of 33
Cytokines and Neutrophil Recruitment. American Journal of Respiratory Cell and Molecular
Biology 2018; 58: 310-319.
40. Knapp S. θ-Defensins—A Magic Bullet for Acute Lung Injury? American Journal of Respiratory Cell
and Molecular Biology 2018; 58: 277-278.
41. Hiruma T, Tsuyuzaki H, Uchida K, Trapnell BC, Yamamura Y, Kusakabe Y, Totsu T, Suzuki T,
Morita S, Doi K, Noiri E, Nakamura K, Nakajima S, Yahagi N, Morimura N, Chang K, Yamada
Y. IFN-beta Improves Sepsis-related Alveolar Macrophage Dysfunction and Postseptic Acute
Respiratory Distress Syndrome-related Mortality. Am J Respir Cell Mol Biol 2018; 59: 45-55.
42. Mould KJ, Janssen WJ. Recombinant IFN-beta for Postseptic Acute Lung Injury-What's the
Mechanism? Am J Respir Cell Mol Biol 2018; 59: 1-2.
43. Bellingan G, Brealey D, Mancebo J, Mercat A, Patroniti N, Pettila V, Quintel M, Vincent JL,
Maksimow M, Jalkanen M, Piippo I, Ranieri VM. Comparison of the efficacy and safety of FP-
1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the
treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol
for a randomized controlled trial. Trials 2017; 18: 536.
44. Okponyia OC, McGraw MD, Dysart MM, Garlick RB, Rioux JS, Murphy AL, Roe GB, White CW,
Veress LA. Oxygen Administration Improves Survival but Worsens Cardiopulmonary Functions
in Chlorine-exposed Rats. Am J Respir Cell Mol Biol 2018; 58: 107-116.
45. Svendsen ER. Chlorine Countermeasures: Supplemental Oxygen Equals Supplemental Lung Injury?
American Journal of Respiratory Cell and Molecular Biology 2018; 58: 10-11.
46. Guerin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A,
Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler
C, Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girard R, Baboi L, Ayzac L, Group
PS. Prone positioning in severe acute respiratory distress syndrome. The New England journal of
medicine 2013; 368: 2159-2168.
23

Page 24 of 33
47. Scholten EL, Beitler JR, Prisk GK, Malhotra A. Treatment of ARDS With Prone Positioning. Chest
2017; 151: 215-224.
48. Xin Y, Cereda M, Hamedani H, Pourfathi M, Siddiqui S, Meeder N, Kadlecek S, Duncan I, Profka H,
Rajaei J, Tustison NJ, Gee JC, Kavanagh BP, Rizi RR. Unstable Inflation Causing Injury. Insight
from Prone Position and Paired Computed Tomography Scans. American journal of respiratory
and critical care medicine 2018; 198: 197-207.
49. Hedenstierna G. Unstable Inflation Is Harmful and More Common Supine Than Prone. American
50. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D,
Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guérin C, Prat G, Morange S, Roch A,
Investigators AS. Neuromuscular blockers in early acute respiratory distress syndrome. The New
England journal of medicine 2010; 363: 1107-1116.
51. Sottile PD, Kiser TH, Burnham EL, Ho PM, Allen RR, Vandivier RW, Moss M. An Observational
Study of the Efficacy of Cisatracurium Compared with Vecuronium in Patients with or at Risk for
Acute Respiratory Distress Syndrome. American journal of respiratory and critical care medicine
2018; 197: 897-904.
52. Combes A, Hajage D, Capellier G, Demoule A, Lavoue S, Guervilly C, Da Silva D, Zafrani L, Tirot
P, Veber B, Maury E, Levy B, Cohen Y, Richard C, Kalfon P, Bouadma L, Mehdaoui H,
Beduneau G, Lebreton G, Brochard L, Ferguson ND, Fan E, Slutsky AS, Brodie D, Mercat A,
Eolia Trial Group R, Ecmonet. Extracorporeal Membrane Oxygenation for Severe Acute
Respiratory Distress Syndrome. The New England journal of medicine 2018; 378: 1965-1975.
53. Schmidt M, Schellongowski P, Patroniti N, Taccone FS, Reis Miranda D, Reuter J, Prodanovic H,
Pierrot M, Dorget A, Park S, Balik M, Demoule A, Crippa IA, Mercat A, Wohlfarth P, Sonneville
R, Combes A, International Ecmo Network tRRN, the ISG. Six-month Outcome of
Immunocompromised Severe ARDS Patients Rescued by ECMO. An International Multicenter
Retrospective Study. American journal of respiratory and critical care medicine 2018.
24

