ATS Adult Reading List

Diagnosis, Long term outcomes, and Pathophysiology
Matthay MA, Arabi Y, Arroliga AC, et al. A new global definition of acute respiratory distress syndrome. An updated definition of ARDS, replaces the original Berlin Definition of 2012. Noteworthy updates are inclusion of patients on high flow oxygen, pulse oximetry for oxygen saturation, use of ultrasound as imaging modality, and adjustments for resource-limited settings. Am J Respir Crit Care Med. 2024;209:37-47.
PMID: 37487152 
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Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011 Apr 7;364(14):1293-304. This study provides the longest and most comprehensive follow-up of ARDS survivors to date, emphasizing the importance of long-term neuromuscular and psychiatric dysfunction despite nearly complete recovery of lung function
PMID: 21470008
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The following two articles provide an in-depth review of gas exchange and lung mechanics in ARDS.
Radermacher P, Maggiore SM, Mercat A. Fifty years of research in ARDS. Gas exchange in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017; 196:964-984.
PMID: 28406724

Henderson WR, Chen L, Amato MBP, et al. Fifty years of research in ARDS. Respiratory mechanics in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017; 196:822-833.
PMID: 28306327

Treatment: Ventilator Strategies

Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967;2:319-23. Original description of ARDS and use of PEEP in treating ARDS.
PMID: 4143721

ARDS Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for ALI and ARDS. N Engl J Med. 2000;342:1301-8. Results of the landmark ARMA study found the use of low (6 ml/kg predicted weight) rather than “standard” (12 ml/kg predicted weight) tidal volumes reduced mortality from 40 to 30%. These results provide much of the basis for use of low- stretch/low tidal volume ventilation strategy in acute lung injury.
PMID: 10793162
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Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372:747-55. This retrospective analysis of previous ARDS trials found driving pressure was the ventilator variable most strongly associated with survival and that changes in ventilator settings resulting in reduction in driving pressure were associated with increased survival. 
PMID: 25693014
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Treatment: Comparison of high vs. low PEEP

The following 4 trials investigated the use of high vs. low PEEP in ARDS. All found no difference in mortality while Meade et al and Mercat et al found less need for rescue therapies.  On the whole, these studies pointed toward the greatest benefit of high PEEP among patients with severe ARDS.

Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-36.
PMID: 15269312
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Meade MO, Cook DJ, Guyatt GH, et al. Lung open ventilation study investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008; 299:637-45.
PMID: 18270352
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Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:646-55.
PMID: 18270353
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Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura EA, Laranjeira LN, et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2017; 318:1335-45. Multicenter trial of 1010 patients with moderate to severe ARDS randomized to low PEEP or a lung recruitment maneuver and PEEP titrated to the best respiratory-system static compliance (intervention). The intervention group had increased mortality at 28 days (55% vs 49%; p=0.041), and increased risk of pneumothorax. ART is the first major study of the “open lung approach” to show harm.  Concerns raised about the study include the relatively high mortality in both groups as well as the method of recruitment.
PMID: 28973363
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Oxygenation goals

Barrot L, Asfar P, Mauny F, et al. LOCO2 Investigators and REVA Research Network. Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med. 2020; 382:999-1008. This LOCO2 trial compared oxygenation targets of PaO2 55-70 mmHg vs. 90-105 mmHg, or their equivalent saturations, Enrollment was stopped for futility after 205 subjects. There was no difference in 28-day mortality (primary outcome) and 5 episodes of mesenteric ischemia in the O2 conservative group.
PMID: 32160661

Prone positioning

Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013; 368:2159-2168. In contrast to previous studies of prone positioning, this group found significantly decreased (and strikingly low) mortality at 28 (32.8 vs.16%) and 90 (41% vs. 23.8%) days without an increase in adverse events among 466 patients with severe ARDS (PaO2/FIO2 < 150 mmHg). The treatment group was placed in the prone position within the first 3-4 days.
PMID: 23688302
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ECMO - ARDS

Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009; 374:1351-63. Highlighting both regionalization of care and use of ECMO, this trial showed that transfer to an ECMO-ready facility (75% of those transferred actually received ECMO) led to an NNT of 6 to prevent one death or severe disability at six months compared to standard care. The study was limited by the lack of a mandated lung-protective strategy in the control group; 93% of those transferred for possible ECMO received a lung-protective strategy, compared to 70% in the control group.
PMID: 19762075
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Combes A, Hajage D, Capellier G et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med. 2018; 378:1965-1975. The multicenter EOLIA randomized 249 patients with very severe ARDS to immediate VV ECMO vs standard care. 60-day mortality was lower in the ECMO group but the difference was not statistically significant (35% vs. 46%, p value 0.09). The study was stopped early for futility despite a trend toward benefit. Of note, 28% of control patients crossed over to ECMO due to refractory hypoxemia, with 43% of this group surviving.
PMID: 29791822
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***For additional information, see ECMO section for general reviews on use of VV and VA circuits.

Neuromuscular blockade

Moss M, Huang DT, Brower RG, et al. Early neuromuscular blockade in acute respiratory distress syndrome (ROSE). N Engl J Med. 2019;380:1997-2008. This RCT of 1006 patients with moderate to severe ARDS found no difference in 90 day mortality with early use of a 48 hour infusion of neuromuscular blockade compared to usual care. This trial was similar to the ACURASYS trial except for the use of lighter sedation targets in the usual care group. There was no difference in rates of ICU-acquired weakness or recall of paralysis. The trial was stopped early for futility.
PMID: 31112383
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Papazian L, Forel JM, Gacouin A, et al; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010; 363:1107-16. Unlike the subsequent ROSE study, this RCT of 340 patients with severe ARDS found the use of neuromuscular blockade initiated within 48 hours of admission and continued for 48 hours reduced mortality.
PMID: 20843245
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Corticosteroids

Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354:1671-84. This study randomized 180 patients with persistent ARDS (7 to 28 days after onset) to methylprednisolone (daily dose 2 mg/kg x 14 days then 1 mg/kg x 7 days) vs. placebo. Hospital mortality and 180-day survival were comparable, but patients enrolled 14 or more days after ARDS onset had increased 60-day mortality (35% vs. 8% placebo, p = .02).
PMID: 16625008
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Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020; 8:267-276. This trial randomized 277 ARDS patients with PaO2/FIO2 < 200 despite PEEP ≥ 10 and FIO2 ≥ 0.5 to 10 days of dexamethasone or routine care. Mean ventilator-free days was 4.8 days higher (95% CI 2.57 to 7.03) in the dexamethasone group and 60 day mortality was lower in the dexamethasone group (21% vs 36% with 95% CI -25.9 to – 4.9). Slow rate of patient recruitment and lack of blinding are limitations.
PMID: 32043986

Guidelines/Strategies
GINA Global Strategy for Asthma Management and Prevention (2025 Update). 
The GINA report is updated annually based on twice-yearly review and systematic evaluation of evidence. Updates for adults contained in the 2025 update focus primarily on clarification of previous recommendations.
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2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. This update to the 2007 guidelines focuses on the use of FeNO, allergen mitigation, use of continuous vs. prn ICS, LAMAs, immunotherapy, and bronchial thermoplasty.
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Holguin F, Cardet JC, Kung JF, et al. Management of severe asthma: A European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020; 55:1900588. This document provides useful recommendations for the management of severe asthma, with an emphasis on selection of patients suitable for biologic therapies, which is defined as asthma requiring high dose inhaled corticosteroids in combination with a second controller and/or systemic corticosteroids.
PMID: 31558662
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As needed use of ICS/LABA
The following 2 large, randomized studies among patients with mild asthma are noteworthy for finding ICS/LABA inhaler used only on a prn basis resulted in an exacerbation rate similar to use of BID ICS maintenance therapy but with substantially lower overall steroid exposure. However, daily asthma symptom scores were better among subjects receiving ICS maintenance therapy.

O'Byrne PM, FitzGerald JM, Bateman ED et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med. 2018; 378:1865-1876.
PMID: 29768149
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Bateman ED, Reddel HK, O'Byrne PM et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med. 2018; 378:1877-1887.
PMID: 29768147
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Papi A, Chipps BE, Beasley R, et al. Albuterol-budesonide fixed-dose combination rescue inhaler for asthma. N Engl J Med. 2022; 386:2071-83. This RCT of over 3,000 patients found prn use of an ICS/albuterol combination inhaler superior to prn albuterol alone for preventing severe asthma exacerbations (HR approximately 0.8 depending on dose of ICS). Unlike previous studies using ICS/LABA rescue inhalers, this study enrolled patients with moderate to severe asthma already receiving ICS at baseline. 
PMID: 35569035
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Combination therapies 
Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012; 367:1198-207. 48 week randomized study of 912 patients with persistent asthma found that the addition of tiotropium (Respimat soft-mist inhaler) demonstrated a statistically significant improvement in FEV1 (230ml) that was less than the minimal clinically important difference, but also a 21% reduction in severe exacerbations.
PMID:22938706
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Azithromycin to reduce asthma exacerbations
Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017; 12;390: 659-668. Randomized double-blind trial of 420 patients with uncontrolled persistent asthma on medium-to-high dose ICS plus a LABA.  Azithromycin 500 mg three times per week reduced moderate/severe exacerbations (1.07 per patient year vs 1.86 per patient year, p<0.0001) and improved asthma QOL. 
PMID: 28687413

Biologic therapies
McGregor MC, Krings JG, Nair P, et al. Role of biologics in asthma. Am J Respir Crit Care Med. 2019; 199:433-445. A review of the action, indications, expected benefits, and side effects of approved biologics for severe uncontrolled asthma.
PMID: 30525902
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Oberle AJ, Abbas F, Adrish M, Agache I, Conroy M, Coz A, Little FF, Mammen MJ, Anand MP, Reddy R, Solanki N, Holguin F. Biologic Management in Severe Asthma for Adults: An American College of Chest Physicians Clinical Practice Guideline. Chest. 2026 169(2):336-348. This guideline offers recommendations on changing biologics based on the specific initial biologic that is producing an inadequate response.  Recommendations are made based on a low level of evidence as would be expected. 
PMID: 41005695

Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma.  N Engl J Med. 2021;384:1800-1809. Tezepelumab is a human monoclonal antibody which blocks thymic stromal lymphopoietin. This RCT of 1,061 patients with severe, uncontrolled asthma found tezepelumab reduced the annual rate of asthma exacerbations (0.93 vs. 2.10 for placebo, p < 0.001). The benefit was significant, but of lower magnitude, with absolute eosinophil counts < 300/microL and multiple measures showed improved symptom burden.
PMID: 33979488

Jackson DJ, Wechsler ME, Jackson DJ, et al. Twice-yearly depemokimab in severe asthma with an eosinophilic phenotype. New Engl J Med. 2024;391:2337-2349. Two phase 3 RCTs of the ultra-long-acting anti-IL-5 biologic agent depemokimab enrolled asthma patients with suboptimal control on medium or high dose ICS and eosinophilia (>150 cells/uL at screening or >300 cells/uL in past 12 months). 502 patients were randomized to depemokimab, dosed at enrollment and 26 weeks, and 260 to placebo. In the SWIFT-1 trial, the rate ratio of annual exacerbations between intervention and placebo arm was 0.42 (95% CI, 0.30-0.59; P<0.001). In the SWIFT-2 trial, the rate ratio was 0.52 (95% CI, 0.36-0.73; P<0.001). Reported symptoms, quality of life, and adverse events did not differ between groups. 
PMID: 39248309

Ramakrishnan S, Russell REK, Mahmood HR, et al. Treating eosinophilic exacerbations of asthma and COPD with benralizumab (ABRA): a double-blind, double-dummy, active placebo-controlled randomised trial. Lancet Respir Med. 2025;13:59–68. RCT of 158 adults presenting with acute eosinophilic exacerbation (peripheral eosinophils ≥300 cells/µL) of asthma or COPD, randomised 1:1:1 to benralizumab plus prednisolone, benralizumab alone, or prednisolone alone. Patients receiving non-invasive or invasive ventilation were excluded. Treatment failure at 90 days was significantly lower in both benralizumab arms vs. prednisolone alone (NNT approximately 4), and benralizumab significantly reduced symptom burden at 28 days regardless of whether prednisolone was co-administered. Post-exacerbation treatment was not specified or reported.  These results suggest biologics may have a role in the treatment of acute exacerbations..
PMID: 39615502

The role of nonadherence in refractory asthma
Gamble J, Stevenson M, McClean E, et al. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med 2009;180:817-22. In a patient population referred for specialist care in the setting of refractory asthma, 35% of patients filled fewer than half of their prescriptions for inhaled corticosteroids. Nonadherent patients had significantly lower asthma-specific quality of life. This study highlights an important and often overlooked factor in asthma refractoriness.
PMID: 19644048

Exercise induced bronchoconstriction 
Parsons JP, Hallstrand TS, Mastronarde JG, et al. An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2013; 187:1016-1027. This guideline offers a succinct, practical overview of EIB management, including the strength of evidence supporting various options for diagnosis and treatment.
PMID: 23634861

Guidelines and reviews 
Barker AF, Karamooz E. Non–Cystic Fibrosis Bronchiectasis in Adults: A Review. JAMA. 2025;334:253–264. This clinically-focused review offers the reader an up to date, evidence-based primer on non-cystic fibrosis bronchiectasis (NCFB) in adults, highlighting conditions that may predispose to or cause NCFB, appropriate initial work up, and treatment strategies for both stable and progressive disease. 
PMID: 40293759 

Choi H, McShane PJ, Aliberti S, Chalmers JD. Bronchiectasis management in adults: state of the art and future directions. Eur Respir J. 2024; 63: 2400518. This review highlights the importance of identifying a patient’s phenotype, endotype and treatable traits in order to achieve better symptom control. The review provides evidence based updates on key management targets of mucociliary clearance, bacterial infection, and airway inflammation. The authors also discuss future directions for bronchiectasis care. 
PMID: 38782469 
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Herrero-Cortina B, Lee AL, Oliveira A, et al. European Respiratory Society statement on airway clearance techniques in adults with bronchiectasis. Eur Respir J. 2023;62:2202053. There is little evidence to indicate one form of airway clearance is superior to another, but this review provides an excellent overview of the available options, including how they work.  Discussion of advantages and disadvantages provides further insight on how to best tailor airway clearance mode to patient preferences. PMID: 37142337
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Therapeutics 
O’Donnell AE, Barker AF, Ilowite JS, et al. Treatment of idiopathic bronchiectasis with aerosolized recombinant human Dnase I. Chest 1998;113:1329-1334. A large multinational trial of patients with idiopathic bronchiectasis found increased exacerbation frequency and an accelerated decrease in FEV1. While noteworthy for its specific findings, this study is widely cited as a reason cystic fibrosis treatment strategies should not be universally applied to all types of bronchiectasis.
PMID: 9596315
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Altenburg J, de Graaff CS, Stienstra Y, et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013;309:1251-9. A RCT of chronic azithromycin treatment in 83 patients with stable non-cystic fibrosis bronchiectasis. Azithromycin was associated with a substantially decreased pulmonary exacerbation rate but increased macrolide resistance.
PMID: 23532241
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Haworth CS, Shteinberg M, Winthrop K, et al. Inhaled colistimethate sodium in patients with bronchiectasis and Pseudomonas aeruginosa infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months. Lancet Respir Med. 2024;12:787-798. These trials assessed the efficacy and safety of colistimethate nebs in decreasing annual bronchiectasis exacerbation rate in adults with non-CF bronchiectasis and chronic lung infection with Pseudomonas aeruginosa. PROMIS-1 showed an impressive decrease in exacerbations by 39% and a decrease in severe exacerbations by 59% in the colistimethate group. These results were not replicated in PROMIS-II (identical exacerbation rate of 0.89/year), which was terminated early due to the Covid-19 pandemic. 
PMID: 39270696 
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Chalmers JD, Burgel PR, Daley CL, et al. Phase 3 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis. N Engl J Med. 2025;392:1569-1581. The ASPEN trial of 1721 patients with non-CF bronchiectasis from 35 different countries compared the anti-neutrophilic dipeptidyl peptidase 1 inhibitor brensocatib (at two doses, 10 mg or 25 mg daily) to placebo.  At 1 year, the patients on brensocatib had a ~20% reduction in exacerbation frequency compared to placebo. Patients on the 25 mg daily dose  had a 38 ml/year lower annual decline in FEV1 compared to placebo, but no difference on the 10 mg dose. Of note, only about 20% of patients in the study were on long term macrolide therapy.
PMID: 40267423

Bradley JM, O'Neill B, McAuley DF, et al. Hypertonic Saline or Carbocisteine in Bronchiectasis. N Engl J Med. 2025;393:1565-1577. This RCT conducted across 20 centers in the United Kingdom randomized adults with non-CF bronchiectasis who had daily sputum production and frequent exacerbations (1 or more per year) to one of four groups: hypertonic saline (6%), carbocisteine, hypertonic saline plus carbocisteine, or standard of care (airway clearance). The primary outcome was the number of pulmonary exacerbations over 52 weeks. Exclusion criteria included active smoking or receiving a mucolytic in the preceding 30 days. There was no significant difference in the primary outcome between hypertonic saline vs no hypertonic saline, or carbocisteine vs no carbocisteine. The study did not specify the timing of the study agents relative to mechanical airway clearance. 
PMID: 41020514

Heart failure
Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005; 294:1625-33. This RCT of 433 patients with acute decompensated CHF (but not shock) found no difference in resolution of symptoms, mortality, or days alive and out of the hospital at 6 months. There was a higher incidence of adverse events in the group randomized to PAC. This data suggests the use of PAC is not indicated for the routine management of decompensated CHF.
PMID: 16204662
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Cardiogenic shock
Thiele H, Hassager C. Cardiogenic Shock. N Engl J Med. 2026;394(1):62-77. This review provides a nice overview of definitions and categories of cardiogenic shock as well as the fundamentals of ICU care.  There is a more in-depth exploration of how best to identify suitable candidates for mechanical circulatory support. 
PMID: 41467651 

Ostadal P, Rokyta R, Karasek J, et al. Extracorporeal membrane oxygenation in the therapy of cardiogenic shock: results of the ECMO-CS Randomized Clinical Trial. Circulation. 2023;147:454-464. This trial of 122 patients with rapidly progressive or severe cardiogenic shock found no advantage to early VA-ECMO compared to standard of care with option for downstream VA ECMO.  A total of 39% of standard care patients eventually received VA-ECMO.
PMID: 36335478
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Thiele H, Zeymer U, Akin I, et al. Extracorporeal life support in infarct-related cardiogenic shock. N Engl J Med. 2023;389:1286-1297. 417 patients with acute MI complicated by cardiogenic shock were placed on early VA-ECMO while in the cath lab, or managed medically. There was no difference in primary outcome of 30 day all-cause mortality. Secondary outcomes of higher rate of limb ischemia, and moderate-severe bleeding were higher in ECLS arm.
PMID: 37634145
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DeBacker D, Biston P, Devriendt J, et al. SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362:779-89. Large multicenter RCT of 1679 patients with shock of any etiology, demonstrated equal mortality and significantly fewer arrhythmias with norepinephrine as first line vasopressor. The subgroup of those with cardiogenic shock had higher mortality with dopamine. Concerns raised have included heterogeneity of shock physiologies included, restricted fluid resuscitation protocol, and open label use of norepinephrine after conservative max doses of study drug. However, this study adds valuable evidence to our currently limited understanding of comparative merits of pressors.
PMID: 20200382
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Thiele H, Zeymer U, Neumann FJ, et al. IABP-SHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012; 367 :1287-96. Randomized study of 600 patients with cardiogenic shock complicating acute myocardial infarction found no difference in all-cause 30-day mortality with use of intraaortic balloon counterpulsation (IABP) compared to no IABP. The IABP group had less multiorgan dysfunction at days 2 and 3 but there was no difference by day 4.
PMID: 22920912
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Moller JE, Engstrom T, Jensen LO, et al. Microaxial flow pump or standard care in infarct-related cardiogenic shock. N Engl J Med. 2024; 390:1382-1393. In the DanGer Shock trial, 360 patients with cardiogenic shock following STEMI who were not comatose and who did not have biventricular failure had lower mortality when treated with microaxial flow pump (Impella CP) compared to standard care. Death from any cause at 180 days occurred in 45.8% of patients in the intervention group and in 58.5% of the standard care group (hazard ratio 0.74; 95% CI, 0.55 to 0.99, p=0.04). Of note, in 85% of cases the Impella was placed prior to revascularization. The intervention group did have significantly more side effects including bleeding, limb ischemia, and need for renal replacement therapy.
PMID: 38587239

Balthazar T, Vandenbriele C, Verbrugge FH, et al. Managing Patients With Short-Term Mechanical Circulatory Support: JACC Review Topic of the Week. J Am Coll Cardiol. 2021;77:1243-1256. This review provides case vignettes and algorithmic approaches to clinical problems for patients with a microaxial flow pump. It is an excellent read for a review of the evidence and physiology behind percutaneous ventricular support devices as well as an article to reference when an issue arises. Of note, this article was published prior to the DanGer Shock trial. 
PMID: 33663742 
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*** For information regarding mechanical circulatory support in the setting of cardiac arrest, please see the Hirsch et al article found in the neurology critical care section.

Myocardial infarction
Ducrocq G, Gonzalez-Juanatey JR, Puymirat E, et al. Effect of a restrictive vs liberal blood transfusion strategy on major cardiovascular events among patients with acute myocardial infarction and anemia: The REALITY randomized clinical trial. JAMA. 2021; 325:552-560. This trial is noteworthy for finding no difference in major adverse cardiovascular events with using a transfusion threshold of 8 gm/dl compared to 10 gm/dl in 688 patients with acute myocardial infarction. Outcomes favored the restrictive approach but did not reach statistical significance.
PMID: 33560322
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Carson JL, Brooks MM, Hébert PC, et al. Restrictive or liberal transfusion strategy in myocardial infarction and anemia. N Engl J Med. 2023;389:2446-2456. This trial randomized 3500 patients with acute MI and hemoglobin less than 10g/dL to restrictive transfusion (threshold of 7 or 8g/dL) or liberal transfusion (10g/dL). Primary outcome of MI or death at 30 days occurred less frequently in liberal transfusion arm (14.5% vs 16.9% in restrictive group), though this difference did not reach statistical significance.
PMID: 37952133
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Mathew R, Di Santo P, Jung RG, et al. Milrinone as compared with dobutamine in the treatment of cardiogenic shock. N Engl J Med. 2022; 385:516-525. Study of 192 patients in cardiogenic shock found comparable outcomes between the two inotropes.
PMID: 34347952
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Suverein MM, Delnoij TSR, Lorusso R, et al. Early extracorporeal CPR for refractory out-of-hospital cardiac arrest. N Engl J Med. 2023;388:299-309. 134 patients with refractory OOH ventricular arrhythmia cardiac arrest were randomized to conventional CPR vs. ECPR. There was no statistically significant difference in favorable neurologic outcome at 30 days (16 and 20%, respectively).
PMID: 36720132
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Post cardiac surgery
The following two-part article provides a comprehensive review of postoperative care in adult cardiac surgical patients.
Stephens RS, Whitman GJ. Postoperative critical care of the adult cardiac surgical patient. Part I: routine postoperative care. Crit Care Med. 2015; 43:1477-97.
PMID: 25962078 

Stephens RS, Whitman GJ. Postoperative critical care of the adult cardiac surgical patient: Part II: procedure-specific considerations, management of complications, and quality improvement. Crit Care Med. 2015; :1995-2014.
PMID: 26136101 

Hajjar LA, Vincent JL, Barbosa Gomes Galas FR et al. Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: The VANCS randomized controlled trial. Anesthesiology. 2017;126:85-93. This double-blind trial of 330 patients with vasoplegic shock after cardiac surgery found use of vasopressin reduced the primary endpoint of mortality or severe complications compared to norepinephrine (32% vs 49%). There was less atrial fibrillation in the vasopressin group and no difference in digital ischemia, mesenteric ischemia, hyponatremia or myocardial infarction.
PMID: 27841822
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***For therapeutic hypothermia following cardiac arrest, see Neurology Critical Care.

Raoof S, Feigin D, Sung A, et al. Interpretation of plain chest roentgenogram. Chest. 2012; 141: 545-558.
PMID: 22315122
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Bankier AA, MacMahon H, Colby T, et al. Fleischner Society: Glossary of Terms for Thoracic Imaging. Radiology. 2024;310(2):e232558. This update from the 2008 version is an excellent reference that standardizes terminology by incorporating new terms, eliminating obsolete terms, and more clearly defining vague or inconsistently used terms. Over 160 figures of CT images nicely illustrate the terminology.
PMID: 38411514 
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Raju S, Ghosh S, Mehta AC, et al. Chest CT signs in pulmonary disease: a pictorial review. Chest. 2017; 151(6):1356-1374.
PMID: 28212835
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Horst C, Patel S, Nair A. Reporting and management of incidental lung findings on computed tomography: beyond lung nodules. Br J Radiol. 2023; 96:20220207. Patients can be referred for evaluation of clinically insignificant or negligible CT findings. This article provides practical insight on how to determine if incidental abnormalities such as subtle focal bronchiectasis, low attenuation areas, and bronchial wall thickening merit further attention.
PMID: 36124681
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Le L, Narula N, Zhou F, et al. Diseases involving the lung peribronchovascular region: a CT imaging pathologic classification. Chest. 2024;166:802-820. This article reviews the anatomy of the peribronchovascular space and the numerous pathologies that occur there. The authors offer an approach to classifying diseases of the peribronchovascular space based on imaging patterns which can assist in generating a differential diagnosis.
PMID: 38909953

Franquet T, Raoof S, Lee KS, et al. Lung nodules and masses in non-HIV immunocompromised patients: A clinical imaging algorithmic approach. Chest. 2025; 167:1142-1160. This review article provides an algorithmic approach to evaluation of pulmonary nodules and masses in non-HIV immunocompromised hosts and stresses the importance of integrating imaging into the clinical context to reach an accurate diagnosis for the patient. 
PMID: 39571725 

Chest Imaging in Interstitial Lung Disease 
Lynch DA, Travis WD, Müller NL, et al. Idiopathic interstitial pneumonias: CT features. Radiology. 2005; 236:10-21.
PMID: 15987960 

Brixey AG, Oh AS, Alsamarraie A, Chung JH. Pictorial review of fibrotic interstitial lung disease on high-resolution CT scan and updated classification. Chest. 2024; 165: 908-923. An approachable, well-organized review of fibrotic interstitial lung diseases including UIP, NSIP, and fibrotic HP. with classic high-resolution CT imaging examples. Additionally, the review article provides an evidence-based algorithmic approach to decision making for patients with symptoms and presence of fibrotic changes on CT scan. 
PMID: 38056824 

Gupta N, Vassallo R, Wikenheiser-Brokamp KA, et al. Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med. 2015; 191(12):1354-66.
PMID: 25906089
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Gupta N, Vassallo R, Wikenheiser-Brokamp KA, et al. Diffuse cystic lung disease. Part II. Am J Respir Crit Care Med. 2015; 192:17-29.
PMID: 25906201
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Criado E, Sánchez M, Ramírez J, et al. Pulmonary sarcoidosis: typical and atypical manifestations at high-resolution CT with pathologic correlation.Radiographics. 2010; 30:1567-86. 
PMID: 21071376 

