ARDS
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.
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
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.
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.
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.
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.
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.
Comparisons 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.
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.
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.
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.
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.
***See also Ventilation and Weaning for oxygen goals in non-ARDS patients
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.
ECMO:
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.
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.
***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. Trial was stopped early for futility.
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.
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).
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.
Fluid management:
Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006; 354:2564-75. FACTT Trial. This randomized study is widely cited as the rationale for aggressive diuresis in ARDS patients. Of note, the study protocol is highly complex and relies on CVP and PA catheter measurements, limiting its direct clinical applicability.
***See also Ventilation and Weaning
Asthma
Guidelines/Strategies:
Global Strategy For Asthma Management and Prevention (2023 Update). Comprehensive updated resource. The most recent update provides additional scientific rationale for recommendations, nomenclature updates, and clarification of care tracks.
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.
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.
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.
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.
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.
Combination therapies:
Bateman ED, Boushey HA, Bousquet J, et al. GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med. 2004;170:836-44. This 1-year, randomized study (n=3,421) of patients with uncontrolled asthma compared the addition of LABA vs escalating steroids in achieving two rigorous, composite, guideline-based measures of control: totally and well-controlled asthma. Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone alone.
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.
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.
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.
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.
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.
Bronchial thermoplasty:
Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. (AIR2 Trial) Am J Respir Crit Care Med 2010;181:116-24. The AIR2 trial was the first RCT of bronchial thermoplasty to include a sham control. 288 patients with asthma symptoms despite standard therapy were followed for 12 months. The treatment group had fewer adverse respiratory events, severe exacerbations, emergency department visits, and hospitalizations, as well as a greater number (81%) of subjects reporting improvement in AQLQ. Notably, 63% of control subjects also reported clinically significant (>0.5) improvement in AQLQ. During treatment, 8.4% of patients in the treatment group were hospitalized for respiratory symptoms compared to 2.0% in the sham group.
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.
***See also Invasive Mechanical Ventilation and Occupational Medicine
Bronchiectasis (Non-Cystic Fibrosis)
Guidelines and Reviews:
Polverino E, Goeminne P, McDonnel M, et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J. 2017; 50:1700629. These guidelines consist of systematic reviews performed to address nine key clinical questions.
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 best to tailor airway clearance mode to patient preferences.
Imam JS, Duarte AG. Non-CF bronchiectasis: Orphan disease no longer. Respir Med. 2020; 166:105940. A thorough, but concise review of the pathogenesis, epidemiology, clinical features, etiologies, approach to diagnosis, and management of non-CF bronchiectasis.
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.
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 decreased pulmonary exacerbation rate but increased macrolide resistance.
Cardiology Critical Care
Heart Failure:
Mebazaa A, Gheorghiade M, Pina IL, et al. Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes. Crit Care Med 2008; 36[Suppl]:S129-139. Intensivists are often involved in the early management of heart failure patients but there are few randomized studies to guide management in this setting. These guidelines are derived primarily from expert opinion and provide recommendations on the use of nitrates, inotropes, pressors, diuretics, and fluids based on various clinical scenarios.
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.
Cardiogenic shock:
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.
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.
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.
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.
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 the setting of acute myocardial infarction. Outcomes favored the restrictive approach but did not reach statistical significance.
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.
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.
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).
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.
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.
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.
***For therapeutic hypothermia following cardiac arrest, see Neurology Critical Care.
Chest Imaging
The following review articles provide an overview of chest imaging.
Raoof S, Feigin D, Sung A, et al. Interpretation of plain chest roentgenogram. Chest. 2012; 141: 545-558.
Raju S, Ghosh S, Mehta AC, et al. Chest CT signs in pulmonary disease: a pictorial review. Chest. 2017; 151(6):1356-1374.
Lynch DA, Travis WD, Müller NL, et al. Idiopathic interstitial pneumonias: CT features. Radiology. 2005; 236:10-21.
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.
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.
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.
Hatabu H, Hunninghake GM, Richeldi L, et al. Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society. 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. Lancet Respir Med. 2020; 8:726-737.
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.
Ye Z, Zhang Y, Wang Y, Huang Z, Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review. Eur Radiol. 2020; 30:4381-4389. This review summarizes, and illustrates, a broad range of radiographic manifestations of COVID-19 infection compiled from multiple early case series.
***See also COVID-19 section
COPD
Guidelines/Strategies:
Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: 2024 Report. This year’s update is noteworthy for expanded information about screening recommendations including spirometry and lung cancer screening, updates regarding PRISm, vaccinations, smoking cessation, managing inhaled therapies.
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.
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).
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%).
