Difficulty weaning from mechanical ventilation; Failure to wean, respiratory failure, ventilator dependence

1. Description of the problem

What every clinician needs to know

Invasive mechanical ventilation for acute respiratory failure provides life-saving supportive care. It is also associated with numerous complications that prolong the duration of time spent on the ventilator and increases mortality. Thus, liberating the patient from the ventilator and removing the endotracheal tube (extubation) as soon as it is safe to do so are of extreme importance. This process of liberation has been termed “weaning” and encompasses all efforts to free the patient from the ventilator.

These efforts can take the form of daily spontaneous breathing trials (SBTs) in which patients go from full support to minimal or no ventilatory support as a test of their capacity to breathe on their own. Recognition of readiness for spontaneous breathing followed by timely SBTs, lasting from 30 to 120 minutes, and conducted on T-piece, CPAP, or low levels of pressure support (with or without automatic tube compensation), has become the preferred method of weaning.

Weaning can also be carried out by a process of progressive withdrawal in which ventilatory support is gradually withdrawn. For example, the level of pressure support may be decreased by 2-4 cm H2O per day as long as the patient does not show signs of intolerance. Conversely, daily T-piece trials of systematically increasing duration can be used.

Difficulty weaning from mechanical ventilation can be defined as failure to tolerate SBTs or failure to tolerate more systematic reduction in the level of ventilatory support. Using a new classification of weaning this group includes patients with difficult weaning (patient takes up to three SBTs or up to seven days from first SBT to be successfully extubated) and prolonged weaning (patient fails at least three SBTs or requires more than 7 days from the first SBT to be successfully extubated). This should be distinguished from simple weaning, where the patient tolerates the initial SBT and is successfully extubated.

Diagnosis of failure to tolerate either SBTs or systematic reduction in the degree of ventilatory support should be based on rigorous objective and subjective criteria. The diagnostic effort is then extended to identify the underlying pathophysiologic cause for difficulty weaning from mechanical ventilation.

Key management points

• Return the patient to full ventilatory support.

• Treat reversible pathophysiologic causes of weaning failure.

• Consider using a weaning protocol to standardize the weaning process.

• Consider daily SBTs.

• Consider systematic reduction in ventilatory support using pressure support ventilation.

• In appropriate patients, consider using non-invasive ventilation as a weaning technique.

3. Diagnosis

There are two components to diagnosis. The first is identifying the patients with difficulty weaning from mechanical ventilation. This diagnosis is made using rigorous objective and subjective criteria. The presence of one or more of these criteria indicates that the patient is not tolerating a trial of spontaneous breathing or slower reductions in the level of respiratory support (e.g., progressive withdrawal). The second component is identifying why the patient is having difficulty weaning from mechanical ventilation. This involves a detailed consideration of the pathophysiology of weaning failure coupled with diagnostic testing. Specifically, the goal is to identify reversible causes of weaning failure.

Diagnostic criteria used to identify the patient with difficulty weaning from mechanical ventilation

The patient must be carefully observed during either an SBT or during a reduction in the level of respiratory support. It is recommended that the cause for weaning intolerance be carefully documented. Such information may inform efforts to identify the etiology of weaning intolerance.

Objective criteria for determining the patient is not tolerating weaning include one or more of the following during weaning:

Development of hypoxemia: PaO2/FiO2 < 120-150* or PaO₂ <60 mmHg (or SaO₂ <0.90) on FiO₂ >0.40-0.50 on PEEP ≤5-8 cmH2O*.

(*PaO2/FiO2 < 120 may be an appropriate threshold in patients with chronic hypoxemia; PEEP values of 6-8 cmH2O may be appropriate in patients with morbid obesity or abdominal distention.)

Development of hypercapnia: When compared to before the start of weaning, an increase in PaCO₂ > 10 mmHg or decrease in pH >0.10.

Development of tachypnea: Respiratory rate > 35 breaths/min for at least 5 minutes.

Development of tachycardia: Heart rate > 140 bpm or an increase > 20% of baseline.

