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Recent advances in mechanical ventilation

  • Carolyn S. Calfee
    Correspondence
    Requests for reprints should be addressed to Carolyn S. Calfee, MD, University of California, San Francisco, Pulmonary Division, 505 Parnassus Avenue, San Francisco, California 94143-0111.
    Affiliations
    Cardiovascular Research Institute, San Francisco, California

    Department of Medicine, University of California at San Francisco, San Francisco, California.
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  • Michael A. Matthay
    Affiliations
    Cardiovascular Research Institute, San Francisco, California

    Department of Medicine, University of California at San Francisco, San Francisco, California.

    Department of Anesthesia, University of California at San Francisco, San Francisco, California.
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      Abstract

      Important advances have been made over the past decade towards understanding the optimal approach to ventilating patients with acute respiratory failure. Evidence now supports the use of noninvasive positive pressure ventilation in selected patients with hypercapnic respiratory failure and chronic obstructive pulmonary disease, cardiogenic pulmonary edema, and for facilitating the discontinuation of ventilatory support in patients with chronic pulmonary disease. The concept of a lung protective ventilatory strategy has revolutionized the management of the acute respiratory distress syndrome. The process of liberation from mechanical ventilation is becoming more standardized, with evidence supporting daily trials of spontaneous breathing in all suitable mechanically ventilated patients. This article critically reviews the most important recent advances in mechanical ventilation and suggests future directions for further research in the field.

      Keywords

      In the past decade, remarkable progress has been made toward understanding the optimal use of noninvasive ventilation, the management of the acute respiratory distress syndrome, and approaches to discontinuation of ventilatory support. This article reviews the evidence behind the most important recent developments in mechanical ventilation and practical issues in the application of this new data. Although this article is not a systematic review by definition, over 300 articles published within the past decade were evaluated via MEDLINE searches, review of Cochrane Library articles, and examination of selected articles’ bibliographies; over 150 articles were considered in detail for inclusion. The goal of this article is to provide a concise review of landmark, representative or particularly illustrative recent trials in ventilator management and their contributions to current clinical practice. Although important advances have been made in recent years in the area of prevention of ventilator-associated pneumonia, this topic has been recently reviewed elsewhere and will not be covered in this article.
      • Dodek P.
      • Keenan S.
      • Cook D.
      • et al.
      Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia.
      • Collard H.R.
      • Saint S.
      • Matthay M.A.
      Prevention of ventilator-associated pneumonia an evidence-based systematic review.

      Noninvasive positive pressure ventilation

      Noninvasive positive pressure ventilation, commonly referred to as bi-level positive airway pressure, has gained broader acceptance in recent years as studies have demonstrated efficacy in several clinical settings. The evidence most strongly supports the use of noninvasive ventilation in acute exacerbations of chronic obstructive pulmonary disease, cardiogenic pulmonary edema, immunocompromised patients with acute respiratory failure, and selected patients with difficulty weaning from the ventilator. Although noninvasive ventilation has been proven effective in various causes of chronic respiratory insufficiency, this article will only address its applications in the acute hospital setting.
      Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation—a consensus conference report.

      Introduction to noninvasive ventilation

      At the outset, a few epidemiologic issues should be considered. First, nearly all studies of noninvasive ventilation are by necessity unblinded, introducing the possibility of bias. Second, most of the studies are small, and their relative contributions should be weighed as such. Finally, many of the studies in this field suffer from a heterogeneity of underlying disease, whether by design or necessity, making the results all the more difficult to interpret or apply with confidence.
      In this review, as in most of the literature on this subject, the term “noninvasive ventilation” will be used to refer to positive pressure ventilatory support delivered through a nasal or full face mask with different levels of pressure support set for inspiration and expiration (frequently 10–15 and 5–8 cm H2O); it may be delivered with or without a backup rate. This type of ventilation should be clearly distinguished from continuous positive airway pressure, in which a constant level of pressure support is delivered without regard for the respiratory cycle.
      Patients should be carefully assessed for possible contraindications to the use of noninvasive ventilation before its implementation (Table 1). When employed in the care of patients with acute respiratory failure, noninvasive ventilation should always be used in a highly monitored setting such as an intensive care unit, step-down unit, or emergency department. Noninvasive ventilation should not be used in patients with impending cardiovascular collapse or respiratory arrest, because those patients will soon require endotracheal intubation. Patients who are unable to protect their airway, usually from altered mental status, should not receive noninvasive ventilation. Although it may be tempting to use noninvasive ventilation in this setting, particularly when hypercarbia is present, such patients are at very high risk for failure of noninvasive ventilation. Other important issues in the management of patients on noninvasive ventilation such as patient-ventilator interface, cost-benefit analyses, and specific ventilator settings are beyond the scope of this article and will not be addressed.
      International Consensus Conferences in Intensive Care Medicine
      Noninvasive positive pressure ventilation in acute respiratory failure.
      Table 1Contraindications to use of noninvasive ventilation
      Impending cardiovascular collapse or respiratory arrest
      Excessive secretions or massive upper gastrointestinal bleeding
      Upper airway obstruction
      Recent facial, upper airway, or upper gastrointestinal surgery
      Patient unable to protect airway, including altered mental status
      No monitored beds available (relative)