Hatabu H, Hunninghake GM, Richeldi L, et al. Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society. Lancet Respir Med. 2020; 8:726-737. Interstitial lung abnormalities, which are often incidentally found in older adults, may, or may not, progress to clinically significant ILD.  This position paper provides a valuable overview on terminology, initial evaluation, monitoring, and management..
PMID: 32649920
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Guidelines/Strategies
Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: GOLD 2026 Report. Notable updates on this year’s report include adjustments to the GOLD A, B, and E classifications (one or more moderate/severe exacerbation qualifies as category E) with new treatment implications, an emphasis on the distinctions between initial and follow up treatment plans, revision of the sections on exacerbations and multimorbidity in COPD, a new figure summarizing evidence for the use of biologic therapy in COPD, and a  section on artificial intelligence and technology in COPD, amongst others. 
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COPDGene 2025 Diagnosis Working Group and CanCOLD Investigators, Bhatt SP, Abadi E, et al. A Multidimensional Diagnostic Approach for Chronic Obstructive Pulmonary Disease. JAMA. 2025;333:2164-2175. This study proposes a multimodal approach to diagnosis of COPD based on 2 longitudinal cohorts (COPDGene and CanCOLD) with over 10,000 participants. A diagnosis of COPD could be reached by (1) the presence of airflow obstruction (FEV1/FVC < 0.70) AND at least 1 of 5 minor criteria (emphysema or bronchitis on CT, dyspnea, poor respiratory QOL, or chronic bronchitis) or (2) at least 3 of 5 minor criteria. Importantly, 8% of patients were newly diagnosed with COPD without obstructive PFTs (i.e. by minor criteria only) and had increased mortality and exacerbations compared to those with normal spirometry. Furthermore, those with impaired spirometry but no minor criteria (no COPD diagnosis by this study) had the same outcomes as those with normal spirometry. 
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Inhaled monotherapy
Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093-103. This RCT randomized over 7000 patients with at least one exacerbation in the previous year to either tiotropium or salmeterol for one year.  The primary endpoint of first exacerbation was increased by 42 days in the tiotropium group (p<0.001). This study suggests anticholinergic therapy may be the better initial long-acting bronchodilator therapy.
PMID: 21428765
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Inhaled combination therapy
Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775-89. The TORCH study randomized over 6,000 patients with baseline FEV1 < 60% predicted to placebo vs. salmeterol alone vs. fluticasone alone vs. a combination of salmeterol and fluticasone over 3 years. Compared to placebo, patients receiving combination therapy had a 0.9% annual reduction in mortality (p = .052). Use of salmeterol, fluticasone, or a combination of the 2 reduced the frequency of exacerbations, but p was >.10 for all 3 for reducing risk of COPD-related death. All-cause mortality and COPD-related death were lower with combination therapy than fluticasone alone (p = .007 and .008, respectively).
PMID: 17314337
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Wedzicha JA, Banerji D, Chapman KR,et al, FLAME Investigators. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med 2016; 374: 2222-2234. The FLAME trial randomized 3300 patients with COPD and high exacerbation risk to indacaterol–glycopyrronium once daily versus salmeterol–fluticasone twice daily and found the LAMA/LABA combination reduced the annual exacerbation rate by 11% compared to ICS/LABA. Additionally, the salmeterol-fluticasone group had a higher rate of pneumonia (4.8 vs 3.2%).
PMID: 27181606
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Lipson DA, Barnhart F, Brealey N et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018; 378:1671-1680. The IMPACT trial randomized over 10.000 subjects to triple therapy (ICS/LAMA/LABA) or dual therapy (LABA/ICS or LABA/LAMA). Triple therapy resulted in fewer exacerbations (0.91/year) compared to LABA/ICS (1.07/year), which in turn was superior to LABA/LAMA (1.21/year).  A critique of the trial is that patients with a history of asthma were not excluded and most patients randomized to dual therapy were on an ICS prior to enrollment, raising the possibility that abrupt withdrawal of ICS accounted for the difference in efficacy.
PMID: 29668352
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Papi A, Vestbo J, Fabbri L et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet. 2018; 391:1076-1084. This year-long trial compared triple therapy to LABA/LAMA among 1,500 patients with severe, symptomatic COPD and found triple therapy had lower rates of moderate to severe exacerbations (0.5/year) as compared to LABA/LAMA group (0.59/year, p = .04) - several years of treatment to prevent 1 exacerbation. The benefit of triple therapy was more pronounced in patients with a chronic bronchitis phenotype or with > 2% eosinophils at baseline.
PMID: 29429593 

Rabe KF, Martinez FJ, Ferguson GT, et al. ETHOS Investigators. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. N Engl J Med. 2020; 383:35-48. The ETHOS 52-week RCT of 8,509 patients is noteworthy for finding annual rates of moderate or severe exacerbation of 1.08 with higher-dose budesonide triple therapy, 1.07 with lower-dose budesonide triple therapy, 1.42 with LAMA/LABA therapy, and 1.24 with high-dose ICS/LABA therapy.  Patients with a history of adult asthma were excluded and benefits of both triple therapy regimens over LAMA/LABA were similar regardless of baseline ICS use. As in the IMPACT trial, all-cause mortality was lower with high-dose triple therapy group compared to LAMA/LABA [1.3% vs 2.3%, HR 0.54 (0.34-0.87)].
PMID: 32579807 
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Inhaled steroid withdrawal 
Chapman KR, Hurst JR, Frent SM et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): A randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198:329-339. This study compared de-escalation to LABA/LAMA vs. continued triple therapy in patients with moderate-to-severe COPD and infrequent exacerbations. Direct de-escalation to LABA/LAMA led to a small decrease in lung function (26 mL), with no difference in exacerbations. Of note, a subgroup of patients with eosinophil counts >300 at baseline had greater lung function loss and higher exacerbation risk.
PMID: 29779416 

Phosphodiesterase inhibitors
Martinez, Fernando J., Calverley PM, Goehring UM, et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015; 385:857-866. This is the first large trial to study the addition of roflumilast to inhaled corticosteroids and long-acting beta-agonists in patients with severe COPD and symptoms of chronic bronchitis. A majority of the 1,945 patients (70%) were also on tiotropium. They found a 14.2% decrease in rate of moderate to severe exacerbations over the course of 1 year in the intervention group. Of note, the study population was limited to those with a chronic bronchitic phenotype, and side effects were common.
PMID: 25684586 

Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phosphodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE Trials). Am J Respir Crit Care Med. 2023;208:406-416. RCT of 1549 patients with moderate to severe COPD found ensifentrine nebulized bid improved the average FEV1 area under the curve by 90 ml (≈ 6%) compared to placebo.  Improvements in the SGRQ did not reach the minimal important difference. Exacerbations were reduced with ensifentrine. Approximately 1/3 of subjects were on no controller therapy and no patients were on LABA/LAMA combination therapy. Treatment withdrawal occurred in approximately 20% in both groups.
PMID: 37364283
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Biologics
Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389:205-214. Trial of 939 COPD patients with eosinophil count > 300, chronic bronchitis phenotype, and elevated risk of exacerbation despite triple inhaler therapy found a rate of moderate to severe exacerbation of 0.71/year with dupilumab vs 1.1/year with placebo. The dupilumab group had modest improvements in lung function and respiratory symptoms compared to placebo.
PMID: 37272521
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Sciurba FC, Criner GJ, Christenson SA et al. Mepolizumab to Prevent Exacerbations of COPD with an Eosinophilic Phenotype. N Engl J Med 2025; 392:1710-20. This RCT included 804 patients with COPD with a history of exacerbations, a blood eosinophil count of 300 cells/uL or greater and who were on triple inhaled therapy. Compared to placebo, mepolizumab 100 mg every 4 weeks significantly reduced the annualized rate of moderate or severe exacerbations (0.80 vs 1.01, rate ratio 0.79, p 0.01). Of note, there was no difference in the subset with severe exacerbations (causing hospitalization for 24 hours or more, or death) or in health related quality of life and symptoms between groups. 
PMID: 40305712 

Azithromycin to prevent COPD exacerbation
Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689-98. In a large study of patients who required continuous oxygen or had required systemic steroids in the last year and had had at least one prior exacerbation, but who were stable for at least a month prior to the study, the use of daily azithromycin was found to increase the time to subsequent exacerbation from six months to nine months. An audiology-confirmed hearing decrement occurred in 25% of study patients and 20% of placebo patients (p=0.04).
PMID: 21864166
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Role of antibiotics in exacerbations
Anthonisen NR, Manfreda J, Warren CPW et al. Antibiotic therapy in exacerbations of COPD. Ann Intern Med 1987;106:196-204. Famous study often cited by proponents of antibiotic use for COPD exacerbations. Randomized, blinded, controlled study found use of antibiotics in the presence of increased dyspnea, increased sputum production, and increased sputum purulence improved outcomes. The improvement was no longer significant, however, after controlling for use of oral steroids.
PMID: 3492164 

Supplemental oxygen
NOTT group. Continuous or nocturnal oxygen therapy in hypoxemic COPD. Ann Intern Med 1980;93: 391-8. Famous multicenter study showing use of continuous oxygen therapy (>17 hr/d) resulted in lower mortality than use of nocturnal therapy (12 hr/d) in pts. with PaO2 55 mmHg or PaO2 59 mmHg and pulmonary hypertension, right-sided failure, or Hct > 55%.
PMID: 6776858 

MRC Working Party. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981;8222:681-5. Another well known study showing improved survival with continuous oxygen in hypoxemic COPD patients.
PMID: 6110912 

Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med 2016; 375: 1617-1627. This multicenter trial randomized 220 patients with resting oxygen saturation 89 to 93% to 24 hours/day supplemental oxygen plus 148 patients with exercise-induced hypoxia (O2 sat 80 - 89% with exertion) to supplemental oxygen during exercise and sleep only and compared these groups to 379 patients randomized to no treatment. They found no difference in time to death, first hospitalization, nor any other outcomes over 1 to 6 years of observation. Of note, the study was powered to detect a 40% mortality difference, an effect matched by few medical interventions. Nonetheless, this study supports limiting supplemental oxygen primarily to COPD patients with severe resting hypoxemia.
PMID: 27783918
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Ekström M, Andersson A, Papadopoulos S, et al. Long-term oxygen therapy for 24 or 15 hours per day in severe hypoxemia. N Engl J Med. 2024;391: 977-988. The REDOX trial randomized 241 adult patients with severe resting hypoxemia (PaO2 < 55 mmHg or SpO2 < 88%) to supplemental oxygen for either 15 hours or 24 hours per day. 71% of the enrolled patients had COPD and 14% had pulmonary fibrosis.  Oxygen for 15 hours per day was not inferior to 24 hours per day for the primary outcome of death or hospitalization at 1 year, and adverse events were balanced between groups. Concerns include changing the goal sample size and primary outcome due to slow enrollment, assessment of oxygen adherence by questionnaires sent at 3 and 12 months which were subject to bias, and the follow up interval of 1 year which is shorter than previous LTOT trials.
PMID: 39254466

Lung volume reduction strategies 
Flandes J, Soto FJ, Cordovilla R et al. Bronchoscopic lung volume reduction. Clin Chest Med. 2018; 39:169-180. Comprehensive review of bronchoscopic lung volume reduction with an emphasis on FDA approved unidirectional endobronchial valves.

***For information on endobronchial valves, see the bronchoscopy articles within the Procedure section
PMID: 29433712 

Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema: NETT Research Group. N Engl J Med 2003;348:2059-73. After excluding 140 pts identified as having high risk of mortality based on an interim analysis, a greater proportion of LVRS patients had improved exercise tolerance compared to the medical therapy arm (16% vs. 3%), but there was no survival advantage after 24 months. Subgroup analysis found patients with predominantly upper lobe disease and low exercise capacity had improved mortality, while patients with non-upper lobe emphysema and high exercise capacity had higher mortality following LVRS compared to medical therapy.
PMID: 12759479
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Klooster K, Slebos DJ. Endobronchial valves for the treatment of advanced emphysema. Chest. 2021;159:1833-1842. This review walks the reader through careful selection of appropriate patients for endobronchial valve treatment, provides a detailed description of tthe procedure itself complete with intra-procedural pictures, and emphasizes important elements of follow up care including management of adverse events related to endobronchial valve placement.
PMID: 33345947 
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 Asthma COPD overlap
Postma DS, Rabe KF. The asthma–COPD overlap syndrome. New Engl J Med. 2015; 373:1241-9. Efforts to define patients with asthma-COPD overlap syndrome (ACOS) have generated confusion and controversy. In this review, the authors note that although debate is long-standing, current data do not support the designation of ACOS as a “disease entity”. They recommend continued efforts to define ACOS including determining treatment response, and emphasize complete and objective documentation of these patients while generating observational data.
PMID: 26398072

Guidelines
IDSA Guidelines on Treatment and Management of Covid-19
IDSA site provides information on treatments for prophylaxis, outpatients with infection, and hospitalized patients with mild to moderate disease, as well as references for negative treatment trials. 

Prevention
Scott J, Donahue S, Atkinson N, et al. Updated evidence for Covid-19, RSV, and influenza vaccines for 2025–2026. N Engl J Med. 2025. 393(22):2221-2242. Systematic review of 511 studies (from an initial pool of >17,000) evaluating vaccine effectiveness for COVID-19, RSV, and influenza against hospitalization in adults and children, informing 2025–2026 vaccine recommendations. Updated COVID-19 formulations provided meaningful protection against hospitalization; RSV vaccines showed robust efficacy against lower respiratory tract disease in older adults. A key safety finding was mRNA COVID-19 vaccine-associated myocarditis occurring at 1.3–3.1 per 100,000 doses in male adolescents, with risk attenuated by longer dosing intervals. This review serves as an important reference for clinicians counseling patients on annual vaccine selection, particularly those managing immunocompromised populations.
PMID: 41160817

Pharmacologic treatment - outpatient 
Antivirals
Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med. 2022; 386:1397-1408. This randomized, controlled trial (EPIC-HR) assessed the impact of nirmatrelvir and ritonavir (paxlovid) dosed every 12 hours for 5 days in 2246 symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe Covid-19. Nirmatrelvir/ritonavir led to an 89.1% relative risk reduction in Covid-19-related hospitalization or death by day 28 compared with placebo, and there was no increase in adverse events.
PMID: 35172054
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Hammond J, Fountaine RJ, Yunis C, et al. Nirmatrelvir for vaccinated or unvaccinated adult outpatients with Covid-19. N Engl J Med. 2024;390:1186-1195. This sister-RCT to the EPIC-HR trial of nearly 1,300 patients found nirmatrelvir-ritonavir (Paxlovid) did not shorten the time to symptom resolution for patients with Covid-19 without risk factors for severe Covid-19 disease (whether vaccinated or unvaccinated) or for vaccinated patients with one risk factor for severe Covid-19.  Of note this study was conducted when the delta variant was the predominant strain of Covid-19 so how Paxlovid affects outpatients with other strains of Covid-19 is uncertain. 
PMID: 38598573 
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Pharmacologic treatment - inpatient 
Dexamethasone
Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19. RECOVERY Collaborative Group. N Engl J Med. 2021; 384:693-704. This adaptive, randomized controlled study of candidate COVID-19 treatments was the first trial to show a mortality benefit from the use of dexamethasone. A regimen of 6 mg of dexamethasone for up to 10 days reduced 28-day mortality among 6,245 hospitalized COVID-19 patients who were receiving oxygen without mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 – 0.94) or on mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 – 0.81). There was no benefit in patients not requiring oxygen.
PMID: 32678530
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Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID=-19: The CoDEX randomized clinical trial. JAMA. 2020; 324:1307-1316. RCT of dexamethasone vs standard care in 299 patients requiring mechanical ventilation due to COVID-19 ARDS was stopped early upon publication of the RECOVERY trial. Dexamethasone was given as a 20 mg infusion for 5 days followed by a 10 mg infusion for 5 days. After 28 days, the dexamethasone group had a greater number of days alive and free of the ventilator (6.6; 95% CI, 5.0 – 8.2) than the standard care group (4.0; 95% CI, 2.9 – 5.4) with P = .04 for difference between groups. All-cause mortality at 28 days was nearly 60% and did not differ between groups.
PMID: 32876695
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The COVID STEROID 2 Trial Group.  Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: The COVID STEROID 2 Randomized Trial. JAMA. 2021;326: 1807-1817. RCT of 1,000 patients compared 6 mg versus 12 mg of IV dexamethasone in COVID-19 patients requiring at least 10 L/min of supplemental oxygen or mechanical ventilation. There was no statistically significant difference in the primary endpoint of days alive without life support at 28 days (adjusted mean difference 1.3 days, p =.07).  The lower 28-day mortality in the 12 mg group did not reach statistical significance (27.1 vs 32.3%, adjusted RR 0.86, 95% CI 0.68 - 1.08).
PMID: 34673895
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Remdesivir
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 – final report. ACTT-1 study group members. N Engl J Med. 2020; 383:1813-1826. The first iteration of NIAID’s Adaptive COVID-19 Treatment Trial (ACTT) compared remdesivir to placebo in 1,062 hospitalized patients with COVID-19 causing lower respiratory tract infection. Patients receiving remdesivir, given as an infusion for up to 10 days, had a 5 to 7 day reduction in time to recovery, but mortality did not differ. No benefit was observed in the subset of patients requiring mechanical ventilation.
PMID: 32445440
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WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalized patients with COVID-19: final results of the WHO Solidarity randomized trial and updated meta-analyses. Lancet. 2022; 399: 1941-53. Solidarity is an open-label trial that enrolled 14,221 patients from 35 countries and randomly assigned them either to remdesivir (ten daily infusions, unless discharged earlier) or to control. This trial confirmed a lack of impact on mortality in ventilated patients and suggested a small benefit in patients who were on oxygen but not mechanically ventilated. Notably, the confidence intervals in this study were wide, and type of oxygen device was not specified, limiting assessment of effects in patients receiving high-flow versus low-flow oxygen. The Solidarity Trial Consortium also performed a meta-analysis of randomized trials with similar findings.
PMID: 35512728
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IL-6 receptor antagonists
REMAP-CAP Investigators, Gordon AC, Mouncey PR, Al-Beidh F, et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021; 384:1491-1502. Early studies of tocilizumab monotherapy were negative. This multifactorial adaptive platform trial of 803 patients compared tocilizumab and another interlukin-6 antagonist, sarilumab, to standard care, which for the majority of patients included steroids. Both IL-6 antagonists were superior to standard care for the primary measures of organ support-free days and in-hospital mortality. The results of this trial, and similar results in the EMPACTA and RECOVERY trials, suggest a benefit from IL-6 receptor antagonists when used in conjunction with steroids.
PMID: 33631065
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Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2021;384(9):795-807. Randomized trial showing faster time to recovery in baricitinib and remdesivir group vs placebo and remdesivir, particularly in patients on high-flow oxygen or non-invasive ventilation.
PMID: 33306283 

Anticoagulation
INSPIRATION Investigators, Sadeghipour P, Talasaz, AH, Rashidi F, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: The INSPIRATION randomized clinical trial. JAMA. 2021; 27:1620-1630. RCT comparing intermediate (enoxaparin, 1 mg/kg daily) vs standard dose (enoxaparin, 40 mg daily) prophylactic anticoagulation in COVID-19 ICU patients, showing no significant difference in venous or arterial thrombosis, treatment with ECMO, or 30 day mortality.
PMID: 33734299 

REMAP-CAP, ATTACC, ACTIV-4a Investigators. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19.  N Engl J Med. 2021; 385: 777-789. This trial used open-label, adaptive, multiplatform, randomized methodology to compare therapeutic heparin to usual pharmacological DVT prophylaxis and reached futility after enrollment of 1,098 patients. Specifically, there was no difference in survival to hospital discharge or number of days free of cardiovascular or respiratory organ support.
PMID: 34351722
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Ventilatory and oxygen support 
Perkins GD, Ji C, Connolly BA, et al. Effect of noninvasive respiratory strategies on intubation or mortality among patients with acute hypoxemic respiratory failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial. JAMA. 2022; 327:546-558. This parallel group, adaptive, RCT of 1273 hospitalized adults with O2 sat 94% or less while receiving at least FIO2 0.4 found the CPAP group (no positive inspiratory pressure used) had a better combined endpoint of intubation or 30-day mortality compared to standard O2 therapy (36.3 vs. 44.%) while there was no difference in the combined endpoint between HFNC and standard therapy.
PMID: 35072713
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Frat JP, Quenot JP, Badie J, et al. Effect of high-flow nasal cannula oxygen vs standard oxygen therapy on mortality in patients with respiratory failure due to COVID-19: The SOHO-COVID Randomized Clinical Trial. JAMA. 2022; 328:1212-1222. This RCT of over 700 patients with P/F < 200 mm Hg found no difference in mortality. The standard oxygen group had a higher rate of intubation (45 vs 53%), but noninvasive support was not used in the study.
PMID: 36166027
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Harrois A, Jouffroy R, Ayed S, et al. Awake Prone Positioning in Patients With COVID-19 Respiratory Failure: A Randomized Clinical Trial. JAMA Netw Open. 2025;8:e2548201.  RCT of awake prone positioning in 445 non-intubated COVID patients with hypoxemic respiratory failure. Awake prone positioning for at least 6 hours/day reduced intubation rates and 28 day mortality (OR 0.74, 95% CI 0.48-1.09) with posterior probability of reducing intubation and death of 93.8%.
PMID: 37101160 
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Reviews
Grasemann H, Ratjen F. Cystic Fibrosis. N Engl J Med. 2023;389(18):1693-1707. A review of cystic fibrosis pathophysiology, diagnosis, and management in the era of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies. 
PMID: 37913507

Guidelines 
Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009; 180:802-8. This document offers graded recommendations for management of exacerbations, but is most noteworthy for highlighting the lack of evidence guiding many fundamental aspects of care.
PMID: 19729669 

Floto RA, Olivier KN, Saiman L, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary. Thorax. 2016;7:88-90. A summary of evidence-based recommendations regarding screening, diagnosis, therapeutics, and transplant considerations for patients with cystic fibrosis with nontuberculous mycobacterial infections.
PMID: 26678435
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Treatment of exacerbations
Goss CH, Heltshe SL, West NE,et al; on behalf of the STOP2 Investigators. A randomized clinical trial of antimicrobial duration for cystic fibrosis pulmonary exacerbation treatment. Am J Respir Crit Care Med 2021; 204: 1295-1305. Noteworthy for being the most robust study of antibiotic duration in CF exacerbations. Among the 214 patients with an early response to IV antibiotics (defined as > 8% improvement in ppFEV1 and significant improvement in symptoms), completing a total of 10 days of IV antibiotics was non-inferior to 14 days.  Among the 705 patients without an early robust response, completing 21 days of IV antibiotics was not superior to a 14-day total course. Of note, the mean ppFEV1 decline from baseline was only 2.5% in those without an early response vs. down 9.3% in the early response group, which raises the possibility the patients assigned to the longer course of treatment were less likely to benefit from IV antibiotics in the first place.
PMID: 34469706

Respiratory complications of CF 
Mingora CM, Flume PA. Pulmonary complications in cystic fibrosis: past, present, and future: adult cystic fibrosis series. Chest. 2021; 160:1232-1240. This review provides an overview of pneumothorax, hemoptysis, pulmonary hypertension, and acute respiratory failure, as well as advanced care planning including consideration of lung transplantation and palliative care.
PMID: 34147501

Therapeutics - CFTR Modulators
Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663-72. The first study to show a substantial benefit from a therapy targeting the underlying cause of clinical CF, this trial showed an absolute increase in predicted FEV1 of 10% in patients with at least one G551D-CFTR mutation receiving ivacaftor, a CFTR potentiator, compared to a small FEV1 decline in the placebo group, over a study period of approximately six months.
PMID: 22047557
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Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381:1809-19. Randomized, double-blind, placebo-controlled trial of 403 patients 12 years or older with single Phe508del allele found elexacaftor-tezacaftor-ivacaftor improved percent predicted FEV1 by 14% at 24 weeks compared to placebo (p<0.001). Rate of exacerbation was 63% lower in the treatment group (p<0.001).
PMID: 31697873 

Barry PJ, Mall MA, Alvarez A, et al. Triple therapy for cystic fibrosis phe508del-gating and-residual function genotypes.  N Engl J Med. 2021; 385: 815-825. RCT noteworthy for showing triple therapy with elexacaftor–tezacaftor–ivacaftor was superior to monotherapy with ivacaftor in this population, including 3.5% higher FEV1% predicted and clinically important differences in respiratory symptom scores.
PMID: 34437784
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Keating C, Yonker LM, Vermeulen F, et al. Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials. Lancet Respir Med. 2025;13:256-271. This trial of 971 patients with a variety of CFTR mutations and baseline FEV1 near 67% predicted found the new, once-daily VTD modulator had similar efficacy to standard ETI (Trikafta) bid therapy with no difference in FEV1% predicted, symptoms, exacerbations, or adverse reactions. VTD use resulted in greater reduction of sweat chloride levels, but it is unknown whether this translates into improved clinical outcomes.   
PMID: 39756424

Mayer-Hamblett N, Ratjen F, Russell R, et al. Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials. Lancet Respir Med. 2023;11:329-340. In patients with CF on Trikafta who are adherent to medications and have preserved lung function (mean % predicted FEV1 was 97%), stopping mucolytic therapies (nebulized hypertonic saline or dornase alpha) was not inferior to continuing mucolytic therapies in terms of disease control (as measured by % predicted FEV1). Important limitations include the short duration of the trial (6 weeks), and only including patients with preserved lung function and a high level of medication adherence. 
PMID: 36343646 
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Pneumotox: This website is considered the go-to source for comprehensive and well-referenced information on drug induced and iatrogenic respiratory disease. It is managed by the Department of Pulmonary and Critical Care at the University of Dijon, France.
http://www.pneumotox.com 

Spagnolo P, Bonniaud P, Rossi G, et al. Drug-induced interstitial lung disease. Eur Respir J. 2022;60:2102776. This comprehensive and well-organized review provides a practical approach to diagnosis and treatment of DI-ILD. The figures and tables serve as a quick reference to review the most common drug culprits and assess the probability that the patient’s clinical presentation is due to a drug related lung injury.  The article also offers a more in depth review of the most common therapeutic classes to cause DI-ILD. 
PMID: 35332071 
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Immune Checkpoint Inhibitor Molecular Targeted Therapy Toxicity
Johkoh T, Lee KS, Nishino M, et al. Chest CT diagnosis and clinical management of drug-related pneumonitis in patients receiving molecular targeting agents and immune checkpoint inhibitors: A position paper from the Fleischner Society. Chest. 2021; 159:1107-1125. As might be expected, this article extensively reviews radiogragphic manifestations of targeted therapy and immune checkpoint inhibitor pulmonary toxicity. Of note, risk factors, pathology, diagnostic evaluation, and management are also nicely covered.
PMID: 33450293
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Casal A, Leiro-Fernández V, Villar-Aguilar L, et al. Lung Toxicity from Immune Checkpoint Inhibitors: A Diagnostic Approach. J Clin Med. 2025;14(17):6133. This review article highlights diagnostic workup and therapeutic algorithm for management of lung toxicity caused by immune checkpoint inhibitors.
PMID: 40943893 
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Reviews of VV and VA ECMO:
Combes A, Supady A, Abrams D, et al. Extracorporeal life support for adult patients with ARDS. Intensive Care Med. 2025;51(9):1674-1686. Updated clinical review from 2025. Summarizes VV ECMO, technical aspects, indications, discusses ECCO2R in ARDS, complications, unique patient factors, anticoagulation and management of MV.  
PMID: 40768066 
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Keebler ME, Haddad EV, Choi CW, et al. Venoarterial extracorporeal membrane oxygenation in cardiogenic shock. JACC Heart Fail. 2018; 6:503-516. This review provides a useful introduction to available VA ECMO configurations as well as key aspects of patient management including targeting support goals, monitoring for complications, and weaning from ECMO.
PMID: 29655828 

Schou A, Mølgaard J, Andersen LW, et al. Ethics in extracorporeal life support: a narrative review. Crit Care. 2021;25(1):256. This review encompasses discussion and consideration of various ethical discourses in ECLS including: trials and evidence for use of ECLS, resource allocation and defining death on ECLS and use of extracorporeal interval support for organ retrieval.
PMID: 34289885 
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For additional resources, please see ARDS and Cardiology sections.

