Pulmonary Pitfalls

Approaches to Weaning and Liberation of Invasive Mechanical Ventilation

AFFILIATIONS:

1Department of Veterans Affairs (VA), Northern California Health System, Mather, CA
2Division of Pulmonary and Critical Care Medicine, University of California, Davis

CITATION:

Harrell D, Sanville B, Kuhn BT. Pulmonary pitfalls: approaches to weaning and liberation of invasive mechanical ventilation. Consultant. 2023;63(6). doi: 10.25270/con.2023.06.000001

Received January 31, 2023. Accepted May 31, 2023. Published online June 6, 2023.

DISCLOSURES:

The authors of this manuscript have no financial or other conflicts of interest that are relevant to the topics of mechanical ventilation and respiratory failure.

CORRESPONDENCE:

Brooks Thomas Kuhn, MD, MAS, University of California, Davis, Division of Pulmonary and Critical Care Medicine, 4150 V St #3400, Sacramento, CA 95817 (btkuhn@ucdavis.edu)


Invasive mechanical ventilation (IMV) is a life-saving intervention for procedural support, acute respiratory failure, chronic ventilatory muscle weakness, airway obstruction, airway compromise from neurological injury, and other indications in the intensive care setting. The length of time on IMV increases the potential for numerous severe and even life-threatening complications, such as volutrauma, barotrauma, infection, damage to vocal cords, and ill effects of sedation. Therefore, even at initiation, IMV should be weaned to the minimal necessary support. Weaning a patient off IMV is challenging, with several pitfalls clinicians need to consider.

Even before the increased demand from the COVID-19 pandemic, in our experience, the volume of patients on IMV required the enlistment of internists, family medicine practitioners, and others who lack advanced training in IMV. In this review, we will provide pragmatic advice to safely and expeditiously move patients toward ventilator liberation.   

Risks of mechanical ventilation 

The life-saving capabilities of mechanical ventilation are not without risk. Mechanical ventilation has been shown to cause diaphragmatic atrophy, which can prolong the time to liberation from the ventilator.1-3 Patients receiving mechanical ventilation require sedating medications for ventilator synchrony and comfort, but this can lead to delirium and prolonged ventilation. Furthermore, mechanical ventilation can lead to several different complications, such as ventilator associated pneumonia (VAP),4 poor nutritional status,5 acute kidney injury (AKI)6, gastric ulcers,7 disordered sleep,8-10 laryngeal dysfunction, and aspiration.11 Mechanical ventilation also delays the initiation of mobility and physical therapy, worsening patients’ functional status.12-14 While mechanical ventilation is often warranted to support a patient through their period of critical illness, it is imperative to remove the patient from the ventilator as soon as possible. 

Readiness for weaning

The decision to extubate a patient can be just as difficult as the decision to intubate. Weaning the patient from the ventilator consists of a two-step approach: (1) Assessing the patient’s readiness for weaning and (2) a spontaneous breathing trial (SBT) performed off sedation. (Figure 1)

fig. 1

Fig. 1 Flowchart for weaning a patient off of IMV

Before a patient is ready to wean, the underlying etiology that required mechanical ventilation must be treated and there should be indications of improvement. Premature weaning without addressing the underlying disease can increase the risk of weaning failure, which generally leads to re-initiation of IMV and likely a longer time on mechanical ventilation.

The patient should ideally demonstrate a strong cough and gag reflex, be able to follow commands off sedation, and have manageable airway secretions.15 They should also be hemodynamically stable and on minimal or no vasoactive medications.  

A cuff leak test should be performed on mechanically ventilated adults who are deemed high risk for post-extubation stridor, which would increase the risk of reintubation. Risk factors for post-extubation stridor and airway edema include traumatic intubation, intubation longer than 6 days, large endotracheal tube, female sex, and reintubation after an unplanned extubation.16-19 Cuff leak tests are performed by deflating the endotracheal tube (ETT) cuff and listening for an audible leak around the ETT while patients are spontaneously breathing20 and/or observing the difference in inspiratory tidal volume and expiratory tidal volume with the cuff deflated.21

A negative cuff leak is defined as either no audible leak around the deflated cuff or a measured cuff leak < 110 ml. Alternatively, a positive cuff leak is defined as the presence of an audible leak around the deflated cuff or a measured cuff leak > 110 ml. While a negative cuff leak can help identify patients who are at risk for post-extubation stridor (and thus reintubation), it may lead to delay in extubation in those with a false-positive result (absence of a cuff leak when there is no laryngeal edema)16. Patients who fail the cuff leak test but are otherwise ready for extubation should receive systemic steroids at least 4 hours before extubation.16 A repeat cuff leak test is not required after the administration of steroids.16