Page 25 of 33
54. Bein T, Weber-Carstens S. Extracorporeal Life Support in Immunocompromised Patients with Severe
Acute Respiratory Distress Syndrome. Decide Wisely, Early, and in a Personalized Way.
55. Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ 2016; 353: i1585.
56. Singer BH, Dickson RP, Denstaedt SJ, Newstead MW, Kim K, Falkowski NR, Erb-Downward JR,
Schmidt TM, Huffnagle GB, Standiford TJ. Bacterial Dissemination to the Brain in Sepsis.
57. Miller RR, 3rd, Lopansri BK, Burke JP, Levy M, Opal S, Rothman RE, D'Alessio FR, Sidhaye VK,
Aggarwal NR, Balk R, Greenberg JA, Yoder M, Patel G, Gilbert E, Afshar M, Parada JP, Martin
GS, Esper AM, Kempker JA, Narasimhan M, Tsegaye A, Hahn S, Mayo P, van der Poll T,
Schultz MJ, Scicluna BP, Klein Klouwenberg P, Rapisarda A, Seldon TA, McHugh LC, Yager
TD, Cermelli S, Sampson D, Rothwell V, Newman R, Bhide S, Fox BA, Kirk JT, Navalkar K,
Davis RF, Brandon RA, Brandon RB. Validation of a Host Response Assay, SeptiCyte LAB, for
Discriminating Sepsis from Systemic Inflammatory Response Syndrome in the ICU. American
58. Greenberg JA, Hohmann SF, James BD, Shah RC, Hall JB, Kress JP, David MZ. Hospital Volume of
Immunosuppressed Patients with Sepsis and Sepsis Mortality. Annals of the American Thoracic
Society 2018; 15: 962-969.
59. Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettila V, Aaen A, Lodahl D,
Berthelsen RE, Christensen H, Madsen MB, Winkel P, Wetterslev J, Perner A, Group CT,
Scandinavian Critical Care Trials G. Restricting volumes of resuscitation fluid in adults with
septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre
feasibility trial. Intensive care medicine 2016; 42: 1695-1705.
60. Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe
sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive
care medicine 2017; 43: 625-632.
25