Intensive insulin therapy
van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006; 354:449-61. RCT of 1200 MICU patients found those randomized to intensive therapy had reduced risk of acute renal injury and shorter duration of ICU stay, but no difference in mortality. Of note, patients with ICU stays < 3 days had higher mortality than controls while those with stays > 3 days had reduced mortality with intensive control.
PMID: 16452557
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Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients.N Engl J Med 2009; 360:1283-97. The NICE-SUGAR trial randomized 6,104 MICU and SICU patients with anticipated ICU stay of > 3 days to tight (81 – 108 mg/dl) or conventional (144 - 180 mg/dl) glucose control and found 90-day mortality of 27.5% with tight control vs. 24.9% with conventional (p = 0.02). The groups did not differ in secondary outcomes including duration of hospital and ICU stay or need for dialysis. In contrast, previous studies by the van den Berghe group targeted a glucose of under 215 mg/dl in the control group, had greater use of parenteral nutrition, and were performed at a single center.
PMID: 19318384
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Gunst, J, Debaveye Y, Guiza F, et al. Tight blood-glucose control without early parenteral nutrition in the ICU. N Engl J Med. 2023;389:1180-90. Trial of 9,230 patients found tight control (glucose maintained at 80 - 110 mg/dl) did not reduce length of stay or affect mortality compared to liberal control (insulin if glucose > 215 mg/dl). There was no difference in 8 secondary outcomes except for a lower rate of severe AKI and cholestatic liver dysfunction in the tight control group.
PMID: 38055263
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***See also Steroids in Sepsis/Septic Shock

Liver Disease
Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403-9. RCT found addition of albumin to cefotaxime vs. antibiotic alone in above population preserved renal function and reduced mortality. Study does not provide information on volume resuscitation in the antibiotic-alone group, however, making it less clear whether albumin has additional benefit beyond what could be achieved with aggressive crystalloids.
PMID: 10432325
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***For updated guidelines on the use of intravenous albumin for conditions related to liver disease and otherwise, the 2024 Chest guidelines which can be found in Sepsis/septic shock.
García-Pagán JC, Caca K, Bureau C, et al. for the Early TIPS (Transjugular Intrahepatic Portosystemic Shunt) Cooperative Study Group. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med 2010;362:2370-9. In a prospective study of 63 patients with acute variceal bleeding, TIPS placement within 72 hours led to a reduction in mortality and rebleeding rate.
PMID: 20573925
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Nadim MK, Durand F, Kellum JA, et al. Management of the critically ill patient with cirrhosis: A multidisciplinary perspective. J Hepatol. 2016; 64:717-35. This multi-society and multidisciplinary consensus statement discusses acute on chronic liver failure (ACLF) and provides a series of graded recommendations on general and organ-specific management issues in the critically ill patient with cirrhosis. It relies heavily on expert opinion, which reflects the complexity of the ACLF population and paucity of available data.
PMID: 26519602
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Wong F, Pappas SC, Curry MP, et al. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome. N Engl J Med. 2021;384(9):818-828. 300 patients with cirrhosis and type 1 HRS were randomized to terlipressin vs placebo for up to 14 days. Primary outcome was reversal of HRS (Serum Cr < 1.5 mg/dL on two consecutive measurements) and survival without renal replacement therapy for 10 days post treatment. HRS reversal occurred in 32% of patients in the terlipressin group vs 17% of patients in the placebo group (p 0.006).  Reversal of HRS without recurrence by day 30 was 52 (26%) with terlipressin vs. 17 (17%) with placebo (P = 0.08). At day 90, 46 patients (23%) in the terlipressin group underwent liver transplantation vs. 29 patients (29%) with placebo, and death occurred in 101 (51%) and 45 (45%), respectively. More patients in the terlipressin group experienced respiratory failure than the placebo group (14% vs 5%). 
PMID: 33657294 

Acute Liver Failure 
Shingina A, Mukhtar N, Wakim-Fleming J, et al. Acute liver failure guidelines. Am J Gastroenterol. 2023;118:1128-1153. American College of Gastroenterology current practice guidelines for the identification and management of acute liver failure.
PMID: 37377263 

Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009; 137:856-64. This RCT of 173 patients is commonly cited as the basis for administering NAC in acute liver failure in patients without acetaminophen exposure. Overall survival did not differ, but 3-week transplant-free survival was improved in the NAC group (40% vs 27%, p = .04).
PMID: 19524577
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Cardoso FS, Gottfried M, Tujios S, et al. US Acute Liver Failure Study Group. Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure. Hepatology. 2018; 67:711-720. This multicenter cohort study of registry patients between 1998 and 2016 found higher ammonia levels were associated with worse hepatic encephalopathy and lower transplant-free survival in patients with acute liver failure. CRRT was associated with reduced 21-day transplant-free mortality (OR 0.47, 95% CI 0.26-0.82) after adjustment for age, etiology, disease severity, and year of enrollment. 
PMID: 28859230
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Gastrointestinal bleeding
Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding.N Engl J Med. 2013; 368:11-21. A large multi-center trial that found a hemoglobin goal of of 7 mg/dL during acute upper gastrointestinal bleed resulted in a lower risk of re-bleeding, adverse events, and a decreased hazard ratio for death at 6 weeks when compared with a 9 mg/dL target. Patients with rapid exsanguination were excluded. The mortality benefit appears greatest in patients with Child-Pugh class A or B cirrhosis.
PMID: 23281973
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HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927-1936. This RCT enrolled 12,000 adult patients with significant upper or lower GI bleeding if the treating clinician was uncertain whether to use TXA or not. The primary outcome, death within 5 days of randomization, did not differ between groups (222 vs 226 patients; risk ratio [RR] 0·99, 95% CI 0·82–1·18). Venous thromboembolic events were higher in the TXA group (48 [0·8%] of 5952 vs 26 [0·4%]; RR 1·85; 95% CI 1·15 to 2·98), and there was also significantly increased risk of seizure in the treatment group (38 [0.6%] vs 22 [0.4%]; RR 1.73; 95% CI 1.03 to 2.93). Of note, variceal bleeding was suspected in nearly half of the patients and accounted for approximately 75% of the deaths within 5 days. 
PMID: 32563378 
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Young PJ, Bagshaw SM, Forbes AB, et al. Effect of stress ulcer prophylaxis with proton pump inhibitors vs histamine-2 receptor blockers on in-hospital mortality among ICU patients receiving invasive mechanical ventilation: The PEPTIC randomized clinical trial. JAMA. 2020; 323:616-626. Large RCT of almost 27,000 patients comparing PPI vs H2RB for stress ulcer prophylaxis found an overall low risk of bleeding but lower in the PPI group (1.3% vs 1.8% for H-2 blocker) without an increase in C.difficile colitis. The difference in 90-day all-cause mortality, the primary outcome, did not differ significantly (18.3% PPI vs 17.5% H-2 blocker). Of note, only 64% in the H2RB group and 82% in the PPI group received their assigned treatment alone.
PMID: 31950977
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Cook D, Deane A, Lauzier F, et al. Stress ulcer prophylaxis during invasive mechanical ventilation. N Engl J Med. 2024;391:9-20. This RCT randomized 4821 adults receiving invasive mechanical ventilation in the ICU to pantoprazole 40 mg IV daily or placebo. The primary outcome was clinically important upper GI bleeding at 90 days (overt bleeding with hemodynamic change or requiring intervention, or readmission to the ICU). Pantoprazole decreased upper GI bleeds with a hazard ratio of 0.30 (95% confidence interval [CI], 0.19 to 0.47; P<0.001). The incidence in each group was 1% and 3.5% respectively. There was no difference in secondary outcomes between groups (death at 90 days, VAP, C. difficile infection, patient-important bleeding). 
PMID: 38875111

Transfusion
Hébert P, Wells G, Blajchmann M, et al. A multicenter randomized controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-17. Landmark study found equal mortality using transfusion thresholds of 7 gm/dl and 10gm/dl and higher mortality with liberal transfusion among younger and less ill patients.
PMID: 9971864
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Coz Yataco AO, Soghier I, Hébert PC, et al. Red blood cell transfusion in critically ill adults: An American College of Chest Physicians Clinical Practice Guideline. Chest. 2025;167:477-489. These guidelines focus on red blood cell transfusions, including patients with GI bleeding, acute coronary syndrome, and cardiac surgery. The guidelines recommend a restrictive transfusion strategy for most groups with the notable exception of patients with acute coronary syndrome.
PMID: 39341492 
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Yataco AC, Soghier I, Hébert PC, et al. Transfusion of fresh frozen plasma and platelets in critically ill adults: An American College of Chest Physicians Clinical Practice Guideline. Chest. 2025 Mar 10:S0012-3692(25)00279-X. A sister article to the red blood cell transfusion guidelines, these guidelines generally recommend against transfusion of FFP and platelets given lack of evidence of benefit and some well-described risks, though there are certain scenarios where each is warranted. The recommendations regarding transfusion for several common ICU procedures is especially helpful.
PMID: 40074060 

Sickle Cell Anemia
Novelli EM and Gladwin MT. Crises in sickle cell disease. Chest. 2016; 149:1082-93. A review that includes discussion of acute chest syndrome, acute anemia, stroke, and infectious complications.
PMID: 26836899
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Mekontso Dessap A, Habibi A, Arlet JB, et al. Comparison of Prophylactic and Therapeutic Doses of Anticoagulation for Acute Chest Syndrome in Sickle Cell Disease: The TASC Double-Blind Controlled Randomized Clinical Trial. Am J Respir Crit Care Med. 2025;211(5):832-841. 172 adult patients with acute chest syndrome (ACS) were randomized to either prophylactic or therapeutic anticoagulation with low molecular weight Tinzaparin for 7d or hospital discharge. Primary outcome was time to ACS resolution and was shorter in the therapeutic anticoagulation group (4.8 vs 6.1 days, HR 0.71). There were no adverse bleeding events in either group. The therapeutic anticoagulation group also used fewer opioids (124 vs 219 mg morphine equivalents). 
PMID: 40209087

Hematologic emergencies: 
Lafarge A, Chean D, Whiting L, Clere-Jehl R; Groupe de Recherche en Réanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH); Clinical Research in Intensive Care and Sepsis - TRIal Group for Global Evaluation and Research in SEPsis (CRICS-TRIGGERSEP). Management of hematological patients requiring emergency chemotherapy in the intensive care unit. Intensive Care Med. 2024;50:849-860. This review describes several of the most common hematologic complications requiring emergency chemotherapy treatment in an intensive care unit including leukostasis, tumor lysis syndrome, hyperviscosity, and hemophagocytic lymphohistiocytosis amongst others. 
PMID: 38748265 
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Guidelines/Reivews 
Weled BJ, Adzhigirey LA, Hodgman TM, et al. Task Force on Models for Critical Care. Critical Care Delivery: The Importance of Process of Care and ICU Structure to Improved Outcomes: An Update From the American College of Critical Care Medicine Task Force on Models of Critical Care. Crit Care Med. 2015;43:1520-5. This guideline on ICU care delivery delineates how the structure and process of care are important factors in determining patient outcomes.
PMID: 25803647

Moss M, Good V, Gozal D, et al. A Critical Care Societies collaborative statement: burnout syndrome in critical care healthcare professionals. A call for action. Am J Resp Crit Care Med. 2016;194:106-13.  A multi-society guideline statement on burnout syndrome (BOS) that describes the diagnostic criteria, prevalence, risk factors, and adverse effects of BOS. It also proposes some possible mitigation strategies that may be helpful for providers and their patients.
PMID: 27367887
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Hwang DY, Oczkowski SJW, Lewis K, et al. Society of Critical Care Medicine Guidelines on family-centered care for adult ICUs: 2024. Crit Care Med. 2025;53:e465-e482. These evidence-based guidelines, curated by a multiprofessional group which included family member partners, offer 17 recommendations for family centered care in the ICU in the post-pandemic setting.  Out of the 17 recommendations, the one strong recommendation was for the liberalization of visitor policies in the ICU to allow for more family presence at the bedside. 
PMID: 39982184 
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ICU Staffing
Gershengorn HB, Garland A, Costa DK, et al. ICU staffing in the United States. Chest. 2024;166:743-753. The results of a 2022-2023 cross-sectional survey of adult ICU clinicians report on the staffing norms among US adult ICU’s. There was a 2.1% survey response rate representing ~600 ICUs. Per the survey results, intensivists cover all patients in approximately 75% of ICUs, with about 50% having 24/7 intensivist staffing. In ~90% of ICUs, the nursing ratio for intubated patients was 1 nurse: 2 patients. Approximately 93% of ICUs have a clinical pharmacist and 99% have respiratory therapists. This updated report provides a general understanding of the staffing norms for intensive care units.
PMID: 38788896 

Gajic O, Assefa B, Hanson AC, et al. Effect of 24-hour mandatory versus on-demand critical care specialist presence on quality of care and family and provider satisfaction in the intensive care unit of a teaching hospital. Crit Care Med. 2008; 36: 36-44. A single ICU cohort study assessing outcomes before and after the introduction of a 24 hour intensivist model in an academic center with existing resident and fellow staffing. They found adherence to evidence-based processes improved from a baseline of 76% up to 84% (p = .002), decreased length of stay, and improved staff satisfaction, but made no difference in mortality. Concerns raised since publication include generalizability to non-academic settings, as well as long-term costs and risk of physician burnout with this staffing model.
PMID: 18007270 

Kerlin MP, Small DS, Cooney E, et al. A randomized trial of nighttime physician staffing in an intensive care unit. New Engl J Med. 2013; 368: 2201-2209. This was a single ICU, randomized, controlled study of 24 hour in-house intensivist coverage compared with standard day + home coverage over 1 year in an academic ICU. The authors found no difference in mortality, length of stay, ICU readmission, or discharge to home. They did not assess patient or provider satisfaction. This adds to the body of evidence that 24 hour intensivist staffing in resident-staffed ICUs has no effect on mortality, and is equivocal in its effect on LOS.
PMID: 23688301
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Landrigan CP, Rahman SA, Sullivan JP, et al. ROSTERS study group. Effect of patient safety of a resident physician schedule without 24-hour shifts. N Engl J Med. 2020;382(26):2514-2523. This study found more errors occurred in the intervention group in which pediatric ICU residents worked a maximum shift of 16 hours compared to standard group that included shifts longer than 24 hours. Residents working shorter shifts had an increased workload (defined as the mean number of ICU patients per resident), and no difference in errors was found between the two schedules once adjusted for workload.
PMID: 32579812  
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Tele-ICU
Thomas EJ, Lucke JF, Wueste L, et al. Association of telemedicine for remote monitoring of intensive care patients with mortality, complications, and length of stay. JAMA. 2009;302:2671–2678. A multi-center, before-after implementation trial on the effect of telemedicine on ICU outcomes of > 4000 patients in 6 ICUs. They utilized proprietary eICU technology and allowed providers to request varying degrees of tele-ICU support. In contrast to prior smaller studies they found no difference in mortality or length of stay. The “Opt In” model of support may have weakened efficacy of the intervention, and as with prior studies, the heterogeneity of the term “tele-ICU” complicates the comparison of trials.
PMID: 20040555
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Lilly CM, Cody S, Zhao H, et al. University of Massachusetts Memorial Critical Care Operations Group. Hospital mortality, length of stay, and preventable complications among critically ill patients before and after tele-ICU reengineering of critical care processes. JAMA. 2011;305: 2175-2183. A single center multi-ICU, pre- and post-intervention trial at an academic medical center. Their intervention included both physiologic monitoring, reviewing of daily goals, and auditing for best-practices use. Significant improvements in mortality (11.8% vs. 13.6%), and length of stay (9.8 d v 13.3d) were seen. All tele-ICU providers also worked in the physical ICUs, which may have improved provider buy-in. The complex, multifaceted intervention may not be generalizable to ICUs without similar resources.
PMID: 21576622 
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Checklists
Cavalcanti AB, Bozza FA, Machado FR, et al. Effect of a quality improvement intervention with daily round checklists, goal setting, and clinician prompting on mortality of critically ill patients: a randomized clinical trial. JAMA. 2016; 315:1480-90. A large cluster randomized study of usual care versus a QI process incorporating a checklist and daily goal setting in 118 ICUs with 6800 patient encounters. There was no effect on mortality. There was significant improvement in other measures such as limiting tidal volumes and sedation, but no change in several outcomes including CLABSI, CAUTI, and VAP. While prior studies had looked at pre- and post-intervention outcomes, this is the first study of checklists that was prospectively randomized.
PMID: 27115264
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APP Integration
McCarthy C, O’Rourke NC, Madison JM. Integrating advanced practice providers into medical critical care teams. Chest. 2013; 143:847-50. This brief article provides a nice review of how best to approach the integration of advanced practice providers in the critical care setting with a focus on reimbursement, coding and billing.
PMID: 23460162 

Critical Care Pharmacists
Sikora A, Ayyala D, Rech MA, et al. Impact of pharmacists to improve patient care in the critically ill: a large multicenter analysis using meaningful metrics with the medication regimen complexity-ICU (MRC-ICU) score. Crit Care Med. 2022; 50:1318-1328. This large, multicenter prospective observational study found increased medication regimen complexity is associated with increased mortality, LOS, pharmacist intervention quantity, and pharmacist intervention intensity. Increased patient:pharmacist ratio was associated with longer length of ICU stay as well as reduced quantity and quality of pharmacist interventions.
PMID: 35678204 

Lee H, Ryu K, Sohn Y, et al. Impact on patient outcomes of pharmacist participation in multidisciplinary critical care teams: a systematic review and meta-analysis. Crit Care Med. 2019; 47:1243-1250. Meta-analysis of 14 studies found the presence of pharmacists on the multiprofessional ICU team was associated with significantly lower mortality odds, shorter ICU stay, and reduced adverse drug events.
PMID: 31135496

Guidelines
Ramirez JA, Musher DM, Evans SE, et al. Treatment of community-acquired pneumonia in immunocompromised adults: a consensus statement regarding initial strategies. Chest. 2020; 158:1896-1911. Immunocompromised patients have been excluded from previous guidelines on CAP management.  This guideline was developed independent of academic societies by 45 clinicians with relevant expertise using Delphi survey methodology. The group defines various degrees of immunocompromise and provides guidance on the corresponding likely pathogens, appropriate evaluation, and empiric treatment.  Given the paucity of evidence, most recommendations are based on expert opinion.
PMID: 32561442
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Diagnostic Strategies
The following reviews nicely outline infectious and non-infectious complications of solid organ and hematopoietic stem cell transplantation.
Azoulay E, Russell L, Van de Louw A, et al. Nine-I Investigators. Diagnosis of severe respiratory infections in immunocompromised patients. Intensive Care Med. 2020;46:298-314. Review of diagnostic strategies with special attention to newly validated diagnostic tests.
PMID: 32034433  
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Chi AK, Soubani AO, White AC, et al. An update on pulmonary complications of hematopoietic stem cell transplantation. Chest. 2013; 144:1913-1922.
PMID: 24297123
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Azoulay E, Mokart D, Lambert J, et al. Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial. Am J Respir Crit Care Med 2010;182:1038-46. In this prospective, randomized study of 216 cancer patients with acute respiratory failure, most of whom had hematologic malignancies and one-fourth of whom had undergone hematopoietic stem cell transplantation, early bronchoscopy with BAL did not lead to an increased risk of intubation, but was not diagnostically superior to an initial noninvasive diagnostic approach, with the exception of diagnosis of Pneumocystis.
PMID: 20581167 

HIV and Pulmonary Disease
Fitzpatrick ME, Kunisaki KM, Morris A. Pulmonary disease in HIV-infected adults in the era of antiretroviral therapy. AIDS. 2018;32:277-292. Review of respiratory symptoms and disease in HIV patients including infectious and non-infectious pulmonary disease with specific attention to COPD, Asthma, and Pulmonary Hypertension.
PMID: 29194119
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Pneumocystis Pneumonia
Gagnon S, Boota AM, Fischl MA, et al. Corticosteroids as adjunctive therapy for severe PCP in AIDS. N Engl J Med 1990;323:1444-50. One of three studies published in the same year establishing the efficacy of steroids in severe PCP in patients with AIDS.
PMID: 2233916
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Lemiale V, Resche-Rigon M, Zerbib Y et al. Adjunctive corticosteroids in non-AIDS patients with severe Pneumocystis jirovecii pneumonia (PIC): a multicentre, double-blind, randomised controlled trial. The Lancet Respir Med. 2025; 13, 800-808. A multicenter RCT where 226 patients with PJP pneumonia were randomized to adjunctive steroids (IV methylprednisolone 30 mg twice per day from days 1 to 5, 30 mg once per day from days 6 to 10, and 20 mg once per day until day 21) vs placebo. While the results were not statistically significant, 28-day all-cause mortality was lower in the steroid group (21% vs 32% with placebo, [95% CI -0·9 to 22·5]; p=0·069). There were no differences in safety outcomes.
PMID: 40652952

CLABSI Prevention & Management
Mermel LA, Bouza AM, Craven DE, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009:49;1-45.
PMID: 19489710
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O’Grady NP, Burns AM, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control. 2011:39;S1-34.
PMID: 21511081
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Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med. 2006;355:2725-32. Landmark large scale study of 103 ICUs in the state of Michigan demonstrated that implementation of an evidence based protocol led to a significant and sustainable 66% relative reduction of catheter-related infections. The protocol centered on 5 steps, comprising the now widely used “central line bundle” (see IHI.org), including hand hygiene, full-barrier precautions during line insertion, skin cleansing with chlorhexidine, avoiding the femoral site if possible, and removal of unnecessary catheters.
PMID: 17192537
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VAP Prevention
Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet 1999;354:1851-8. This study found that supine position is an independent risk factor for VAP and that positioning at 45 degrees reduces the risk, especially in patients receiving tube feeds.
PMID: 10584721 

van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, et al. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit Care Med 2006;34:396-402. In this seven-day study cited by HOB-elevation skeptics, a randomized trial of over 200 patients found no reduction in VAP with HOB elevation, though the angle difference between intervention and control patients was small (28° vs 10° at day one, 23° vs 16° at day seven).
PMID: 16424720 

De Smet AM, Kluytmans JA, Cooper BS, et al. Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med 2009; 360:20-31. This large (5,939 patients) multicenter Dutch study found SDD and selective oropharyngeal decontamination (SOD) reduced 28-day mortality by about 3% after logistic regression. There was no emergence of resistant organisms, but the duration of monitoring was limited to the 6 months of the study.
PMID: 19118302
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SuDDICU Investigators for the Australia and New Zealand Intensive Care Society Clinical Trials Group and the Canadian Critical Care Trials Group; Cuthbertson BH et al. Selective Decontamination of the Digestive Tract during Ventilation in the ICU. N Engl J Med. 2025 Oct 29. International update to the 2022 study by these groups, now with 20,000 patients and the same intervention of selective decontamination of the digestive tract. Again there was no significant reduction in in-hospital mortality 27.9% with SDD vs 29.5% with standard care (OR 0.93, 95% CI 0.84-1.05; P=0.27). New bloodstream infections were lower with SDD (4.9% vs 6.8%), and cultures of antibiotic-resistant organisms were also lower (16.8% vs 26.8%), however in the ecologic analysis noninferiority for emergence of new antibiotic-resistant organisms was not confirmed.
PMID 41159880

Ehrmann S, Barbier F, Demiselle J, et al. Inhaled amikacin to prevent ventilator-associated pneumonia. N Engl J Med. 2024;390:769-770. RCT that compared daily inhaled amikacin x 3 days to placebo in 847 patients who had undergone invasive mechanical ventilation for at least 72 hours. VAP occurred in 15% of the amikacin group vs 22% for placebo in the first 28 days of follow up. Of secondary outcomes, there was no difference in ICU mortality, duration of mechanical ventilation, length of stay, or overall antibiotic use.
PMID: 38381689
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Dahyot-Fizelier C, Lasocki S, Kerforne T, et al. Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled, assessor-masked superiority trial. Lancet Respir Med. 2024;12:375-385. The PROPHY-VAP study included 319 adult patients with acute brain injury who were intubated for less than 12 hours at the time of enrollment and compared a single 2g dose of ceftriaxone vs placebo in incidence of early VAP (2nd-7th day). They found a decreased incidence of VAP in the intervention group (14% vs 32% (HR 0.60; 95% CI 0.38 to 0.95), (NNT 5.6 patients). They also found a statistically significant increase in antibiotic and ventilator-free days as well as lower mortality in the intervention group (15% vs 25%), though the study was not powered for these secondary outcomes. Criticisms of the study include the adjudication committee that decided cases of VAP was not independent of the study (160 cases of VAP reported, 93 confirmed after adjudication), oropharyngeal decontamination varied between centers, and diagnosis of VAP required microbiologic confirmation which may have been affected by administration of ceftriaxone. 
PMID: 38262428 

General Measures
Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med. 2013; 368:2255-2265. A cluster randomized trial comparing the effects of 1) MRSA screening and targeted isolation, 2) MRSA screening with targeted isolation plus treatment, and 3) universal decolonization treatment. Treatment consisted of chlorhexidine baths and nasal mupirocin. Universal decolonization treatment significantly reduced overall bloodstream infections with non significant decreases in MRSA-positive cultures and MRSA bloodstream infections. Strengths include multiple centers (43) and large number of patients (> 43,000). Weaknesses include lack of monitoring for chlorhexidine resistance, inconsistent use of isolation, and unclear definition of “clinical MRSA positive culture”.
PMID: 23718152
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Noto MJ, Domenico HJ, Byrne DW, et al. Chlorhexidine bathing and health care–associated infections: a randomized clinical trial. JAMA 2015; 313:369-378. This was a cluster randomized, controlled trial comparing the daily use of chlorhexidine-impregnated bathing cloths with non-antimicrobial cloths in multiple ICUs. There was no significant difference in the compound primary outcome of CLABSI, CAUTI, VAP, or C difficile infections (intervention 2.86 vs control 2.90, p= 0.95). In contrast to prior studies, these findings do not support daily chlorhexidine bathing of ICU patients. Critics note that the mean LOS was briefer and background MDRO prevalence higher in prior studies, one of which included BMT units. Other concerns include lack of adherence data and blinding.
PMID: 25602496

Overview
Ryerson CJ, Adegunsoye A, Piciucchi S, et al. Update of the international multidisciplinary classification of the interstitial pneumonias: an ERS/ATS statement. Eur Respir J. 2025;66(6):2500158. This update builds upon the previous classification approach outlined by ATS/ERS in 2013 by describing major advances in the classification of interstitial pneumonia over the past decade. 
PMID: 40774805 
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Diagnosis
Meyer KC, Raghu G, Baughman RP, et al. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med 2012;185:1004-14. This article offers some help in selecting patients most suitable for bronchoalveolar lavage. Arguably the greatest strength of the guideline is how it nicely pulls together clinical presentation and typical BAL findings for a wide spectrum of interstitial lung diseases, which is difficult to find assembled in one place.
PMID: 22550210 

Raj R,  Raparia K, Lynch DA,  et al. Surgical lung biopsy for interstitial lung diseases. Chest. 2017; 151:1131-40. Reviews the role of surgical lung biopsy in the diagnosis and treatment of interstitial lung disease with specific focus on when a biopsy can be diagnostic as well as when it should be avoided.
PMID: 27471113 

Troy LK, Grainge C, Corte TJ, et al. Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study. Lancet Respir Med. 2020; 8:171-181. Direct comparisons of cryobiopsy and surgical biopsy results in the same patient are scarce. This study compared diagnostic accuracy by doing sequential procedures in 65 patients with mean FVC 84% predicted. Masked pathologists examined the slides with histopathologic agreement achieved in 70.8% of patients. With incorporation of pathology into multi-disciplinary discussions, diagnostic agreement was 76.4%. Among the 40% (26 patients) with a non-diagnostic cryobiopsy, surgical biopsy provided a confident diagnosis in 26% (6 patients). Of note, the study was not designed to assess the safety of the individual procedures.
PMID: 31578168 

Kalverda KA, Ninaber MK, Wijmans L, et al. Transbronchial cryobiopsy followed by as-needed surgical lung biopsy versus immediate surgical lung biopsy for diagnosing interstitial lung disease (the COLD study): a randomised controlled trial. Lancet Respir Med. 2024;12:513-522. 55 patients with ILD and an indication for lung biopsy from 6 centers in the Netherlands were randomized to a step up approach (cryobiopsy first, then surgical biopsy if non-diagnostic) or surgical biopsy. The primary outcome was unexpected chest tube drainage (chest tube required in the cryobiopsy group, or chest tube for > 1d in the surgical group). The secondary outcomes included diagnostic yield, hospital LOS, and adverse events. The step up group required chest tube placement in 11% of cases, whereas chest tube for >1d was required in 46% of patients in the surgical biopsy group (35% ARR for unexpected chest tube drainage). Cryobiopsy achieved a diagnosis 82% of the time, higher than previous reports of diagnostic value of cryobiopsy, vs 88% of the time for the surgical group. 86% of the cryo patients did not need a chest tube and could go home the same day. The step up therapy reduced hospital LOS by 4d. 
PMID: 38640934

Idiopathic Pulmonary Fibrosis - Guidelines and Presentation
Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022; 205:e18-e47. This guideline provides updates on IPF including diagnostic criteria, conditional recommendation for use of cryobiopsy, as well as a conditional recommendation against anti-acid therapy and surgery. Progressive pulmonary fibrosis is defined for deteriorating patients with ILD other than IPF, with a conditional recommendation for nintedanib treatment in this group. 
PMID: 35486072
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Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005;142:963-7. This retrospective study of 168 patients with mild to moderate disease from the placebo arm of the IFN-gamma 1b study found minimal change in physiologic variables among survivors during the 72 weeks of follow-up. 19% of patients died of IPF-related causes, of whom 47% experienced rapid clinical deterioration. These results indicate IPF exacerbations in patients with milder disease are not uncommon.
PMID: 15968010