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.
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.
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)].
Inhaled steroid withdrawal:
Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014; 371:1285-94. The WISDOM trial randomized 2,485 patients with severe or very severe COPD and an exacerbation within the preceding year to either triple therapy with tiotropium, serevent, and high-dose fluticasone or continued long-acting bronchodilators with stepwise withdrawal of fluticasone over 3 months. After 1 year of follow-up, there was no significant difference in time to first moderate or severe exacerbation. There were no clinically-significant changes in dyspnea or health status between groups. Mean FEV1 was 38 ml higher in the triple therapy group.
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.
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.
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.
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 dupilimab group had modest improvements in lung function and respiratory symptoms compared to placebo.
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).
Systemic corticosteroids in exacerbations:
Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013; 309:2223-31. When compared with a 14 day systemic glucocorticoid course, 5 days was non-inferior in 6 month re-exacerbation rate. There was no difference in glucocorticoid related adverse effects.
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.
Daniels JM, Snijders D, de Graaff CS, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;181:150-7. This RCT of 265 patients with acute exacerbation found the addition of 7 days of doxycycline to prednisone did not lead to a significant improvement in 30-day clinical response, although secondary outcomes of clinical cure and clinical success at day 10 were improved in the antibiotic arm. Concerns raised regarding study design include exclusion of severe exacerbations, patients with objective evidence of infection, and concern about doxycycline resistance.
Butler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med. 2019; 381:111-120. The use of CRP levels to guide antibiotic use in COPD exacerbations is gaining attention. In this RCT, 653 patients with acute exacerbation of COPD during a primary care clinic visit were assigned to usual care guided by CRP point of care testing vs usual care alone. Fewer patients in the CRP-guided group reported antibiotic use than in the usual care group (57% vs 77%, adjusted OR 0.31) without any difference in COPD related health status (as measured by Clinical COPD Questionnaire). The lack of widely available POC CRP testing in the United States may limit applicability.
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%.
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.
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.
Lung volume reduction surgery:
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 recently FDA approved unidirectional endobronchial valves.
***For information on endobronchial valves, see the bronchoscopy articles within the Procedure section
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.
Asthma-COPD Overlap Syndrome:
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.
Cough
Gibson P, Wang G, McGarvey L, et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest; 2016:149:27-44. This guideline aims to clarify the best evidence for assessment and treatment of unexplained chronic cough (UCC). It highlights the significant morbidity of the condition and the limited evidence available to guide management.
Vertigan AE, Kapela SL, Ryan NM, et al. Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial. CHEST. 2016; 149:639-48. This RCT of speech therapy with or without pregabalin in 40 patients with chronic refractory cough found improved cough severity, frequency, and quality of life in both groups. However, cough severity and quality of life were significantly better in the combined treatment group. The small sample size and stringent eligibility criteria may limit the generalizability of these findings.
Chamberlain Mitchell, Garrod R, Clark L, et al. Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial. Thorax. 2017; 72:129-136. RCT of 34 patients with refractory cough found the combination of physiotherapy, speech and language therapy reduced cough frequency and improved health related quality of life. This trial highlights the potential benefit of non-pharmacologic therapy for refractory chronic cough.
COVID-19
Guidelines:
IDSA Guidelines on Treatment and Management of Covid-19
IDSA site provides additional information on treatments for prophylaxis, outpatients with infection, and hospitalized patients with mild to moderate disease, as well as references for negative treatment trials.
Resource Management:
Maves RC, Downar J, Dichter JR, et al. Triage of scare critical care resources in COVID-19 an implementation guide for regional allocation: An expert panel report of the Task Force for Mass Critical Care and the American College of Chest Physicians. Chest. 2020;158:212-225. A guide to the creation of a triage system including family and healthcare provider support needs.
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.
Monoclonal Antibodies:
Updated information about monoclonal antibodies and efficacy in the latest COVID-19 variants can be found at: https://www.idsociety.org/covid-19-real-time-learning-network/therapeutics-and-interventions/monoclonal-antibodies/
Ivermectin:
Reis G, Silva EASM, Silva DCM, et al. Effect of early treatment with ivermectin among patients with Covid-19. N Engl J Med. 2022; 386:1721-1731 This segment of a randomized platform study included 1,358 outpatients with confirmed COVID-19 infection and at least 1 risk factor for developing severe infection. Ivermectin for 3 days did not decrease covid-related hospital admissions or emergency department visits.
Pharmacologic Treatment - Inpatients:
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.
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.
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).
Remdesivir:
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 – final report. ACTT-1 study group members. Mehta AK, Zingman BS, Kalil AC, et al. 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.