Page 26 of 33
61. Byrne L, Obonyo NG, Diab SD, Dunster KR, Passmore MR, Boon AC, Hoe LS, Pedersen S, Fauzi
MH, Pimenta LP, Van Haren F, Anstey CM, Cullen L, Tung JP, Shekar K, Maitland K, Fraser JF.
Unintended Consequences: Fluid Resuscitation Worsens Shock in an Ovine Model of
Endotoxemia. American journal of respiratory and critical care medicine 2018; 198: 1043-1054.
62. Self WH, Semler MW, Bellomo R, Brown SM, deBoisblanc BP, Exline MC, Ginde AA, Grissom CK,
Janz DR, Jones AE, Liu KD, Macdonald SPJ, Miller CD, Park PK, Reineck LA, Rice TW,
Steingrub JS, Talmor D, Yealy DM, Douglas IS, Shapiro NI, Investigators CPCaNPaEToALIPN.
Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for
a Randomized Trial. Ann Emerg Med 2018.
63. McIntyre LA, Stewart DJ, Mei SHJ, Courtman D, Watpool I, Granton J, Marshall J, Dos Santos C,
Walley KR, Winston BW, Schlosser K, Fergusson DA. Cellular Immunotherapy for Septic
Shock. A Phase I Clinical Trial. American journal of respiratory and critical care medicine 2018;
197: 337-347.
64. Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, Rogers AJ, Gotts JE, Wiener-
Kronish JP, Bajwa EK, Donahoe MP, McVerry BJ, Ortiz LA, Exline M, Christman JW, Abbott J,
Delucchi KL, Caballero L, McMillan M, McKenna DH, Liu KD. Treatment with allogeneic
mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START
study): a randomised phase 2a safety trial. Lancet Respir Med 2019; 7: 154-162.
65. Levy MM, Gesten FC, Phillips GS, Terry KM, Seymour CW, Prescott HC, Friedrich M, Iwashyna TJ,
Osborn T, Lemeshow S. Mortality Changes Associated with Mandated Public Reporting for
Sepsis. The Results of the New York State Initiative. American journal of respiratory and critical
care medicine 2018; 198: 1406-1412.
66. Anesi GL, Liu VX, Gabler NB, Delgado MK, Kohn R, Weissman GE, Bayes B, Escobar GJ, Halpern
SD. Associations of Intensive Care Unit Capacity Strain with Disposition and Outcomes of
Patients with Sepsis Presenting to the Emergency Department. Annals of the American Thoracic
Society 2018; 15: 1328-1335.
26

Page 27 of 33
67. Valley TS. The Search for the Optimal Intensive Care Unit Triage Model. Annals of the American
Thoracic Society 2018; 15: 1280-1282.
68. Peltan ID, Mitchell KH, Rudd KE, Mann BA, Carlbom DJ, Rea TD, Butler AM, Hough CL, Brown
SM. Prehospital Care and Emergency Department Door-to-Antibiotic Time in Sepsis. Annals of
the American Thoracic Society 2018; 15: 1443-1450.
69. Wendlandt B, Ceppe A, Choudhury S, Nelson JE, Cox CE, Hanson LC, Danis M, Tulsky JA, Carson
SS. Risk Factors for Post-Traumatic Stress Disorder Symptoms in Surrogate Decision-Makers of
Patients with Chronic Critical Illness. Annals of the American Thoracic Society 2018; 15: 1451-
1458.
70. Kentish-Barnes N, Chevret S, Cheisson G, Joseph L, Martin-Lefevre L, Si Larbi AG, Viquesnel G,
Marque S, Donati S, Charpentier J, Pichon N, Zuber B, Lesieur O, Ouendo M, Renault A, Le
Maguet P, Kandelman S, Thuong M, Floccard B, Mezher C, Galon M, Duranteau J, Azoulay E.
Grief Symptoms in Relatives Who Experienced Organ Donation Requests in the ICU. American
71. Hua M, Ma X, Morrison RS, Li G, Wunsch H. Association between the Availability of Hospital-
based Palliative Care and Treatment Intensity for Critically Ill Patients. Annals of the American
Thoracic Society 2018; 15: 1067-1074.
72. Cox CE. Defining the Value Proposition for Specialist Palliative Care Delivered in Intensive Care
Units. Annals of the American Thoracic Society 2018; 15: 1031-1032.
73. Cox CE, Jones DM, Reagan W, Key MD, Chow V, McFarlin J, Casarett D, Creutzfeldt CJ, Docherty
SL. Palliative Care Planner: A Pilot Study to Evaluate Acceptability and Usability of an
Electronic Health Records System-integrated, Needs-targeted App Platform. Annals of the
American Thoracic Society 2018; 15: 59-68.
74. Cox CE, Hough CL, Carson SS, White DB, Kahn JM, Olsen MK, Jones DM, Somers TJ, Kelleher
SA, Porter LS. Effects of a Telephone- and Web-based Coping Skills Training Program
Compared with an Education Program for Survivors of Critical Illness and Their Family
27