Development of hyper- or hypotension: Systolic blood pressure < 90 mmHg or > 160 mmHg or change of > 20% from baseline.

Subjective criteria for determining the patient is not tolerating weaning include one or more of the following during weaning:

Development of signs of increased work of breathing: presence of thoracoabdominal paradox or excessive use of accessory respiratory muscles.

Development of other signs of distress: diaphoresis or agitation.

Diagnosing the cause for difficulty weaning from mechanical ventilation: Detecting the pathophysiology of weaning failure

Diagnosing the cause for difficulty weaning from mechanical ventilation: detecting the pathophysiology of weaning failure

Once a patient fails a SBT or a reduction in ventilatory support a systematic investigation should be undertaken to identify the underlying pathophysiology. The vast majority of patients with difficulty weaning manifest an imbalance between the work of breathing and the neuromuscular capacity to do that work: the work of breathing is elevated and/or neuromuscular capacity is decreased. Increased work of breathing can result from either increased airways resistance or increased elastance (elastance is the inverse of compliance).

In these instances, the work of each breath is increased: increased ventilatory demand, increased minute ventilation and therefore increased work per minute. In either case increased work of breathing predisposes to the development of respiratory muscle fatigue and, if respiratory muscle rest is not provided, structural injury to the muscles. Additional factors that can result in failure to wean include cardiac dysfunction (heart failure or ischemia) or psychological mechanisms.

• Hypoxemia

• Increased work of breathing:

  Increased ventilatory demand

  Increased resistive load

  Increased elastic load

• Decreased neuromuscular capacity

  Respiratory muscle weakness

  Decreased ventilatory drive

• Cardiac dysfunction

• Psychological dysfunction

Hypoxemia

Hypoxemia may cause difficulty weaning, more often by preventing weaning efforts (adequate oxygenation is prerequisite for initiating weaning) and occasionally when it develops during a trial of weaning. Hypoxemia increases the work of breathing per minute by increasing total minute ventilation. In the presence of hypoxemia oxygen delivery to the respiratory muscles may be inadequate, predisposing to muscle fatigue or failure. Patients with morbid obesity or abdominal distention are predisposed to atelectasis during weaning, with resulting shunt causing hypoxemia. Worsening airflow obstruction (from asthma or COPD) during weaning can increase ventilation-perfusion mismatch and result in hypoxemia. Processes that increase peripheral oxygen utilization such as agitation, fever and sepsis will cause worsening hypoxemia (by decreasing mixed venous oxygen content) in the setting of pre-existing ventilation-perfusion mismatch.

Increased ventilatory demand

Factors that increase ventilatory demand include:

• Increased carbon dioxide production (secondary to sepsis, overfeeding, fever, hyperthyroidism)

• Metabolic acidosis (e.g., secondary to renal failure, ketoacidosis, lactic acidosis)

• Anxiety/Delirium

• Pain

• Hypoxemia

• Increased dead space (secondary to dynamic hyperinflation, pulmonaryembolism, intravascular volume depletion, heat and moisture exchangers).

Increase elastic work of breathing

Factors that Increase elastic work of breathing include:

• Increased dynamic hyperinflation or intrinsic PEEP

• Pneumonia

• Pulmonary edema (secondary to volume overload, congestive heart failure, or acute lung injury)

• Atelectasis

• Pleural effusion(s)

• Pneumothorax

• Abdominal distention (secondary to ascites, ileus, morbid obesity, pregnancy)

Increased elastic work of breathing can be detected by measuring static compliance (Cstat):

Cstat = Tidal Volume/(Plateau pressure – PEEPi) where Plateau pressure is the pressure recorded during an inspiratory hold maneuver and PEEPi is the level of intrinsic PEEP (determined during an expiratory hold maneuver). Cstat values < 70 ml/cmH2O are abnormal. The presence of PEEPi is suggested by examining the Flow-Time graphic on the ventilator and noting that expiratory flow is still active (e.g., flow has not returned to zero) at the time the next breath is taken/delivered.