Podolanczuk AJ, Hunninghake GM, et al. Approach to the Evaluation and Management of Interstitial Lung Abnormalities: An Official American Thoracic Society Clinical Statement. Am J Respir Crit Care Med. 2025 Jul;211(7):1132-1155. Review of updated evidence on interstitial lung abnormalities with criteria to distinguish from ILD and suggestions for screening, evaluation, and management of ILAs. 
PMID: 40387336 
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Antifibrotic Therapy in IPF
King TE, Jr., Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-92. Year-long RCT of 555 patients with FVC 50 – 90% and DLCO 30 – 90% found pirfenidone slowed the rate of decline in FVC (23% vs. 9.7% placebo with no decline in FVC; 17% vs. 32% placebo for > 10% decline). Pirfenidone also improved the decline in 6-minute walk distance.
PMID: 24836312
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Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370:2071-82. Year-long RCT of 515 patients with FVC > 50% and DLCO 30 – 79% found nintedanib slowed the rate of decline in FVC (- 115 ml vs – 240 ml for placebo over 1 year). Over 60% of nintedanib subjects experienced diarrhea vs. 19% in placebo group but < 5% discontinued study drug.
PMID: 24836310
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Richeldi L, Kreuter M, Valenzuela C, et al. Nerandomilast in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2025;392(22):2193-2202.  RCT of 1,177 patients with IPF, 78% of whom were already receiving an approved antifibrotic (nintedanib or pirfenidone), randomised patients to nerandomilast 18 mg, 9 mg, or placebo twice daily for 52 weeks. Both doses significantly slowed FVC decline vs. placebo (adjusted difference +69 mL for 18 mg, +45 mL for 9 mg), with diarrhea as the most frequent adverse event. This trial is significant for demonstrating that PDE4B inhibition provides additional antifibrotic benefit on top of existing standard-of-care therapy, raising the prospect of combination antifibrotic strategies targeting distinct disease pathways in IPF.
PMID: 40387033

Nathan SD, Smith P, Deng C., et al; TETON-2 Trial Investigators. Inhaled Treprostinil for Idiopathic Pulmonary Fibrosis. N Engl J Med. 2026 Mar 11. RCT of 463 patients with IPF to receive inhaled treprostinil (12 breaths four times daily) or placebo over 52 weeks. 75% of the patients were receiving background antifibrotic therapy. The median change in FVC at week 52 was -49.9 ml in the treprostinil group and -136.4 ml in the placebo group; the between-group difference in the change in FVC was 95.6 ml (95% CI, 52.2 to 139.0; P<0.001). Clinical worsening occurred in 81 patients (27.2%) in the treprostinil group and 115 patients (39.0%) in the placebo group (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; P = 0.02). Cough was the most common adverse event (48% in treprostinil vs 24% in placebo group). This trial adds to the prospect of combination antifibrotic therapy targeting distinct disease pathways in IPF.
PMID: 41812190 

Antifibrotic Therapy in non-IPF ILD
Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung disease. N Engl J Med. 2019;381(18):1718-1727. The INBUILD RCT enrolled 663 included patients with fibrosing lung disease affecting > 10% of  lung volume with progression in the past 24 months despite treatment. Randomization was stratified by UIP vs other fibrotic pattern. Overall adjusted rate of decline in FVC was -80.8 ml/year with nintedanib vs -187.8 ml/year with placebo (p<0.001). In patients with UIP pattern, adjusted rate of FVC decline was -82.9 ml/year with nintedanib vs -211.1 ml/year with placebo. Diarrhea was the most common side effect.
PMID: 31566307
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Wells AU, Flaherty KR, Brown KK, et al. INBUILD trial investigators. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomized, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. 2020; 8:453-460. This subgroup analysis within the INBUILD trial suggests nintedanib slows ILD progression regardless of underlying ILD diagnosis.
PMID: 32145830
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Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019; 380:2518-2528. RCT randomized 576 patients with systemic sclerosis and fibrosis affecting at least 10% of the lungs to nintedanib vs placebo. 48% of patients were on mycophenolate at baseline. The adjusted annual rate of change in FVC was -52.4 ml/year in nintedanib group vs -93.3 ml/year in placebo group (p=0.04). No difference in Rodnan skin score or SGRQ at 52 weeks. Most common side effect was diarrhea.
PMID: 31112379
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Maher TM, Corte TJ, Kreuter M, et al. Nerandomilast in patients with progressive pulmonary fibrosis. N Engl J Med. 2025; 392(22):2203-2214. RCT of 1,176 patients with non-IPF progressive pulmonary fibrosis (PPF) were randomized to nerandomilast 18 mg, 9 mg, or placebo twice daily for 52 weeks. Both doses significantly slowed FVC decline vs. placebo (adjusted difference +67.2 mL and +81.8 mL, respectively), with diarrhea rates of 37%, 30%, and 25% by group. Further subgroup analyses will be important to define which PPF endotypes derive the greatest benefit.
PMID: 40388329 

Connective Tissue-Related ILD 
Mankikian J, Caille A, Reynaud-Gaubert M, et al. Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial. Eur Respir J. 2023;61:2202071. This trial randomized 122 patients with connective tissue-related ILD or idiopathic interstitial pneumonia with NSIP pattern to rituximab plus MMF vs placebo plus MMF . The addition of rituximab led to absolute difference in least-squares mean change in FVC of + 3.6% predicted over 6 months.  There were 9 infections in the rituximab/MMF group vs 4 in the MMF alone group.
PMID: 37230499
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Mansy L, Caille A, Reynaud-Gaubert M, et al. Rituximab and mycophenolate mofetil in interstitial lung disease (EVER-ILD): 1-year follow-up results of a randomised controlled trial. Eur Respir J. 2024;64:2401368. 12 month results were available for 52/65 patients in the Rituximab+MMF group, and 51/61 patients in the placebo+MMF group. The preservation of FVC % predicted in the Rituximab group seen at 6 months was not sustained at 12 months, though the study suffers from loss of patients, cross overs between 6 and 12 months, and incomplete data and is not powered to detect a significant change at 12 months. They did detect a trend towards better progression free survival in the Rituximab group. 
PMID: 39231630

Raghu G, Montesi SB, Silver RM, et al. Treatment of systemic sclerosis-associated interstitial lung disease: evidence-based recommendations. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2024;209:137-152. These evidence-based clinical practice guidelines for treatment of SSc-ILD are laid out in a question format with a clinical question followed by a succinct summary of the literature and rationale for the committee’s decision. 
PMID: 37772985 
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Johnson SR, Bernstein EJ, Bolster MB, et al. 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Treatment of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases. Arthritis Care Res (Hoboken). 2024;76(8):1051-1069. Evidence based guidelines regarding first and 2nd line treatment of ILD in adults with systemic autoimmune rheumatic diseases (SARDs).
PMID: 38973731 
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Sarcoidosis
Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An Official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020; 201:e26-e51. This comprehensive diagnostic guideline includes recommendations on when to perform lymph node biopsy and screen for extra-pulmonary disease, as well as extensive differentials to consider based on biopsy and clinical findings. The strength of recommendations is uniformly low owing to a lack of supporting studies.
PMID: 32293205
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Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J. 2021;58:2004079. 12 recommendations for treatment of sarcoidosis generated by a European Respiratory Society Task Force Committee which included patients with sarcoidosis. The recommendations include treatment approaches for cardiac, pulmonary, cutaneous, and neurologic sarcoidosis. 
PMID: 34140301 
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Kahlmann V, Janssen Bonás M, Moor CC, et al. PREDMETH Collaborators. First-Line Treatment of Pulmonary Sarcoidosis with Prednisone or Methotrexate. N Engl J Med. 2025;393(3):231-242. This open-label, multicenter RCT of 138 treatment-naive patients with pulmonary sarcoidosis found treatment at 24 weeks with methotrexate was non-inferior to prednisone, with mean change in % predicted FVC 6.17 percentage points and 6.7 percentage points, respectively. Weight gain and insomnia were more common in the prednisone group whereas nausea, fatigue, and LFT abnormalities were more common with methotrexate use. 
PMID: 40387020 

Hypersensitivity Pneumonitis
Raghu G, Remy-Jardin M, Ryerson CJ, et al. Diagnosis of hypersensitivity pneumonitis in adults. An Official ATS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2020; 202:e36-e69. This guideline provides a detailed review of diagnostic strategies for hypersensitivity pneumonitis with a focus on potential antigens, high resolution CT findings, and histopathological criteria. Noteworthy for changing HP nomenclature to fibrosing and non-fibrosing types with recommendations tailored to these categories.
PMID: 33385222
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Fernández Pérez ER, Travis WD, Lynch DA, et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest 2021; 160:e97-e156. This guideline addresses 14 PICO-based questions and offers practical guidance, although primarily comprised of weak recommendations in light of limited evidence.
PMID: 33861992

Lung Cancer Outcomes
Debieuvre D, Falchero L, Molinier O, et al. Survival of Patients with Lung Adenocarcinoma Diagnosed in 2000, 2010, and 2020. NEJM Evid. 2025;4(7):EVIDoa2400443. Understanding the extent to which lung cancer outcomes are improving over time can be useful in counseling patients. This French study included over 5000 patients with lung adenocarcinoma. They compared survival rates for those diagnosed in 2000, 2010 and 2020 and found the median overall survival more than doubled in 20 years, from ~9 months to ~20 months. Factors associated with increased survival included earlier stage disease and higher performance status, and among those with metastatic disease, the presence of specific genetic mutations amenable to targeted therapies.
PMID: 40552964

Staging 
Detterbeck FC, Woodard GA, Bader AS, et al. The proposed ninth edition TNM classification of lung cancer. Chest. 2024;166:882-895. The key differences in the 9th edition TNM classification are subdivision of N2 into single and multi-station N2 disease, and subdivision of M1c into single vs multi-organ system M1c. These changes are meant to more clearly communicate the anatomic extent of disease and inform management decisions.
PMID: 38885896

Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd Ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e211S-50S. ACCP evidence-based clinical practice guidelines (3rd Edition) reviewing the evidence for both invasive and non-invasive staging of non-small cell lung cancer with CT and PET scanning as well as TTNA, TBNA, EBUS, EUS, VATS, Chamberlain procedure, mediastinoscopy and extended cervical mediastinoscopy.
PMID:23649440
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Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010;304:2245-52. An RCT of EUS/EBUS/surgical staging vs. surgical staging alone in 241 patients with potentially resectable NSCLC found a sensitivity and NPV of 94% and 93% with the combined approach, a substantial improvement over surgical staging alone (79% and 86%). In the 123 patients assigned to the combined modality arm, endosonography identified mediastinal metastases in half, precluding the need for mediastinoscopy. In the 65 patients with negative EUS/EBUS-FNA, mediastinoscopy identified cancer in six patients. The study was performed at tertiary centers using conscious sedation for endosonography.
PMID: 21098770
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Surgical Risk Assessment
Brunelli A, Kim AW, Berger KI, Addrizzo-Harris DJ. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e166S-90S. These guidelines provide methods of identifying low-risk and high-risk patients for lung resection surgery, as well as appropriate further testing once identified.
PMID: 23649437 

Altorki N, Wang X, Kozono D, et al. Lobar or sublobar resection for peripheral stage IA non-small-cell lung cancer. N Engl J Med. 2023; 388:489-498. This RCT of 697 patients with stage T1aN0 (tumor < 2cm) NSCLC found no difference in disease-free and overall survival with lobar vs. sublobar resection. Patients undergoing sublobar had a 2% higher postoperative FEV1. This study may result in greater use of sublobar resection, but whether it will influence the process for determining suitability for resection in higher-risk patients is unclear.
PMID: 36780674
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Surveillance
Schneider BJ, Ismaila N, Aerts J, et al. Lung cancer surveillance after definitive curative-intent therapy: ASCO Guideline. J Clin Oncol. 2020; 38:753-766. The multidisciplinary panel found mostly low-quality evidence to guide recommendations but offer practical expert opinion on who, when, and how these patients should be followed.
PMID: 31829901 

Screening for lung cancer
Mazzone PJ, Silvestri GA, Souter LH, et al. Screening for lung cancer: CHEST guideline and expert panel report. Chest. 2021; 160:e427-e494. Updated CHEST guidelines on lung cancer screening.
PMID: 34270968 

Krist AH, Davidson KW, Mangione CM, et al. Screening for lung cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2021; 325:962-970. Noteworthy changes from the previous USPSTF statement include reducing the age of screening from 55 to 50 years of age and reducing pack-year history from 30 to 20.  These changes substantially increase eligibility and have the potential to reduce existing sex, race, and ethnicity-based disparities in lung cancer screening.
PMID: 33687470 

National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. This large trial compared annual CT versus CXR over two years (baseline, one-year, and two-year screening). Analyzing only those who underwent at least one screening test, the absolute risk reduction for lung cancer-associated mortality was 0.3% (relative reduction of 20%), yielding a number needed to screen to prevent one death of approximately 320, with a CT false positive rate of 96.4%.
PMID: 21714641
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de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020; 382:503-513. The NELSON randomized trial compared the mortality benefit from volume-based, low dose CT scanning at baseline, 1 year, 3 years, and 5.5 years to no screening in 13,195 men aged 50-74 who were former or current smokers.  After a minimum of 10 years of follow-up, the cumulative rate ratio of death from lung cancer was 0.76 in the screening group (C.I 0.61 – 0.94; P = 0.01).  A total of 2.1% of subjects were diagnosed with lung cancer and the false-positive rate was lower than in the NLST with, on average, less than 10% of subjects requiring additional testing.
PMID 31995683 

Rivera MP, Katki HA, Tanner NT, et al. Addressing disparities in lung cancer screening eligibility and healthcare access: An official American Thoracic Society statement. Am J Respir Crit Care Med. 2020; 202:e95-e112. A review of current disparities in lung cancer screening with strategies to increase equity and reduce barriers to care. The concern surrounding lung cancer screening disparities contributed to recent recommendations by the United States Preventive Services Task Force to expand screening to individuals with at least a 20 pack-year smoking history and those aged 50-80 years old.
PMID: 33000953 

Solitary pulmonary nodule
Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e93S-120S. Guideline for how best to work up nodule(s) that nicely distills the large number of trials on this topic.
PMID: 23649456 

MacMahon H, Naidich DP, Goo JM, et al. Guidelines for management of incidental pulmonary nodules detected on CT Images: From the Fleischner Society 2017. Radiology. 2017; 284: 228-43. This statement gives recommendations on management of incidental pulmonary nodules. Significant changes include increasing the threshold size of nodules that need follow up and widening the range of timing of follow up scans. These new changes should translate into fewer nodules followed and fewer scans among patients undergoing follow up.
PMID: 28240562
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Lung-RADS v2022. Initially developed in 2014 by the American College of Radiology for management of screen-detected lung nodules, these 2022 updates to Lung-RADS include guidance for the management of atypical pulmonary cysts, juxtapleural nodules, airway-centric nodules, stable nodules, amongst others. 
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Lentz RJ, Frederick-Dyer K, Planz VB et al. Navigational Bronchoscopy vs Transthoracic Biopsy for Lung Nodules. N Engl J Med 2025; 392(21): 2100-2112. This randomized non-inferiority multicenter U.S. trial included 234 patients with 10-30 mm peripheral lung nodules who were randomized to either navigational bronchoscopy vs transthoracic biopsy. The primary outcome was proportion of biopsies yielding a specific diagnosis and the secondary outcome was incidence of procedural complications. They found that navigational bronchoscopy was not inferior to transthoracic biopsy in terms of the primary outcome (but was not superior to transthoracic biopsy). The incidence of pneumothorax was 3.4% of patients in the navigational bronchoscopy group vs 34.8% of patients in the transthoracic biopsy group.
PMID: 40387025 
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Overview
Christie JD, Van Raemdonck D, Fisher AJ. Lung transplantation. N Engl J Med. 2024;391:1822-1836. This digestible, well-organized review covers the most pertinent topics in lung transplantation including candidacy, surgical approaches, post-transplantation complications, and immunosuppression. It highlights the advances made over the past 30 years and where more research is needed. 
PMID: 39536228

Annual ISHLT Registry Reports
The ISHLT registry has links to slide sets that summarize overall adult lung transplant statistics as well as the annual Focus Theme topics.  The 2025 update includes a special report: Perch M, Hayes D Jr, Cherikh WS, et al. International Society for Heart and Lung Transplantation. International experience of donation after circulatory death for lung transplantation. A special report from the International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2025 Apr 28:S1053-2498.
PMID: 40306562 
ISHLT Registry Slides 

Recipient Selection
Leard LE, Holm AM, Valapour M, et al. Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2021; 40:1349-1379.  Provides updated disease-specific summaries of indications and contraindications for transplantation, as well as recommendations for timing of referral.
PMID: 34419372
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Florissi I, Chidi AP, Liu Y, et al. Racial disparities in waiting list outcomes of patients listed for lung transplantation. Ann Thorac Surg. 2024;117:619-626.  This retrospective review of weightlisted lung transplant candidates in the United States between 2005, when use of the Lung Allocation Score was initiated, to 2021 and found that African-American and Hispanic populations were less commonly listed (27,074 (82%) White, 3,350 (10%) African-American, and 2,734 (8%) Hispanic). After multivariable adjustment they were less likely to receive lung transplants than white candidates [adjusted subhazard ratio (95% Confidence Interval): (African-American) 0.86 (0.82, 0.91); (Hispanic) 0.82 (0.78, 0.87)]. 
PMID: 37673311 
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Donor Selection and Management
Courtwright A, Cantu E. Evaluation and Management of the Potential Lung Donor. Clin Chest Med. 2017 Dec;38(4):751-759. Provides a review on the selection, assessment, and management of potential donor organs.

Post Transplant Management Reviews
Adegunsoye A,  Strek ME, Garrity E, et al. Comprehensive care of the lung transplant patient. Chest. 2017; 152:150-64. This review provides a concise overview of the management of patients awaiting transplant as well as recipients.
PMID: 27729262 

Mahajan AK, Folch E, Khandhar SJ, et al. The diagnosis and management of airway complications following lung transplantation. Chest 2017; 152:627-38. This article reviews the risk factors, clinical manifestations, and treatments of airway complications following lung transplantation.
PMID: 28274791 

Hathorn KE, Chan WW, Lo WK. Role of gastroesophageal reflux disease in lung transplantation. World J Transplant. 2017; 7:103-16. GERD is associated with worse outcomes following transplant. This paper reviews the pathophysiology, evaluation, and management of GERD in this population.
PMID: 28507913
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Acute and Chronic Graft Rejection
Kotecha S, Ivulich S, Snell G. Review: immunosuppression for the lung transplant patient. J Thorac Dis. 2021; 13:6628-6644. A concise overview of the induction, intra-operative, and post-operative immunosuppression regimens for lung transplant recipients.
PMID: 34992841
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GM Verleden, AR Glanville, ED Lease, et al. Chronic lung allograft dysfunction: definition, diagnostic criteria and approaches to treatment. A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. 2019; 38:493-503. This document provides the most updated definition, staging, diagnosis, and treatment of CLAD, including a summary of the primary phenotypes, bronchiolitis obliterans syndrome and restrictive allograft dysfunction.
PMID: 30962148 

Glanville AR, Verleden GM, Todd JL, et al. Chronic lung allograft dysfunction: Definition and update of restrictive allograft syndrome-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. 2019; 38:483-92. This document provides a consensus definition of restrictive allograft syndrome and discusses the underlying pathology, pathophysiology, diagnosis, and treatment.
PMID: 31027539 

Levy L, Huszti E, Tikkanen J, et al. The impact of first untreated subclinical minimal acute rejection on risks of chronic lung allograft dysfunction or death after lung transplantation. Am J Transplant. 2020; 20:241-249. This large, retrospective, single-center, cohort study is noteworthy for providing evidence that low-grade acute rejection may not require treatment. Untreated stable A1 rejection (no clinical/PFT changes) was not associated with an increased risk of death or CLAD compared to patients without acute rejection.
PMID: 31397939
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Dellgren G, Lund TK, Raivio P, et al. Effect of once-per-day tacrolimus versus twice-per-day ciclosporin on 3-year incidence of chronic lung allograft dysfunction after lung transplantation in Scandinavia (ScanCLAD): a multicentre randomised controlled trial. Lancet Respir Med. 2024;12:34-44. The open-label study of 249 patients compared tacrolimus plus mycophenolate and corticosteroids to cyclosporine plus mycophenolate and corticosteroids following induction with anti-thymocyte globulin, starting on post-operative day one. CLAD, as assessed by serial PFTs, occurred less frequently in the tacroliumus group (HR 0.29 95% CI 0.15-0.52). 3-year mortality did not differ, but allograft function, based on PFTs, was better in the tacrolimus group (HR 0·49 [95% CI 0·26-0·91], log-rank p=0·021).
PMID: 37703908
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Tikkanen JM, Singer LG, Kim SJ, et al. De novo DQ donor-specific antibodies are associated with chronic lung allograft dysfunction after lung transplantation. Am J Respir Crit Care Med. 2016;194:596-606. A single-center cohort of 340 lung transplant recipients who underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The cumulative incidence of de novo DSA was 47% at a median of 86 days after lung transplantation with 76% of recipients with DQ-DSA. Developing de novo DSA was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appears to be driven by the development of DQ-dnDSA.
PMID: 26967790 

Outcomes 
Raynaud M, Belousova N, Glorion M, et al. Trajectories of FEV1 after lung transplantation and patient outcomes. J Heart Lung Transplant. 2025;44(11):1749-1762. 2305 adult patients who received bilateral lung transplant between 2010-2021 across several centers in France, Belgium, Austria and the United States were followed with serial FEV1 measurements. The study outlines 7 FEV1 trajectories that are associated with clinical outcomes. The outlined trajectories may be a useful tool for earlier identification of transplant recipients who may need closer monitoring or earlier intervention to preserve graft function.
PMID: 40592371

Non-tuberculous mycobacterium
Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: An official ATS/ERS/ESCMID/IDSA clinical practice guideline. Clin Infect Dis 2020; 71:905-913. An updated version of the 2007 guidelines with a primary focus on treatment including recommendations for specific organisms. Diagnostic criteria are included in the 2020 update but the 2007 guidelines contain greater detail on aspects of taxonomy, diagnosis, and prevention.
PMID: 17277290 

Griffith DE, Eagle G, Thomson R, et al. Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium Avium Complex (CONVERT). Am J Respir Crit Care Med 2018; 198: 1559-1569. This randomized, open-label study of patients with persistent sputum culture positivity after 6 months of guideline-based therapy for MAC lung disease demonstrated that addition of inhaled amikacin led to culture conversion in 29% compared to 8.9% with guideline-based therapy alone after an additional six months.
PMID: 30216086 

Latent tuberculosis:
Lewinsohn DM, Leonard MK, LoBue PA et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64:111-115. Updated ATS/IDSA guidelines focusing on diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis.
PMID: 28052967
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Sterling TR, Njie G, Zenner D, et al. Guidelines for the treatment of latent tuberculosis infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR, 2020; 69:1-11. The most noteworthy change to the newest latent TB treatment guideline is preferential use of three rifamycin-based regimens of 3-4 month duration over isoniazid monotherapy for 6-9 months.
PMID: 31027539
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Active Tuberculosis- Diagnosis
Lewinsohn DM, Leonard MK, LoBue PA et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017; 64:111-115. Updated ATS/IDSA guidelines focusing on diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis.
PMID: 28052967
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Active Tuberculosis- Treatment 
Saukonnen JJ, Duarte R, Munsiff SS, et al. Updates on the treatment of drug-susceptible and drug-resistant tuberculosis: An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am J Respir Crit Care Med. 2024. 211:15-33. This is an update to the 2016 treatment guidelines with an emphasis on shorter treatment regimens, including 4-month regimens for adults with pulmonary tuberculosis and children with nonsevere tuberculosis. Novel regimens for drug-resistant tuberculosis are also included. 
ATS access

Reviews
Gaudry S, Pavelsky PM, and Dreyfuss D. Extracorporeal kidney-replacement therapy for acute kidney injury. New Engl J Med. 2022; 386:964-75. This review summarizes the types of continuous renal replacement, including the mechanism of fluid and solute transport, as well as indications and outcomes. 
PMID: 35263520 

Ronco C, Ricci Z, De Backer D, et al. Renal replacement therapy in acute kidney injury: controversy and consensus. Crit Care 2015; 19: 146. A review of strategies for RRT in the ICU, including modalities, adverse effects, and approaches for specific clinical situations.
PMID: 25887923
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Modaliaty and Timing
Vinsonneau C, Camus C, Combes A, et al. Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome. Lancet 2006; 368 :379-85. Like previous RCTs addressing this issue, this multicenter study of 360 ICU patients found no advantage to continuous venovenous dialysis in terms of 60-day survival. A limitation of the study is that the delivered dialysis dose may have been suboptimal for both arms.
PMID: 16876666 

Bagshaw SM, Wald R, Adhikari NKJ, et al. Timing of initiation of renal replacement therapy in acute kidney injury. STARRT-AKI Investigators.  N Engl J Med. 2020; 383:240-251. This multicenter RCT of nearly 3,000 patients is the latest to show no mortality benefit to early initiation of dialysis in patients with AKI but no emergent need for dialysis. As with previous studies, patients in the early dialysis group experienced more adverse events and were more likely to be dialysis dependent at 90 days. Unlike similar preceding trials, clinical equipoise on the part of the treating provider was also required for enrollment.
PMID: 32668114
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Gaudry S, Hajage D, Martin-Lefevre L, et al. Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial. Lancet. 2021; 397:1293-1300. This trial compared maximal delay in initiating HD (waiting until an absolute indication or BUN > 140 mg/dl) vs. initiating HD for oliguria present > 72 hours or BUN > 112 mg/dl.  More patients in the maximal-delay group avoided HD (21 vs. 2%), but there was no difference in days free of renal replacement therapy and a multivariable analysis found reduced risk of death in the less-delayed group.
PMID: 33812488 

Liu KD, Siew ED, Tuot DS, Vijayan A, Matzumura Umemoto G, Birkelo BC, Lee BJ, Kwong YD, McCoy IE, Delucchi K, Zhuo H, Hsu CY. A Conservative Dialysis Strategy and Kidney Function Recovery in Dialysis-Requiring Acute Kidney Injury: The Liberation From Acute Dialysis (LIBERATE-D) Randomized Clinical Trial. JAMA. 2026 Jan 27;335(4):326-335. This multicenter trial compared a conservative dialysis strategy (participants received intermittent dialysis only when certain metabolic or clinical indications were met) or conventional dialysis strategy (participants received dialysis three times per week) in hemodynamically stable patients with dialysis-requiring acute kidney injury. The trial found that a conservative dialysis strategy resulted in a shorter time to and higher rate of recovery of kidney function. 
PMID: 41201895 
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Prevention
Finfer S, Micallef S, Hammond N, et al; PLUS Study Investigators and the Australian New Zealand Intensive Care Society Clinical Trials Group. Balanced multielectrolyte solution versus saline in critically ill adults. N Engl J Med. 2022; 386:815-826. This large, double-blind, RCT showed no difference in mortality rates or need for dialysis in ICU adults when comparing use of balanced multi-electrolyte solution to normal saline. The groups received similar amounts of fluid following randomization (approximately 3.8 L/patient). This is the second large randomized trial since 2021 (see BaSICS trial below) showing no advantage to using balanced solutions.
PMID: 35041780
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Zampieri FG, Machado FR, Biondi RS, et al. Effect of intravenous fluid treatment with a balanced solution vs 0.9% saline solution on mortality in critically ill patients: the BaSICS randomized clinical trial. JAMA 2021;326:1-12. This large, multicenter trial found no difference between fluid choices in 90-day mortality or need for renal replacement and subgroup analysis revealed worse outcomes with use of balanced crystalloids in patients with traumatic brain injury. Of note, nearly 50% of patients were admitted for elective surgery, 45% had received > 1 liter of fluids prior to enrollment, and patients received a median of only 1.5 L of fluid in the first 24 hours after enrollment.
PMID: 34375394
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Jung B, Jabaudon M, De Jong, A et al. Sodium Bicarbonate for Metabolic Acidemia and Acute Kidney Injury: The BICARICU-2 Randomized Clinical Trial. JAMA. 2025;334(22):2000-2010. RCT  of 627  ICU patients with severe metabolic acidosis ( pH < 7.20) and moderate to severe AKI found infusion of 4.2%, bicarbonate solution titrated to pH 7.30 or higher did not improve 90-day mortality compared to placebo (62% in both groups). There were no differences in 18 secondary outcomes except for reduced need for kidney replacement therapy in the bicarbonate group (35% vs. 50% with absolute difference, -15.5; 95% CI, -23.1 to -7.8)
PMID: 33812488 

Qian ET, Casey JD, Wright A, et al. Cefepime vs piperacillin-tazobactam for acute infection in hospitalized adults. JAMA. 2023;330:1557-67. 2511 patients who received empiric antipseudomonal therapy were randomized to pipercillin-tazobactam or cefepime. There was no difference in the risk of AKI, including when co-administered with vancomycin (75% of patients).  The cefepime group had fewer days alive without delirium or coma with an absolute difference of 0.3 days.  Of note, the average SOFA score was 2, fewer than 10% were receiving mechanical ventilation, and only 54% of patients met sepsis criteria.
PMID: 38411650
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Brain Death
Greer DM, Shemie SD, Lewis A, et al. Determination of Brain Death/Death by neurologic criteria: The World Brain Death Project. JAMA. 2020; 324:1078-1097. A comprehensive review conducted by a multi-disciplinary panel with recommendations on the clinical criteria, testing, and documentation required to determine brain death. Specific circumstances including ECMO and therapeutic hypothermia are discussed as well as ongoing somatic support.