      Noninvasive ventilation in chronic obstructive pulmonary disease

      Noninvasive ventilation was first and has been most extensively demonstrated to be effective in acute, severe exacerbations of chronic obstructive pulmonary disease. Many randomized controlled trials have compared noninvasive ventilation to usual care in this setting and found noninvasive ventilation to be associated with a reduced rate of endotracheal intubation.
      • Brochard L.
      • Mancebo J.
      • Wysocki M.
      • et al.
      Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease.
      • Celikel T.
      • Sungur M.
      • Ceyhan B.
      • Karakurt S.
      Comparison of noninvasive positive pressure ventilation with standard medical therapy in hypercapnic acute respiratory failure.
      • Kramer N.
      • Meyer T.J.
      • Meharg J.
      • Cece R.D.
      • Hill N.S.
      Randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure.
      • Plant P.K.
      • Owen J.L.
      • Elliott M.W.
      Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards a multicentre randomised controlled trial.
      • Avdeev S.N.
      • Tret’iakov A.V.
      • Grigor’iants R.A.
      • Kutsenko M.A.
      • Chuchalin A.G.
      [Study of the use of noninvasive ventilation of the lungs in acute respiratory insufficiency due exacerbation of chronic obstructive pulmonary disease].
      In addition, most published trials have suggested a reduction in mortality with noninvasive ventilation compared with conventional therapy.
      • Brochard L.
      • Mancebo J.
      • Wysocki M.
      • et al.
      Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease.
      • Plant P.K.
      • Owen J.L.
      • Elliott M.W.
      Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards a multicentre randomised controlled trial.
      • Avdeev S.N.
      • Tret’iakov A.V.
      • Grigor’iants R.A.
      • Kutsenko M.A.
      • Chuchalin A.G.
      [Study of the use of noninvasive ventilation of the lungs in acute respiratory insufficiency due exacerbation of chronic obstructive pulmonary disease].
      • Bott J.
      • Carroll M.P.
      • Conway J.H.
      • et al.
      Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease.
      In the past 2 years, 3 systematic reviews were published confirming that noninvasive ventilation reduces in-hospital mortality and decreases the need for intubation in patients with acute, severe chronic obstructive pulmonary disease exacerbations.
      • Lightowler J.V.
      • Wedzicha J.A.
      • Elliott M.W.
      • Ram F.S.
      Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease Cochrane systematic review and meta-analysis.
      • Keenan S.P.
      • Sinuff T.
      • Cook D.J.
      • Hill N.S.
      Which patients with acute exacerbation of chronic obstructive pulmonary disease benefit from noninvasive positive-pressure ventilation? A systematic review of the literature.
      • Ram F.
      • Picot J.
      • Lightowler J.
      • Wedzicha J.
      Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease.
      One meta-analysis suggested that most of the benefits of noninvasive ventilation extend to those patients with severe chronic obstructive pulmonary disease exacerbations as measured by a pH of <7.3;
      • Keenan S.P.
      • Sinuff T.
      • Cook D.J.
      • Hill N.S.
      Which patients with acute exacerbation of chronic obstructive pulmonary disease benefit from noninvasive positive-pressure ventilation? A systematic review of the literature.
      this finding was not, however, confirmed in a more recent systematic review of 14 randomized controlled trials.
      • Ram F.
      • Picot J.
      • Lightowler J.
      • Wedzicha J.
      Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease.
      In addition, multiple articles have noted that the response to noninvasive ventilation within the first 2 hours as measured by improvements in pH and PaCO2 is predictive of the modality’s success or failure.
      • Poponick J.M.
      • Renston J.P.
      • Bennett R.P.
      • Emerman C.L.
      Use of a ventilatory support system (BiPAP) for acute respiratory failure in the emergency department.
      • Anton A.
      • Guell R.
      • Gomez J.
      • et al.
      Predicting the result of noninvasive ventilation in severe acute exacerbations of patients with chronic airflow limitation.
      This concept may also be applied to the use of noninvasive ventilation in other disorders.
      • Liesching T.
      • Kwok H.
      • Hill N.S.
      Acute applications of noninvasive positive pressure ventilation.