This qualitative assessment of PEEPi should be followed by a quantitative determination. By applying the expiratory pause button on the ventilator, the amount of PEEPi present can be detected. For this measurement to accurately reflect the degree of dynamic hyperinflation the patient must be relaxed during the maneuver and not actively expiring.

The presence of elevated PEEPi increases the elastic work of breathing while also presenting an inspiratory threshold load for the patient; that is, work must be performed to stop the inward recoil of the lung and chest wall before inspiration can occur. Increased elastic work load can also manifest as a pattern of rapid and shallow breathing resulting in a high frequency to tidal volume ratio (f/Vt > 100 breaths/L/min).

Increased resistive work of breathing

Increased resistive work of breathing results from any process that narrows the airways and thus increases airways resistance:

• Increased respiratory secretions (secondary to tracheitis, bronchitis, pneumonia)

• Bronchoconstriction (secondary to asthma, COPD)

• Narrow endotracheal tube (< 7.5 mm internal diameter tubes) Note: larger tubes (e.g., 7.5-8 mm internal diameter) can rapidly narrow as a result of secretions adhering to the inner aspect of the lumen.

• Ventilator apparatus (heat and moisture exchanger or HME, ventilator tubing)

Increased airways resistance can be detected by several methods:

• Presence of wheezing on physical examination

• A large difference between peak airway pressure and plateau pressure

• Direct measurement of airways resistance (R) using an application available on most ventilators. An airways resistance value greater than 20 cm H2O/L/s has been associated with difficulty weaning from mechanical ventilation.

Increased airways resistance during expiration results in expiratory airflow limitation leading to dynamic hyperinflation (or elevated intrinsic PEEP). The presence of intrinsic PEEP increases the inspiratory work of breathing by making it more difficult for the patient to trigger the ventilator.

Worsening dynamic hyperinflation also predisposes to difficulty weaning by increasing elastic work of breathing (more work is needed to inflate the already overinflated lung) and decreasing diaphragmatic function. Increased resistive work load may also manifest as a pattern of rapid and shallow breathing resulting in a high frequency to tidal volume ratio (f/Vt > 100 breaths/L/min).

Decreased neuromuscular capacity and decreased ventilatory drive

• Decreased neuromuscular capacity:

  Critical illness neuromyopathy

  Electrolyte abnormalities (hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia)

  Medications (steroids-induced myopathy, neuromuscular blocking agents)

  Malnutrition (atrophy of respiratory muscles)

  Ventilator-induced diaphragmatic dysfunction (secondary to excessive ventilatory support)

  Hypothyroidism

  Adrenal insufficiency

  Sepsis

• Decreased ventilatory drive:

  Central nervous system injury (secondary to increased intracranial pressure, stroke, infection, toxic-metabolic encephalopathy)

  Excessive sedation

  Metabolic alkalosis

  Obesity hypoventilation syndrome

Failed weaning can be associated with the development of respiratory muscle fatigue, which could predispose to structural muscle injury and hinder future weaning efforts. In fact, it appears that fatigue rarely occurs during a well-monitored SBT as long as the patient is expeditiously returned to ventilatory support.

Decreased neuromuscular capacity can be identified by measuring negative inspiratory force, with the ability to generate a force more negative than -20 to -30 cmH2O indicative of muscle weakness. The test is best done in a cooperative patient. Use of a device with a one-way valve (allowing expiration but not inspiration) can induce a maximal effort in the uncooperative patient.

The ability to generate a normal negative inspiratory force does not guarantee normal respiratory muscle function as the test does not detect problems with the endurance of muscle contraction. Decreased neuromuscular capacity may also manifest as a pattern of rapid and shallow breathing resulting in a high frequency to tidal volume ratio (f/Vt > 100 breaths/L/min).

In response to decreased neuromuscular capacity and/or increased work of breathing, patients with weaning intolerance often manifest increased respiratory drive. Increased respiratory drive, resulting from physiologic (hypoxemia, increased CO2 production, metaboic acidosis, increased dead space) or non-physiologic (anxiety), can lead to difficult weaning, especially in the patient with expiratory airflow obstruction (asthma or COPD). In this setting, increased minute ventilation can worsen dynamic hyperinflation.