Coma/Anoxic Brain Injury
Sandroni C, D’Arrigo S, Nolan JP. Prognostication after cardiac arrest. Crit Care. 2018; 22:150.  This review provides an excellent overview of the predictive value and limitations of the various predictors of neurologic outcome including physical exam, EEG, evoked potentials, biomarkers, and imaging. A multimodality strategy for deriving prognosis is outlined.
PMID: 29871657
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Rajajee V, Muehlschlegel S, Wartenberg KE, et al. Guidelines for neuroprognostication in comatose adult survivors of cardiac arrest. Neurocrit Care. 2023;38:533-563. This guideline categorizes different markers of neuroprognosis as reliable, moderately reliable, and unreliable and provides recommended language for surrogate decision-makers based on these findings.  Absence of pupillary reflex at 72 hours and bilateral absence of the N20 response with evoked potential testing are deemed reliable with recommended language that poor neurologic outcome is “very likely but uncertainty exists”. A clinical picture of severe, widespread injury plus severe EEG abnormalities or imaging consistent with diffuse anoxic injury were deemed moderately reliable with recommended language for poor outcome “likely but significant uncertainty exists”.  Other variables were deemed unreliable.
PMID: 36949360
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Hirsch KG, Amorim E, Coppler PJ, et al. Part 11: Post-Cardiac Arrest Care: 2025 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2025;152(16_suppl_2):S673-S718. Updated guidelines include recommendations for neuroprognostication (NfL and NSE monitoring), maintaining targeted temperature management for at least 36 hours in patients unresponsive to verbal command, detection and management of post-cardiac arrest myoclonus, and guidance on use of cardiac catheterization, as well as, mechanical circulatory support in out of hospital cardiac arrest patients.
PMID: 41122894 
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Jabre P, Bougouin W, Dumas F, et al. Early identification of patients with out-of-hospital cardiac arrest with no chance of survival and consideration for organ donation. Ann Intern Med. 2016; 165: 770-8. This retrospective analysis of a French registry from 2011 to 2014 found no survivors to hospital discharge among 772 patients who met all of the following 3 criteria: 1) OHCA not witnessed by medics, 2) non-shockable initial cardiac rhythm, and 3) no ROSC prior to receipt of a 3rd 1-mg dose of epinephrine. Validation in an additional 2,000 patients who met these criteria from other registries and trials found 1 survivor, in a persistent vegetative state.
PMID: 27618681 

Coplin WM, Pierson DJ, Cooley KD, et al. Implications of extubation delay in brain-injured patients meeting standard weaning criteria. Am J Respir Crit Care Med 2000;161:1530-6. Prospective cohort study found patients with "delayed" extubation had increased incidence of nosocomial pneumonia, longer ICU and hospital stays, and greater hospital charges.
PMID: 10806150
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Therapeutic hypothermia following cardiac arrest 
Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021; 384:2283-2294. TTM2 Trial found no difference in 6-month survival or functional outcomes among 1,850 patients randomized to targeted hypothermia at 33°C for 28 hours followed by controlled rewarming or targeted normothermia with early treatment of fever (body temperature > 37.8°C).  Temperature was managed for a total of 72 hours in both groups. Notably this trial included both patients with shockable and nonshockable rhythms.
PMID: 34133859 

Acute hemorrhagic stroke 
Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the management of patients with spontaneous intracerebral hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2022;53:e282-e361. These guidelines serve as a useful overview of diagnosis and early risk prognostication, provide updated recommendations for acute reversal of anticoagulation, review evidence based guidelines for historical medical therapies that have benefit and those that confer harm, and place an emphasis on the importance of healthcare systems in optimal stroke care.
PMID: 35579034 
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Qureshi A, Palesch Y, Barsan W, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med. 2016;375:1033-43. The ATACH-2 randomized open label trial of aggressive (110-139 mmHg) versus standard (140-179 mmHg) BP management of patients with spontaneous supratentorial cerebral hemorrhage within 4.5 hours of onset. The mean SBP at 2 hours was 128 mm Hg in the aggressive group and 141 mmHg in the standard group. There were no differences in death or disability at 3 months, and the rate of renal adverse events within 7 days of randomization were higher in the aggressive control group.
PMID: 27276234
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Acute Ischemic Stroke - Thrombolytic Therapy
The following two landmark studies established the use of thrombolytics within 3 hours and between 3 and 4.5 hours following onset of acute ischemic stroke.

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-7.
PMID: 7477192
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Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 2 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359:1317-29.
PMID: 18815396
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Zhou Y, He Y, Campbell BCV, et al; HOPE investigators. Alteplase for acute ischemic stroke at 4.5 to 24 hours: the HOPE randomized clinical trial. JAMA. 2025;334:788-797. RCT studying alteplase vs no thrombolytics in 372 patients in the 4.5-24 hour period after acute ischemic CVA. The intervention group demonstrated improved functional score at 90 days (40% mRS 0-1 vs 26%), however at the cost of higher rates of symptomatic intracranial hemorrhage (3.8% vs 0.51%). There was no significant difference in mortality.
PMID: 40773205 
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Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018; 379:611-622. The WAKE-UP trial was a RCT of 503 patients with ischemic stroke with unknown time of onset but MRI indicative of onset within the previous 4.5 hours. Excluded patients in whom thrombectomy was planned. Favorable neurologic outcome (modified Rankin scale of 0 or 1) at 90 days was seen in 53.3% in alteplase group vs 41.8% in placebo group. Rate of symptomatic intracranial hemorrhage was 2% vs 0.4% in alteplase vs placebo.
PMID: 29766770
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Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019; 380:1795-1803. The EXTEND trial was a RCT of 225 patients with ischemic stroke and salvageable brain tissue on automated perfusion scanning. The use of alteplase (vs placebo) between 4.5 hours and 9 hours after stroke onset or at the time patient awoke from stroke symptoms resulted in higher percentage of patients with modified Rankin scale of 0 or 1 at 90 days (35.4% vs 29.5%). Symptomatic cerebral hemorrhage occurred in 6.2% in alteplase group vs 0.9% in placebo. This study was stopped early due to publication of WAKE-UP trial.
PMID: 31067369
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Acute Ischemic Stroke - Thrombectomy
Nogueira RG, Jadhav AP, Haussen DC, et al.Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018; 378:11-21. The DAWN trial looked at 206 patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery last known to be well 6 to 24 hours earlier who also had a mismatch between the severity of the clinical deficit and the infarct volume. Patients were randomly assigned to thrombectomy plus standard care or to standard care alone. The coprimary endpoints were the mean score for disability on the utility-weighted modified Rankin scale and the rate of functional independence at 90 days. Functional independence at 90 days was 49% in the thrombectomy group compared to 13% in the control group.
PMID: 29129157
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Qiu Z, Li F, Sang H, et al. Intravenous Tenecteplase before Thrombectomy in Stroke. N Engl J Med. 2025;393(2):139-150. RCT studying 550 patients presenting within 4.5 hours of acute ischemic CVA. 272 received thrombectomy alone and 278 received IV tenecteplase prior to thrombectomy. The Tenecteplase + thrombectomy group demonstrated improved functional independence (52.9% mRS 0-2) at 90 days vs the thrombectomy alone group (44.1%); Risk ratio: ~1.18 (95% CI ~1.01–1.39); P ≈0.04. 6.1% of the Tenecteplase group had reperfusion prior to thrombectomy vs 1.1% in the control group. Notably, there was no statistically significant higher risk of symptomatic intracranial hemorrhage in the Tenecteplase +thrombectomy group (8.5% vs 6.7%). The was no significant 90 day mortality difference between the two groups (22.3% vs 19.9%)
PMID: 40396577 

Subarachnoid Hemorrhage
Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989; 298:636-42. Although published in1989, this sentinel study is still cited as the basis for calcium channel blocker use in SAH. The study found ischemic stroke developed in 22% of patients receiving nimodipine compared to 33% in the placebo group.
PMID: 2496789
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Primary neuromuscular disease
Khan A, Frazer-Green L, Amin R, et al. Respiratory management of patients with neuromuscular weakness: an ACCP Clinical Practice Guideline and Expert Panel Report. Chest. 2023;164:394-413. Updated CHEST guidelines for respiratory management of patients with neuromuscular disease.
PMID: 36921894 
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Transfusion in acute brain injury 
The following three studies all investigate liberal vs restrictive transfusion strategies in various types of acute brain injury. The Taccone study included TBI, SAH, and ICH patients and demonstrated favorable outcomes with liberal transfusion strategy. However, the Turgeon study (only TBI patients) and English study (only SAH patients) both did not demonstrate a significant difference between liberal and restrictive strategies.

Turgeon AF, Fergusson DA, Clayton L, et al. Liberal or restrictive transfusion strategy in patients with traumatic brain injury. N Engl J Med. 2024;391:722-735. 
PMID: 38869931

Taccone FS, Rynkowski CB, Møller K, et al. Restrictive vs liberal transfusion strategy in patients with acute brain injury: The TRAIN Randomized Clinical Trial. JAMA. 2024;332:1623-1633. 
PMID: 39382241 
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English SW, Delaney A, Fergusson DA, et al. Liberal or Restrictive Transfusion Strategy in Aneurysmal Subarachnoid Hemorrhage. N Engl J Med. 2025;392(11):1079-1088.
PMID: 39655786

Guidelines
Taylor B, McClave S, Martindale R, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). Crit Care Med. 2016; 44:390-438. This update expands commentary on general ICU nutrition issues and specific subsets of medical and surgical patients. There is continued emphasis on early enteral nutrition, full protein content, and relatively early parenteral route in high-risk patients in whom enteral is not an option.
PMID: 26771786 

Singer P, Blaser AR, Berger MM, et al. ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit. Clin Nutr. 2023;42(9):1671-1689. Revised, updated, and condensed clinical nutrition guidelines for ICU patients from the ESPEN group. These guidelines are meant to be practical and allow for easier application of important nutrition goals to individual ICU patients. 
PMID: 37517372 
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Strategies for Nutrition in the ICU
Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365: 506-17. This large, randomized study found supplementation of enteral nutrition with parenteral nutrition to reach target during the first week of ICU admission was associated with slower recovery, more complications, and more cost compared to continuing sub-target enteral nutrition alone. The study has been criticized for including patients with low risk of malnutrition and for the composition of the parenteral nutrition delivered.
PMID: 21714640
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Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically ill adults. New Engl J Med. 2014; 371:1673-84. This multicenter RCT randomized 2500 mostly non-surgical ICU patients to 5 days of parenteral vs. enteral nutrition within 36 hours of admission and found no difference in mortality. Hypoglycemia and vomiting were more common in patients receiving enteral nutrition. Of note, the rate of infections did not differ.
PMID:25271389
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Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012;307: 795-803. This study was noteworthy for finding no difference in outcomes among ICU patients with ARDS receiving 6 days of full vs. trophic feeds.
PMID: 22307571
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Arabi YM, Aldawood AS, Solaiman O, et al. Permissive underfeeding or standard enteral feeding in critical illness. New Engl J Med. 2015; 372:2398-2408. This multicenter non-blinded RCT compared restriction of non-protein calories vs. full enteral nutrition and found no difference in mortality (in-ICU to 180 days) or adverse events. In a post-hoc analysis the permissive underfeeding group had a significantly lower rate of renal replacement therapy. The study population was not limited to patients with high baseline nutritional risk.
PMID: 25992505
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The following two trials studied the effects of higher vs standard protein intake via enteral nutrition in ICU patients. Both studies did not show any significant difference in mortality, and the EFFORT Protein study, which limited enrollment to patients at high nutritional risk, found higher protein intake may have worsened outcomes in the subset of patients with AKI and high organ failure scores.
Heyland DK, Patel J, Compher C, et al. The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicentre, pragmatic, registry-based randomised trial. Lancet. 2023; 401:568-576. 
PMID: 36708732 

Summers MJ, Chapple LS, Karahalios A, et al. Augmented Enteral Protein During Critical Illness: The TARGET Protein Randomized Clinical Trial. JAMA. 2025;334(4):319–328. 
PMID: 40495743 
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Practical Issues in ICU Nutrition
Davies AR, Morrison SS, Bailey MJ, et al; ENTERIC Study Investigators; ANZICS Clinical Trials Group. A multicenter, randomized controlled trial comparing early nasojejunal with nasogastric nutrition in critical illness. Crit Care Med. 2012; 2342-8. Randomized study of 181 mechanically ventilated patients found no difference in delivered nutrition between nasojejunal and nasogastric routes of feeding. Rates of ventilator associated pneumonia, vomiting, aspiration, and mortality were similar amongst the groups while minor GI hemorrhage was higher in the NJ feeding group (13% vs 3%, p = .02).
PMID: 22809907 

Reignier J, Mercier E, Le Gouge A, et al. Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial. JAMA. 2013; 309:249-56. This large randomized study found that not monitoring residual volume in patients receiving enteral feeds was not inferior to protocolized residual monitoring in rates of ventilator associated pneumonia. Morbidity, ICU length of stay, duration of mechanical ventilation, and infection rate were also similar. A significantly greater proportion of patients in the intervention group met their calorie goal.
PMID: 23321763
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Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 211: Critical care in pregnancy. The American College of Obstetricians and Gynecologists. 2019. Obstet Gynecol. 2019;133:e303-e319. Review of available evidence for managing critical illness during pregnancy, with both disease-specific guidance and recommendations for multidisciplinary management between intensivists and obstetricians. 
PMID: 31022122 

Jeejeebhoy FM, Zelop CM, Lipman S, et al. Cardiac Arrest in Pregnancy: A Scientific Statement From the American Heart Association. Circulation. 2015;132:1747-73. A scientific update on guidelines and recommendations for all aspects of maternal resuscitation. They emphasize the use of BLS and ACLS as the foundation for any resuscitation, and focus on manual left uterine displacement, airway management, and perimortem cesarean delivery as areas of special attention.
PMID: 26443610
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WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomized, double-blind, placebo-controlled trial. Lancet. 2017; 389:2105-116. This trial of over 20,000 women found tranexamic acid reduced the risk of death due to bleeding (1.5% vs 1.9%, p = 0.045). There was no difference in risk of hysterectomy or in the risk of adverse events, including thromboembolism.
PMID: 28456509
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Tolcher MC, McKinney JR, Eppes CS, et al. Prone positioning for pregnant women with hypoxemia due to coronavirus disease 2019 (COVID-19). Obstet Gynecol. 2020; 136:259-261. This review provides practical advice for placing pregnant patients in prone position. This includes links to instructional videos that are presumably applicable to other causes of severe hypoxemia.
PMID: 32516274 

***See Leung et al in Pulmonary Embolism for information related to suspected pulmonary embolism in pregnancy.

Asthma/RADS/Upper airway disease
Tarlo SM, Lemiere C. Occupational asthma. New Engl J Med 2014; 370:640-9. This succinct review provides an overview of the diagnosis, management, and prevention of sensitizer-induce and irritant-induced asthma.
PMID: 24521110 

Vandenplas O, Wiszniewska M, Raulf M, et al. EAACI position paper: irritant-induced asthma. Allergy 2014; 69:1141-53. Expert panel provides revised classification of irritant (occupational) asthma including replacement of reactive airways dysfunction syndrome with the term acute-onset irritant-induced asthma. Diagnosis, natural history, treatment, and prevention are also addressed.
PMID: 24854136
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Chan-Yeung M. Fate of occupational asthma. A follow-up study of patients with occupational asthma due to Western Red Cedar (Thuja Plicata). Am Rev Respir Dis 1977;116:1023-6.This classic article demonstrated the frequent persistence of occupational asthma even months after removal from exposure to western red cedar. Subsequent studies found similar findings for other OA asthmagens, prompting heightened vigilance.
PMID: 931178 

Burge PS, O’Brien IM, Harries MG. Peak flow rate records in the diagnosis of occupational asthma due to isocyanates. Thorax 1979;34:317-24. Landmark study was the first to show peak flow is a suitable alternative to provocation testing in the diagnosis of OA.
PMID: 483205
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Lau A, Tarlo SM. Work-related upper-airway disorders. Clin Chest Med. 2020; 41:651-660. This review provides an overview of the presentation, diagnosis, and treatment of work related rhinitis and laryngeal syndromes. Noteworthy aspects include discussion of how laryngeal syndromes can mimic, as well as coexist with, occupational asthma and the role of occupational irritants in chronic cough that extends beyond working hours.
PMID: 33153685 

De Matteis S, Ronsmans S, Nemery B. Respiratory health effects of exposure to cleaning products. Clin Chest Med. 2020; 41:641-650. Review summarizes presentation and pathogenesis, as well as the challenges with determining the epidemiology, diagnosis, and treatment.
PMID: 33153684 

Associations with interstitial lung disease and neoplasia:
Selikoff IJ, Hammond EC, Churg J. Asbestos exposure, smoking, and neoplasia. JAMA 1968;204:106-12. Landmark study showing the synergistic effect of smoking and asbestos exposure.
PMID: 5694532 

Krefft S, Wolff J, Rose C. Silicosis: An update and guide for clinicians. Clin Chest Med. 2020; 41:709-722. This review summarizes the current epidemiology of silicosis as well as the wide array of pulmonary and extrapulmonary manifestations of exposure.

Fazio JC, Gandhi SA, Flattery J, et al. Silicosis among immigrant engineered stone (quartz) countertop fabrication workers in California. JAMA Inter Med. 2023; 183:991-998.
Case series of 52 countertop fabrication workers who developed silicosis with median work exposure of 15 years. 58% of patients experienced delayed diagnosis and 19% of patients died. Of 11 patients referred for lung transplant evaluation, 7 were declined, 3 were transplanted, and 1 patient died during the evaluation process. 
PMID: 37486642 
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PMID: 33153689 

Moitra S, Puri R, Paul D, et al. Global perspectives of emerging occupational and environmental lung diseases. Curr Opin Pulm Med 2015; 21:114-20. Review of emerging environmental and occupational lung diseases from silicosis due to sandblasting jeans to potential health effects of hydraulic fracturing (fracking).
PMID: 25575364 

Falvo MJ, Sotolongo AM, Osterholzer JJ, et al. Consensus statements on deployment-related respiratory disease, inclusive of constrictive bronchiolitis: a modified Delphi study. Chest. 2023; 163:599-609. This statement is noteworthy for introducing the term Deployment-Related Respiratory Disease (DRRD) to capture a variety of syndromes and conditions experienced by previously deployed individuals. Consensus statements provide guidance on the evaluation of suspected constrictive bronchiolitis.
PMID: 36343686
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Air pollution and cardiopulmonary disease
Liu C, Chen R, Sera F, et al. Ambient particulate air pollution and daily mortality in 652 cities. N Engl J Med. 2019; 381:705-715. Study of 652 cities in 24 countries or regions. On average, an increase in 10 μg per cubic meter of both inhalable and fine particulate matter was associated with increased daily all-cause mortality, daily cardiovascular mortality, and daily respiratory mortality.
PMID: 31433918
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Gan WQ, FitzGerald JM, Carlsten C, et al. Associations of ambient air pollution with chronic obstructive pulmonary disease hospitalization and mortality. Am J Respir Crit Care Med 2013; 187:721-7. This prospective longitudinal cohort study is noteworthy for finding long-term exposure to traffic-related fine particulate pollution and woodsmoke pollution increased the risk of COPD.
PMID:23392442 

Bayram H., Bauer AK, Abdalati W, et al. Environment, global climate change, and cardiopulmonary health. Am J Respir Crit Care Med. 2017; 195:718-724. Review article describing major cardiopulmonary impacts of climate change. They provide suggestions to initiate improved education for pulmonary physicians, clinician scientists, and public health officials to enable them with appropriate resources to develop an understanding of climate change impacts on human health to increase future advocacy.
PMID: 27654004
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Society Statements & Guidelines
Truog RD, Campbell ML, Curtis JR, et al. Recommendations for end-of-life care in the intensive care unit: a consensus statement by the American College of Critical Care Medicine. Crit Care Med 2008; 36:953-63. Provides an overview of ethical issues as well as a compassionate approach to practical aspects of end-of-life care.
PMID: 18431285 

Lanken PN, Terry PB, DeLisser HM, et al. An official American Thoracic Society clinical policy statement: palliative care for patients with respiratory diseases and critical illnesses. Am J Respir Crit Care Med 2008;177:912-27. Overlap with above ACCM statement but offers additional worthwhile discussion of hospice eligibility and on timing and settings for palliative care.
PMID: 18390964 

Marshall MF, Davis FD, Fogelman PA, et al. Society of Critical Care Medicine Clinical Practice Guidelines on Adult End-of-Life Care in the ICU. Crit Care Med. 2025;53(12):e2734-e2746. Evidence-based practice has evolved significantly since the release of the 2008 American College of Critical Care Medicine (ACCM) Consensus Statement of recommendations for end-of-life (EOL) care in the ICU. These guidelines represent new knowledge and address previously unconsidered issues 
PMID: 41342842 
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Sullivan DR, Iyer AS, Enguidanos S, et al. Palliative Care Early in the Care Continuum among Patients with Serious Respiratory Illness: An Official ATS/AAHPM/HPNA/SWHPN Policy Statement. Am J Respir Crit Care Med. 2022;206(6):e44-e69. This policy statement aims to improve integration of palliative care early in the management of patients with serious respiratory illness prior to end of life to improve patient outcomes. It provides a helpful framework for how clinicians could implement this change into their practice.
PMID: 36112774 
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Bosslet, GT, Pope T, Rubenfeld GD, et al. An official ATS/AACN/ACCP/ESICM/SCCM policy statement: Responding to requests for potentially inappropriate treatments in intensive care units. Am J Respir Crit Care Med 2015; 191:1318-1330. This consensus statement differentiates between the terms, “futile”, and, “potentially inappropriate”, reserving the former for when “surrogates request interventions that simply cannot accomplish their intended physiologic goal.” They also recommend implementing proactive strategies to prevent conflict at the institutional level, while engaging the public to implement change at the health policy and legislative level.
PMID: 25978438 

End of Life Discussions with Patients and Families
Clinical Trials
White DB, Angus DC, Shields AM et al. A randomized trial of a family-support intervention in intensive care units. N Engl J Med. 2018; 378:2365-2375. Cluster-randomized trial involving the surrogates of 1,400 patients with a high risk of death compared a nurse-led multicomponent family-support intervention to usual care. The intervention did not significantly affect the surrogates' burden of psychological symptoms, but did improve surrogates' ratings of the quality of communication and patient- and family-centeredness of care. Of note, the length of ICU stay was 0.7 days shorter in the intervention group (p = .045) but 6-month mortality did not differ, suggesting the intervention did not lead to premature transition to comfort care.
PMID: 29791247
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Carson S, Cox C, Wallenstein S, et al. Effect of palliative care–led meetings for families of patients with chronic critical illness: a randomized clinical trial. JAMA. 2016; 316:51-62. This trial of usual care (ICU-led family meetings + brochure) vs Palliative Care-led conferences + brochure for patients with chronic critical illness and their families found no difference in family anxiety or depression. The Palliative Care intervention group may have increased risk of PTSD. The authors conclude that routine palliative care consult is not indicated, but remains important for select cases.
PMID: 27380343
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Courtright KR, Madden V, Bayes B, et al. Default palliative care consultation for seriously ill hospitalized patients: A pragmatic cluster randomized trial. JAMA. 2024;331:224-232. In a pragmatic, cluster randomized trial of more than 34,000 patients, default (opt-out) palliative care consultations for patients 65 years or older with advanced COPD, dementia, or kidney failure, there was no difference in the primary outcome, length of stay, or in in-hospital mortality. The intervention group had increased palliative care consultation (43.9 vs 16.6%), increased discharge on hospice (6.8 vs. 6.9%, adjusted OR 1.3), and higher rates of do-not-resuscitate orders on discharge (37 vs 30%). 
PMID: 38227032 
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Detsky ME, Harhay MO, Bayard DF, et al. Discriminative accuracy of physician and nurse predictions for survival and functional outcomes 6 months after an ICU admission. JAMA. 2017; 317: 2187-2195. Prospective cohort study of 303 critically ill patients in which the discriminative accuracy of intensive care unit physicians and nurses in predicting 6-month patient mortality and morbidity was examined. As might be expected, when providers had low confidence in their decision, prognostic accuracy was poor. However, when confidence was high (particularly if both nurses and intensivists agreed), the prognostic accuracy was quite good.  These findings can be useful for framing goals of care discussions.
PMID: 28528347
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Practical Guidance
Scheunemann LP, Arnold RM, White DB. The facilitated values history: helping surrogates make authentic decisions for incapacitated patients with advanced illness. Am J Respir Crit Care Med. 2012;186:480-6 This article offers a practical framework for how best to assist surrogate decision-makers with the challenge of determining, and applying, patients’ values to medical decision-making in this population.
PMID: 22822020 

Billings JA, Block SD. The end-of-life family meeting in intensive care part III: A guide for structured discussions. J Palliat Med 2011; 14:1058-64. Offers an explicit step-by-step blueprint for approaching family conferences while recognizing the need for flexibility depending on family and patient circumstances. Provides sample language useful for navigating difficult aspects of decision-making.
PMID: 21910613
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Pleural effusion
Light RW, MacGregor MI, Luchsinger PC, et al. Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med 1972;77:507-13. This paper is the basis for using pleural fluid LDH and protein to classify effusions as transudative or exudative.
PMID: 4642731 

Lentz RJ, Lerner AD, Pannu JK, et al. Routine monitoring with pleural manometry during therapeutic large-volume thoracentesis to prevent pleural-pressure-related complications: a multicentre, single-blind randomised controlled trial. Lancet Respir Med. 2019; 7:447-455. This study randomized 124 patients with free-flowing effusions with estimated volume > 500 ml (63% with malignant effusion) to thoracentesis drainage based on symptoms alone vs. symptoms plus pleural manometry. There was no significant difference in chest discomfort, volume of fluid drained, proportion of patients with complete lung expansion, or clinically significant complications. Of note, the mean volume of fluid drained was 1,100 ml (SD 500 ml) and patients with known re-expandable lung, such as those with a large hepatic hydrothorax, were excluded.
PMID: 30772283 