      Noninvasive ventilation in immunosuppressed patients with acute respiratory failure

      Noninvasive ventilation may be useful in patients who are profoundly immunosuppressed, particularly those who have undergone solid organ transplantation or those with hematologic malignancy, in whom mortality after endotracheal intubation is particularly high. One study randomized 40 patients with acute hypoxemic respiratory failure after solid organ transplant to conventional treatment, including high flow oxygen by face mask, or noninvasive ventilation.
      • Antonelli M.
      • Conti G.
      • Bufi M.
      • et al.
      Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation a randomized trial.
      Patients randomized to noninvasive ventilation had a lower rate of endotracheal intubation, shorter intensive care unit stays, and lower intensive care unit mortality, although in-hospital mortality did not differ significantly between the two groups (Figure 1). A second study also randomly assigned patients to either noninvasive ventilation or usual care but included febrile immunosuppressed patients with acute hypoxemic respiratory failure and pulmonary infiltrates.
      • Hilbert G.
      • Gruson D.
      • Vargas F.
      • et al.
      Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure.
      Most patients in the study were immunosuppressed as a result of therapy for hematologic malignancy. In this study sample, intermittent noninvasive ventilation was associated with lower rates of endotracheal intubation, serious complications, and intensive care unit and all-cause mortality (Figure 1). Although these 2 studies were fairly small and captured slightly different patient samples, taken together they suggest that noninvasive ventilation may be beneficial in severely immunocompromised patients with acute hypoxemic respiratory failure.
      Figure thumbnail gr1
      Figure 1Outcomes of noninvasive ventilation versus usual medical care in immunocompromised adults with acute respiratory failure. In Antonelli et al., P = 0.002 for endotracheal intubation; P = 0.05 for ICU mortality; P = 0.17 for hospital mortality. In Hilbert et al., P <0.03 for all comparisons between noninvasive ventilation and control arm. Data from Antonelli et al., 2000 (top);
      • Antonelli M.
      • Conti G.
      • Bufi M.
      • et al.
      Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation a randomized trial.
      Hilbert et al., 2001 (bottom).
      • Hilbert G.
      • Gruson D.
      • Vargas F.
      • et al.
      Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure.

      Noninvasive ventilation in acute hypoxemic respiratory failure

      Noninvasive ventilation has also been evaluated as a potential therapy for acute hypoxemic respiratory failure of any etiology. Put differently, what would happen if every patient presenting with respiratory failure and moderate to severe hypoxemia received a trial of noninvasive ventilatory support?
      The first major randomized trial in this patient population studied 41 patients with a room air PaO2 of <60 mm Hg who were randomized to noninvasive ventilation or conventional treatment.
      • Wysocki M.
      • Tric L.
      • Wolff M.A.
      • Millet H.
      • Herman B.
      Noninvasive pressure support ventilation in patients with acute respiratory failure. A randomized comparison with conventional therapy.
      There were no significant differences in rates of endotracheal intubation, length of intensive care unit stay or mortality, although a post hoc analysis indicated that hypercapnic patients seemed to benefit from noninvasive ventilation. A subsequent similar study of 61 patients who were either hypoxemic (PaO2:FiO2 <200) or hypercarbic (excluding only patients with an arterial pH <7.2) found that noninvasive ventilation was associated with a decreased rate of endotracheal intubation compared with usual medical care but had no significant impact on mortality.
      • Martin T.J.
      • Hovis J.D.
      • Costantino J.P.
      • et al.
      A randomized, prospective evaluation of noninvasive ventilation for acute respiratory failure.
      One of these studies reported that patients with hypercarbia appeared to benefit most from noninvasive ventilation,
      • Wysocki M.
      • Tric L.
      • Wolff M.A.
      • Millet H.
      • Herman B.
      Noninvasive pressure support ventilation in patients with acute respiratory failure. A randomized comparison with conventional therapy.
      whereas the other found that those with hypoxia but not chronic obstructive pulmonary disease benefited most.
      • Martin T.J.
      • Hovis J.D.
      • Costantino J.P.
      • et al.
      A randomized, prospective evaluation of noninvasive ventilation for acute respiratory failure.
      However, these conclusions were drawn from post hoc sub-group analyses in small numbers of patients.
      The largest and most rigorous study examined 105 patients with acute hypoxemic respiratory failure (PaO2 <60 mm Hg or oxyhemoglobin saturation <90% on oxygen by face mask) who were assigned randomly to noninvasive ventilation or usual care;
      • Ferrer M.
      • Esquinas A.
      • Leon M.
      • Gonzalez G.
      • Alarcon A.
      • Torres A.
      Noninvasive ventilation in severe hypoxemic respiratory failure a randomized clinical trial.
      patients with hypercapnia were excluded. Marked reductions in the rates of endotracheal intubation, septic shock, intensive care unit and cumulative 90-day mortality were demonstrated in those patients treated with noninvasive ventilation (Figure 2).
      Figure thumbnail gr2
      Figure 2Outcomes of noninvasive ventilation compared with usual medical care in patients with acute hypoxemic respiratory failure. P <0.03 for all comparisons between noninvasive ventilation and usual medical care. Data from Ferrer et al., 2003.
      • Ferrer M.
      • Esquinas A.
      • Leon M.
      • Gonzalez G.
      • Alarcon A.
      • Torres A.
      Noninvasive ventilation in severe hypoxemic respiratory failure a randomized clinical trial.
      A different question is whether noninvasive ventilation can be utilized in patients who would otherwise need intubation for acute hypoxemic respiratory failure. This question was studied in 64 patients, excluding patients with chronic obstructive pulmonary disease, randomized to noninvasive ventilation or endotracheal intubation.
      • Antonelli M.
      • Conti G.
      • Rocco M.
      • et al.
      A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure.
      The authors defined acute hypoxemic respiratory failure as the acute onset of tachypnea and a PaO2:FiO2 ratio of less than 200. Patients randomized to noninvasive ventilation had less pneumonia and sinusitis and shorter intensive care unit stays; however, no mortality difference was found.
      In sum, while some evidence suggests that noninvasive ventilation may be beneficial in the setting of acute hypoxemic respiratory failure, lingering doubts about its utility persist, in part due to the variable rigor of the existing literature on the subject and in part due to the heterogeneity of the patients studied. A large, multicenter trial of noninvasive ventilation utilizing objective criteria for hypoxemia and specifically excluding patients with cardiogenic pulmonary edema and chronic obstructive pulmonary disease would clarify this issue.