Decreased ventilatory drive usually impedes the weaning process by delaying the initiation of weaning, though on occasion it can manifest as intolerance to weaning (e.g., patient does not tolerate a SBT or progressive withdrawal). Recognition of this relationship has led clinicians to utilize strategies to decrease sedation. This can be achieved by using a sedation algorithm that targets a patient who is awake, alert (or easily arousable), and cooperative. Alternatively, the same goal can be achieved by daily interruption of sedation.

Cardiac dysfunction

In up to 10% of patients difficult weaning can result from the presence of underlying cardiac disease. This cardiac limitation to weaning is a result of a complex cardiopulmonary interaction. During weaning oxygen consumption by the respiratory muscles can be considerable (up to 50% of total oxygen consumption). Therefore, in the presence of significant cardiac dysfunction, there may be inadequate blood flow and oxygen delivery to the respiratory muscles, predisposing to their fatigue and failure.

Indeed, patients who wean successfully will increase cardiac output and stroke volume during the trial. Conversely, patients who fail weaning often fail to appropriately increase cardiac output during weaning. The increased respiratory work of weaning and need for increased oxygen delivery can precipitate ischemia in the presence of high-grade coronary stenoses. In addition, the increased work of breathing associated with weaning constitutes a significant stress test with elevations of plamsa cortisol, glucose, and insulin and increased release of catecholamines.

The transition from positive-pressure ventilation to the negative swings in intrathoracic pressure seen during an SBT may precipitate cardiogenic pulmonary edema. Negative intrathoracic pressure results in increases in both cardiac preload and afterload. Positive fluid balance has been associated with weaning failure.

Methods of detection:

• Myocardial ischemia

  Continuous multi-channel EKG

  Nuclear medicine scanning

• Pulmonary edema

  Echocardiogram (transthoracic or transesophageal)

  Non-invasive measurements of cardiac output

  Measurement of BNP or N-terminal pro-BNP prior to weaning or at the end of the weaning trial.

Psychological factors

There is increasing recognition that psychological factors may contribute to difficulty weaning. These may be in the setting of underlying psychiatric disease (e.g., anxiety, depression) or acquired disturbances (e.g., delirium, depression). Psychological factors can cause physiologic abnormalities (e.g., increased O2 consumption, increased CO2 production, increased minute ventilation) that can contribute to weaning failure. Conversely, psychological distress can produce findings that mimic those seen with weaning failure for other reasons. Signs and symptoms thought to be indicative of weaning failure such as agitation, diaphoresis, tachycardia and tachypnea can also be a result of psychological distress.

4. Specific Management

Return the patient to full ventilatory support

Once patients have developed signs of intolerance to weaning, they should immediately be returned to full ventilatory support. A well-monitored weaning trial with immediate return to full ventilatory support at the first signs of intolerance does not appear to result in respiratory muscle fatigue. This observation is important because it means that another attempt at weaning (after appropriate efforts to identify and treat the cause) can be safely initiated within the next 24 hours. In contrast, should the patient not be rapidly returned to full ventilatory support, there is a risk that fatigue may develop. Under those circumstances, the patient should be rested on full ventilatory support for at least 24 hours before further attempts at weaning. Failure to do so increases the likelihood that future attempts will fail.

Treat reversible causes of weaning failure

Further attempts at weaning are likely to be unsuccessful until the underlying pathophysiologic cause for weaning failure has been addressed. (See Table I.)

Management of Cardiac Limitation to Weaning

The clinician should maintain a high index of suspicion that the cardiopulmonary interaction may be limiting weaning, especially in patients with underlying cardiac disease. Treatment of cardiogenic pulmonary edema should consist of diuretics and afterload reduction. When cardiac ischemia is present, nitrates and beta blockers should be used. In general, beta-1 selective agents are well tolerated in patients with underlying COPD. If concern about using such agents is present, a trial of the short-acting agent esmolol may be considered. If beta blockade results in increased airflow obstruction, inhaled anticholinergics should be administered. Because positive-pressure ventilation can effectively decrease preload and afterload, non-invasive ventilation may be used after extubation in patients at high risk for cardiogenic pulmonary edema.