Page 28 of 33
Members. A Randomized Clinical Trial. American journal of respiratory and critical care
medicine 2018; 197: 66-78.
75. Wade DM, Mouncey PR, Richards-Belle A, Wulff J, Harrison DA, Sadique MZ, Grieve RD, Emerson
LM, Mason AJ, Aaronovitch D, Als N, Brewin CR, Harvey SE, Howell DCJ, Hudson N, Mythen
MG, Smyth D, Weinman J, Welch J, Whitman C, Rowan KM, Investigators ftPT. Effect of a
Nurse-Led Preventive Psychological Intervention on Symptoms of Posttraumatic Stress Disorder
Among Critically Ill Patients: A Randomized Clinical TrialEffect of a Nurse-Led Preventive
Psychological Intervention on Post-ICU PTSD SymptomsEffect of a Nurse-Led Preventive
Psychological Intervention on Post-ICU PTSD Symptoms. JAMA : the journal of the American
Medical Association 2019; 321: 665-675.
76. White DB, Angus DC, Shields AM, Buddadhumaruk P, Pidro C, Paner C, Chaitin E, Chang CH, Pike
F, Weissfeld L, Kahn JM, Darby JM, Kowinsky A, Martin S, Arnold RM, Investigators P. A
Randomized Trial of a Family-Support Intervention in Intensive Care Units. The New England
journal of medicine 2018; 378: 2365-2375.
77. Lief L, Berlin DA, Maciejewski RC, Westman L, Su A, Cooper ZR, Ouyang DJ, Epping G, Derry H,
Russell D, Gentzler E, Maciejewski PK, Prigerson HG. Dying Patient and Family Contributions
to Nurse Distress in the ICU. Annals of the American Thoracic Society 2018; 15: 1459-1464.
78. Mehter HM, McCannon JB, Clark JA, Wiener RS. Physician Approaches to Conflict with Families
Surrounding End-of-Life Decision-making in the Intensive Care Unit. A Qualitative Study.
Annals of the American Thoracic Society 2018; 15: 241-249.
79. Lalani HS, Waweru-Siika W, Mwogi T, Kituyi P, Egger JR, Park LP, Kussin PS. Intensive Care
Outcomes and Mortality Prediction at a National Referral Hospital in Western Kenya. Annals of
the American Thoracic Society 2018; 15: 1336-1343.
80. Rojas JC, Carey KA, Edelson DP, Venable LR, Howell MD, Churpek MM. Predicting Intensive Care
Unit Readmission with Machine Learning Using Electronic Health Record Data. Annals of the
28

Page 29 of 33
81. Cosgriff CV, Celi LA, Sauer CM. Boosting Clinical Decision-making: Machine Learning for
Intensive Care Unit Discharge. Annals of the American Thoracic Society 2018; 15: 804-805.
82. McKown AC, Casey JD, Russell DW, Joffe AM, Janz DR, Rice TW, Semler MW. Risk Factors for
and Prediction of Hypoxemia during Tracheal Intubation of Critically Ill Adults. Annals of the
83. Schenck EJ, Berlin DA. Oxygen at Risk. Annals of the American Thoracic Society 2018; 15: 1278-
1280.
84. Azoulay E, Roux A, Vincent F, Kouatchet A, Argaud L, Rabbat A, Mayaux J, Perez P, Pene F,
Nyunga M, Bruneel F, Klouche K, Mokart D, Darmon M, Chevret S, Lemiale V. A Multivariable
Prediction Model for Pneumocystis jirovecii Pneumonia in Hematology Patients with Acute
Respiratory Failure. American journal of respiratory and critical care medicine 2018; 198: 1519-
1526.
85. Ferrante LE, Murphy TE, Gahbauer EA, Leo-Summers LS, Pisani MA, Gill TM. Pre-Intensive Care
Unit Cognitive Status, Subsequent Disability, and New Nursing Home Admission among
Critically Ill Older Adults. Annals of the American Thoracic Society 2018; 15: 622-629.
86. Dale CM, King J, Nonoyama M, Carbone S, McKim D, Road J, Rose L, group CA. Transitions to
Home Mechanical Ventilation: The Experiences of Canadian Ventilator-Assisted Adults and
Their Family Caregivers. Annals of the American Thoracic Society 2017.
87. Burns KEA, Raptis S, Nisenbaum R, Rizvi L, Jones A, Bakshi J, Tan W, Meret A, Cook DJ,
Lellouche F, Epstein SK, Gattas D, Kapadia FN, Villar J, Brochard L, Lessard MR, Meade MO.
International Practice Variation in Weaning Critically Ill Adults from Invasive Mechanical
Ventilation. Annals of the American Thoracic Society 2018; 15: 494-502.
88. Kerlin MP, Epstein A, Kahn JM, Iwashyna TJ, Asch DA, Harhay MO, Ratcliffe SJ, Halpern SD.
Physician-Level Variation in Outcomes of Mechanically Ventilated Patients. Annals of the
29