      Noninvasive ventilation versus continuous positive airway pressure in cardiogenic pulmonary edema

      Continuous positive airway pressure has demonstrated efficacy in cardiogenic pulmonary edema, reducing the rate of endotracheal intubation and showing a trend in a meta-analysis toward decreasing mortality.
      • Pang D.
      • Keenan S.P.
      • Cook D.J.
      • Sibbald W.J.
      The effect of positive pressure airway support on mortality and the need for intubation in cardiogenic pulmonary edema a systematic review.
      Although the data on bi-level noninvasive ventilation is more mixed, it may be beneficial in this setting as well. One early study demonstrated an increased rate of acute myocardial infarction in patients with cardiogenic pulmonary edema treated with bi-level noninvasive ventilation, generating anxiety about further trials in this area.
      • Mehta S.
      • Jay G.D.
      • Woolard R.H.
      • et al.
      Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema.
      Since then, however, several trials have been published that both refute the increased risk of myocardial infarction with noninvasive ventilation and suggest some benefit. Two small randomized controlled trials of about 40 patients each found that noninvasive ventilation (as compared with usual medical care, including oxygen) reduced the rate of intubation in patients with severe cardiogenic pulmonary edema; neither study found an increased rate of myocardial infarction in patients on noninvasive ventilation.
      • Levitt M.A.
      A prospective, randomized trial of BiPAP in severe acute congestive heart failure.
      • Masip J.
      • Betbese A.J.
      • Paez J.
      • et al.
      Non-invasive pressure support ventilation versus conventional oxygen therapy in acute cardiogenic pulmonary oedema a randomised trial.
      Recently, a larger multicenter trial randomizing 130 patients with cardiogenic pulmonary edema to bi-level noninvasive ventilation or conventional therapy found that noninvasive ventilation was associated with faster improvements in oxygenation, respiratory rate, and dyspnea; there was no difference between the two groups in the rate of intubation, hospital mortality, length of stay, or myocardial infarction.
      • Nava S.
      • Carbone G.
      • Dibattista N.
      • et al.
      Noninvasive ventilation in cardiogenic pulmonary edema a multicenter, randomized trial.
      Although bi-level and continuous positive airway pressure have been compared with each other in 2 small studies and several unpublished abstracts, a definitive direct comparison between the 2 approaches is still lacking.
      • Mehta S.
      • Jay G.D.
      • Woolard R.H.
      • et al.
      Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema.