Pleural infection
Rahman NM, Maskell NA, West A et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011;365:518-26. Randomized double blinded trial of 210 patients found an 8% greater reduction in the proportion of the hemithorax occupied by pleural fluid on chest radiograph with tissue plasminogen activator (TPA) and DNAse administered intrapleurally compared to placebo. TPA and DNAse used in isolation did not differ from placebo. Patients receiving placebo were more likely to be referred to surgery than the TPA-DNAse group, but the rate of surgical intervention and mortality did not differ.
PMID: 21830966
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Bedawi EO, Ricciardi S, Hassan M, et al. ERS/ESTS statement on the management of pleural infection in adults. Eur Respir J. 2023;61(2):2201062. The European Respiratory Society (ERS) and European Society of Thoracic Surgeons (ESTS) multidisciplinary review of management of pleural infection.
PMID: 36229045 
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Malignant pleural effusion
Feller-Kopman DJ, Reddy CB, DeCamp MM et al. Management of malignant pleural effusions. An Official ATS/STS/STR Clinical Practice Guideline. Am J Respir Crit Care Med. 2018; 198:839-849.
PMID: 30272503
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Thomas R, Fysh ETH, Smith NA, et al. Effect of an indwelling pleural catheter vs talc pleurodesis on hospitalization days in patients with malignant pleural effusion: The AMPLE randomized clinical trial. JAMA. 2017; 318:1903-1912. Trial of 146 patients with symptomatic malignant pleural effusion randomized to either indwelling pleural catheters (IPC) or talc pleurodesis and followed for up to 12 months. The IPC group spent significantly fewer days in hospital than the pleurodesis group (10.0 vs 12.0; P = .03) but without significant differences in improvements in breathlessness or quality of life.
PMID: 29164255
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Bhatnagar R, Piotrowska H, Laskawiec-Szkonter M, et al. Effect of thoracoscopic talc poudrage vs talc slurry via chest tube on pleurodesis failure rate among patients with malignant pleural effusions: a randomized clinical trial. JAMA 2020; 323:60-69. Open label clinical trial randomized 330 patients with malignant pleural effusion to receive talc poudrage during thoracoscopy versus bedside chest tube insertion followed by talc slurry. At 90 days, pleurodesis failure occurred in 22% of talc poudrage group versus 24% in talc slurry group (p=0.74).
PMID: 31804680
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Spontaneous pneumothorax
Walker S, Hallifax R, Ricciardi S, et al. Joint ERS/EACTS/ESTS clinical practice guidelines on adults with spontaneous pneumothorax. Eur Respir J. 2024; 63:2300797. Highlights of these updated guidelines focus on primary spontaneous pneumothorax and include conditional recommendation for conservative management if the patient is minimally symptomatic, strong recommendation for aspiration over chest tube placement, and conditional recommendation for outpatient management in select patients.
PMID: 38806203
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Hallifax RJ, McKeown E, Sivakumar P, et al. Ambulatory management of primary spontaneous pneumothorax: an open-label, randomised controlled trial. Lancet. 2020; 396:39-49. This study randomized 236 patients with primary spontaneous pneumothorax to either placement of an 8F catheter attached to a one-way valve followed by discharge if there was insufficient lung re-expansion vs. management based on BTS guidelines above. Enrollment criteria included pneumothorax > 2 cm from chest wall at the level of the hilum and/or significant symptoms. Although 12% of the ambulatory group subsequently required admission for a serious adverse event, this group overall had a lower median number of hospital days (0 days [IQR 0 – 3] vs. 4 days [IQR 0 -8]; p<0.0001).
PMID 32622394
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Brown SGA, Ball EL, Perrin K, et al. Conservative versus interventional treatment for spontaneous pneumothorax. N Engl J Med. 2020; 382:405-415. This trial randomized 316 patients with primary spontaneous pneumothorax > 32% of the hemithorax and without severe distress to conservative vs. interventional management. Conservative management entailed discharge if symptoms, pneumothorax size, and room air oxygen saturations were stable after 4 hours of observation. The intervention group received a small-bore catheter and were admitted unless the tube could be removed after 4 hours based on full lung re-expansion and absence of an air leak. In the conservative group, 85% did not require an intervention and, if excluding the 19% of patients lost to follow-up, conservative was non-inferior to interventional management (94.4% vs. 98.5% complete reexpansion at 8 weeks, respectively, p = 0.02).
PMID: 31995689

Community Acquired Pneumonia - Treatment
Jones BE, Self WH, Wunderink RG, et al. Diagnosis and management of community-acquired pneumonia: an official American Thoracic Society clinical practice guideline update. Am J Respir Crit Care Med. 2026;203. This update to the 2019 guidelines pays specific attention to lung ultrasound as a diagnostic tool, whether antibiotics are appropriate in the setting of positive viral testing, antibiotic duration, and use of systemic corticosteroids. 
PMID: 40679934 

Klompas M, Cosgrove SE, et al. Why the Infectious Diseases Society of America did not endorse the 2025 American Thoracic Society community-acquired pneumonia guideline update. Clin Infect Dis. 2025. This statement explains the lack of endorsement stems from the IDSA’s position that empiric antibiotics should not be used in outpatients with co-morbidities that are diagnosed with CAP and test positive for a respiratory virus or for inpatients with non-severe CAP and a positive test for a respiratory virus. Their rationale is that coinfections are rare and that nondiscriminatory use of antibiotics in the setting of positive viral testing portends more risk than benefit. 
PMID: 41340493 

Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med. 2023; 388:1931-41. RCT of 800 patients found a 28-day mortality of 6.2% among patients receiving an infusion of hydrocortisone 200 mg/daily for 4 to 8 days compared to 11.9% for placebo (p = .0006). A quarter of patients had obstructive lung disease. Fewer than half of patients were intubated or receiving noninvasive ventilation at enrollment.  Among non-intubated patients, the hydrocortisone group had reduced subsequent need for intubation (18% vs 29%).
PMID: 36942789 

Radiographic Resolution
Mittl RL, Schwab RJ, Duchin JS et al. Radiographic resolution of community-acquired pneumonia. Am J Respir Crit Care Med 1994;149:630-5. Prospective follow-up of both inpatients and outpatients with diagnosis of CAP is cited as a guide for when to look for endobronchial lesions in the setting of slowly clearing pneumonia. The study found age and multilobar disease were independent predictors of delayed resolution. Radiographic resolution seen in 51% at 2 weeks, 67% at 4 weeks, and 90% at 12 weeks.
PMID: 8118630 

Ventilator Associated Pneumonia
Diagnosis
Canadian Critical Care Trials Group. A randomized trial of diagnostic techniques for ventilator-associated pneumonia. N Engl J Med. 2006; 355:2619-30. Randomized trial (N= 740) found the use of bronchoalveolar-lavage with quantitative culture vs. routine culture of endotracheal-aspiration resulted in similar clinical outcomes and antibiotic use when used for the diagnosis of ventilator-associated pneumonia. The exclusion of immunocompromised patients and those infected or colonized with MRSA or Pseudomonas, the format for empiric antibiotic use, and the criterion for a positive BAL culture are concerns raised about the applicability of the findings.
PMID: 17182987
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Treatment
Kalil A, Metersky M, Klompas M, et al. Executive summary: management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016; 63:575-82. This revision of the 2004 guidelines eliminates the designation of healthcare-associated pneumonia and is noteworthy for recommending a 7-day course of therapy for uncomplicated cases regardless of the presence of MRSA and pseudomonas. It also recommends each hospital generate its own antibiogram and addresses the use of biomarkers, such as procalcitonin, to guide therapy.
PMID: 27521441
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Chastre J, Wolff M, Fagon J et al. Comparison of 8 vs. 15 days of antibiotic therapy for ventilator-associated pneumonia in adults. JAMA 2003;290:2588-98. RCT comparing 8 vs. 15 days of antibiotic in 401 immunocompetent patients with VAP (diagnosed by bronchoscopic quantitative cultures) found no difference in pulmonary infection recurrence, 28-day mortality, ventilator free-days, organ failure-free days, and length of ICU stay between groups. The 8-day group had a higher recurrence of pulmonary infections due to non-lactose fermenting gram negative rods, including Pseudomonas aeruginosa (41% vs. 25%), although the 2016 IDSA/ATS guidelines recommend limiting treatment to 7 days.
PMID: 14625336
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Fungal Pneumonia
Hage CA, Carmona EM, Epelbaum O, et al. Microbiological laboratory testing in the diagnosis of fungal infections in pulmonary and critical care practice. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2019; 200:535-550. Noteworthy addition includes an overview of using PCR in the diagnosis of invasive aspergillus infections.
PMID: 31469325
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Azar MM. A diagnostic approach to fungal pneumonia: an infectious diseases perspective. Chest. 2024;165:559-572. This comprehensive review of fungal pneumonia is especially helpful in outlining an approach to diagnostic testing.
PMID: 37813181

Bronchoscopy
Best of ATS Video Lecture Series: Bronchoscopy.Part of a larger collection of videos curated by ATS. These videos introduce strategies for preparation, examination, and bronchoalveolar lavage.
Weiss SM, Hert RC, Gianola FJ et al. Complications of fiberoptic bronchoscopy in thrombocytopenic patients. Chest 1993;104:1025-8. Established safety of transnasal bronchoscopy for bronchoalveolar lavage in thrombocytopenic patients.
PMID: 8404159
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Herth FJF, Becker HD, Ernst A. Aspirin does not increase bleeding complications after transbronchial biopsy. Chest 2002;122:1461-4. Prospective study compared 285 patients taking ASA within 24 hrs of TBB to 932 non-ASA users and found no difference in the risk of minor, moderate, or major bleeding.
PMID: 12377879
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***See also Lung Cancer Staging

Interventional Bronchoscopy
The following 3 articles serve as an introduction for budding interventionalists and as a resource for non-interventionalists considering a referral.

Katsis JM, Rickman OB, Maldonado F, et al. Bronchoscopic biopsy of peripheral pulmonary lesions in 2020: a review of existing technologies. J Thorac Dis. 2020;12:3253-3262. A succinct overview of the available advanced bronchoscopic techniques (not including robotic bronchoscopy) to sample peripheral pulmonary lesions.
PMID: 32642248
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Diddams MJ, Lee HJ. Robotic Bronchoscopy: Review of Three Systems. Life (Basel). 2023;13(2):354. This review compares the three available robotic bronchoscopy systems and reviews the advantages and limitations of robotic bronchoscopy as compared to other biopsy methods.
PMID: 36836710 
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Mahmood K, Frazer-Green L, Gonzalez AV, et al. Management of central airway obstruction: an American College of Chest Physicians Clinical Practice Guideline. Chest. 2025;167:283-295. After review of over 9,000 abstracts and 150 full text articles, 31 studies were included in the creation of these clinical practice guidelines. Although the authors note low quality of evidence, they offer a review of options and guidance for selection of therapeutic interventions after diagnosis of central airway obstruction.
PMID: 39029785 

Endotracheal intubation:
Mosier JM, Sakles JC, Law JA, et al. Tracheal intubation in the critically ill. where we came from and where we should go. Am J Respir Crit Care Med. 2020; 201:775-788. This review summarizes the relevant evidence and guideline recommendations, but the practical pearls are especially valuable.
PMID: 31895986 

Casey JD, Janz DR, Russell DW et al. Bag-mask ventilation during tracheal intubation of critically ill adults. N Engl J Med. 2019; 380: 811-821. This pragmatic, multicenter randomized clinical assigned 401 patients undergoing intubation to receive ventilation with a bag-mask device or no-ventilation between induction and laryngoscopy. Bag-mask ventilation increased the median lowest oxygen saturation (from 93% to 96%) and reduced rates of severe hypoxemia (from 22.8% to 10.9%, RR 0.48 CI 0.3-0.77) without an increase in aspiration. Most patients in the no-ventilation group received supplemental oxygen via non-rebreather or nasal cannula. 
PMID: 30779528 

Gibbs KW, Semler MW, Driver BE, et al. Noninvasive ventilation for preoxygenation during emergency intubation. N Engl J Med. 2024;390:2165-2177. The PREOXI study enrolled 1301 patients across 24 centers in the United States and randomized them to non-invasive ventilation or oxygen mask for preoxygenation prior to tracheal intubation. The primary outcome was hypoxia during intubation (SpO2 less than 85% from induction of anesthesia to two minutes after intubation). The primary outcome occurred in ~9% of patients in the non-invasive ventilation group and ~18% in the oxygen mask group (difference, −9.4 percentage points; 95% confidence interval [CI], −13.2 to −5.6; P<0.001). Incidence of aspiration and cardiac arrest were similar between the two groups.
PMID: 38869091 

Prekker ME, Driver BE, Trent SA et al. Video versus direct laryngoscopy for tracheal intubation of critically ill adults.  N Engl J Med 2023; 389:418-29. This pragmatic, multicenter, randomized trial in 17 emergency departments and ICUs randomly assigned 1417 critically ill adults undergoing intubation to the video-laryngoscope group or the direct-laryngoscope group. Use of the video-laryngoscope resulted in a higher incidence of successful intubation on the first attempt (85.1% vs 70.8% in the direct-laryngoscope group). There were no differences in rates of complications.
PMID: 37326325

Casey JD, Seitz KP, Driver BE, et al. Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults. N Engl J Med.2025; Dec 9:10.1056/NEJMoa2511420. Pragmatic multicenter randomized parallel-group trial examining ketamine (1173 patients) vs etomidate (1186 patients) for RSI in critically ill patients. Between the two groups there was no significant difference in 28 day mortality.  However, cardiovascular collapse (defined as systolic blood pressure < 65 mm Hg; receipt of new or increased vasopressors; or cardiac arrest within 2 minutes of intubation), surprisingly occurred more often with ketamine than etomidate (22.1% vs, 17.0%; 95% CI, 1.9 to 8.3).

PMID: 41369227 
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Percutaneous tracheostomies
Ghattas C, Alsunaid S, Pickering EM, et al. State of the art: percutaneous tracheostomy in the intensive care unit. J Thorac Dis. 2021;13:5261-76. Provides a comprehensive overview including pre-procedural preparation, procedural technique, and post-tracheostomy management.
PMID: 34527365
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Central Lines
Parienti JJ, Mongardon N, Mégarbane B, et al. Intravascular complications of central venous catheterization by insertion site. N Engl J Med. 2015; 373:1220-9. This study randomized 3027 patients to internal jugular, subclavian, or femoral venous sites in a 1:1:1, or 1:1 fashion depending on the number of sites available. Subclavian lines had a lower rate of infectious complications and a higher rate of mechanical complications than either femoral or internal jugular sites. Concerns include the inconsistent use of ultrasound for subclavian lines, and the potential bias of determining if 2 vs. 3 sites were “suitable”. Interestingly, femoral and internal jugular lines had similar rates of infectious complications.
PMID: 26398070
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Van Baarle FLF, van de Weerdt EK, van der Velden WJFM et al. Platelet transfusion before CVC placement in patients with thrombocytopenia. N Engl J Med. 2023; 388:1956-65. This multicenter RCT assigned 338 patients in ICUs or hematology wards with severe thrombocytopenia (10,000 to 50,000) to receive one unit of prophylactic platelets or no platelet transfusion before central line placement. Platelet transfusion resulted in lower rates of catheter-related bleeding of grade 2 to 4 (bleeding requiring at least prolonged manual compression>20 minutes, reduced from 11.9% to 4.8%) and grade 3 or 4 (bleeding resulting in operative intervention or red-cell transfusion, reduced from 4.9% to 2.1%) at 24 hours.
PMID: 37224197 

Thoracentesis
Swiderek J, Morcos S, Donthireddy V, et al. Prospective study to determine the volume of pleural fluid required to diagnose malignancy. Chest 2010; 137:68-73. Prospective single center study of 103 patients with known or suspected malignant effusion found aliquots of 60 mL or >150 mL had significantly higher sensitivity and negative predictive value than aliquots of 10 mL, suggesting larger volumes are of diagnostic benefit. This is in contrast to earlier retrospective and smaller prospective studies suggesting diagnosis was independent of volume (See Chest 2002;122:1913-7, Chest 2009; 135:999-1001)
PMID: 19741064
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Lentz RJ, Lerner AD, Pannu JK, et al. Routine monitoring with pleural manometry during therapeutic large-volume thoracentesis to prevent pleural-pressure-related complications: a multicentre, single-blind randomised controlled trial. Lancet Respir Med. 2019; 7:447-455. This study randomized 124 patients with free-flowing effusions with estimated volume > 500 ml (63% with malignant effusion) to thoracentesis drainage based on symptoms alone vs. symptoms plus pleural manometry. There was no significant difference in chest discomfort, volume of fluid drained, proportion of patients with complete lung expansion, or clinically significant complications. Of note, the mean volume of fluid drained was 1,100 ml (SD 500 ml) and patients with known re-expandable lung, such as those with a large hepatic hydrothorax, were excluded.
PMID: 30772283 

Williams JG, Lerner AD. Managing complications of pleural procedures. J Thorac Dis. 2021; 13:5242-50.  This article reviews the relevant anatomy followed by diagnosis and management of complications including pneumothorax, bleeding, re-expansion pulmonary edema, pain, and infection.
PMID:34527363
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***For additional information, see Pleural disease section 

Procedure Videos
The New England Journal of Medicine has developed and published a series of Videos in Clinical Medicine, intended to facilitate teaching and learning of common procedural techniques. Videos and accompanying text provide an excellent review of indications, pertinent techniques, and potential complications. Links to those procedures most applicable to critical care medicine are provided below. Access requires subscription.

1. Arterial line insertion
2. Arterial line insertion: ultrasound guided
3. Bag-mask ventilation
4. Central venous catheter insertion: internal jugular
5. Central venous catheter insertion: femoral
6. Central venous catheter insertion: subclavian
7. Central venous catheter insertion: ultrasound guided subclavian
8. Chest tube insertion
9. Chest tube insertion: ultrasound guided
10. Cricothyroidotomy
11. Intubation: fiberoptic
12. Intubation: standard orotracheal
13. Lumbar puncture
14. Paracentesis
15. Percutaneous tracheostomy
16. Prone positioning with elevated BMI
17. Thoracentesis

Guideline
Creager MA, Bhatt DL, Beckman JA, et al. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN guideline for the evaluation and management of acute pulmonary embolism in adults. Circulation. 2026;153(12):e977–e1051. This is the first dedicated AHA/ACC clinical practice guideline for acute PE, consolidating recommendations from 10 specialty societies. It introduces a new five-category severity classification system, replacing the traditional low/submassive/massive schema, with a goal of better linking risk stratification to therapeutic decision-making. Key actionable recommendations include: Class I support for DOACs over VKAs for eligible patients, LMWH preferred over UFH for initial therapy, extended anticoagulation beyond 3–6 months for unprovoked PE or persistent risk factors, PERT activation where available, and structured follow-up within one week of discharge and again at 3 months. Notably, the guideline formally incorporates post-PE syndrome, with symptom and functional assessment at every visit for at least one year to screen for CTEPD, and explicitly addresses psychological sequelae as part of follow-up care.
PMID: 41712677
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Algorithms for Diagnosis of Suspected Pulmonary Embolism
Righini M, Van Es J, Den Exter PL, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA 2014; 311:1117-24. This study explored the reliability of using a higher normal cut-off d-dimer level for patients > 50 years old with low clinical probability of PE (age-adjusted d-dimer level = patient age x 10). Among 337 patients with d-dimer levels above the standard cut-off of 500 mcg/L but below their age-adjusted cut-off in whom treatment was withheld, 0.3% had a DVT or PE during the ensuing 3 months. The age-adjusted cut point increased the proportion of negative d-dimer studies by 12%. The study utilized 6 different assays and it is unclear whether the variability in the proportion of patients with negative results was due to assay characteristics vs. differences in patient characteristics.
PMID: 24643601
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van der Hulle T,  Cheung WY, Kooij S,  et al. Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study. Lancet. 2017; 390(10091):289-297. Prospective, multicenter cohort study including 3,616 consecutive patients with suspected pulmonary embolism combined use of the YEARS criteria (clinical signs of DVT, hemoptysis, and whether PE was the most likely diagnosis) with D-dimer. PE was excluded if the YEARS criteria was 0 and D-dimer <1000 or the YEARS criteria was 1 and D-dimer <500. Of the 2946 patients ruled out for PE, only 18 (0.61%) were diagnosed with DVT/PE by 3 months follow up. This approach resulted in 14% fewer CTPA studies than if screening with the Well’s criteria and D-dimer cutoff of 500 had been used.
PMID: 28549662 

Kearon C, de Wit K, Parpia S, et al. Diagnosis of pulmonary embolism with d-dimer adjusted to clinical probability. N Engl J Med. 2019; 381:2125-2134. Prospective study of 2017 patients. In patients with a low clinical pre-test probability (Wells score of 0 to 4) and a d-dimer level less than 1000 ng/ml, none had venous thromboembolism at 3 month follow-up. Use of this algorithm would reduce the number of chest-imaging studies performed on patients with suspected pulmonary embolism by 18%.
PMID: 31774957
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Pulmonary embolism in pregnancy
Leung AN, Bull TM, Jaeschke R, et al. An official American Thoracic Society/Society of Thoracic Radiology clinical practice guideline: evaluation of suspected pulmonary embolism in pregnancy. Am J Respir Crit Care Med 2011; 184:1200-8. This clinical practice guideline is noteworthy for recommending V/Q scan as the initial step in diagnosis in pregnant women suspected of having PE who have no leg symptoms and a normal CXR. This recommendation is based primarily on the future malignancy risk posed to young mothers.
PMID: 22086989 

Van der Pol L, Tromeur C, Bistervels I, et al.  Pregnancy-adapted YEARS algorithm for diagnosis for suspected pulmonary embolism. N Engl J Med. 2019; 380:1139-1149. The study used a d-dimer cut-off adjusted to whether the patient had 0 vs. 1 of the 3 YEARS criteria, as well as ultrasound as the first-line test rather than CT if DVT symptoms were present. The algorithm safely ruled out PE across all three trimesters of pregnancy and, assuming all patients with suspected PE would otherwise have undergone CT, reduced the number of scans by 39%. CT angiogram was avoided in 65% of 1st trimester patients and 32% in the 3rd trimester.
PMID: 30893534
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Diagnostic Imaging
PIOPED Investigators. Value of the ventilation/perfusion scans in pulmonary embolism: results of the PIOPED. JAMA 1990;263:2753-9. This ubiquitously-cited study found that VQ scans are useful when they are high probability and normal, but that most of the time PE can't be ruled in or out by VQ scan. Includes a useful table comparing clinical suspicion and the VQ scan result relative to the pulmonary arteriogram result.
PMID: 2332918 

Anderson DR, Kahn SR, Rodger MA, et al. Computed tomographic pulmonary angiography vs. ventilation-perfusion lung scanning in patients with suspected pulmonary embolism. JAMA 2007; 298:2743-53. This RCT found that of 531 patients with a positive d-dimer but negative CT, only 1.3% had a positive lower extremity ultrasound. Of note, patients randomized to CT were more likely to be diagnosed with PE than with VQ scanning (19.2% vs. 14.2%), but there was no significant difference in the diagnosis of venous thromboembolism in the subsequent 3-month follow-up period. This raises the possibility of false-positive results or identification of clinically insignificant clot with CT.
PMID: 18165667
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Acute Management of Submassive/Intermediate Risk PE
Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002; 347:1143-50. This randomized, double blind study is cited by both advocates and skeptics of fibrinolytic therapy in submassive PE. The study found lytics did not improve mortality. Patients randomized to lytics were significantly less likely than the placebo group to require escalation of therapy, which primarily entailed administration of lytics. The indication for rescue therapy was worsening respiratory symptoms, short of intubation, two-thirds of the time.
PMID: 12374874
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Meyer G, Vicaut E, Danays T, et al. PEITHO investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014; 370:1402-11. Multicenter trial randomized 1006 hemodynamically stable patients with elevated troponin levels and evidence of right-heart strain by echo or chest CT to unfractionated heparin plus either tenecteplase or placebo. Subsequent hemodynamic instability was more common in the placebo group (5.0 vs 1.6%), while stroke (2.4 vs 0.2%) as well as major extracranial bleeding (6.3 vs. 1.2%) were more likely in the lytic group, and all-cause mortality (less than 2%) did not differ between groups.
PMID: 24716681
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Jaber WA, Gonsalves CF, Stortecky S, et al. Large-bore mechanical thrombectomy versus catheter-directed thrombolysis in the management of intermediate-risk pulmonary embolism: primary results of the PEERLESS randomized controlled trial. Circulation 2024; 151:260-273. 
This prospective RCT of 550 patients with intermediate-risk PE compared the impact of large-bore mechanical thrombectomy vs. catheter-directed thrombolysis.  There was no anticoagulation-only or systemic thrombolytic arm. Lower rates of clinical deterioration and escalation to bailout (1.8% in thrombectomy group versus 5.4% in catheter-directed thrombolysis group) and lower ICU utilization (41% in thrombectomy group versus 98.6% in catheter-directed thrombolysis group) drove a win ratio of 5.01 favoring large-bore mechanical thrombectomy. There were no significant differences in 30-day mortality (0.4 vs. 0.8%), intracranial hemorrhage, or major bleeding. 
PMID: 39470698 
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Lookstein RA, Rana K, Giri J, et al. Randomized controlled trial of mechanical thrombectomy with anticoagulation versus anticoagulation alone for acute intermediate-high risk pulmonary embolism: primary outcomes from the STORM-PE trial. Circulation. 2026;153(1):21-34. RCT of 100 patients with acute normotensive intermediate-high risk PE (RV/LV ratio >1 plus elevated cardiac biomarkers) randomized to mechanical thrombectomy plus anticoagulation vs. anticoagulation alone. The thrombectomy group had a greater reduction in RV/LV ratio and earlier normalization of vital signs at 48 hours, but there was no significant difference in ICU length of stay, hospital stay, or major adverse events at 7 days. There were 2 PE-related deaths in the thrombectomy group. Median time between PE diagnosis and start of procedure was 19 hours. 
PMID: 41183181 
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Chaudhury P, Gadre SK, Schneider E, et al. Impact of multidisciplinary pulmonary embolism response team availability on management and outcomes. Am J Cardiol 2019; 124:1465-69. This single-center retrospective study of outcomes before and after institution of pulmoanry embolism response team (PERT) is cited by advocates for use of response teams. Among 769 consecutive inpatients with PE, PERT-era patients had significantly lower rates of major bleeding, shorter time to therapeutic anticoagulation, decreased use of IVC filters, and decrease in 30 day/inpatient all-cause mortality. Of note, the PERT team was activated in only 15% of patients with intermediate or high-risk PE.
PMID: 31495443 

Anticoagulation
Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: Second update of the CHEST guideline and expert panel report. Chest. 2021;160:e545-e608. This update adds a few new recommendations and strengthens the level of others compared to the 2016 edition.
PMID: 34352279 

Piazza G, Bikdeli B, Pandey AK, et al. Apixaban for extended treatment of provoked venous thromboembolism (HI-PRO). N Engl J Med. 2025 ;393(12):1166-1176. Single-center double-blind placebo-controlled RCT of 600 patients who had completed ≥3 months of anticoagulation for a first provoked VTE due to a major transient risk factor (surgery, trauma, acute illness, or immobility) but retained an enduring risk factor, broadly defined to include atherosclerotic cardiovascular disease, obesity, diabetes, hypertension, and chronic kidney disease, randomized to apixaban 2.5 mg BID vs. placebo for 12 months. Recurrent VTE occurred in 1.3% of the apixaban group vs. 10% of the placebo group, with one major bleeding event in each arm. Concerns raised about the study include the unexpectedly high recurrence rate in the placebo group, single-center design, and the ubiquity of qualifying "enduring risk factors". 
PMID: 40888734 

Couturaud F, Sanchez O, Presles E, et al. Extended treatment of venous thromboembolism with reduced-dose versus full-dose oral anticoagulants in patients at high risk of recurrence: a non-inferiority multicentre, randomised, open-label, blinded endpoint trial (RENOVe). Lancet. 2025. doi:10.1016/S0140-6736(24)02842-3. Multicenter open-label RCT of 2,768 patients with acute PE and a clear indication for extended anticoagulation were randomised to reduced-dose vs. full-dose rivaroxaban or apixaban. Recurrent VTE at 5 years was uncommon in both groups, occurring in 2.2% in the reduced-dose group vs.1.8% with full dose. The 0.4% difference failed to meet the pre-specified non-inferiority margin. However, clinically relevant bleeding was significantly lower with reduced-dose therapy (9.9% vs. 15.2%). 
PMID: 40023651 
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DVT Prophylaxis
Arabi YM, Al-Hameed F, Burns KEA, et al. Adjunctive intermittent pneumatic compression for venous thromboprophylaxis. N Engl J Med. 2019; 380:1305-1315. Randomized trial of 2003 patients who were assigned within 48 hours of ICU admission to intermittent pneumatic compression for at least 18 hours per day in addition to unfractionated or low molecular weight heparin vs pharmacologic thromboprophylaxis alone. Adjunctive intermittent pneumatic compression did not result in significantly lower rate of proximal lower-limb DVT than pharmacologic thromboprophylaxis alone.
PMID: 30779530
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Prevention with vena caval filters 
Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA 2015; 313:1627-1635. This randomized, open-label, blinded trial compared anticoagulation with and without IVC filter placement in 399 patients admitted to the hospital with acute symptomatic pulmonary embolism with residual lower limb venous thrombosis plus at least one risk factor for severity (roughly ⅔ had evidence of right ventricular dysfunction).  Hemodynamic data were not included. Filter removal was attempted at 3 months and patients were followed for 6 months. The authors found no difference in the rate of recurrent thrombosis at 3 or 6 months.
PMID: 25919526
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General reviews
The following ATS/ERS statements are widely recognized as the standard by which clinicians and researchers perform and interpret pulmonary functions tests:
Miller MR, Crapo R, Hankinson J, et al. ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005; 26:153-61.
PMID: 15994402
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Graham B, Steenbruggen I, Miller M, et al. Standardization of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med. 2019; 200:e70-e88.
PMID: 31613151
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Wanger J, Clausen JL, Coates A, et al. ATS/ERS Task Force. Standardization of the measurement of lung volumes. Eur Respir J. 2005; 26:511-22.
PMID: 16135736
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Graham BL, Brusasco V, Burgos F,  et al. 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017; 49(1).
PMID: 28049168
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Coates AL, Wanger J, Cockcroft DW, et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J  2017; 49:1601526. New recommendations noteworthy for basing result on the delivered dose of methacholine during the course of the test rather than upon a methacholine concentration. Also includes practical information such as how far in advance various bronchodilators need to be discontinued.
PMID: 28461290
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Stanojevic S, Kaminsky DA, Miller MR, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J. 2022; 60:2101499. Provides a comprehensive review of reference equations, types of ventilatory defects, PFT and DLCO interpretation. New recommendations include use of Z-scores to classify severity of impairment and a new criterion for bronchodilator response.
PMID: 34949706 