Page 30 of 33
89. Gershengorn HB. Is My Intensivist Better Than Your Intensivist? Annals of the American Thoracic
Society 2018; 15: 312-314.
90. Goligher EC, Dres M, Fan E, Rubenfeld GD, Scales DC, Herridge MS, Vorona S, Sklar MC,
Rittayamai N, Lanys A, Murray A, Brace D, Urrea C, Reid WD, Tomlinson G, Slutsky AS,
Kavanagh BP, Brochard LJ, Ferguson ND. Mechanical Ventilation-induced Diaphragm Atrophy
Strongly Impacts Clinical Outcomes. American journal of respiratory and critical care medicine
2018; 197: 204-213.
91. Heunks L, Ottenheijm C. Diaphragm-Protective Mechanical Ventilation to Improve Outcomes in ICU
Patients? American journal of respiratory and critical care medicine 2018; 197: 150-152.
92. Lindqvist J, van den Berg M, van der Pijl R, Hooijman PE, Beishuizen A, Elshof J, de Waard M,
Girbes A, Spoelstra-de Man A, Shi ZH, van den Brom C, Bogaards S, Shen S, Strom J, Granzier
H, Kole J, Musters RJP, Paul MA, Heunks LMA, Ottenheijm CAC. Positive End-Expiratory
Pressure Ventilation Induces Longitudinal Atrophy in Diaphragm Fibers. American journal of
93. Petrof BJ, Sassoon CS. Diaphragm Remodeling during Application of Positive End-Expiratory
Pressure. A Case of Normal Physiologic Adaptation Gone Awry? American journal of
94. Morais CCA, Koyama Y, Yoshida T, Plens GM, Gomes S, Lima CAS, Ramos OPS, Pereira SM,
Kawaguchi N, Yamamoto H, Uchiyama A, Borges JB, Vidal Melo MF, Tucci MR, Amato MBP,
Kavanagh BP, Costa ELV, Fujino Y. High Positive End-Expiratory Pressure Renders
Spontaneous Effort Noninjurious. American journal of respiratory and critical care medicine
2018; 197: 1285-1296.
95. Vorona S, Sabatini U, Al-Maqbali S, Bertoni M, Dres M, Bissett B, Van Haren F, Martin AD, Urrea
C, Brace D, Parotto M, Herridge MS, Adhikari NKJ, Fan E, Melo LT, Reid WD, Brochard LJ,
Ferguson ND, Goligher EC. Inspiratory Muscle Rehabilitation in Critically Ill Adults. A
30