      Noninvasive ventilation in other causes of acute respiratory failure

      Although noninvasive ventilation might theoretically be of benefit in other cases of acute respiratory failure, the evidence supports only the uses described above. Insufficient evidence exists to recommend noninvasive ventilation for acute respiratory failure associated with cystic fibrosis or restrictive lung disease or in the setting of acute lung injury or the acute respiratory distress syndrome.
      • Liesching T.
      • Kwok H.
      • Hill N.S.
      Acute applications of noninvasive positive pressure ventilation.
      In other instances, noninvasive ventilation seems clearly not to be of benefit. For one, noninvasive ventilation has been examined in the setting of severe community-acquired pneumonia and was not beneficial, except in those patients with an accompanying chronic obstructive pulmonary disease exacerbation.
      • Confalonieri M.
      • Potena A.
      • Carbone G.
      • Porta R.D.
      • Tolley E.A.
      • Umberto Meduri G.
      Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized evaluation of noninvasive ventilation.
      Similarly, noninvasive ventilation was of no benefit when applied to patients with post-extubation respiratory distress and may even be harmful when applied in lieu of endotracheal intubation in this setting.
      • Keenan S.P.
      • Powers C.
      • McCormack D.G.
      • Block G.
      Noninvasive positive-pressure ventilation for postextubation respiratory distress a randomized controlled trial.
      • Esteban A.
      • Frutos-Vivar F.
      • Ferguson N.D.
      • et al.
      Noninvasive positive-pressure ventilation for respiratory failure after extubation.

      Acute respiratory distress syndrome

      The standard of care for mechanical ventilation in patients with acute lung injury and the acute respiratory distress syndrome has undergone a transformation over the past decade. The prior standard of ventilation emphasized higher tidal volumes (12 mL/kg ideal body weight) because this approach was associated with better oxygenation. However, several animal studies suggested that these higher tidal volumes, which were associated with higher inspiratory airway pressures, may aggravate the initial lung injury.
      • Webb H.H.
      • Tierney D.F.
      Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure.
      • Parker J.C.
      • Hernandez L.A.
      • Longenecker G.L.
      • Peevy K.
      • Johnson W.
      Lung edema caused by high peak inspiratory pressures in dogs. Role of increased microvascular filtration pressure and permeability.
      • Kolobow T.
      • Moretti M.P.
      • Fumagalli R.
      • et al.
      Severe impairment in lung function induced by high peak airway pressure during mechanical ventilation. An experimental study.
      • Dreyfuss D.
      • Soler P.
      • Saumon G.
      Mechanical ventilation-induced pulmonary edema. Interaction with previous lung alterations.
      In 2000, the Acute Respiratory Distress Syndrome Network published the largest study to date in this patient population, comparing a low tidal volume ventilation strategy with standard of care.
      Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network.
      The study randomized 861 patients to either a low tidal volume (6 mL/kg predicted body weight) ventilation protocol (Table 2) with a plateau pressure of less than 30 cm H2O or a conventional treatment arm (12 mL/kg predicted body weight). After an interim analysis, the trial was stopped early due to a significantly lower mortality in the low tidal volume, plateau pressure limited group (31% vs. 40%, P = 0.007). A subsequent secondary analysis of the data from this trial found that the benefit of low tidal volume ventilation extended to patients with different clinical risk factors for the acute respiratory distress syndrome.
      • Eisner M.D.
      • Thompson T.
      • Hudson L.D.
      • et al.
      Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome.
      Since that time, low tidal volume ventilation per the Acute Respiratory Distress Syndrome Network protocol has become a standard for many patients with this clinical disorder.
      Table 2Low tidal volume and plateau pressure limited ventilation for acute lung injury and the acute respiratory distress syndrome: protocol summary
      VariableProtocol
      Ventilator modeVolume assist-control
      Tidal volume≤6 mL/kg predicted body weight
      Plateau pressure≤30 cm H2O
      Ventilation set rate/pH goal6–35/min, adjusted to achieve arterial pH ≥7.30 if possible
      Inspiratory flowAdjust flow to achieve ratio of duration of inspiration to expiration of 1:1–1:3
      Oxygenation goal55 ≤PaO2 ≤80 mm Hg or 88 ≤ oxyhemoglobin saturation by pulse oximetry ≤95%
      Fraction of inspired oxygen/Positive end-expiratory pressure combinations0.3/5, 0.4/5, 0.4/8, 0.5/8, 0.5/10, 0.6/10, 0.7/10, 0.7/12, 0.7/14, 0.8/14, 0.9/14, 0.9/16, 0.9/18, 1.0/18, 1.0/22, 1.0/24. Further increases in positive end-expiratory pressure to 34 cm H2O were allowed but not required.
      WeaningAttempts to wean by pressure support required when the fraction of inspired oxygen was ≤0.40 and the positive end-expiratory pressure was ≤8
      Adapted with permission from Brower et al., 2001.
      • Brower R.G.
      • Ware L.B.
      • Berthiaume Y.
      • Matthay M.A.
      Treatment of ARDS.
      Building on this study, the Acute Respiratory Distress Syndrome Network has recently reported the results of another large study designed to examine whether higher levels of positive end-expiratory pressure confer additional benefit when used in conjunction with a low tidal volume strategy.
      A trial of mechanical ventilation with higher versus lower positive end-expiratory pressures in patients with acute lung injury and acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network.
      Higher positive end-expiratory pressure levels might theoretically be beneficial by reducing regions of nonaerated lung and decreasing the need for supplemental oxygen, thereby reducing oxygen toxicity. Although designed to reach an enrollment of 750 patients, the trial was stopped after the enrollment of 549 patients given the equivalence of the 2 treatment arms and a very small chance of finding a significant effect. While no benefit to a high positive end-expiratory pressure strategy was found, this trial did confirm the benefit of a low tidal volume and plateau pressure limited strategy, finding a mortality rate of 26% across the board in acute respiratory distress syndrome, notably lower than the mortality rates in this condition before the low tidal volume era.
      While low tidal volume ventilation has gained widespread acceptance as a lung protective ventilatory strategy for the acute respiratory distress syndrome, several other therapies have been investigated as potential accessory modalities for patients with particularly severe disease. Nitric oxide, thought to perhaps ameliorate ventilation-perfusion mismatch via its vasodilatory properties, has been employed as an adjunct to mechanical ventilation in severe acute respiratory distress syndrome. A recent systematic review of nitric oxide in acute hypoxemic respiratory failure (predominantly the acute respiratory distress syndrome or acute lung injury) found only 5 trials that met standards for inclusion in the review and found no impact on mortality; however, there was a transient improvement in oxygenation.
      • Sokol J.
      • Jacobs S.E.
      • Bohn D.
      Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults.
      Similarly, prone ventilation has been considered a rescue option for patients with the acute respiratory distress syndrome who are particularly difficult to oxygenate. In the largest, most rigorous trial to date of this technique in patients with acute lung injury, 6 hours per day of prone positioning was associated with a transient improvement in oxygenation but no mortality benefit.
      • Gattinoni L.
      • Tognoni G.
      • Pesenti A.
      • et al.
      Effect of prone positioning on the survival of patients with acute respiratory failure.
      Finally, high-frequency oscillatory ventilation, a technique in which patients are ventilated with very low tidal volumes at 4–250 times usual respiratory rates, has been shown in observational studies to lead to transient improvements in oxygenation. However, a recent systematic review concluded that there was insufficient evidence to recommend its use in the acute respiratory distress syndrome.
      • Wunsch H.
      • Mapstone J.
      High-frequency ventilation versus conventional ventilation for treatment of acute lung injury and acute respiratory distress syndrome.
      Thus, although nitric oxide, prone positioning, and high-frequency ventilation may improve oxygenation in patients with the acute respiratory distress syndrome, at this time the evidence does not support their routine use, and none of these strategies have yet demonstrated a mortality benefit.