Prior to weaning, the patient’s lung mechanics should be optimized. Pulmonary compliance can be optimized with loop diuretics if the patient is volume overloaded, thoracentesis if the patient has large pleural effusions, or paracentesis if the patient has tense ascites22. Increased airway resistance can be addressed with bronchodilators if chronic obstructive pulmonary disease (COPD)/asthma, chest physiotherapy/pulmonary hygiene, increased positive end-expiratory pressure (PEEP) if patient is at risk for auto-PEEP (ie, COPD), and sometimes bronchoscopy to clear obstructing mucus plugs.22 

If the patient has difficult-to-control agitation that may make SBT difficult, benzodiazepines should be avoided. An anxiolytic such as dexmedetomidine, clonidine, or haloperidol can be used in this situation.22 Dexmedetomidine does not suppress respiratory drive, thus it can be continued during the SBT and in the post-extubation period.  

Many weaning parameters are available, with the Rapid Shallow Breathing Index (RSBI) being the most studied and popular parameter.23 The RSBI is calculated by dividing the respiratory rate by the tidal volume measured in liters to predict readiness to wean. A value of less than 105 predicts successful weaning, whereas a value greater than 105 predicts unsuccessful weaning and extubation failure.24

The Spontaneous Breathing Trial

A spontaneous breathing trial (SBT) is used to assess a patient’s ability to breath while receiving minimal to no support from the ventilator. This may be explained to the patient or patient’s families by stating that “we are going to change some settings on the ventilator to simulate you breathing on your own to see if you are ready to be extubated.”

Once criteria for SBT are met, a paired Spontaneous Awakening Trial (SAT) and SBT should be performed daily until a patient is ultimately extubated, even if you do not anticipate the patient to be extubated that day.25 A spontaneous awakening trial (aka sedation holiday) occurs when sedative infusions are temporarily stopped to facilitate the SBT and then restarted at lower infusion rates once the trial is over.25 Indeed, SBTs are commonly performed using pressure support (PS)/ continuous positive airway pressure or T piece. A T piece trial is performed with the ETT attached to blow-by oxygen while receiving no additional positive pressure support from the ventilator. The use of pressure support (PS) or continuous positive airway pressure (CPAP) during SBT reduces the patient’s inspiratory work by 30-40%,26,27 sometimes leading to false reassurance that the patient is ready to be extubated.

Patients fail T piece trials more frequently than they fail trials on PS or CPAP,28 supporting the belief that T piece trials are more rigorous for the patient. Because of this, some expert clinicians advocate for the use of T piece trials in SBTs,29especially if the patient is at high risk for reintubation or flash pulmonary edema once positive pressure is removed (HFrEF population). It is important to note that there is no evidence favoring one mode over others;30,31 clinicians are encouraged to use whatever mode their facility is most familiar or comfortable using.

SBTs are typically performed for at least 30 minutes and sometimes up to 120 minutes. There is no benefit to performing an SBT for longer than 120 minutes.32,33 During the SBT, the respiratory therapist observes the patient’s general appearance, vitals, apparent work of breathing, and mental status. Subjective measures of failing the SBT include anxiety, agitation, altered mental status diaphoresis, cyanosis, and increased work of breathing.34 Objective measures of failing the SBT include tachypnea, tachycardia, hypotension, hypoxemia, and hypercapnia.34 Some clinicians elect to obtain an arterial blood gas following the SBT, but this is not officially part of the SBT criteria.35 

If the patient fails the SBT, they should be placed back on a supportive mode of mechanical ventilation. If the patient passes the SBT, extubation should be considered. After passing the SBT, placing the patient back on pre-SBT ventilator settings for one hour prior to extubation can reduce rates of reintubation.36 

Patient characteristics to consider prior to extubation

In assessing a patient’s readiness for vent liberation, several factors must be considered and addressed prior to moving forward with extubation:

  • Have you treated or at least partially reversed the cause of the patient’s respiratory failure? 
  • Is the patient hemodynamically stable on minimal or no vasopressor support? 
  • Did you optimize the patient’s pulmonary mechanics (volume status, airway resistance)? 
  • Can the patient follow commands? 
  • Does the patient have manageable agitation or delirium? 
  • Does the patient have good cough and gag reflex?  
  • Does the patient have excess secretions? 
  • Does this patient need a cuff leak test? And if so, is a cuff leak present?  
  • Did the patient pass their SBT? 
  • What modality of oxygenation will the patient be extubated to (nasal cannula, HFNC, BiPAP, etc.)?