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.
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.
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.
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 vs standard dose prophylactic anticoagulation in COVID-19 ICU patients, showing no significant difference in venous or arterial thrombosis, treatment with ECMO, or 30 day mortality.
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.
***For additional information, see the Infectious Diseases Society of America guidelines for COVID-19 treatment.
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.
Arabi YM, Aldekhyl S, Al Qahtani S, et al.. Effect of helmet noninvasive ventilation vs usual respiratory support on mortality among patients with acute hypoxemic respiratory failure due to COVID-19: The HELMET-COVID Randomized Clinical Trial. JAMA. 2022; 328:1063-1072. Unlike the 2021 HENIVOT trial (Free Full Text), this larger study of 320 patients found use of helmet noninvasive ventilation did not reduce the rate of endotracheal intubation compared to usual care which included noninvasive ventilation, HFNC, and standard O2. Of note, HENIVOT did not includej HFNC only for usual care. Neither study found a difference in mortality.
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.
Proning:
Alhazzani W, Parhar KKS, Weatherald J et al. Effect of awake prone positioning on endotracheal intubation in patients with COVID-19 and acute respiratory failure: a randomized clinical trial. JAMA. 2022; 327: 2104-2113. This pragmatic, unblinded multicenter trial studied whether awake prone positioning could improve outcomes in 400 non-intubated patients with COVID-19 requiring oxygen (40% or more FiO2) or NIV. When compared to usual care, prone positioning did not significantly reduce endotracheal intubation at 30 days, mortality at 60 days, days free from IMV or NIV, or days free from the ICU or hospital at 60 days. The intervention group proned for a median of 4.8 hours per day. Whether longer duration of daily proning or selection of certain subgroups would show benefit is unknown.
Cystic Fibrosis
Guidelines:
Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187:680-9. This document offers graded recommendations for medication use according to patient age and severity of lung disease. It also summarizes areas of uncertainty.
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.
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.
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 robust 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.
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.
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.
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).
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.
Drug Induced Lung Disease
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.
Immune Checkpoint Inhibitor Molecular Targeted Therapy Toxicity
Delaunay M, Prevot G, Collot S, et al. Management of pulmonary toxicity associated with immune checkpoint inhibitors. Eur Respir Rev. 2019;28(154). Overview of incidence, diagnosis, and proposed treatment of ILD induced by immune checkpoint inhibitors.
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.
***For information on EVALI, see ARDS section
ECMO
Reviews of VV and VA ECMO:
Fan E, Gattinoni L, Combes A, et al. Venovenous extracorporeal membrane oxygenation for acute respiratory failure : A clinical review from an international group of experts. Intensive Care Med. 2016; 42:712-724. This concise review nicely summarizes the physiology of VV ECMO as well as the indications, technical aspects of cannulation, complications, and supportive aspects of care including mechanical ventilation, anticoagulation, and blood transfusion.
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.
For additional resources, please see ARDS and Cardiology sections
Endocrine Critical Care
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.
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.
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.
***See also Steroids in Sepsis/Septic Shock
Gastroenterology Critical Care
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.
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(3):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).
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.
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 promotes the emerging concept of 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.
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.
Krag M, Marker S, Perner A et al. Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU. N Engl J Med. 2018; 379:2199-2208. This multicenter blinded trial randomized ~3300 ICU patients at risk for gastrointestinal bleeding to 40 mg of intravenous pantoprazole or placebo daily during the ICU stay. There was no difference in 90 day mortality. Significant bleeding was uncommon, affecting 2.5% of the PPI group and 4.2% for placebo. There was no significant difference in incidence of C. difficile infection or pneumonia.
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.
Hematology Critical Care
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.
Siegal DM, Belley-Côté EP, Lee SF, et al. Small-volume blood collection tubes to reduce transfusions in intensive care: The STRATUS Randomized Clinical Trial. JAMA. 2023;330:1872–1881. Pragmatic RCT of 27,000 ICU patients compared standard volume (4-6 mL) to small volume (1.8-3.5 mL) tubes for lab collection. The primary analysis excluded 6,000 patients enrolled early in the COVID-19 pandemic and found no difference in RBC transfusions. A secondary analysis which included all patients found that use of small volume tubes reduced the number of RBC units transfused per patient per ICU stay (RR, 0.88, P = .04; absolute reduction of 9.84 RBC units/100 patients per ICU stay) without increasing the number of inadequate samples. The authors point out that the magnitude of effect was similar between analyses, but the p value in the secondary analysis was nominally significant.
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.
ICU Administration
Guidelines:
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.