      Discontinuation of ventilatory support and weaning

      The timing of and approach to discontinuation of mechanical ventilation are among the most extensively studied and controversial areas of modern ventilator management. The basic questions investigators have been attempting to answer are the following: when should a patient be evaluated for possible extubation, and how should their readiness for extubation be assessed?

      When to consider extubation, and the spontaneous breathing trial

      Contemplating tests of readiness for extubation presumes that the patient has met multiple preconditions (Table 3): the underlying disease process that necessitated intubation is improving; the patient is hemodynamically stable and neurologically capable of spontaneous breathing and airway protection; and the patient is able to oxygenate well on minimal ventilatory support.
      • MacIntyre N.R.
      Issues in ventilator weaning.
      Once these conditions have been met, the patient should undergo a spontaneous breathing trial with minimal ventilatory support; measurements made during that trial can then be used to evaluate the likelihood of successful extubation. The spontaneous breathing trial may be conducted using either a T-piece or low levels of continuous positive airway pressure and need be no longer than 30 minutes.
      • Esteban A.
      • Alia I.
      • Gordo F.
      • et al.
      The Spanish Lung Failure Collaborative Group
      Extubation outcome after spontaneous breathing trials with T-tube or pressure support ventilation.
      • Esteban A.
      • Alia I.
      • Tobin M.J.
      • et al.
      Spanish Lung Failure Collaborative Group
      Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation.
      In a landmark trial published in 1996, implementation of a protocol in which all patients on mechanical ventilation were screened daily for appropriateness of a spontaneous breathing trial decreased the total number of ventilated days as well as the complications of mechanical ventilation, including reintubation.
      • Ely E.W.
      • Baker A.M.
      • Dunagan D.P.
      • et al.
      Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously.
      Later trials subsequently confirmed that these spontaneous breathing trial protocols can be driven by nonphysician personnel (eg, respiratory therapists) with no loss of safety or efficacy.
      • Ely E.W.
      • Bennett P.A.
      • Bowton D.L.
      • Murphy S.M.
      • Florance A.M.
      • Haponik E.F.
      Large scale implementation of a respiratory therapist-driven protocol for ventilator weaning.
      Table 3Suggested criteria for consideration of extubation readiness
      Underlying disease process that necessitated intubation is improving
      Hemodynamically stable
      Appropriate mental status
      Capable of upper airway protection
      Ventilator settings: fraction of inspired oxygen ≤0.40; positive end-expiratory pressure ≤8 cm H2O