Management of Psychological Limitation to Weaning

Psychological factors should be considered in patients with underlying psychiatric disease or when delirium (or any process leading to abnormal mental status) is present. Psychological factors should be considered when extensive evaluation cannot detect a pathophysiologic explanation in patients failing weaning trials. Uncontrolled observations suggest that interventions such as biofeedback, relaxation techniques and hypnosis may be beneficial in some patients. Similarly, treatment for depression may be helpful, though the ideal agent has not been identified. Treatment of delirium using haloperidol or olanzepine may facilitate weaning. Dexmedetomidine appears to be associated with less delirium and shorter time to extubation compared to benzodiazepines.

Consider using a protocol

Protocols provide a standard approach to the weaning process and have been shown to reduce weaning time and total duration of mechanical ventilation.

Weaning protocols

After evaluation for reversible causes of weaning failure, it is recommended that a protocolized approach to weaning be used. There are several elements to a weaning protocol (screening, SBTs, and progressive withdrawal):

1. Screening (can be conducted by physicians, ICU nurses or respiratory therapists)

At least once per day the patient should be screened for readiness for weaning. Screening should be deferred if the patient has active myocardial ischemia, has a newly developing significant medical problem (e.g., just diagnosed with ventilator-associated pneumonia) or is anticipated to require travel outside the ICU for testing (e.g., CT scan). The following screening criteria should be used:

– Adequate oxygenation as evidence by PaO2/FiO2 < 120-150* or PaO₂ <60 mmHg (or SaO₂ <0.90) on FiO₂ >0.40-0.50 on PEEP ≤5-8 cmH2O*

(* PaO2/FiO2 < 120 may be an appropriate threshold in patients with chronic hypoxemia; PEEP values of 6-8 cmH2O may be appropriate in patients with morbid obesity or abdominal distention)

– Hemodynamic stability as evidenced by absence of hypotension. No or only low doses of vasoactive agents should be necessary to maintain an adequate blood pressure.

– Evidence of adequate respiratory drive (triggers the ventilator when the level of machine support is reduced)

(Note: Some experts also use one or more weaning parameters, with the frequency-tidal volume ratio most common [f/Vt <100 breaths/L/min], in determining whether or not to perform an SBT.)

(Note: There is no clear evidence that fever, anemia [hemoglobin < 10 mg/dl] or abnormal mental status should exclude efforts to wean. Patients with active uncontrolled infection; ongoing blood loss/bleeding; or deteriorating mental status should have screening deferred.)

2. Patients passing the readiness screen should undergo either an SBT or progressive withdrawal of ventilatory support.

3. The SBT should be conducted on T-piece, PSV ≤ 7 cmH2O (PEEP ≤ 5 cmH2O), CPAP 5 cmH2O or ATC (automatic tube compensation) for 120 minutes (using the “Diagnostic criteria used to identify the patient with difficulty weaning from mechanical ventilation” to determine if the patient has tolerated the trial). Multiple daily SBTs are acceptable as long as there is no clinical evidence for respiratory muscle fatigue. Patients tolerating a SBT should be considered for extubation (see below).

4. Progressive withdrawal should be carried out using one of two techniques:

A. Pressure Support Ventilation (PSV)

– Initiate PSV at a level resulting in a respiratory rate < 25-35 breaths/min.

– Decrease the PSV level by 2-4 cmH2O each day as long as the patient tolerates the reduction as assessed using the “Diagnostic criteria used to identify the patient with difficulty weaning from mechanical ventilation.”

-If the decrease in PSV is not tolerated, increase the level of PSV until the respiratory rate is < 25-35 breaths/min.

– Once PSV ≤ 7 cmH2O is tolerated for 2-24 hours, consider extubation (see below).

B. T-piece

-Initiate short periods of T-piece breathing (e.g., 5-10 minutes) using “Diagnostic criteria used to identify the patient with difficulty weaning from mechanical ventilation” to assess if the patient is tolerating the trial.