24 Hour Intensivist Staffing:
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.
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.
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.
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.
Resident ICU Schedules:
The following studies examined the effect of resident shift length on the occurrence of medical errors. The 2004 study determined interns made substantially more errors when they worked frequent shifts of 24 hours or more than when they worked shorter shifts. A study in 2020 showed that more errors occurred in residents not working extended shifts of 24 hours or more. 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.
Landrigan CP, Rothschild JM, Cronin JW, et al. Effect of reducing interns' work hours on serious medical errors in intensive care units. N Engl J Med. 2004; 351:1838-48.
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.
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.
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.
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.
Immunocompromised Host
Guideline:
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.
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(2):298-314. Review of diagnostic strategies with special attention to newly validated diagnostic tests.
Chi AK, Soubani AO, White AC, et al. An update on pulmonary complications of hematopoietic stem cell transplantation. Chest. 2013; 144:1913-1922.
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.
HIV and Pulmonary Disease:
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.
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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Infection Control
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.
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.
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.
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.
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).
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.
The SuDDICU Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group. Effect of selective decontamination of the digestive tract on hospital mortality in critically ill patients receiving mechanical ventilation: a randomized clinical trial. JAMA. 2022; 328:1911–1921. Multicenter study of 5,982 patients in which ICUs used SDD on a 12-month on/off basis found a statistically non-significant reduction in in-hospital mortality in the SDD group (27.0% vs. 29.1%, p = 0.12). No increase in resistant organisms or C. difficile colitis was observed.
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.
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”.
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.
Interstitial Lung Disease
Diagnosis and Overview:
An Official American Thoracic Society/European Respiratory Society Statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188:744-748. Written to standardize and update the diagnostic criteria and terminology for idiopathic interstitial pneumonias, this article nicely summarizes the clinical, radiologic, and histologic features of the ILD alphabet soup. Discusses more recently described rare entities.
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.
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.
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.
Idiopathic Pulmonary Fibrosis:
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.
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, which has implications for listing for lung transplantation.
IPF Treatment:
The following studies of pirfenidone and nintedanib are the first to clearly establish treatment benefit for patients with mild to moderate disease.
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 for no decline in FVC; 17% vs. 32% placebo for > 10% decline). Pirfenidone also improved the decline in 6-minute walk distance.
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.
Non-IPF Fibrotic Lung Disease Management
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.
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.
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.
More on Connective Tissue-Related ILD
Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016; 4:708-19. RCT of 126 patients with scleroderma-related lung disease found 2 years of mycophenolate mofetil (MMF) treatment vs 1 year of cyclophosphamide treatment yielded similar small improvements in percent predicted FVC (2.19 vs 2.88 points, respectively, p = 0.24). MMF was better tolerated, suggesting it may be the preferred agent for scleroderma related ILD.
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.
Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020; 8:963-974. The primary outcome of improved skin score was negative in this trial of 210 patients with systemic sclerosis, but the study is noteworthy for being the basis for the FDA approval of tocilizumab for treatment of SSc-induced ILD. The mean decline in % predicted FVC was - 3.9 in the placebo group vs. – 0.6 in the tocilizumab group at 48 weeks.
Lee AS, Scofield RH, Hammitt KM, et al. Consensus guidelines for evaluation and management of pulmonary disease in Sjögren's. Chest. 2021; 159: 683–698. This article provides comprehensive guidance on the evaluation and management of the full spectrum of Sjögren's patients, from at risk but disease free to those with advanced fibrotic lung disease.
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.
Wijsenbeek MS, Culver DA. Treatment of sarcoidosis. Clin Chest Med. 2015;36:751-67. A review addressing a number of questions related to the treatment of sarcoidosis, including when to initiate treatment, treatment strategies, and the use of collaborative decision making.
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.
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.
Lung Cancer/Solitary Pulmonary Nodule
Staging:
Detterbeck FC, Boffa DJ, Kim AW, et al. The eighth edition lung cancer stage classification. Chest. 2017; 151:193-203. This quick and comprehensive reference is invaluable for determining stage based on the updated TNM classification.
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.
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.
Surgical Risk Assessment:
Donington J, Ferguson M, Mazzone P, et al. American College of Chest Physicians And Society Of Thoracic Surgeons consensus statement for evaluation and management for high-risk patients with stage I non-small cell lung cancer. Chest 2012; 142:1620-35. This summary is a useful resource for identifying and weighing treatment options for stage I patients unlikely to tolerate lobectomy, including the relative merits of wedge resection vs. segmentectomy, as well as use of adjuvant therapies, radiation therapy, and percutaneous ablative therapy.