Page 31 of 33
Systematic Review and Meta-Analysis. Annals of the American Thoracic Society 2018; 15: 735-
744.
96. Morgan RW, Sutton RM, Karlsson M, Lautz AJ, Mavroudis CD, Landis WP, Lin Y, Jeong S, Craig
N, Nadkarni VM, Kilbaugh TJ, Berg RA. Pulmonary Vasodilator Therapy in Shock-associated
Cardiac Arrest. American journal of respiratory and critical care medicine 2018; 197: 905-912.
97. Debaty G, Paul M, Cariou A. Shock-associated Cardiac Arrest: Vasodilator Therapy May Help.
98. van den Boogaard M, Slooter AJC, Bruggemann RJM, Schoonhoven L, Beishuizen A, Vermeijden
JW, Pretorius D, de Koning J, Simons KS, Dennesen PJW, Van der Voort PHJ, Houterman S,
van der Hoeven JG, Pickkers P, Investigators RS, van der Woude MCE, Besselink A, Hofstra LS,
Spronk PE, van den Bergh W, Donker DW, Fuchs M, Karakus A, Koeman M, van Duijnhoven
M, Hannink G. Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk
of Delirium: The REDUCE Randomized Clinical Trial. JAMA : the journal of the American
Medical Association 2018; 319: 680-690.
99. Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, Douglas IS, Malhotra A, Owens
RL, Feinstein DJ, Khan B, Pisani MA, Hyzy RC, Schmidt GA, Schweickert WD, Hite RD,
Bowton DL, Masica AL, Thompson JL, Chandrasekhar R, Pun BT, Strength C, Boehm LM,
Jackson JC, Pandharipande PP, Brummel NE, Hughes CG, Patel MB, Stollings JL, Bernard GR,
Dittus RS, Ely EW, Investigators M-U. Haloperidol and Ziprasidone for Treatment of Delirium in
Critical Illness. The New England journal of medicine 2018; 379: 2506-2516.
100. Skrobik Y, Duprey MS, Hill NS, Devlin JW. Low-Dose Nocturnal Dexmedetomidine Prevents ICU
Delirium. A Randomized, Placebo-controlled Trial. American journal of respiratory and critical
care medicine 2018; 197: 1147-1156.
101. Nuzzo E, Girard TD. The Sandman in the ICU: A Novel Use of Dexmedetomidine? American
31

Page 32 of 33
102. Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Verney C, Pons B, Boulet E, Boyer A, Chevrel
G, Lerolle N, Carpentier D, de Prost N, Lautrette A, Bretagnol A, Mayaux J, Nseir S, Megarbane
B, Thirion M, Forel JM, Maizel J, Yonis H, Markowicz P, Thiery G, Tubach F, Ricard JD,
Dreyfuss D. Timing of Renal Support and Outcome of Septic Shock and Acute Respiratory
Distress Syndrome. A Post Hoc Analysis of the AKIKI Randomized Clinical Trial. American
103. Lameire N, Vanmassenhove J. Timing of Dialysis in Sepsis and Acute Respiratory Distress
Syndrome. American journal of respiratory and critical care medicine 2018; 198: 4-5.
104. Loftus TJ, Mira JC, Miller ES, Kannan KB, Plazas JM, Delitto D, Stortz JA, Hagen JE, Parvataneni
HK, Sadasivan KK, Brakenridge SC, Moore FA, Moldawer LL, Efron PA, Mohr AM. The
Postinjury Inflammatory State and the Bone Marrow Response to Anemia. American journal of
105. Napolitano LM. Understanding Anemia in the ICU to Develop Future Treatment Strategies.
106. Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, Jose J, Pinto R,
Al-Omari A, Kharaba A, Almotairi A, Al Khatib K, Alraddadi B, Shalhoub S, Abdulmomen A,
Qushmaq I, Mady A, Solaiman O, Al-Aithan AM, Al-Raddadi R, Ragab A, Balkhy HH, Al
Harthy A, Deeb AM, Al Mutairi H, Al-Dawood A, Merson L, Hayden FG, Fowler RA.
Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome.
107. Hui DS. Systemic Corticosteroid Therapy May Delay Viral Clearance in Patients with Middle East
Respiratory Syndrome Coronavirus Infection. American journal of respiratory and critical care
medicine 2018; 197: 700-701.
108. Powell J, Garnett JP, Mather MW, Cooles FAH, Nelson A, Verdon B, Scott J, Jiwa K, Ruchaud-
Sparagano MH, Cummings SP, Perry JD, Wright SE, Wilson JA, Pearson J, Ward C, Simpson
32

Page 33 of 33
AJ. Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated
Patients. American journal of respiratory and critical care medicine 2018; 198: 340-349.
109. Kitsios GD, McVerry BJ. Host-Microbiome Interactions in the Subglottic Space. Bacteria Ante
Portas! American journal of respiratory and critical care medicine 2018; 198: 294-297.
33

ARDS Review

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

ARDS Review

Uploaded by

Copyright:

Available Formats

AJRCCM Articles in Press. Published on 08-April-2019 as 10.1164/rccm.