Iyer VN, Schroeder DR, Parker KO, et al. The nonspecific pulmonary function test: longitudinal follow-up and outcomes. Chest, 2011; 139:878-88. This study of nearly 1,300 patients sheds light on the commonly encountered combination of reduced FVC but normal FEV/FVC and TLC. Roughly 2/3 of patients maintained this pattern during a median of 3 years of follow-up while the remaining 1/3 evolved into restrictive and obstructive patterns in equal numbers.
PMID: 20724741 

Race Adjustments in PFTs
Bhakta NR, Bime C, Kaminsky DA, et al. Race and ethnicity in pulmonary function test interpretation: An Official American Thoracic Society Statement. Am J Respir Crit Care Med. 2023; 207:978-995. This ATS statement is noteworthy for supporting the adoption of a race-neutral approach to PFT interpretation by reporting and interpreting results using average reference equations. The statement provides historical context, summarizes the multiple limitations and negative consequences of race-based interpretation, and cautions against the over reliance on PFTs to make clinical decisions on an individual basis.
PMID: 36973004
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Diao JA, Rao N, Khazanchi R, et al. Implications of race adjustment in lung function equations. N Engl J Med. 2024;390(22):2083-2097. Retrospective longitudinal analysis of spirometry data from 370,000 patients ages 6–79 examining downstream clinical and administrative consequences of reclassifying from race-specific to race-neutral GLI-Global reference equations. Switching equations is projected to increase non-obstructive ventilatory impairment classification among Black patients by 141% and decrease it by 69% among White patients, and was estimated to increase Social Security disability payments to Black veterans by over $1 billion while reducing payments to White veterans by $500 million. Critically, the change in reference equation did not improve accuracy for predicting symptoms, healthcare utilization, or mortality. 
PMID: 38767252 
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Pulse oximetry
Sjoding MW, Dickson RP, Iwashyna TJ, et al. Racial bias in pulse oximetry measurement. N Engl J Med. 2020; 383:2477-2478. This analysis of 2 cohorts found patients self-identified as Black were significantly more likely than self-identified white patients to have an arterial blood gas saturation  < 88% despite a concurrent SpO2 of 92 – 96% by pulse oximetry (11.7% vs 3.7% and 17% vs. 6.2%, respectively, in the 2 cohorts).
PMID 33326721
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Exercise Testing
ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003; 167:211-77. Somewhere between a textbook and a clinical review, this article provides more details on CPET than the above Weisman article.
PMID: 12524257 

Holland AE, Spruit MA, Troosters T, et al. An official European Respiratory Society/American Thoracic Society technical standard field walking tests in chronic respiratory disease. Eur Respir J. 2014; 44:1428-46. This document standardizes procedures for performing the 6-minute walk test as well as incremental and endurance shuttle walks. The potential for differences in methodology to produce large changes in results is emphasized.
PMID: 25359355
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Singh SJ, Puhan MA, Andrianopoulos V, et al. An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease. Eur Respir J. 2014; 44:1447-78.  This review summarizes the literature that is the basis for the technical standard above by Holland et al.
PMID: 25359356
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Classification and Guidelines
Kovacs G, Bartolome S, Denton CP, et al. Definition, classification and diagnosis of pulmonary hypertension. Eur Respir J. 2024;64(4):2401324. The 7th World Symposium on Pulmonary Hypertension retains the previously established definitions of pulmonary hypertension and focuses on a diagnostic approach which reminds readers of the utility and predictive value of non-invasive tests such as a chest x-ray and EKG, and emphasizes early referral to a specialty pulmonary hypertension center for patients with signs of severe disease.
PMID: 39209475 
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Chin KM, Gaine SP, Gerges C, et al. Treatment algorithm for pulmonary arterial hypertension. Eur Respir J. 2024;64:2401325. These updated treatment guidelines provide an evidence-based approach to treating PAH that emphasizes risk stratification and places and use of combination therapy with medications which act on different signaling pathways. The review also discusses treatment of PAH based on etiology (CTD, Schistosomiasis, PVOD, etc).
PMID: 39209476 
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Diagnosis
Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease . Am J Respir Crit Care Med 2003; 167:735-40. The cardiology literature indicates that echocardiography-derived estimates of pulmonary artery pressures are accurate. This study found 52% of echo estimates were inaccurate (off by > 10 mmHg) in 166 lung transplant candidates and the difference was > 20 mmHg in 28%. In patients without hypertension, echo was more likely to overestimate pressures while in patients with pulmonary hypertension it was as likely to over- as underestimate pressures. Accuracy and ability to obtain an estimate varied with the underlying disease. Of note this study was published in 2003 but the data remains informative to current practice.
PMID: 12480614 

Fisher MR, Forfia PR, Chamera E, et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med 2009; 179:615-21. This prospective study of 65 patients undergoing right-heart catheterization for the diagnosis or management of pulmonary hypertension extends the findings of Arcasoy et al. above to patients without end-stage lung disease. Echo results over- or underestimated pulmonary artery pressure by > 10 mm Hg 52% of the time. The majority of patients had pulmonary arterial hypertension (WHO Group 1).
PMID: 19164700
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Treatment of pulmonary arterial hypertension
Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. New Engl J Med 2015: 373:834-844. This randomized trial is novel for focusing on the role of upfront combination therapy in symptomatic treatment-naive patients.  Patients received ambrisentan and tadalafil alone or in combination. The primary outcome (a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response) occurred in 18% of the combination group vs 31% in the pooled monotherapy group (hazard ratio 0.50, p < .001). This was driven by a decrease in hospitalization. There was no mortality difference or change in WHO functional class.
PMID: 26308684
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Waxman A, Restrepo-Jaramillo R, Thenappan T,  et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. New Engl J Med. 2021; 348:325-34. RCT of 326 patients with pulmonary hypertension and ILD found inhalation of treprostinil qid resulted in a 31-meter difference in the 6 minute walk (the primary study outcome), improving by about 20 meters in the intervention group vs. 10 meter decline in controls (minimally important clinical difference is 30 meters). The accompanying editorial notes short trial duration (16 weeks), lack of improved quality of life, missing outcome data, and need to assess hospitalization and mortality as reasons for further trials.
PMID: 33440084 

Humbert M, McLaughlin VV, Badesch DB, et al. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. N Engl J Med. 2025;392(20):1987-2000. Patients with group I PAH and WHO functional class III or IV on maximal tolerated PH therapy and high 1 year risk of death were randomized to either Sotatercept vs placebo. The primary endpoint was a composite risk of death, lung transplant or hospitalization for PH. The trial was stopped at the prespecified interim analysis as the Sotatercept group had a significantly lower incidence of the primary outcome (HR 0.24, 95% CI 0.13-0.43, p<0.001). At baseline, roughly 60% of these patients were on prostacyclin infusion therapy, and 75% were on three PH specific medications prior to starting sotatercept.
PMID: 40167274

McLaughlin VV, Hoeper MM, Badesch DB, et al. Sotatercept for Pulmonary Arterial Hypertension within the First Year after Diagnosis. N Engl J Med. 2025;393(16):1599-1611. RCT of 320 patients diagnosed with PAH within the past year and WHO functional class II or III on double or triple therapy found that compared to placebo, sotatercept significantly lowered the risk of the primary outcome, which was a composite of death, hospitalization for PH, atrial septostomy, lung transplant, or worsening of exercise testing (HR 0.24, 95% CI 0.14-0.41, P<0.001). The reduced risk mainly came from preserved exercise testing and decreased hospitalization in the intervention arm. 
PMID: 41025556 

Kim NH, D'Armini AM, Delcroix M, et al. Chronic thromboembolic pulmonary disease. Eur Respir J. 2024;64(4):2401294.  This review focuses on chronic thromboembolic pulmonary hypertension and emphasizes the use of a multidisciplinary team to determine the use of pulmonary endarterectomy, balloon pulmonary angioplasty, and targeted medical therapy.
PMID: 39209473
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Rochester CL, Alison JA, Carlin B, et al. Pulmonary rehabilitation for adults with chronic respiratory disease: An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2023;208:e7-e26. These updated guidelines are meant to highlight the known benefits of pulmonary rehabilitation (PR) and its role in evidenced based health care. The guidelines make several strong recommendations, including PR for adults with stable COPD and after hospitalization for COPD exacerbation, PR for adults with ILD, and for offering patients the choice between center-based PR vs telerehabilitation.
PMID: 37581410 
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McCarthy B, Casey D, Devane D, et al. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015; 2:CD003793. This review is comprised of many smaller studies (65 RCTs, 3,822 patients) and found rehab participation yielded clinically significant improvements in quality of life, symptoms, and exercise capacity.
PMID: 25705944
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Holland AE, Mahal A, Hill CJ, et al. Home-based rehabilitation for COPD using minimal resources: a randomized controlled equivalence trial. Thorax  2017; 72:57-65. Pulmonary rehabilitation remains underutilized but a home-based approach has the potential to increase patient enrollment. This RCT of 166 patients, as well as other similar trials, found similar gains between health center-based and home-based groups. Unfortunately, neither group has sustained gains when measured at 12 months.
PMID: 27672116
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Zanaboni P, Dinesen B, Hoaas H, et al. Long-term telerehabilitation or unsupervised training at home for patients with chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med. 2023;207:865-875. 120 patients were randomized to telerehab, unsupervised training, or standard of care for a 2 year period. There was a lower incidence of hospitalizations and emergency department presentations in both the telerehab and unsupervised training group. Additionally, these groups had better health status and improved exercise capacity.
PMID: 36480957
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Stefan MS, Pekow PS, Priya A, et al. Association between initiation of pulmonary rehabilitation and rehospitalizations in patients hospitalized with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2021; 204:1015-1023. This study used a large Medicare database from 2014 and found that patients completing pulmonary rehabilitation within 90 days of COPD admission (1.5% of all patients) had a mean cumulative number of hospitalizations at 1 year of 0.95 compared to 1.15 for matched controls that did not complete rehab.
PMID: 34283694 

***See also Pulmonary Function Tests section on Exercise Tests

Guidelines
Devlin JW, Skrobik Y, Gélinas C et al. Clinical practice guidelines for the prevention and management of pain/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med 2018; 46:e825-e873
PMID: 30113379 

Lewis K, Balas MC, Stollings JL, et al. A Focused Update to the Clinical Practice Guidelines for the Prevention and Management of Pain, Anxiety, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2025 Mar 1;53(3):e711-e727. Highlights of this update to the 2018 guidelines include conditional recommendation for dexmedetomidine over propofol if light sedation or minimizing delirium is a priority. See below for prominent individual trials comparing these medications. 
PMID: 39982143 

Comparison Between Administration Methods
Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471-7. Single-center RCT of 128 patients found daily interruption of sedation in a MICU population resulted in shorter duration of mechanical ventilation and ICU stay, less total dose of sedation, and less use of diagnostic tests to work-up impaired mental status compared to the control group. No increase in short term adverse outcomes in the intervention group identified but patients were not evaluated for subtle or long-term adverse outcomes.
PMID: 10816184
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Mehta S, Burry L, Cook D, et al. SLEAP Investigators. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA 2012; 308:1985-92. Multicenter trial randomized 430 critically ill, mechanically ventilated adults to protocolized sedation vs protocolized sedation plus daily sedation interruption. There was no difference in time to successful extubation, length of ICU stay, length of hospital stay, or incidence of delirium. The daily sedation interruption group received higher doses of sedatives and opiates, and required greater nursing care based on a visual analog scale.
PMID: 23180503 

Comparison Between Agents
Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301:489-99. This study is noteworthy for finding use of dexmedetomidine reduced the prevalence of delirium (54% vs 77% with midazolam) and for providing further evidence of the safety of using dexmedetomidine at higher doses and longer duration. There was no difference in the primary outcome, time spent at target level of sedation. Duration of mechanical ventilation was shorter with dexmedetomidine but length of ICU stay was similar.
PMID: 19188334
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Walsh TS, Parker RA, Aitken LM, et al.. Dexmedetomidine- or clonidine-based sedation compared with propofol in critically ill patients: the A2B randomized clinical trial. JAMA. 2025;334(1):32–45. Pragmatic open-label multicenter RCT of 1,404 mechanically ventilated adults randomised 1:1:1 to dexmedetomidine-, clonidine-, or propofol-based sedation within 48 hours of intubation. Median time to successful extubation was 136, 146, and 162 hours respectively, differences that were not statistically significant. The 180-day mortality did not differ across groups (approximately 29–30%). Rates of agitation and clinically significant bradycardia were higher in both α2-agonist arms. Patients in the dexmedetomidine arm also received propofol to reach target sedation on 77% of the days. 
PMID: 40388916 

Hughes CG, Mailloux PT, Devlin JW, et al. Dexmedetomidine or propofol for sedation in mechanically ventilated adults with sepsis.  N Engl J Med. 2021; 384:1424-1436. Multicenter RCT of 422 patients found no difference in delirium, ventilator-free days, survival, or cognitive function at 6 months with use of the 2 agents.
PMID: 33528922
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Shehabi Y, Howe BD, Bellomo R, et al. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med. 2019; 380:2506-17. RCT of 4000 ICU patients undergoing ventilation for less than 12 hours compared dexmedetomidine as sole or primary agent vs usual care with target RASS score of -2 to +1. There was no difference in all cause mortality at 90 days but bradycardia and hypotension were more common in the dexmedetomidine group. Nearly ⅔ of the dexmedetomidine group and 80% of the usual care group received propofol.
PMID: 31112380
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Delirium in the ICU
Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753-62. This study confirmed a high prevalence of ICU delirium (over 80% as identified by I-CAM) and was the first to show delirium is an independent risk factor for mortality. Specifically, ICU delirium was associated with 3-fold higher 6-month mortality. After adjusting for co-morbidities, illness severity, coma, and use of sedatives and analgesics, delirium was also associated with prolonged ICU and hospital stays, as well as cognitive impairment at hospital discharge.
PMID: 15082703
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Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369:1306-16. A prospective two center study of patients with respiratory failure or shock found that at 3 months 40% of patients had deficits in cognition similar to those seen in moderate traumatic brain injury, and 26% had deficits similar to mild Alzheimer’s disease. A similar pattern was evident at 12 months. Duration of delirium was associated with worse cognitive and executive function at both time points. Type of sedative and analgesic medications was not associated with degree of subsequent cognitive deficit.
PMID: 24088092
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Girard TD, Exline MC, Carson SS et al. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018; 379:2506-2516. This study randomized 566 patients with acute respiratory failure or shock and hypoactive (89%) or hyperactive delirium (11%) to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The primary endpoint was the number of days alive without delirium or coma during the 14-day intervention period. Compared to placebo, neither haloperidol or ziprasidone increased the number of days alive without delirium or coma during the 14-day intervention period. Outcomes did not differ in the smaller subset of patients with agitated delirium.
PMID: 30346242
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Andersen-Ranberg NC, Poulsen LM, Perner A, et al; AID-ICU Trial Group. Haloperidol for the treatment of delirium in ICU patients. N Engl J Med. 2022; 387:2425-2435.This RCT of 1,000 patients found haloperidol had no effect on the primary endpoint of days alive and out of the hospital at 90 days. This study is noteworthy for including a greater proportion of patients with hyperactive delirium (45%) than the previous study by Girard et al. Days alive without mechanical ventilation and days alive without delirium favored the haloperidol group but differences were not statistically significant. There was an unexpected 6.9% absolute lower 90-day mortality in the haloperidol group, but the study authors note that this finding is inconclusive.
PMID: 36286254

Guidelines
Singer M, Deutschman C, Seymour C, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016; 315:801-10. An update of the 2001 definition, Sepsis-3 defines sepsis as “life-threatening organ dysfunction caused by a dysregulated host response to infection”. Sepsis-3 uses the retrospectively validated “qSOFA” score (altered mentation, SBP < 100 mmHg, respiratory rate > 22) to identify patients outside of the ICU for risk of death or prolonged ICU stay. In the ICU they recommend using a SOFA score increase of at least 2 to identify organ dysfunction. They also disavow the much-maligned SIRS criteria as a method for identifying septic patients. Criticism of this update includes over-reliance on qSOFA score, which had not been prospectively validated prior to publication.
PMID: 26903338
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Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2026. Intensive Care Med. 2026 Mar 23. Includes 129 updated and 46 new statements.
PMID: 41870560 

Steroids
Venkatesh B, Finfer S, Cohen J et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018; 378:797-808. From 2013 - 2017, the ADRENAL trial randomized 3,800 patients with septic shock receiving mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day via continuous infusion) or placebo for 7 days or until death or ICU discharge. There was no difference in 90-day mortality (near 28% for both groups). The steroid group spent less time on vasopressors but duration of ICU stay and days free of mechanical ventilation did not differ.
PMID: 29347874
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Annane D, Renault A, Brun-Buisson C et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018; 378:809-818. The APROCCHSS trial initially randomized patients to various combinations of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), and placebo but subsequently compared only hydrocortisone-fludrocortisone to placebo in 1,241 patients after drotrecogin was withdrawn from the market in 2011. The steroid group had lower 90-day mortality (43% vs 49%, p = 0.03) and had fewer days on vasopressors but days of mechanical ventilation did not differ significantly. The role of mineralocorticoid in improving outcomes is unclear. Concerns raised about this trial include long duration of enrollment and high observed mortality in both groups.
PMID: 29490185
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Antibiotics
Kumar A, Roberts D, Wood KE et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006; 34: 1589-1596.  This landmark retrospective cohort study of 2,731 patients helped establish septic shock as a medical emergency.  Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge. Each hour of delay in antimicrobial administration was associated with an average decrease in survival of 7.6%. This study demonstrated the need for timely antibiotics in septic shock, which was later confirmed in multiple other studies.
PMID: 16625125 

Dark P, Hossain A, McAuley DF, et al; ADAPT-Sepsis Collaborators. Biomarker-guided antibiotic duration for hospitalized patients with suspected sepsis: the ADAPT-Sepsis randomized clinical trial. JAMA. 2025;333:682-693. Multicenter RCT of 2700 patients found use of daily procalcitonin levels combined with daily written messages from the research team to guide antibiotic duration reduced antibiotic use by 0.88 days (10.7 vs 9.8 days, 95% CI 0.19–1.58; P=.01). PCT-guided group had 28-day all cause mortality of 20.9% vs 19.4% with usual care (95% CI −2.18 to 5.320. This met the study noninferiority margin of 5.4%.
PMID: 39652885 
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Daneman N, Rishu A, Pinto R, et al. Antibiotic treatment for 7 versus 14 days in patients with bloodstream infections. N Engl J Med. 2025;392:1065-1078. This non-inferiority multicenter trial randomized 3608 bacteremic patients growing Gram-positive, as well as Gram-negative, organisms, to 7 vs 14 days of antibiotic therapy. The primary outcome was all-cause mortality at 90d after diagnosis of bacteremia. Exclusion criteria included severely immunocompromised state, S. aureus bacteremia, and suspected contaminant cultures. At 90 days, ~14% of patients in the 7 day group and 16% in the 14 day group had died, with a difference under the prespecified non-inferiority margin of 4%. Of note, 23% of patients in the 7 day group and 11% of patients in the 14 day group received antibiotics longer than the assigned duration.
PMID: 39565030 

Early resuscitation
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-77. This RCT of 263 patients found benefit from early (in E.D.) aggressive resuscitation (in-hospital mortality of 30% in the goal-directed group compared to 46% in the standard therapy group). The intervention arm was noteworthy for prn use of blood transfusion and/or inotropes to maintain central venous O2 sat >70%. Authors speculate the earlier aggressiveness accounts for better outcomes than previous studies of goal-directed hemodynamic optimization.
PMID: 11794169
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The following large RCTs found that, compared to early goal-directed therapy, management that does not include continuous central venous O2 monitoring, require central venous pressure monitoring, and entailed less frequent blood transfusions and inotrope use nonetheless produced equivalent outcomes, even without the use of protocolized resuscitation.
ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014; 370:1683-93.
PMID: 24635773
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ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014; 371:1496-506.
PMID: 25272316
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Mouncey PR, Osborn TM, Power GS, et al for the ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. New Engl J Med 2015; 372: 1301-1311.
PMID: 25776532
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ANDROMEDA-SHOCK-2 Investigators. Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial. JAMA. 2025; 334(22):1988-1999. International RCT of 1,467 patients demonstrated that resuscitation targeting capillary refill time in the first 6-hours of resuscitation significantly reduced the need for “vital support” (defined as vasopressors, mechanical ventilation, and renal replacement therapy). The capillary refill time arm incorporated systematic use of pulse pressure monitoring, frequent assessment of fluid responsiveness, and use of echocardiography to guide therapy. The accompanying editorial notes the frequent early intensivist involvement in the intervention arm may account for the observed difference.
PMID: 41159835 
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The National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Early restrictive or liberal fluid management for sepsis-induced hypotension. N Engl J Med. 2023; 388: 499-510. An unblinded multicenter superiority trial assigned 1563 patients with sepsis-induced hypotension to a restrictive fluid strategy (prioritizing vasopressors) or a liberal fluid strategy (prioritizing use of IV fluids) for 24 hours. Both groups received 2L of fluid prior to randomization. 2L less fluid was administered in the restrictive fluid group. All-cause mortality before discharge home by day 90 was similar between groups as were adverse events.  The trial was halted early for futility. Of note, 500 patients received vasopressors via peripheral catheters with no significant complications, adding to a growing literature suggesting safety of this practice.
PMID: 36688507
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Meyhoff TS, Hjortrup PB, Wetterslev J, et al; CLASSIC Trial Group. Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med. 2022; 386:2459-2470. There is concern that excessive fluid resuscitation worsens outcomes in septic shock. This RCT of over 1,500 patients found no difference in 90-day mortality or adverse events with use of a restrictive fluid strategy.  Of note, both groups had received 3 liters of fluid on average prior to enrollment and the difference between restrictive and usual care was only 2 liters following enrollment. One concern raised is that the usual care arm was more restrictive than typical practice.
PMID: 35709019 

***For discussion of crystalloid fluid choice in septic shock, refer to Nephrology Critical Care.

Adjunctive Therapy
Albumin for Fluid Resuscitation
Callum J, Skubas NJ, Bathla A, et al. Use of intravenous albumin: A guideline from the international collaboration for transfusion medicine guidelines. Chest. 2024;166(2):321-338. 14 evidence based recommendations for the appropriate use of intravenous albumin in various clinical scenarios including critical care, cardiovascular surgery, renal replacement therapy, and complications of cirrhosis
PMID: 38447639 
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Vasopressors
Russel JA, Walley KR, Singer J, et al. VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87. Large scale randomized blinded study of low dose vasopressin added to norepinephrine versus norepinephrine alone in septic shock. No significant differences in overall mortality or serious adverse events were identified; however, post hoc analysis suggested possible 28 and 90 day mortality benefit in a subset of patients with less severe septic shock.
PMID: 18305265
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DeBacker D, Biston P, Devriendt J, et al. SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362:779-89. Large multicenter RCT of 1679 patients with shock of any etiology, demonstrated equal mortality and significantly fewer arrhythmias with norepinephrine as first line vasopressor. Subgroup of those with cardiogenic shock had higher mortality with dopamine. Concerns raised have included heterogeneity of shock physiologies included, restricted fluid resuscitation protocol, and open label use of norepinephrine after conservative max doses of study drug. However, this study adds valuable evidence to our currently limited understanding of comparative merits of pressors.
PMID: 20200382
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Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017; 377:419-30. Noteworthy for being the basis for recent FDA approval of a new class of vasopressor. ATHOS-3 trial randomized 321 patients with vasodilatory shock receiving > 0.2 μg/kg/min of norepinephrine or comparable dose of another vasopressor to either angiotensin II or placebo. The primary endpoint was increase in mean arterial pressure of 10 mm Hg or attaining MAP of 75 mmHg at 3 hours without increase in baseline pressor. Angiotensin II achieved this endpoint in 69% vs. 23% for placebo (OR 7.95) but had no effect on 28 day mortality.
PMID: 28528561
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***See also Cardiology Critical Care

Hemodynamic Monitoring
Vincent JL, Joosten A, Saugel B. Hemodynamic monitoring and support. Crit Care Med. 2021; 49:1638-1650. This review provides historical and contemporary perspectives on hemodynamic monitoring methods in critically-ill patients, including evidence supporting, or not supporting use.
PMID: 34269718

Muller G, Contou D, Ehrmann S, et al. Deferring Arterial Catheterization in Critically Ill Patients with Shock. N Engl J Med. 2025 Nov 13;393(19):1875-1888. This RCT of 1010 patients recently admitted with shock found no difference in mortality in patients randomized to arterial catheter placement vs. use of a brachial cuff (36.9% vs. 34.3%, 95% confidence interval, -8.9 to 2.5). After allowing for crossover, only 14.7% of patients in the noninvasive arm underwent placement of an arterial catheter. 
PMID: 41159885

Obstructive sleep apnea - Epidemiology
Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005; 365:1046-53. This landmark prospective observational study found that patients with severe untreated OSA had a higher incidence of fatal and non-fatal cardiovascular events in multivariate analysis, as compared to patients with mild disease, and those treated with CPAP.
PMID: 15781100. 

Obstructive Sleep Apnea - Diagnosis
Iber C, O'Brien C, Schluter J, et al. Single night studies in obstructive sleep apnea. Sleep 1991;14:383-5. Contrary to the accompanying editorial, this study first documented the effectiveness of split-night studies for the evaluation of OSA and helped establish split-night studies as the standard of care.
PMID: 1759089.