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.
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.
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.
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.
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.
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%.
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.
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.
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.
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.
Lung-RADS Version 1.1 Assessment Categories (2019 Release). Guidelines developed by the American College of Radiology for management of lung nodules in the setting of lung cancer screening CT scans and facilitates standardized reporting of abnormal findings.
Lung Transplantation
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 slides list the citation for the Focus Theme articles that are published annually in the Journal of Heart and Lung Transplantation. The 2023 update is a special report: Death/Retransplant Among Pulmonary, Deceased Donor Transplant Recipients.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
Mycobacterial Diseases
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.
Haworth CS, Banks J, Capstick T, et al. British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax. 2017; 72 (Suppl 2):ii1-ii64. This guideline includes useful recommendations on indications for treatment, susceptibility testing, treatment regimens for various organisms, and monitoring during treatment.
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.
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.
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.
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.
Conde MB, Loivos AC, Rezende VM, et al. Yield of sputum induction in the diagnosis of pleural tuberculosis. Am J Respir Crit Care Med 2003;167:723-5. Prospective study of 84 patients with pleural tuberculosis found induced sputum culture was helpful in patients with no infiltrate on CXR; 55% of patients with effusion and otherwise clear CXR were culture positive, although only 12% had a rapid diagnosis via positive smears.
Active Tuberculosis- Treatment:
Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016; 63:853-67. This update to the 2003 guideline focuses primarily on non-drug resistant disease and emphasizes the importance of case management and avoiding excessive delay of ART in HIV-positive patients initiating treatment of active tuberculosis.
Dorman SE, Nahid P, Kurbatova EV, et al. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N Engl J Med. 2021; 384:1705-1718. Large, international RCT found treatment of non-resistent TB with 4 months of rifapentine plus moxifloxacin was non-inferior to standard 6- month, 4-drug therapy.
Nephrology Critical Care
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.
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.
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.
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.
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.
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.
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 zosyn 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.
Neurology Critical Care
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.
Dhar R, Marklin GF, Klinkenberg WD, et al. Intravenous levothyroxine for unstable brain-dead heart donors. N Engl J Med. 2023;389:2029-2038. 852 brain-dead, hemodynamically unstable organ donors were randomized to levothyroxine infusion or normal saline. There was no difference in the primary outcome of survival to heart transplant, and no difference in secondary outcomes including number of organs donated, vasopressor needs, and left ventricular ejection fraction. There was a higher rate of adverse events in the levothyroxine group (hypertension and tachycardia).
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.
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 to provide 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
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.
Therapeutic hypothermia following cardiac arrest:
The following two large trials are noteworthy for finding no improvement in outcomes with therapeutic hypothermia compared to normothermia.
Nielsen N, Wettersley J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369: 2197-206.
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.
Lascarrou JB, Merdji H, Le Grouge A, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019; 381:2327-2337. RCT of 581 patients with out-of-hospital or in-hospital cardiac arrest with nonshockable rhythm admitted to the ICU with coma were randomized to target temperature of 33°C for 24 hours or 37°C with total targeted temperature time of 48 hours. At 90 days, favorable neurological outcome occurred in 10.2% in the hypothermia group vs 5.7% in normothermia group with no difference in mortality. Of note, the fragility index value was 1.
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.
Acute hemorrhagic stroke:
Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015; 46:2032-60. These guidelines provide a useful overview on initial imaging, prognostication, surgical intervention, and medical management including reversal of anticoagulation and blood pressure management.
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.
Acute Ischemic Stroke:
Thrombolytic Therapy:
The following 2 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.
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.
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.
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.
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.
Albers GW, Marks MP, Kemp S et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018; 378:708-718. The DEFUSE 3 multicenter RCT included 182 patients last known to be well 6 to 16 hours earlier who also had remaining ischemic brain tissue that was not yet infarcted. Patients randomized to thrombectomy + standard medical therapy were more likely to be functionally independent at 90 days (45% vs 17%, p < .001) and had lower 90-day mortality (14% vs 26%, p = 0.5) compared to standard medical therapy alone.
Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015; 372: 2285-95. 196 patients evaluated within 6 hours of symptom onset were randomized to t-PA alone or t-PA combined with endovascular thrombectomy with the use of a stent retriever. Imaging confirmed proximal anterior occlusions without a large infarct. Thrombectomy increased the proportion of patients with functional independence (60% vs 35%, p <.001) based on modified Rankin score without difference in mortality.
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.
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.
Nutrition in Critical Illness
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.
Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin. Nutr. 2019; 38:48-79. Provides another source of guidance on nutritional support in the ICU.
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.