      Predictors of successful extubation

      Once a spontaneous breathing trial is performed, how should its results be judged? Perhaps the best known and most widely used measure of extubation readiness is the respiratory rate to tidal volume ratio, also known as the rapid shallow breathing index or the Yang-Tobin index.
      • Yang K.L.
      • Tobin M.J.
      A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation.
      In their well-known study, Yang and Tobin challenged the traditional markers of extubation readiness, minute ventilation, and maximal inspiratory pressure, and proposed the rapid shallow breathing index as an alternative. They defined the index as respiratory rate over tidal volume (in liters), measured during spontaneous breathing for 1 minute; low values are thereby derived from a low respiratory rate and high tidal volume. Using a cutoff for the rapid shallow breathing index of ≤105 maximized sensitivity and specificity. Their finding has since been confirmed in other prospective studies, including one that suggested that the rapid shallow breathing index measured after 30 minutes of minimal support outperforms the rapid shallow breathing index measured immediately after support is decreased.
      • Chatila W.
      • Jacob B.
      • Guaglionone D.
      • Manthous C.A.
      The unassisted respiratory rate-tidal volume ratio accurately predicts weaning outcome.
      In one of a series of systematic reviews on the topic of ventilator discontinuation published in 2001, the rapid shallow breathing index and respiratory rate alone were found to have the largest area under the receiver-operator curve, suggesting the best combination of sensitivity and specificity.
      • Meade M.
      • Guyatt G.
      • Cook D.
      • et al.
      Predicting success in weaning from mechanical ventilation.
      However, the rapid shallow breathing index is by no means the only well-studied marker of extubation readiness; in fact, a 1999 systematic review from McMaster University found 66 measures with at least some evidence to support their use.
      • Cook D.
      • Meade M.
      • Guyatt G.
      • et al.
      Evidence Report on Criteria for Weaning from Mechanical Ventilation.
      Of those 66 proposed measurements, 8 were found to have consistently positive (but low) likelihood ratios for predicting successful extubation (Table 4).
      • MacIntyre N.R.
      • Cook D.J.
      • Ely Jr, E.W.
      • et al.
      Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine.
      Because of the plethora of potential markers and the variable performance of any one of those markers in an individual patient, the 2001 consensus statement on this subject by the American College of Chest Physicians recommended a more holistic approach to interpretation of the success or failure of a spontaneous breathing trial, incorporating both objective measures of clinical stability and subjective assessments of the patient’s comfort, work of breathing, and mental status
      • MacIntyre N.R.
      • Cook D.J.
      • Ely Jr, E.W.
      • et al.
      Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine.
      (Table 5).
      Table 4Predictors of successful extubation
      ParameterNo. studiesThreshold valuesLikelihood ratio range
      The range of likelihood ratios reported for the given parameter in published studies.
      Measured on ventilator
       Minute ventilation20≤10–15 L/min0.8–2.4
       Negative inspiratory force10≥−20 to −30 cm H2O0.2–35.8
       Maximal inspiratory pressure16≥−15 to −30 cm H2O1.0–3.0
       Mouth occlusion pressure 0.1 seconds after onset of inspiratory effort/maximal inspiratory pressure4≤0.302.1–25.3
       CROP score (index incorporating compliance, rate, oxygenation, and pressure)2≥131.1–19.7
      Measured during spontaneous breathing
       Respiratory rate24≤30–38 breaths/min1.0–3.9
       Tidal volume18≥325–408 mL (4–6 mL/kg)0.7–3.8
       Respiratory rate/tidal volume20≤60–1050.8–4.7
      Adapted with permission from MacIntyre et al., 2001.
      • MacIntyre N.R.
      • Cook D.J.
      • Ely Jr, E.W.
      • et al.
      Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine.
      low asterisk The range of likelihood ratios reported for the given parameter in published studies.
      Table 5Subjective and objective criteria for tolerance of a spontaneous breathing trial
      CriteriaDescription
      Objective measurementsAdequate gas exchange (oxyhemoglobin saturation ≥88% to 90% or PaO2 ≥55 mm Hg on ≤40% inspired oxygen; increase in PaCO2 ≤10 mm Hg)
      Hemodynamic stability (failure to develop new tachycardia, hypertension or hypotension on spontaneous breathing trial; no pressors required)
      Stable ventilatory pattern (respiratory rate <30–35 breaths/min)
      Subjective clinical assessmentsChange in mental status (eg, somnolence, coma, agitation, anxiety)
      Diaphoresis
      Signs of increasing work of breathing (use of accessory muscles, abdominal paradox)
      Onset or worsening of discomfort
      Adapted with permission from MacIntyre et al., 2001.
      • MacIntyre N.R.
      • Cook D.J.
      • Ely Jr, E.W.
      • et al.
      Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine.