Most importantly, the underlying disease process that initially prompted intubation must be reversed or shown to be improving. Additionally, the patient’s respiratory mechanics should be optimized to decrease risk of extubation failure. Volume overload is a very common residual problem that delays extubation; this can be determined via physical exam (dependent edema, rales on auscultation), chest radiography (with interstitial edema or pleural effusions), and monitoring intake/output trends.

Once the patient’s underlying process begins to improve, one should be mindful of the intake and output and make efforts to achieve a negative fluid balance. The patient’s mental status should be assessed prior to extubation; this should be assessed off sedation. The patient should be able to follow commands and ideally be able to lift their head off the pillow. If the patient is delirious or agitated, one could consider using a dexmedetomidine infusion or anxiolytics to address this.

The patient should demonstrate a good cough prior to extubation as inability to clear secretions is a common reason for reintubation. The respiratory therapist and physician should assess the amount of secretions and how frequently suctioning is required; secretion burden and frequency of suctioning should be low prior to extubation.

If the patient has been intubated for a prolonged period or had a traumatic intubation, a cuff leak test should be performed to assess for upper airway edema. If a cuff leak is not present, steroids should be administered prior to extubation.

Regarding the various illnesses that necessitate mechanical ventilation, one should be mindful of several factors both before and after extubation (Table 1).

Table 1. Pre-extubation considerations and post-extubation modalities

Diagnosis

Pre-extubation considerations

Post-extubation modalities

Pneumonia

Secretion management

Pulmonary Hygiene

HFNC or NC (depending on severity)

Interstitial edema

Diuresis

Mindful consideration of intake/output

Address metabolic alkalosis (may contribute to apnea)

Eval for additional pleural effusions (see below)

Nasal cannula

HFNC

BiPAP (if HFrEF with risk of flash pulmonary edema

Pleural effusion

Thoracentesis +/- pleural catheter placement

HFNC

BiPAP (if concomitant HFrEF)

Nasal cannula

COPD/Emphysema

Bronchodilators

Secretion management

Additional PEEP if significant air trapping

BiPAP preferable

HFNC (if BiPAP is not tolerable)

Nasal cannula

Neuromuscular weakness

  • Amyotrophic lateral sclerosis
  • Critical illness myopathy
  • Diaphragmatic dysfunction
  • Autoimmune diseases

NIF/FVC trends

Address and treat underlying disease process (if autoimmune/GBS)

BiPAP

The physician should consult with respiratory therapists to assess secretion burden and perform adequate pulmonary hygiene. This becomes important for patients with pneumonia or COPD with bronchitis. If there is a significant burden of secretions (ie, requiring q1h suctioning), this may be a reason to delay intubation. Bronchoscopy is occasionally required to remove obstructing mucus plugs. With regards to COPD patients with emphysema, they may experience air trapping that can impair pulmonary mechanics and ventilation; this will become evident with increased respiratory rates or increased work of breathing. One can increase the PEEP in efforts to match the patient’s intrinsic PEEP and offset the degree of air trapping.

For patients with heart failure and clinically significant interstitial edema, diuresis will be a cornerstone of treatment. The physician should be very mindful of the daily intake/outputs to ensure that a net negative fluid balance is achieved. A 1-1.5 L daily fluid restriction can be helpful in minimizing daily intake. The use of a loop diuretic can cause an increased level of serum HCO3 levels, commonly referred to as a “contraction alkalosis.” Once the patient moves closer to ventilator liberation, this alkalosis can become problematic in the sense that it can cause apnea when transitioning to a support mode of ventilation or performing an SBT. Daily labs should be monitored and if the serum bicarb is increasing with loop diuretic use, one could consider the use of a carbonic anhydrase inhibitor like acetazolamide in efforts to decrease the bicarb levels.

Furthermore, patients with heart failure and significant volume overload will commonly have bilateral pleural effusions. If these effusions are large enough to impair the ventilatory mechanics, one could consider thoracentesis or placement of a pleural catheter for drainage prior to extubation.