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.
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.
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.
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. This trial of 1,300 patients found that delivery of high-protein enteral feeds to mechanically ventilated ICU patients did not improve the time to discharge alive from hospital compared to usual-dose protein feeds. Whereas previous trials have been criticized for enrolling patients at low nutritional risk, this study is noteworthy for including exclusively high-risk patients. Subgroup analysis suggests high-protein feeds might have worsened outcomes for patients with AKI and high organ failure scores.
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).
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.
Obstetrics and Critical Care
The following two articles are concise reviews of the general approach to the critically ill pregnant patient, and management of conditions encountered during the prenatal period, delivery, and puerperium.
Guntupalli KK, Hall N, Karnad DR, et al. Critical Illness in Pregnancy: part I: An Approach to a Pregnant Patient in the ICU and Common Obstetric Disorders. Chest 2015;148: 1093-104.
Guntupalli KK, Karnad DR, Bandi V, et al. Critical Illness in Pregnancy: part II: Common Medical Conditions Complicating Pregnancy and Puerperium. Chest 2015;148:1333-45. Review of medical conditions that affect pregnant women or that worsen during pregnancy.
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.
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.
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.
***See Leung et al in Pulmonary Embolism for information related to suspected pulmonary embolism in pregnancy.
Occupational and Environmental Medicine
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.
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.
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.
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.
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.
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.
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.
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.
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. Timely review of emerging environmental and occupational lung diseases from silicosis due to sandblasting jeans to potential health effects of hydraulic fracturing (fracking).
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.
Air pollution and cardiopulmonary disease:
Dockery DW, Pope CA 3rd, Xu X, et al. An association between air pollution and mortality in six U.S. cities. N Engl J Med 1993; 329:1753-9. This seminal article linked fine particulate air-pollution with lung cancer and cardiopulmonary mortality, associations that have been duplicated in subsequent studies and been highly influential in public health policy.
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.
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.
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.
Environmental tobacco smoke:
The following 2 articles are good examples of research documenting the impact of legislation to limit secondhand smoke on the health of nonsmoking bar workers. See also Smoking Cessation.
Eisner MD, Smith AK, Blanc PD. Bartenders’ respiratory health after establishment of smoke-free bars and taverns. JAMA 1998; 280:1909-14.
Menzies D, Nair A, Williamson PA, et al. Respiratory symptoms, pulmonary function, and markers of inflammation among bar workers before and after a legislative ban on smoking in public places. JAMA 2006; 296:1742-8.
Palliative/End of Life Care in the ICU
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.
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.
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.
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.
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.
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.
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.
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.
Pleural Diseases
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.
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.
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.
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.
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.
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).
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.
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).
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).
Pneumonia
Community Acquired Pneumonia:
Treatment:
Metlay J, Waterer G, Long A, et al. Diagnosis and treatment of adults with community acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Disease Society of America. Am J Respir Crit Care Med. 2019; 200:e45-67. Notable updates from 2007 guidelines include: recommendation against use of procalcitonin to guide initial antibacterial therapy, recommendation against use of corticosteroids, narrower indications for empiric MRSA and pseudomonas coverage, and abandoning use of HCAP category.
Dinh A, Ropers J, Duran C, et al. Discontinuing β-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial. Lancet. 2021; 397:1195-1203. Study most relevant to hospitalists but noteworthy for finding 3 days of antibiotics non-inferior to treating for 8 days among 310, mostly elderly, admitted patients that had achieved stability after 3 days of treatment.
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%).
Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385: 1511-8. This trial randomized 785 patients with community acquired pneumonia of varying severity (only 5% in the ICU) to prednisone 50 mg x 7 days vs placebo and found a 1.4 day reduction in “time to clinical stability” (24 consecutive hours of stable vitals) and a 1-day reduction in duration of hospital stay in the steroid group. Death, ICU admission, duration of ICU admission, and duration of antibiotics did not differ.
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.
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.
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.
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.
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.
Procedures
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 bronchs for bronchoalveolar lavage in thrombocytopenic patients.
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.
***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.
Criner GJ, Eberhardt R, Fernandez-Bussy S, et al. Interventional bronchoscopy. Am J Respir Crit Care Med. 2020; 202:29-50. Provides an excellent broad overview of advanced bronchoscopy, including bronchial thermoplasty, cryobiopsy, lung volume reduction and others.
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.
Agrawal A, Hogarth DK, Murgu S. Robotic bronchoscopy for pulmonary lesions: a review of existing technologies and clinical data. J Thorac Dis. 2020;12:3279-3286. A review of 2 of the available robotic bronchoscopic modalities for sampling peripheral lesions.