      Noninvasive ventilation and ventilator discontinuation

      In the past several years, several studies have examined the potential role of noninvasive ventilation in ventilator discontinuation, particularly for patients with acute or chronic respiratory failure secondary to chronic obstructive pulmonary disease. The first major study in this area randomized 50 patients with a chronic obstructive pulmonary disease exacerbation who had failed a spontaneous breathing trial to either extubation and immediate noninvasive ventilation, or continued daily spontaneous breathing trials.
      • Nava S.
      • Ambrosino N.
      • Clini E.
      • et al.
      Noninvasive mechanical ventilation in the weaning of patients with respiratory failure due to chronic obstructive pulmonary disease. A randomized, controlled trial.
      Noninvasive ventilation was associated with a lower number of patients requiring ventilatory support at 3 weeks and lower 60-day mortality. A second similar study of 33 patients with underlying lung disease (mostly chronic obstructive pulmonary disease) found that noninvasive ventilation shortened the duration of intubation but increased the total duration of ventilatory support without impacting mortality.
      • Girault C.
      • Daudenthun I.
      • Chevron V.
      • Tamion F.
      • Leroy J.
      • Bonmarchand G.
      Noninvasive ventilation as a systematic extubation and weaning technique in acute-on-chronic respiratory failure a prospective, randomized controlled study.
      In a third similarly designed, recently published trial of 43 patients with underlying lung disease (the majority of which was chronic obstructive pulmonary disease), noninvasive ventilation was associated with significant reductions in duration of invasive ventilation, intensive care and hospital length of stay, intensive care unit mortality, serious complications of mechanical ventilation, and cumulative 90-day survival.
      • Ferrer M.
      • Esquinas A.
      • Arancibia F.
      • et al.
      Noninvasive ventilation during persistent weaning failure a randomized controlled trial.
      A meta-analysis of these 3 studies and 2 smaller studies found that noninvasive ventilation in this setting seems to decrease mortality, hospital length of stay, incidence of ventilator-associated pneumonia, and total duration of mechanical ventilation.
      • Burns K.
      • Adhikari N.
      • Meade M.
      Noninvasive positive pressure ventilation as a weaning strategy for intubated adults with respiratory failure.
      Although the results of these trials are noteworthy and largely concordant, some important caveats remain. Patients enrolled in these trials were by definition those that had failed spontaneous breathing trials; therefore, those randomized to the “conventional weaning” arms were consigned to undergo tests that they had already been shown not to pass. In other words, perhaps noninvasive ventilation is successful in this setting in part because it mandates extubating patients who could be successfully extubated but did not meet conventional extubation criteria, which may be inappropriate for patients with chronic lung disease. Secondly, patients in these studies were both carefully selected as otherwise good candidates for extubation and closely monitored for signs of impending need for reintubation, important issues to consider in the practical application of this data.

      Conclusions

      Major advances have been made in the past decade in determining the optimal ventilatory strategy for some of the most common causes of acute respiratory failure. Noninvasive ventilation can be strongly recommended as an effective therapy for severe chronic obstructive pulmonary disease exacerbations and cardiogenic pulmonary edema; it should be considered as potentially beneficial in acute respiratory failure in immunocompromised patients and as a weaning modality in patients with underlying chronic lung disease. Lung protective ventilation with a low tidal volume and plateau pressure limited strategy has revolutionized the management of the acute respiratory distress syndrome with an associated sharp decrease in mortality, while adjunctive therapies like nitric oxide and high-frequency ventilation have not reduced mortality. Mechanically ventilated patients should be evaluated on a daily basis for the appropriateness of a spontaneous breathing trial, and the success or failure of the trial should be judged based both on subjective criteria and objective measurements like the rapid shallow breathing index.

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