Corral J, Sanchez-Quiroga MA, Carmona-Bernal C, et al. Conventional polysomnography is not necessary for the management of most patients with suspected obstructive sleep apnea. Noninferiority, randomized controlled trial. Am J Respir Crit Care Med 2017; 196:1181-90. This 6-month study of 430 patients with moderate to high suspicion for OSA found use of home sleep study for diagnosis was noninferior to use of laboratory polysomnography and was less expensive. All patients diagnosed with OSA underwent a separate single CPAP auto-titration home session.
PMID: 28636405 

Obstructive Sleep Apnea - Treatment
Sullivan CE, Berthon-Jones M, Issa FQ et al. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1981 April 18; 1(8225):862-5. First description of CPAP in the treatment of OSA.
PMID: 6112294 

McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med. 2016; 375: 919-31. 2717 adults between 45 and 75 years of age with moderate-to-severe OSA and established coronary or cerebrovascular disease were randomized to CPAP treatment plus usual care or usual care alone and followed for an average of 3.7 years. There was no difference in death from cardiovascular causes, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack, and no difference in a composite of these outcomes.  CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood.
PMID: 27571048
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Weaver TE, Mancini C, Maislin G, et al. Continuous positive airway pressure treatment of sleepy patients with milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP) randomized clinical trial. Am J Respir Crit Care Med. 2012;186:677-83. This prospective blinded trial of sleepy patients with mild obstructive sleep apnea found improvement in functional outcome after 8 weeks with CPAP when compared with sham CPAP.
PMID: 22837377
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Barbe F, Duran-Cantolla J, Sanchez-de-le-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in non-sleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA. 2012;307:2161-2168.The efficacy of CPAP in non-sleepy patients with OSA is unclear. This trial of 725 patients with low Epworth scores and AHI > 20 found no reduction in the incidence of hypertension or cardiovascular events over a median 4-year follow-up, although the authors note the study may have been underpowered.
PMID: 22618923
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Traaen GM, Aakeroy L, Hunt TE,, et al. Effect of continuous positive airway pressure on arrhythmia in atrial fibrillation and sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med 2021; 204:573-582. Trial included 108 patients with paroxysmal atrial fibrillation and moderate to severe sleep apnea plus tolerance of CPAP during a run-in period. After 5 months of therapy, there was no significant differences in time spent in atrial fibrillation during the final 3 months of treatment.
PMID: 33938787 

Phillips CL, Grunstein RR, Darendeliler MA, et al. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med. 2013; 187:879-87. Crossover study of predominantly moderate OSA patients found better subjectively-reported adherence with use of a mandibular advancement device and no overall difference in daytime sleepiness and quality of life despite greater reduction in AHI with CPAP. Blood pressure was unchanged in both groups but patients were normotensive at baseline. Patients with severe OSA still had moderate OSA while using an oral appliance.
PMID:23413266 

Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391:1193-1205. The SURMOUNT-OSA trials enrolled 469 patients with moderate to severe OSA and obesity to either tirzepatide or placebo for 52 weeks. Those who were not on CPAP at baseline were enrolled in trial 1, and those already on CPAP were enrolled in trial 2. Mean BMI was approximately 39 and the mean AHI at baseline was approximately 50. The primary outcome was change in AHI as assessed by in lab polysomnogram at 52 weeks. AHI decreased by an average of 25 events per hour in the tirzepitide group compared to 5 in the placebo group in trial one, and results were similar in trial 2. Up to 50% of those in the treatment group improved to the point where ongoing PAP therapy may not be needed (AHI < 5/hour or AHI 5-14 and ESS of 10 or less). The main side effect in the treatment group was mild to moderate gastrointestinal symptoms. 
PMID: 38912654 
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Strollo PJ Jr, Soose RJ, Maurer JT et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med 2014; 370: 139-49. This uncontrolled cohort study assessed the efficacy of hypoglossal nerve stimulation in a highly selected group of patients with difficulty accepting or adhering to CPAP. Subjects had moderate-to-severe sleep apnea, and those with a BMI > 32 were excluded. In addition to PSG, bronchoscopy during propofol-induced sleep was part of the evaluation. They found a decrease in mean AHI from 29 to 9 and improvement in QoL measures. Although these results suggest treatment efficacy, randomized comparative trials are needed to clarify the role of hypoglossal nerve stimulator in OSA management.
PMID: 24401051
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Central sleep apnea
Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005; 353:2025-33. The oft-cited, randomized CANPAP study of 258 patients found use of CPAP in patients with CHF and Cheyne-Stokes Respirations did not improve mortality. Some believe the lack of benefit compared to previous studies is due to advances in CHF treatment.
PMID: 16282177
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Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure (SERVE-HF). New Engl J Med 2015; 373:1095-1105. A randomized trial of guideline based medical care with and without ASV in patients with EF< 45%, AHI> 15/hr and predominance of central apneas. There was no significant difference in the time to death, lifesaving cardiovascular intervention or unplanned hospitalization for worsening heart failure. There was, however, a significant increase in both all-cause and cardiovascular mortality in the ASV group. This unexpected finding has led to reassessment of ASV and a recommendation against ASV in patients with LVEF < 45%.
PMID: 26323938
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Bradley TD, Logan AG, Lorenzi Filho G, et al. Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial. Lancet Respir Med. 2024;12:153-166. This trial randomized 731 adults with heart failure, an LVEF of 45% or less, and sleep disordered breathing with an AHI of 15 events/hour or more to either standard optimal treatment for heart failure or addition of ASV to optimal heart failure treatment. The primary outcome was a composite of all-cause mortality, first cardiac hospitalization, new afib/flutter, and appropriate defibrillator shock. There was no difference between groups in the primary outcome or in all cause mortality, however ASV was successful at treating OSA and CSA and improved sleep quality and quality of life. Importantly, patients with CSA-predominant sleep disordered breathing did not have increased mortality with ASV which is in contrast to the findings of the SERVE-HF study. 
PMID: 38142697 

Obesity hypoventilation syndrome
Mokhlesi B, Masa JF, Brozek JL, et al. Evaluation and management of obesity hypoventilation syndrome. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2019; 200:e6-e24. This article reviews the current evidence supporting different modes of positive airway pressure therapy used in managing individuals with OHS and includes a recommendation for CPAP as firs-tline treatment rather than noninvasive ventilation in stable OHS patients with concomitant severe OSA.
PMID: 31368798
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Insomnia:
Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17:255-262. This guideline summarizes the basis of the panels’ strong recommendation for multicomponent cognitive behavioral therapy for chronic insomnia in patients with, and without, comorbidities. The panel did not make recommendations for specific delivery methods, including digital CBT.
PMID: 33164742
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Perlis ML, Posner D, Riemann D, et al. Insomnia. Lancet. 2022; 400(10357):1047-1060. This review provides an overview of types and subtypes of insomnia, reinforces CBT as first-line treatment, but also offers an overview of the pharmacological treatment options for insomnia.
PMID: 36115372 

Parasomnias and Sleep Related Movement Disorders
Anguizola E SS, Botta P LM, Castro-Villacañas A, et al The clinical evaluation of sleep-related movement disorders. Sleep Med Clin. 2021; 16:223-231. Provides a nice overview of the presentation, diagnosis, and classification of restless legs syndrome, periodic limb movement disorder, REM sleep behavior disorder, and others.
PMID: 33985649 

Garcia-Borreguero D, Kohnen R, Silber MH, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Medicine. 2013; 14:675-684. Overview of pharmacologic therapies for RLS.
PMID: 23859128 

Howell, M, Avidan, AY, Foldvary-Schaefer, N, et al. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2023;19:759-768. Overview of pharmacologic therapies for RBD.
PMID: 36515157 

Central Hypersomnolence Disorders
Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17:1895-1945. This article provides an in-depth review of treatment options for central hypersomnolence disorders including narcolepsy, idiopathic hypersomnia, and hypersomnia due to various medical conditions.
PMID: 34743790
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Circadian rhythm disorders
Auger RR, Burgess HJ, Emens JS, et al. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). an update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2015; 11:1199-236. This is an update to the previous American Academy of Sleep Medicine guidelines on intrinsic circadian rhythm sleep-wake disorders.
PMID: 26414986

Risk Factors
United States Surgeon General's Advisory Committee on Smoking and Health. Office of the Surgeon General, 1964. Official Report. This landmark U.S. Surgeon General’s report added to the growing international recognition of the multiple hazards of cigarette smoking: http://profiles.nlm.nih.gov/NN/B/B/M/Q/segments.html

Guidelines
Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2020; 202:e5-e31. This guideline is most noteworthy for recommending preferential use of varenicline, including in patients with a comorbid psychiatric condition and in patients who are not ready to quit smoking, over other pharmacologic treatments and e-cigs. Combination therapy and duration of therapy are also addressed.
PMID: 32663106
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Electronic Cigarettes and Smoking Cessation
Prochaska JJ. The public health consequences of e-cigarettes: a review by the National Academies of Sciences. A call for more research, a need for regulatory action. Addiction. 2019; 114:587-89. This FDA-sponsored review summarizes the findings of more than 800 research studies on the safety of electronic nicotine delivery systems (published before widespread recognition of EVALI). The paper calls attention to the uncertain balance between harm reduction (e-cigarettes less toxic than continued tobacco smoking) and the risk of exposure in younger generations.
PMID 30347473
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Farber HJ, Gallego MCP, Galiatsatos P, et al. Harms of electronic cigarettes: what the healthcare provider needs to know.  Ann Am Thorac Soc. 2021; 18:567-572. Review summarizes risks of e-cigarette use as well as efficacy of e-cigs for smoking cessation.
PMID: 33284731 

Halpern SD, Harhay MO, Saulsgiver K et al.  A pragmatic trial of e-cigarettes, incentives, and drugs for smoking cessation. N Engl J Med. 2018; 378:2302-2310. This study is noteworthy for finding low levels of abstinence at 6 months regardless of the strategy employed. Over 6,000 smokers were randomized to usual care or usual care plus one of the following groups: 1) free cessation aids (nicotine-replacement therapy or pharmacotherapy, with e-cigarettes if standard therapies failed); 2) free e-cigarettes, without a requirement that standard therapies had been tried; 3) free cessation aids plus $600 in rewards for sustained abstinence; or 4) free cessation aids plus $600 deposited as redeemable funds with money removed if cessation milestones were not met. Sustained 6-month abstinence was uniformly low - usual care with 0.1%, group 1 with 0.5%, group 2 with 1.0%, group 3 with 2%, and group 4 with 2.9%. There was no statistical difference between receiving e-cigarettes and usual care or free cessation aids.
PMID: 29791259
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Hajek P, Phillips-Waller A, Przulj D, et al. A randomized trial of e-cigarettes versus nicotine-replacement therapy. N Engl J Med. 2019; 380:629-637. In contrast to the Halpern study above, this RCT was noteworthy for finding higher rates of abstinence, particularly in those assigned to e-cigarettes. Of the 886 participants, abstinence rates were 18% among those randomized to e-cigarette group vs 9.9% in NRT group. Of note, among participants who were abstinent at one year, those in the e-cigarette group were more likely than NRT group to be using their assigned product (80% vs 9%).
PMID: 30699054
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Pharmacologic Interventions
Single drug
Transdermal Nicotine Study Group. Transdermal nicotine for smoking cessation. Six-month results from two multicenter controlled clinical trials. JAMA 1991; 266:3133-8. This landmark study was the first to assess rates of continuous smoking abstinence among patients who had successfully quit after a 6-week trial of transdermal nicotine replacement.
PMID: 1956099 

Combination therapy
Walker N, Parag V, Verbiest M, et al. Nicotine patches used in combination with e-cigarettes (with and without nicotine) for smoking cessation: a pragmatic, randomised trial. Lancet Respir Med. 2020; 8:54-64.  This trial examined nicotine replacement alone vs in combination with nicotine or nonnicotine e-cigarettes. Six-month abstinence was achieved in 7% of those on NRT/nicotine e-cig, 4% NRT/non-nicotine e-cig, and 2% on sole NRT. There was a greater loss to follow up in the NRT only group which could have impacted the results.
PMID: 31515173 

Baker TB, Piper ME, Smith SS, et al. Effects of combined varenicline with nicotine patch and of extended treatment duration on smoking cessation: a randomized clinical trial. JAMA. 2021; 326;1485-93. This trial found no difference in abstinence at 52 weeks with either adding nicotine replacement to varenicline or in extending duration of therapy from 12 to 24 weeks. Smoking cessation, based on carbon monoxide-confirmed self-reported 7-day point prevalence abstinence, was near 24% in all groups, higher than many other cessation trials.
PMID: 34665204 

Long-term effects of smoking cessation interventions
Anthonisen NR, Skeans MA, Wise RA, et al. The effects of a smoking cessation intervention on 14.5 year mortality. Ann Intern Med 2005; 142:233-9. This article is noteworthy for showing smoking cessation reduces mortality even when the intervention is successful in only a minority of patients. The study compared a 10-week intervention that combined counseling and nicotine gum with usual care among smokers with obstructive lung disease. Quit rates at 5 years were 21.7% and 5.4% in the intervention and usual care groups, respectively. At 14.5 years, the hazard ratio for all-cause mortality in the usual care group vs. the intervention group was 1.18 (95% CI 1.02 to 1.37).
PMID: 15710956
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Cho ER, Brill IK, Graham IT, et al. Smoking cessation and short- and longer-term mortality. NEJM Evidence. 2024; 3(3). Pooled cohort study from the US, UK, Norway, and Canada with 1.5 million adults followed for 15 years. Smoking cessation of under three years potentially averted five years of life lost; cessation for more than 10 years averted 10 years of life lost. Smoking cessation at any age was associated with longer survival. 
PMID: 38329816 
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ATS Seminars - Intensive Care Ultrasound
A series of six articles with accompanying images and video clips illustrating the most common applications of intensive care ultrasound.
Introduction to ATS Seminars: Intensive Care Ultrasound 
Intensive Care Ultrasound: I. Physics, Equipment, and Image Quality 
Intensive Care Ultrasound: II. Central Vascular Access and Venous Diagnostic Ultrasound 
Intensive Care Ultrasound: III. Lung and Pleural Ultrasound for the Intensivist 
Intensive Care Ultrasound: IV. Abdominal Ultrasound in Critical Care 
Intensive Care Ultrasound: V. Goal-directed Echocardiography 
Intensive Care Ultrasound: VI. Fluid Responsiveness and Shock Assessment 

Thoracic Ultrasound
DA Lichtenstein, GA Mezièere. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol. Chest 2008; 134:117–125. This observational study of 301 consecutive ICU patients compared a focused lung ultrasound protocol (BLUE) with the discharge diagnosis based on the medical record. They describe mostly favorable sensitivity and specificity, particularly for pulmonary edema (SN 97%, SP 95%), and pneumothorax (SN 88%, 100%). US was performed by highly experienced providers, and the protocol requires familiarity with BLUE-specific nomenclature, raising concerns about generalizability to other settings. The authors emphasize that US can be used rapidly at the bedside and is useful not in isolation but as an adjunct to current diagnostic strategies.
PMID: 18403664
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Mojoli F, Bouhemad B, Mongodi S, et al. Lung ultrasound for critically ill patients. Am J Respir Crit Care Med. 2019; 199:701-714. Reviews basic lung ultrasound signs and their applications in critical care, including detection and management of pneumothorax, ventilator associated pneumonia, atelectasis, and pleural effusions.
PMID: 30372119
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Santana PV, Cardenas LZ, de Albuquerque ALP et al. Diaphragmatic ultrasound: a review of its methodological aspects and clinical uses.  J Bras Pneumol. 2020; 46: e2020064. This is a review of the evidence supporting ultrasound assessment of diaphragmatic function, the technique, and the potential clinical applications.
PMID: 33237154
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Díaz-Gómez JL, Mayo PH, Narasimhan M, et al. Society of Critical Care Medicine guidelines on adult critical care ultrasonography: focused update 2024. Crit Care Med. 2025;53(2):e340–e361.
Update to SCCM evidence-based clinical practice guidelines for adult critical care point-of-care ultrasound (POCUS), covering pulmonary, cardiac, vascular access, and procedural guidance domains. Key updates address ultrasound-guided prediction of fluid responsiveness, lung ultrasound protocols for VAP assessment, and integration of POCUS with conventional hemodynamic monitoring. This guideline is the most current SCCM framework for critical care POCUS practice and is a useful reference for clinicians seeking to implement or standardize bedside ultrasound in the ICU.
PMID: 39982182

Invasive mechanical ventilation
See Mechanical Ventilation Tutorials  for in-depth coverage of ventilator modes, waveform interpretation, and dyssynchrony. 

Disease-Specific Strategies for Invasive Ventilation
Darioli R, Perret C. Mechanical controlled hypoventilation in status asthmaticus. Am Rev Respir Dis 1984;129:385-7.  Noteworthy for being the first description of permissive hypercapnea with an emphasis on avoiding high airway pressures, in contrast to the contemporary emphasis on normalizing blood gases.
PMID: 6703497 

Writing Group for the PReVENT Investigators. Effect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS. JAMA 2018; 320:1872-80. Previous smaller studies suggest lower tidal volumes improve outcomes even in patients without ARDS. This RCT of near 1,000 patients found no difference in outcomes between patients assigned to a target of 4 ml/kg vs 10 ml/kg predicted weight. One study limitation is that a substantial proportion of patients received tidal volumes above the low-group and below the high-group targets within the first day of enrollment.
PMID: 30357256
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See “ARDS-Mechanical Ventilation” 

Care of the intubated patient
Heiblum G, Chalumeau-Lemoine L, Joos V, et al. Comparison of routine and on-demand prescription of chest radiographs in mechanically ventilated adults: a multicentre cluster-randomised, two-period crossover study. Lancet 2009; 374:1687-93. This study randomized 849 patients to daily vs. on-demand chest radiographs as clinically indicated. The on-demand strategy reduced the mean number of radiographs per day of ventilation from 1.09 to 0.75 (32% absolute reduction) with no change in length of ventilation, ICU stay, or mortality.
PMID:19896184 

Mackle D, Bellomo R, Bailey M, et al. Conservative oxygen therapy during mechanical ventilation in the ICU. N Engl J Med. 2020; 382:989-998. There is concern excess supplemental oxygen may cause lung injury in intubated patients.  The ICU-ROX study compared conservative oxygen management, which entailed adjusting FIO2 to maintain saturation 90 – 96%, to routine oxygen management in 1,000 mechanically ventilated patients. There was no difference in ventilator-free days or mortality.
PMID: 31613432 

Semler MW, Casey JD, Lloyd BD, et al. Oxygen-saturation targets for critically ill adults receiving mechanical ventilation. N Engl J Med. 2022;387:1759-1769. This large, pragmatic trial of oxygen saturation targets for critically ill adults randomized patients to SpO2 targets of either 90%, 94% or 98% and compared the number of days alive and free of mechanical ventilation through day 28. It is notable for its inclusivity (98.8% of those screened were enrolled), early application of intervention (SpO2 goal was targeted within 15 minutes of intubation), its rigorous data collection (7.8 million SpO2 values from 2541 patients), and its inclusion of an “intermediate” oxygenation target rather than low vs high. They found no significant difference in ventilator free days or mortality (a secondary outcome) through day 28.
PMID: 36278971 
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Martin DS, Gould DW, Shahid T, et al. Conservative Oxygen Therapy in Mechanically Ventilated Critically Ill Adult Patients: The UK-ROX Randomized Clinical Trial. JAMA.2025;334(5):398-408. Pragmatic RCT of 16,500 ICU patients across 97 centers in the UK randomized patients to a conservative oxygen target (lowest FiO2 to achieve SpO2 88-92%) vs standard care (oxygen delivery at the discretion of the treating clinician). The primary outcome was all cause mortality at 90d. The intervention group had a mean oxygen saturation of 93.3% while the usual care group had a mean oxygen saturation of 95.1%. There was no difference between groups (or pre-specified subgroups) in the primary or secondary outcomes (days in the ICU or hospital, ventilator free days). Of note, 49,223 patients met inclusion criteria and 10582 (~22%) were excluded because it was felt one treatment arm was indicated over another.
PMID: 40501321 
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Ventilator weaning
Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med 1991; 324:1445-50. Study in a VA population found the rapid shallow breathing index (RSBI = RR/Vtidal) was the single best predictor of weaning success (sensitivity 0.97, specificity 0.64).
PMID: 2023603
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Brochard L, Rauss A, Benito S, et al. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med 1994; 150:896-903. Prospective, randomized study found weaning with pressure support mode superior to SIMV mode and T-piece trials.
PMID: 7921460 

Thille AW, Gacouin A, Coudroy R,et al; REVA Research Network. Spontaneous-breathing trials with pressure-support ventilation or a t-piece. N Engl J Med. 2022; 387:1843-1854. This large RCT found that among patients at high risk of extubation failure, there was no difference in ventilator-free days at 28 days with use of pressure support ventilation (PS 8, 0 PEEP) vs. T-piece for weaning trials. Reintubation rates also did not differ.
PMID: 36286317 

Girard T, Kress J, Fuchs B, et al. Efficacy and safety of paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awake and Breathing Controlled trial): a randomized controlled trial. Lancet 2008;371:126-34. This RCT found the combination of daily sedation holiday and daily weaning trials resulted in reduced ventilator days and reduced mortality compared to daily weaning trials alone (HR 0.68, p = .01, NNT to save one life 7).
PMID: 18191684 

Jubran A, Grant BJB, Duffner LA, et al. Effect of pressure support versus unassisted breathing through a tracheostomy collar on weaning duration in patients requiring prolonged mechanical ventilation: A randomized trial. JAMA. 2013;309:671–677. This single center study of LTACH patients randomized 316 patients over a 10 year period and found a higher rate of weaning success (8% absolute difference) and a shorter weaning time (15 vs. 19 days, P = .004) when using unassisted breathing via tracheostomy (“T-piece”) vs. pressure support method. Mortality did not differ between groups at 6 and 12 months (>50% of patients in both groups had died after 6 months).
PMID:23340588
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Perkins GD, Mistry D, Gates S et al. Effect of protocolized weaning with early extubation to noninvasive ventilation vs invasive weaning on time to liberation from mechanical ventilation among patients with respiratory failure: the Breathe randomized clinical trial. JAMA. 2018; 320:1881-8. This study took place over a 3.5 year period in 41 different ICUs and included a total of 364 patients who had received invasive mechanical ventilation > 48 hours and had failed a spontaneous breathing trial. Early extubation to noninvasive ventilation did not shorten the time to successful liberation from all forms of mechanical ventilation compared to patients that were not extubated until passing a breathing trial.
PMID: 30347090 

Hernández Martínez G, Rodriguez ML, Vaquero MC, et al. High-flow oxygen with capping or suctioning for tracheostomy decannulation. N Engl J Med. 2020; 383:1009-1017. RCT of 330 ICU patients with a tracheostomy tube but liberated from the ventilator compared decannulation if tolerating capping for 24 hours to decannulation if needing suctioning fewer than twice every 8 hours. The capped group received HFNC when not capped and the uncapped group received HFNC continuously. The time to decannulation was a median of 7 days earlier in the non-capped group (95% CI 5 – 9 days).  A potential important limitation is that 7.0 mm ID fenestrated trach tubes were maintained throughout the study rather than downsized, making capping trials potentially more demanding.
PMID: 32905673 

Rehabilitation in the critically-ill
Studies from the early 2000’s suggested that early mobilization reduces ventilator days and improves functional outcomes at hospital discharge. However, the following subsequent trials have shown no benefit, possibly due to greater incorporation of early mobilization into usual care. The most recent RCT by Hodgson et al showed that even more aggressive mobilization did not increase the number of days alive or days outside of the hospital. 

Moss M, Nordon-Craft A, Malone D, et al. A randomized trial of an intensive physical therapy program for patients with acute respiratory failure. Am J Resp Crit Care Med. 2016; 193:1101-10.
PMID: 26651376 

Morris PE, Berry MJ, Files DC, et al. Standardized rehabilitation and hospital length of stay among patients with acute respiratory failure: a randomized clinical trial. JAMA. 2016; 315:2694-702.
PMID: 27367766 

TEAM Study Investigators and the ANZICS Clinical Trials Group; Hodgson CL, Bailey M, Bellomo R, et al. Early active mobilization during mechanical ventilation in the ICU. N Engl J Med. 2022; 387:1747-1758.
PMID: 36286256 

Tracheostomy
Terragni P, Antonelli M, Fumagalli R, et al. Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult ICU patients: a randomized controlled trial. JAMA 2010;303:1483-9. This trial of over 400 patients found a statistically non-significant reduction in VAP with early bedside tracheotomy (within 6-8 days of intubation) compared to late tracheostomy (13-15 days of intubation) (14% vs. 21%, p = 0.07). The early tracheotomy group had greater ventilator-free and ICU-free days but there was no difference in mortality or hospital length of stay. Only 69% assigned to the early group and 57% to the late group actually underwent tracheostomy, highlighting the difficulty of predicting the need for tracheostomy early in the course of illness.
PMID: 20407057
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Young D, Harrison DA, Cuthbertson BH. Effect of early vs late tracheostomy placement on survival in patients receiving mechanical ventilation: the TracMan randomized trial. JAMA. 2013; 309;2121-2129. Open, randomized, multicenter clinical trial randomized 909 patients predicted to require >7 days of ventilation to early (day 4) or late (day 10) tracheostomy. There was no change in mortality, and, of note, only 44.9% of patients randomized to the late tracheostomy group required it, as opposed to 94% of the early tracheostomy group.
PMID: 23695482
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Noninvasive mechanical ventilation and High Flow Nasal Oxygen
COPD
Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of COPD. N Engl J Med 1995; 333:817-22. Landmark prospective, randomized study found use of NIPPV in selected patients with COPD exacerbations resulted in fewer intubations, complications, days in hospital, and lower in-hospital mortality compared to standard treatment.
PMID: 7651472
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Heart Disease
Bersten AD, Holt AW, Vedig AE, et al. Treatment of severe cardiogenic pulmonary edema with CPAP delivered by facemask. N Engl J Med 1991; 325:1825-30. Randomized study of 39 patients with hypercapnic cardiogenic respiratory failure found use of CPAP plus oxygen resulted in better gas exchange in the first 24 hours and less need for intubation than use of oxygen alone.
PMID: 1961221
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Gray A, Goodacre S, Newby DE, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med 2008; 359:142-51. The 3CPO study, performed in 26 emergency departments, randomized 1,156 patients to standard oxygen therapy, CPAP, or NIPPV. Neither form of noninvasive support reduced 7 or 30-day mortality, and patients receiving CPAP and NIPPV did not differ in need for intubation. The lack of benefit persisted after adjusting for severity of illness. These results differ from prior positive studies, possibly due to differences in study populations and design. Intubation rates and 30-day mortality were lower in the current study, and patients deteriorating with standard oxygen therapy were allowed rescue use of noninvasive support.
PMID: 18614781
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***See also “Cowie MR, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure.” In Sleep Medicine.

Hypoxemic respiratory failure (all types)
Ferrer M, Esquinas A, Leon M, et al. Non-invasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial. Am J Respir Crit Care Med 2003; 168:1140-4. Study of 105 non-hypercapnic patients found NIPPV decreased need for intubation and improved 90-day survival compared to oxygen therapy alone. Unlike some prior studies, subgroup analysis found the 34 patients with pneumonia had the greatest benefit while mask ventilation did not appear to reduce the need for intubation in patients with ARDS and cardiogenic edema.
PMID: 14500259 

Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015; 372:2185-2196. This trial randomized patients with hypoxic respiratory failure to oxygen by facemask, NIPPV, or high flow nasal cannula. This was the first study to compare HFNC to NIPPV in this setting.  Investigators found no difference in the rate of intubation, although a post hoc analysis did find a significantly decreased rate in patients with severe hypoxemia treated with HFNC. The HFNC group also had significantly more ventilator-free days and an unexpected decrease in 90 day all-cause mortality. Weaknesses in this essentially negative trial include a low power to detect inter-group differences in intubation, and some crossover between interventions.
PMID: 25981908
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Jaber S, Lescot T, Futier T et al.  Effect of noninvasive ventilation on tracheal reintubation among patients with hypoxemic respiratory failure following abdominal surgery: a randomized clinical trial.  JAMA 2016; 315: 1345-53. Oft-cited study of bilevel noninvasive ventilation for post-operative respiratory failure randomized nearly 300 patients with new hypoxemic respiratory failure within 7 days of abdominal surgery to non-invasive ventilation or oxygen therapy.  Patients receiving non-invasive ventilation required intubation less often (33.1 vs. 45.5%, p = .03) and were less likely to develop nosocomial infection.  Mortality did not differ.
PMID: 26975890
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Following extubation
Ferrer M, Sellarés J, Valencia M, et al. Non-invasive ventilation after extubation in hypercapnic patients with chronic respiratory disorders: randomized controlled trial. Lancet 2009; 374:1082-8. In a randomized trial of over 100 patients with chronic lung disease who passed a spontaneous breathing trial but had hypercapnea post-extubation, NIPPV led to a significant reduction in subsequent respiratory failure (15% vs 48% in the control group). Rescue NIPPV averted the need for re-intubation in 17 of 27 control patients with post-extubation respiratory failure. In contrast to the Esteban study below, NIPPV in post-extubation hypercapnic respiratory failure appeared beneficial. Whether there is an advantage to immediate over prn NIPPV use in this population is unclear.
PMID: 19682735 

Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 2004; 350:2452-60. This trial of 221 patients with respiratory failure within 48 hours of being extubated after receiving at least 48 hours of mechanical ventilation randomized patients to noninvasive ventilation by face mask or standard medical therapy. Noninvasive ventilation did not reduce the need for re-intubation and the standard-therapy group had lower ICU mortality (14% vs. 25% in noninvasive group). These results suggest noninvasive positive-pressure ventilation should not be used in unselected patients failing extubation.
PMID: 15190137
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Hernández G, Vaquero C, Colinas L, et al. Effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial. JAMA. 2016; 316:1565-74. A randomized multicenter noninferiority trial of 24 hours of non-invasive ventilation or HFNC following extubation in “high risk” patients, which included those with COPD and heart failure. They found that HFNC was noninferior to NIV with respect to preventing reintubation and post-extubation respiratory failure. The HFNC group had fewer adverse effects leading to withdrawal of therapy.
PMID: 27706464
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Casey JD, Vaughan EM, Lloyd BD, et al. Protocolized postextubation respiratory support to prevent reintubation: a randomized clinical trial. Am J Respir Crit Care Med. 2021; 204:294-302. This single-center cross-over study compared protocolized support with noninvasive ventilation when hypercapnia was suspected and HFNC for all others to ordering support at the clinicians’ discretion (usual care). There was no difference in reintubation (15.9% protocolized vs. 13.3% usual care).  Use of noninvasive support was similar between groups but HFNC use was 74.7% in the protocolized group vs. 2.8% with usual care.
PMID: 33794131 

Thille AW, Muller G, Gacouin A, et al. Effect of postextubation high-flow nasal oxygen with noninvasive ventilation vs high-flow nasal oxygen alone on reintubation among patients at high risk of extubation failure: a randomized clinical trial. JAMA. 2019; 322:1465-75. Randomized multicenter trial comparing HFNC with NIV to HFNC alone for prevention of reintubation in 641 patients considered “high risk” (older than 65 years or any underlying chronic cardiac or lung disease) for extubation failure. At 7 days, the rate of reintubation was lower in the HFNC with NIV group compared to the HFNC-alone group (11.8% vs 18.2%).  
PMID: 31577036
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