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.
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.
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.
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.
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.
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.
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)
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.
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.
***For additional information, see Pleural disease section
General Procedural Safety:
Wolfe K, Kress J. Risk of procedural hemorrhage. Chest 2016;150:237-46. Review article addressing the risk factors for hemorrhage associated with procedures commonly performed in the ICU, including central line placement, thoracentesis, paracentesis, lumbar puncture, and others.
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.
- Arterial line insertion
- Arterial line insertion: ultrasound guided
- Bag-mask ventilation
- Central venous catheter insertion: internal jugular
- Central venous catheter insertion: femoral
- Central venous catheter insertion: subclavian
- Central venous catheter insertion: ultrasound guided subclavian
- Chest tube insertion
- Chest tube insertion: ultrasound guided
- Cricothyroidotomy
- Intubation: fiberoptic
- Intubation: standard orotracheal
- Lumbar puncture
- Paracentesis
- Percutaneous tracheostomy
- Prone positioning with elevated BMI
- Thoracentesis
Pulmonary Embolism
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.
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.
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%.
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.
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.
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.
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.
Acute Management of submassive 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.
Meyer G, Vicaut E, Danays T, et al. PLEITHO 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.
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.
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.
Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012; 366:1959-67. Randomized 2-year trial evaluated 100 mg daily aspirin vs. placebo for thromboembolism prophylaxis in 405 patients who had completed 6 – 18 months of oral anticoagulant treatment following a first ever unprovoked venous thromboembolism (VTE). VTE occurred in significantly fewer patients receiving aspirin (6.6%/year vs 11.2%/year for placebo), but there were no significant differences in incidence of pulmonary embolism or in mortality. Major bleeding was uncommon and did not differ between groups.
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.
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.
Pulmonary Function Testing
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.
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.
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.
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).
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.
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.
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.
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.
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).
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.
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.
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.
Pulmonary Hypertension
Classification and Guidelines:
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Repir J. 2019;53(1). The 6th World Symposium on Pulmonary Hypertension proposes a new threshold of mPAP of 20mmHg as the upper limit of normal value.
Klinger JR, Elliott CG, Levine DJ, et al. Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline and expert panel report. Chest. 2019;155:565-586. This is a timely update to the 2014 guideline that summarizes the indications for each of the many therapeutic classes based on severity of symptoms, vasoreactivity, and prior treatment. There is a new emphasis on earlier use of combination therapy.
Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37(1):67-119. This consensus document is still included as it contains recommendations on diagnostic evaluation.
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 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. Accuracy and ability to obtain an estimate varied with the underlying disease.
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).
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.
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.
Hoeper MM, Badesch DB, Ghofrani HA, et al; STELLAR Trial Investigators. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023; 388:1478-1490. Sotatercept, which inhibits cellular proliferation, improved the primary endpoint of 6-minute walk distance by 34 meters in this 24-week RCT of 323 patients. Of note, sotatercept was added to patients’ baseline PAH regimens for the study.
Thromboendarterectomy for chronic thromboembolic disease:
Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011;141:702-10. This registry data from a large number of centers predominantly in Europe found frequent perioperative complications but 1-year mortality of 7% and significant clinical improvement in survivors.
Pulmonary Rehabilitation
Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013; e13-e64. This guideline replaces the 2006 version, provides an updated definition of pulmonary rehabilitation, and highlights new data demonstrating the efficacy of pulmonary rehab in patients with COPD. It also addresses the use of pulmonary rehabilitation in other pulmonary diseases.
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.
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.
Nolan CM, Kliaraju D, Jones SE, et al. Home versus outpatient pulmonary rehabilitation in COPD: a propensity-matched cohort study. Thorax 2019; 74:996-998. This study explored whether the benefits of home pulmonary rehabilitation could be reproduced outside of a clinical trial. This observational study of 154 patients found similar improvements in quality of life but smaller improvements in exercise capacity in the home group compared to the matched supervised group. Based on this, the authors recommend home-based rehab be reserved for those unable to attend structured programs.
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.
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.
***See also Pulmonary Function Tests section on Exercise Tests
Sedation / Analgesia / Delirium
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
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. RCT 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.
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.
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.
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.
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 patients undergoing ventilation in the ICU for less than 12 hours to receive 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 received supplemental propofol to reach target sedation.
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.
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.
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.
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.
Sepsis / Septic Shock
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.
Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021; 49:e1063-e1143. The 93 recommendations do not depart dramatically from the 2017 guidelines. Includes additional guidance on timing of antibiotics in patients with possible sepsis without shock and lower suspicion of sepsis.
