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.
PMID: 6703497

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

Care of the intubated patient:

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

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.
PMID: 17398307

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

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).
PMID: 33471452

Ventilator weaning:

Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med 1991; 324:1445-50. Study in a VA population found the rapid shallow breathing index (RSBI = RR/Vtidal) was the single best predictor of weaning success (sensitivity 0.97, specificity 0.64).
PMID: 2023603
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Brochard L, Rauss A, Benito S, et al. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med 1994; 150:896-903. Prospective, randomized study found weaning with pressure support mode superior to SIMV mode and T-piece trials.
PMID: 7921460

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

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).
PMID: 8948561

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

Jubran A, Grant BJB, Duffner LA, et al. Effect of pressure support versus unassisted breathing through a tracheostomy collar on weaning duration in patients requiring prolonged mechanical ventilation: A randomized trial. JAMA. 2013;309:671–677. This single center study 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).
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Perkins GD, Mistry D, Gates S et al. Effect of protocolized weaning with early extubation to noninvasive ventilation vs invasive weaning on time to liberation from mechanical ventilation among patients with respiratory failure: the Breathe randomized clinical trial. JAMA. 2018; 320:1881-8. This study took place over a 3.5 year period in 41 different ICUs and included a total of 364 patients who had received invasive mechanical ventilation > 48 hours and had failed a spontaneous breathing trial. Early extubation to noninvasive ventilation did not shorten the time to successful liberation from all forms of mechanical ventilation compared to patients that were not extubated until passing a breathing trial.
PMID: 30347090

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

Rehabilitation in the critically-ill:

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

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

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

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


Terragni P, Antonelli M, Fumagalli R, et al. Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult ICU patients: a randomized controlled trial. JAMA 2010;303:1483-9. This trial of over 400 patients found a statistically non-significant reduction in VAP with early bedside tracheotomy (within 6-8 days of intubation) compared to late tracheostomy (13-15 days of intubation) (14% vs. 21%, p = 0.07). The early tracheotomy group had greater ventilator-free and ICU-free days but there was no difference in mortality or hospital length of stay. Only 69% assigned to the early group and 57% to the late group actually underwent tracheostomy, highlighting the difficulty of predicting the need for tracheostomy early in the course of illness.
PMID: 20407057
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Young D, Harrison DA, Cuthbertson BH. Effect of early vs late tracheostomy placement on survival in patients receiving mechanical ventilation: the TracMan randomized trial. JAMA. 2013; 309;2121-2129. Open, randomized, multicenter clinical trial randomized 909 patients predicted to require >7 days of ventilation to early (day 4) or late (day 10) tracheostomy. There was no change in mortality, and, of note, only 44.9% of patients randomized to the late tracheostomy group required it, as opposed to 94% of the early tracheostomy group.
PMID: 23695482
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Noninvasive mechanical ventilation and High Flow Nasal Oxygen:


Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of COPD. N Engl J Med 1995; 333:817-22. Landmark prospective, randomized study found use of NIPPV in selected patients with COPD exacerbations resulted in fewer intubations, complications, days in hospital, and lower in-hospital mortality compared to standard treatment.
PMID: 7651472
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Heart Disease:

Bersten AD, Holt AW, Vedig AE, et al. Treatment of severe cardiogenic pulmonary edema with CPAP delivered by facemask. N Engl J Med 1991; 325:1825-30. Randomized study of 39 patients with hypercapnic cardiogenic respiratory failure found use of CPAP plus oxygen resulted in better gas exchange in the first 24 hours and less need for intubation than use of oxygen alone.
PMID: 1961221
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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.
PMID: 11191538

Gray A, Goodacre S, Newby DE, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med 2008; 359:142-51. The 3CPO study, performed in 26 emergency departments, randomized 1,156 patients to standard oxygen therapy, CPAP, or NIPPV. Neither form of noninvasive support reduced 7 or 30-day mortality, and patients receiving CPAP and NIPPV did not differ in need for intubation. The lack of benefit persisted after adjusting for severity of illness. These results differ from prior positive studies, possibly due to differences in study populations and design. Intubation rates and 30-day mortality were lower in the current study, and patients deteriorating with standard oxygen therapy were allowed rescue use of noninvasive support.
PMID: 18614781
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***See also “Cowie MR, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure.” In Sleep Medicine.

Hypoxemic respiratory failure (all types):

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

Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015; 372:2185-2196. This trial randomized patients with hypoxic respiratory failure to oxygen by facemask, NIPPV, or high flow nasal cannula. This was the first study to compare HFNC to NIPPV in this setting.  Investigators found no difference in the rate of intubation, although a post hoc analysis did find a significantly decreased rate in patients with severe hypoxemia treated with HFNC. The HFNC group also had significantly more ventilator-free days and an unexpected decrease in 90 day all-cause mortality. Weaknesses in this essentially negative trial include a low power to detect inter-group differences in intubation, and some crossover between interventions.
PMID: 25981908
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Jaber S, Lescot T, Futier T et al.  Effect of noninvasive ventilation on tracheal reintubation among patients with hypoxemic respiratory failure following abdominal surgery: a randomized clinical trial.  JAMA 2016; 315: 1345-53. Oft-cited study of bilevel noninvasive ventilation for post-operative respiratory failure randomized nearly 300 patients with new hypoxemic respiratory failure within 7 days of abdominal surgery to non-invasive ventilation or oxygen therapy.  Patients receiving non-invasive ventilation required intubation less often (33.1 vs. 45.5%, p = .03) and were less likely to develop nosocomial infection.  Mortality did not differ.
PMID: 26975890
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Following extubation:

Ferrer M, Sellarés J, Valencia M, et al. Non-invasive ventilation after extubation in hypercapnic patients with chronic respiratory disorders: randomized controlled trial. Lancet 2009; 374:1082-8. In a randomized trial of over 100 patients with chronic lung disease who passed a spontaneous breathing trial but had hypercapnea post-extubation, NIPPV led to a significant reduction in subsequent respiratory failure (15% vs 48% in the control group). Rescue NIPPV averted the need for re-intubation in 17 of 27 control patients with post-extubation respiratory failure. In contrast to the Esteban study below, NIPPV in post-extubation hypercapnic respiratory failure appeared beneficial. Whether there is an advantage to immediate over prn NIPPV use in this population is unclear.
PMID: 19682735

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

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