Occasionally an underlying neuromuscular disease may explain persistent mechanical ventilation needs. Potential etiologies that we frequently consider are amyotrophic lateral sclerosis (ALS), autoimmune (Guillain-Barre Syndrome, Myasthenia Gravis), diaphragmatic dysfunction, and critical illness myopathy. In the case of autoimmune etiologies, the patient may improve with treatment of the underlying process (immunosuppression, plasmapheresis, or intravenous immune globulin). However, patients with ALS or acquired critical illness myopathy may prove to be more difficult to liberate from the ventilator and occasionally require tracheostomy. We frequently use metrics such as negative inspiratory force (NIF) and forced vital capacity (FVC) as a rough estimate of respiratory muscle strength; these are by no means perfect tests and are very effort dependent. These tests are performed by respiratory therapists and the value trends are far more useful than a single measurement. If these patients are optimized and pass and SBT, they should be extubated to bilevel positive airway pressure (BiPAP) to augment ventilation. If the patient has a progressive neuromuscular disease and are unable to be liberated from the ventilator, tracheostomy tube placement would be a reasonable option.

Once a patient passes an SBT and the decision is made to extubate the patient, one should consider which modality of non-invasive ventilatory support a patient will be extubated to. Extubating a patient to non-invasive ventilation, whether in the form of high-flow nasal cannula (HFNC) or CPAP/BiPAP, can reduce the risk of extubation failure. For patients with disease processes that require frequent secretion suctioning (pneumonia, bronchitis), CPAP/BiPAP would be unwise as this may impair secretion clearance; HFNC is preferred in this patient population. For patients with heart failure (especially reduced ejection fraction), emphysema, or neuromuscular weakness, extubation to BiPAP is preferred to augment ventilation. Of note, in the heart failure population, CPAP and BiPAP demonstrate similar efficacy in decreasing rates of reintubation.

From a practical standpoint, once a patient is extubated to HFNC or NIV and are doing well for 3-6 hours, one could consider transitioning to simple nasal cannula based on the patient’s needs.

Promoting Early Liberation

There are steps the clinician should take to promote early liberation from the ventilator:

  • Initiate early mobilization
  • Minimize sedatives and analgesics
  • Avoid the use of benzodiazepines for sedation
  • Perform daily sedation holidays
  • Initiate VAP prevention bundles

Implementation of early mobilization protocols is associated with shorter duration of mechanical ventilation and shorter ICU length of stay.25, 37-40 Sedation should be minimalized, as it is associated with longer ICU length of stay and longer duration of mechanical ventilation.25, 41-43 Physicians should utilize daily sedation holidays (ideally paired with SBTs when appropriate) or protocol-driven sedation practices.25 The use of benzodiazepines for sedation are associated with increased rates of delirium and longer duration of mechanical ventilation,44-46 and should be avoided whenever possible. Ventilator associated pneumonia prevention bundles, including elevating the head of bed, oral care with chlorhexidine, and subglottic suctioning, reduce the rate of VAP and thus time spent endotracheally intubated.25, 47-50 

Conclusion

Equally important with supporting the driving physiologic impairment leading to IMV is providing the minimal amount and time on mechanical ventilation. Weaning and liberation are not passive efforts, but rather a team effort of physicians, nurses, and respiratory therapists to continually titrate the ventilator settings to the patient’s changing needs (SBT, RSBI) and prepare the patient for independent respiration (diuresis, airway clearance, sedation holiday/minimalization). Non-critical care trained clinicians can use their comprehensive understanding of pathophysiology, in combination with a practical understanding of mechanical ventilation in commonly encountered disease states, to successfully manage weaning and liberation from mechanical ventilation in respiratory failure.  