Update in Critical Care / ARDS 2018

Jason Mansoori, MD1 and Hayley B. Gershengorn, MD5.

MC 4000, 601 Broadway Denver, CO 80204;

Montefiore, NW 628, Pittsburgh, PA 15213.

Copyright © 2019 by the American Thoracic Society

diagnostics and therapeutics are a particular focus of this invited review.

Acute Respiratory Distress Syndrome and Experimental Acute Lung Injury

transparency in method reporting and thoughtful design (2).

chromatography–coupled tandem mass spectrometry, the protein composition and biomarker

Copyright © 2019 by the American Thoracic Society

HME fluid as a valuable sampling source (4).

effective in vascular barrier restoration (9, 10).

characterized. The cytozyme nicotinamide phsphoribosyltransferase (NAMPT) is one such candidate.

Copyright © 2019 by the American Thoracic Society

pulmonary injury in sepsis (12, 13).

to preserve barrier integrity. Functioning in cell-cell adhesion, the erythropoietin-producing hepatoma

A damage-associated molecular pattern (DAMP), CpG-containing cell-free mitochondrial DNA

Mechanisms of Lung Injury and Prevention in Humans

Copyright © 2019 by the American Thoracic Society

for aspirin (21).

development after severe trauma (23).

stereological modeling of lung architecture demonstrated correlation of heterogeneity of alveolar units

Copyright © 2019 by the American Thoracic Society

injury characterized by acute left ventricular decompensation, elevated pulmonary microvascular

relevance of abrupt lung deflation (34).

Potential Therapeutic Interventions in Pre-clinical Models

vascular endothelial cell development. Elafin, an elastase-specific protease inhibitor, preserves

Copyright © 2019 by the American Thoracic Society

with ARDS to combat alveolar-capillary barrier dysfunction (37, 38).

responses followed by relative immunosuppression. While numerous anti-inflammatory therapeutics have

increase ventilator free days in ARDS patients (43).

questions regarding oxygen delivery in other forms of ARDS (44, 45).

Therapeutic Role of Prone Positioning, Paralytics, and ECMO in Human ARDS

Copyright © 2019 by the American Thoracic Society

Neuromuscular blockade eliminates patient-ventilator interactions and reduces VILI (50). In a

including ECMO (54).

evaluate if sepsis-associated brain dysfunction is related to sterile inflammatory mediators or bacterial

Copyright © 2019 by the American Thoracic Society

general sepsis population.

Copyright © 2019 by the American Thoracic Society

severity and other temporal changes in care delivery.

Coping with Death and Chronic Critical Illness

Copyright © 2019 by the American Thoracic Society

Copyright © 2019 by the American Thoracic Society

families most likely to derive benefit.

(79), supporting development of illness severity indicators specific to resource-limited settings.

Copyright © 2019 by the American Thoracic Society

application in clinical practice.

Variable Provider Practices

Copyright © 2019 by the American Thoracic Society

Inspiratory Muscle Impairment and PEEP

clinical consequences during weaning from MV (93).

Copyright © 2019 by the American Thoracic Society

who have difficulty being liberated from MV.

General and Non-pulmonary Critical Care

Copyright © 2019 by the American Thoracic Society

of DEX in this population. (101)

justifying a “wait and see” approach to RRT (103).

“neuroendocrine activation and systemic inflammation propagat[ing] iron dysregulation, mobilization of

Copyright © 2019 by the American Thoracic Society

molecule expression (105) .

accumulation, MUC5B mucin hypersecretion, mucus hyperviscosity, reduced microbiological diversity,