– Increase the length of these periods until 120 minutes are tolerated, then consider extubation (see below).

5. Many experts will combine SBTs with progressive withdrawal. With this strategy, the patient passing the SBT is considered for extubation. The patient failing the SBT is returned to mechanical ventilation, where efforts at progressive withdrawal continue.

6. SIMV (or IMV) alone should not be used as a weaning technique. The combination of PSV and SIMV is not recommended.

7. The decision to extubate should be based on the following:

– Ability to follow simple commands (awake and easily arousable)

– Adequate cough

– Absence of excessive respiratory secretions (requiring airway suctioning less often than every two hours)

Extubation success is greatest when all three are present and risk for extubation failure is greatest when all three are absent. Patients with poor mental status but minimal secretions and adequate cough can often be successfully extubated.

In addition, patients should not have evidence of upper airway obstruction. Those deemed to be at increased risk for upper airway obstruction (prolonged intubation, traumatic intubation, multiple intubations, large endotracheal tube for native airway size) should undergo a cuff leak test to assess patency of the upper airway.

8. Patients not passing the readiness screen or intolerant of either SBTs or decreases in ventilatory support should continue to undergo investigation to identify reversible causes of weaning failure.

9. In select patients intubated with COPD exacerbation, and acute-on-chronic respiratory failure, consideration may be given to using non-invasive ventilation (NIV) as a weaning technique. The patient should have satisfied the screening criteria for readiness and the criteria for extubation. The patient must be able to tolerate spontaneous breathing for at least 5-10 minutes to allow for NIV interface and ventilator adjustments. Once placed on NIV the patient demonstrates unequivocal improvement within 1-4 hours (decreased dyspnea, decreased respiratory rate, decreased use of accessory respiratory muscles and improving ventilation as assessed by arterial blood gases).

Additional protocols

Sedation

Protocols to reduce sedation shorten the duration of mechanical ventilation. These strategies seek to avoid continuous intravenous sedation, which has been associated with worse outcomes. Sedation may be reduced by daily cessation – all sedation stopped until the patient awakens or becomes agitated. If sedation must be resumed, it is restarted at 50% of the previous doses. A strategy combining daily cessation (spontaneous awakening trials) with daily SBTs improves outcome. An alternative approach is a sedation algorithm designed to reduce sedation to the level needed to keep the patient in an alert, calm and cooperative state (e.g., Sedation Agitation Score = 4; Richmond Agitation Sedation Score = 0).

Glycemia

Protocols designed to avoid hyperglycemia improve outcomes (accelerates weaning and shortens the duration of mechanical ventilation). It appears that strategies designed to keep serum glucose < 180 mg/dl appear effective and are associated with less risk for hypoglycemia than seen with tighter protocols (serum glucose 80-110 mg/dl).

Early Physical and Occupational Therapy

There is increasing evidence that early physical and occupational therapy is safe and associated with improved outcomes. This approach must be combined with one designed to reduce the level of sedation to allow for a patient capable of participating in rehabilitation activities.

Should the patient undergo tracheostomy?

To date there is no convincing evidence that early tracheostomy (performed on days 3-7) improves outcome when compared to that performed later (after 10-14 days). One problem is that early in the patient’s course it can be dfficult to accurately predict the duration of mechanical ventilation (or which patients may have difficulty with weaning). Thus early tracheostomy may subject the patient to an unnecessary procedure. Nevertheless, for some patients with difficulty weaning tracheostomy may facilitate liberating the patient from mechanical ventilation.

Tracheostomy has been associated with:

– Decreased airways resistance

– Decreased work of breathing (resistive and elastic)

– Improved expiratory flow, thus reducing dynamic hyperinflation (decreased PEEPi)

– Improved patient/ventilator interaction

– Improved airway suctioning

– Decreased need for sedation

These benefits may directly address the pathophysiologic cause of weaning failure in a given patient. If such a factor cannot otherwise be rapidly corrected (or the patient is anticipated to require another more than another 5-7 days of mechanical ventilation) then the patient should be considered for tracheostomy.