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.
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.
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.
Kyriazopoulou E, Liaskou-Antoniou L, Adamis G, et al. Procalcitonin to reduce long-term infection-associated adverse events in sepsis: a randomized trial. Am J Respir Crit Care Med. 2021; 203:202-210. Multicenter trial of 266 septic patients, of whom 61% had pneumonia and 7% septic shock, found the procalcitonin-guided group had reduced median antibiotic duration by 5 days and reduced subsequent risk of a composite of infection or death from C. difficile colitis and MDR organisms (7.2 vs 15.2%). Surprisingly, the procalcitonin-guided group also had lower 28-day mortality (15.2 vs 28.2%).
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.
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.
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.
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.
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.
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.
***For discussion of crystalloid fluid choice in septic shock, refer to Nephrology Critical Care.
Adjunctive Therapy:
Albumin for Fluid Resuscitation:
The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247-56. In approximately 7000 unselected ICU patients requiring volume administration—including trauma, sepsis, and most other diagnoses—a randomized, blinded study of albumin versus saline found no difference in the primary outcome of 28-day mortality or in secondary outcomes. However, in a subgroup analysis of approximately 1200 patients with severe sepsis, there was a trend toward decreased mortality in the albumin group (relative risk 0.87, p=0.06).
Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014; 370:1412-21. Multicenter open-label RCT randomized 1,818 patients to daily 20% albumin to maintain a serum albumin > 3 gm/dl plus crystalloids vs. crystalloids alone for the duration of their ICU stay and found no difference in mortality. The albumin group had shorter duration of vasopressor support but duration of mechanical ventilation or need for renal replacement therapy did not differ.
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.
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.
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.
***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, their use.
Sleep Medicine
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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%.
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.
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.
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.
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.
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.
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.
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.
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.
Smoking Cessation
Risk Factors:
United States. Surgeon General's Advisory Committee on Smoking and Health, and United States. Public Health Service. Office of the Surgeon General. Smoking and Health. United States. Public Health Service. 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.
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.
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.
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.
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%).
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.
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/nonnicotine 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.
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.
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).
Ultrasound in the ICU
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.
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.
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.
Ventilation and Weaning
Invasive mechanical ventilation:
See Mechanical Ventilation Tutorials for an excellent 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.
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.
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.
Francois B, Bellissant E, Gissot V, et al. 12-h pretreatment with methylprednisolone versus placebo for prevention of post-extubation laryngeal oedema: a randomized double-blind trial. Lancet 2008; 369:1083-89. The largest multicenter RCT of steroids for prevention of laryngeal edema. 698 adults intubated >36 hrs received methylprednisolone (20 mg IV) or placebo every 4 hours for 12 hours preceding extubation. Laryngeal edema was significantly reduced (22% vs 3%), as were overall reintubation rate (8% vs 4%) and reintubation due to laryngeal edema (54% vs 8%). Subsequent meta-analyses emphasize the benefit of multiple-dose rather than single-dose steroid administration.
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.
Schjorring OL, Klitgaard TL, Perner A., et al. Lower or higher oxygenation targets for acute hypoxemic respiratory failure. N Engl J Med. 2021; 384:1301-1311. The HOT-ICU study found no difference in 90-day mortality (primary outcome) targeting a PaO2 of 60 mmHg vs. 90 mmHg. There was also no difference in secondary outcomes (episodes of shock, intestinal ischemia, ischemic stroke, or myocardial ischemia).
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).
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.
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.
Ely EW, Baker AM, Dunagan DP, et al. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996; 335:1864-9. RCT found a protocol of daily weaning parameters followed by trials of spontaneous breathing in appropriate patients and subsequent notification of physicians of successful trials reduced the duration of mechanical ventilation compared to usual care (daily weaning parameters only).
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).
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 required 10 years for patient recruitment. They found a shorter weaning time when using unassisted breathing via tracheostomy (“T-piece”) as opposed to a pressure support method. These findings are balanced against a lack of mortality benefit at 6 and 12 months (>50% of patients in both groups had died after 6 months).
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.
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.
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.
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.
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.
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.
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.
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.
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.
Masip J, Betbese AJ, Paez J, et al. Non-invasive pressure support ventilation versus conventional oxygen therapy in acute cardiogenic pulmonary edema: a randomized trial. Lancet 2000; 356:2126-32. Study of 37 patients (of whom 43% had hypercapnia) found pressure support by mask reduced the need for intubation (5% vs. 33%). There was no difference in duration of hospital stay or mortality.
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.
***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.
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.
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.
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.
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.
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.
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.
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%).