Special considerations for nursing and allied health professionals.

ICU nurses and respiratory therapist play a major role in determining patient readiness for weaning and in assessing the patient’s tolerance for weaning. This role is best demonstrated in RCTs of weaning protocols and of those used to minimize sedation.

What's the evidence?

MacIntyre, NR, Cook, DJ, Ely, EW. “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”. Chest. vol. 120. 2001. pp. 375S-395S. (Consensus conference recommendations.)

Boles, JM, Bion, J, Connors, A. “Weaning from mechanical ventilation”. Eur Respir J. vol. 29. 2007. pp. 1033-56. (Consensus conference recommendations.)

Upadya, A, Tilluckdharry, L, Muralidharan, V. “Fluid balance and weaning outcomes”. Intensive Care Med. vol. 31. 2005. pp. 1643-7. (Observational study showing positive fluid balance in the 24, 48, and 72 h prior to weaning was significantly greater in weaning failure when compared to weaning success.)

Jubran, A, Mathru, M, Dries, D. “Continuous recordings of mixed venous oxygen saturation during weaning from mechanical ventilation and the ramifications thereof”. Am J Respir Crit Care Med. vol. 158. 1998. pp. 1763-9. (One of several studies indicating that failure to increase cardiac output during weaning is associated with weaning failure.)

De Jonghe, B, Bastuji-Garin, S, Durand, MC. “Respiratory weakness is associated with limb weakness and delayed weaning in critical illness”. Crit Care Med. vol. 35. 2007. pp. 2007-15. (Observational study showing that critical illness neuromyopathy is associated with prolonged weaning and delayed extubation.)

Laghi, F, Cattapan, SE, Jubran, A. “Is weaning failure caused by low-frequency fatigue of the diaphragm?”. Am J Respir Crit Care Med. vol. 167. 2003. pp. 120-7. (Patients failing weaning trials did not demonstrate evidence for respiratory muscle fatigue.)

Lemaire, F, Teboul, JL, Cinotti, L. “Acute left ventricular dysfunction during unsuccessful weaning from mechanical ventilation”. Anesthesiology. vol. 69. 1988. pp. 171-9. (The change from positive-pressure mechanical ventilation to T-piece, negative intrathoracic pressure, resulted in a dramatic increase in the transmural pulmonary artery occlusion pressure.)

Mekontso-Dessap, A, de Prost, N, Girou, E. “B-type natriuretic peptide and weaning from mechanical ventilation”. Intensive Care Med. vol. 32. 2006. pp. 1529-36. (The plasma B-type natriuretic peptide, BNP, level measured prior to weaning was higher in patients with subsequent weaning failure.)

Grasso, S, Leone, A, De Michele, M. “Use of N-terminal pro-brain natriuretic peptide to detect acute cardiac dysfunction during weaning failure in difficult-to-wean patients with chronic obstructive pulmonary disease”. Crit Care Med. vol. 35. 2007. pp. 96-105. (Serial measurements of N-terminal pro-brain natriuretic peptide plasma levels identified COPD patients with weaning failure secondary to acute cardiac dysfunction.)

Jubran, A, Tobin, MJ. “Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation”. Am J Respir Crit Care Med. vol. 155. 1997. pp. 906-15. (Observational study of COPD patients showing those failing to wean develop worsening respiratory mechanics, including increases in the resistive and elastic work of breathing.)

Vassilakopoulos, T, Zakynthinos, S, Roussos, C. “The tension-time index and the frequency/tidal volume ratio are the major pathophysiologic determinants of weaning failure and success”. Am J Respir Crit Care Med. vol. 158. 1998. pp. 378-85. (Observational study of heterogenous patients showing that weaning failure is associated with an imbalance between respiratory muscle capacity and load on the system.)

Epstein, SK. “Weaning from ventilatory support”. Curr Opin Crit Care.. vol. 15. 2009. pp. 36-43. (Detailed review of weaning process.)

Ely, EW, Baker, AM, Dunagan, DP. “Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously”. N Engl J Med. vol. 335. 1996. pp. 1864-9. (Randomized controlled trial showing that compared to usual care, a weaning protocal combining daily screening and spontaneous breathing trials shortens the duration of weaning.)

Brochard, L, Rauss, A, Benito, S. “Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation”. Am J Respir Crit Care Med. vol. 150. 1994. pp. 896-903. (Randomized controlled trial showing that progressive withdrawal consisting of systematic reduction in the level of PSV was superior to T-piece and IMV weaning.)

Tanios, MA, Nevins, ML, Hendra, KP. “A randomized, controlled trial of the role of weaning predictors in clinical decision making”. Crit Care Med. vol. 34. 2006. pp. 2530-5. (Randomized controlled trial demonstrating that use of the frequency-tidal volume ratio as part of a daily screen slowed the process of weaning and did not shorten the duration of mechanical ventilation.)

Esteban, A, Frutos, F, Tobin, MJ. “A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group”. N Engl J Med. vol. 332. 1995. pp. 345-50. (Randomized controlled trial showing that T-piece trials, once or multiple times daily, was a superior weaning strategy to PSV or IMV. This and the similar study by Brochard demonstrate that approximately 75% of patients do not require a slow weaning process.)

Meade, M, Guyatt, G, Cook, D. “Predicting success in weaning from mechanical ventilation”. Chest. vol. 120. 2001. pp. 400S-424S. (Systematic review of parameters used to determine readiness for weaning.)

Brook, AD, Ahrens, TS, Schaiff, R. “Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation”. Crit Care Med. vol. 27. 1999. pp. 2609-15. (Randomized controlled trials showing that a sedation algorithm, targeted to a sedation scoring system, shortens the duration of mechanical ventilation.)

Kress, JP, Pohlman, AS, O’Connor, MF. “Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation”. N Engl J Med. vol. 342. 2000. pp. 1471-7. (Randomized controlled trial showing that daily cessation of sedation shortens the duration of mechanical ventilation. Subsequent analyses from the same group demonstrated that this approach did not precipitate myocardial ischemia and reduced the number of neurodiagnostic procedures needed.)

de Wit, M, Gennings, C, Jenvey, WI. “Randomized trial comparing daily interruption of sedation and nursing-implemented sedation algorithm in medical intensive care unit patients”. Crit Care. vol. 12. 2008. pp. R70(Small randomized controlled trial showing that a sedation algorithm was superior to daily cessation of sedation. Of note, the patient population studied had a very high proportion of patients with substance abuse.)

Girard, TD, Kress, JP, Fuchs, BD. “Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial”. Lancet. vol. 371. 2008. pp. 126-34. (Randomized controlled trial demonstrating that a strategy combining daily cessation of sedation and daily SBTs was superior to SBTs alone.)

Finfer, S, Chittock, DR, Su, SY. “Intensive versus conventional glucose control in critically ill patients”. N Engl J Med. vol. 360. 2009. pp. 1283-97. (Randomized controlled trial showing that intensive glucose control increased mortality among critically ill adults. The authors also found that a blood glucose target of 180 mg/dl or less was associated with lower mortality than a target blood glucose of 81-108 mg/dl.)

Schweikert, WD, Pohlman, MC, Pohlman, AS. “Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial”. Lancet. vol. 373. 2009. pp. 1874-82. (Randomized controlled trial demonstrating that a strategy for whole-body rehabilitation resulted in better functional outcomes at hospital discharge and more ventilator-free days.)

Griffiths, J, Barber, VS, Morgan, L. “Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation”. BMJ. vol. 330. 2005. pp. 1243(Meta-analysis showing that early tracheostomy was not associated with improvement in clinically significant outcomes.)

Diehl, JL, El Atrous, S, Touchard, D. “Changes in the work of breathing induced by tracheotomy in ventilator-dependent patients”. Am J Respir Crit Care Med. vol. 159. 1999. pp. 383-8. (Observational study showing that compared to the endotracheal tube, the tracheostomy reduced resistive and elastic work of breathing, reduced PEEPi and improved patient ventilator interaction.)

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