References

  1. Hermans G, Agten A, Testelmans D, Decramer M, Gayan-Ramirez G. Increased duration of mechanical ventilation is associated with decreased diaphragmatic force: a prospective observational study. Crit Care. 2010;14(4):R127. doi:10.1186/cc9094
  2. Jaber S, Petrof BJ, Jung B, et al. Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med. 2011;183(3):364-371. doi:10.1164/rccm.201004-0670OC
  3. Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327-1335. doi:10.1056/NEJMoa070447
  4. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital‐acquired, ventilator‐associated, and healthcare‐associated pneumonia. Am J Respir Crit Care Med. 2005;171:388–416
  5. Btaiche IF, Chan L-N, Pleva M, Kraft MD. Critical illness, gastrointestinal complications, and medication therapy during enteral feeding in critically ill adult patients. Nutr Clin Pract. 2010;25(1):32-49. doi:10.1177/0884533609357565
  6. Kuiper JW, Groeneveld ABJ, Slutsky AS, Plötz FB. Mechanical ventilation and acute renal failure. Crit Care Med. 2005;33(6):1408-1415
  7. Chu Y-F, Jiang Y, Meng M, et al. Incidence and risk factors of gastrointestinal bleeding in mechanically ventilated patients. World J Emerg Med. 2010;1(1):32-36
  8. Rittayamai N, Wilcox E, Drouot X, Mehta S, Goffi A, Brochard L. Positive and negative effects of mechanical ventilation on sleep in the ICU: a review with clinical recommendations. Intensive Care Med. 2016;42(4):531-541. doi:10.1007/s00134-015-4179-1
  9. Hardin KA, Seyal M, Stewart T, Bonekat HW. Sleep in critically ill chemically paralyzed patients requiring mechanical ventilation. Chest. 2006;129(6):1468-1477. doi:10.1378/chest.129.6.1468.
  10. Cooper AB, Thornley KS, Young GB, Slutsky AS, Stewart TE, Hanly PJ. Sleep in critically ill patients requiring mechanical ventilation. Chest. 2000;117(3):809-818
  11. Wallace S, McGrath BA. Laryngeal complications after tracheal intubation and tracheostomy. BJA Education. 2021;21(7):250-257
  12. Bailey P, Thomsen GE, Spuhler VJ, et al. Early activity is feasible and safe in respiratory failure patients. Crit Care Med. 2007;35(1):139-145
  13. Berney SC, Rose JW, Bernhardt J, Denehy L. Prospective observation of physical activity in critically ill patients who were intubated for more than 48 hours. J Crit Care. 2015;30(4):658-663
  14. Puthucheary ZA, Rawal J, McPhail M, et al. Acute skeletal muscle wasting in critical illness. JAMA. 2013;310(15):1591-1600
  15. Salam A, Tilluckdharry L, Amoateng-Adjepong Y, Manthous CA. Neurologic status, cough, secretions and extubation outcomes. Intensive Care Med. 2004;30(7):1334-1339
  16. Schmidt G, et al. Official executive summary of an American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from mechanical ventilation in critically ill adults.
  17. Darmon JY, Rauss A, Dreyfuss D, et al. Evaluation of risk factors for laryngeal edema after tracheal extubation in adults and its prevention by dexamethasone: a placebo-controlled, double-blind, multicenter study. Anesthesiology. 1992;77:245–251.
  18. Kriner EJ, Shafazand S, Colice GL. The endotracheal tube cuff-leak test as a predictor for postextubation stridor. Respir Care 2005;50:1632-1638.
  19. Higenbottam T, Payne J. Glottis narrowing in lung disease. Am Rev Respir Dis. 1982;125:746-750.
  20. Potgieter PD, Hammond JM. “Cuff” test for safe extubation following laryngeal edema. Crit Care Med. 1988;16(8):818.
  21. Miller RL, Cole RP. Association between reduced cuff leak volume and postextubation stridor. Chest. 1996;110(4):1035-1040
  22. Heunks L, van der Hoeven JG, Clinical Review: The ABC of weaning failure – a structured approach, Critical Care. 2010;14:245
  23. Baptistella AR, Sarmento FJ, da Silva KR, Baptistella SF, Taglietti M, Zuquello RÁ, Nunes Filho JR. Predictive factors of weaning from mechanical ventilation and extubation outcome: A systematic review. J Crit Care. 2018;48:56-62.
  24. Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. NEJM. 1991;324(21):1445-1450.
  25. Marra A, Ely EW, Pandharipande PP, Patel MB. The ABCDEF bundle in critical care. Crit Care Clin. 2017;33(2):225-243.
  26. Salam A, Tilluckdharry L, Amoateng-Adjepong Y, Manthous CA. Neurologic status, cough, secretions and extubation outcomes. Intensive Care Med. 2004;30(7):1334-1339.
  27. Girard TD, Alhazzani W, Kress JP, et al. An Official American Thoracic Society/American College of Chest Physicians clinical practice guideline: liberation from mechanical ventilation in critically ill adults. rehabilitation protocols, ventilator liberation protocols, and cuff leak tests. Am J Respir Crit Care Med. 2017;195(1):120-133.
  28. Tobin MJ. Extubation and the myth of "minimal ventilator settings". Am J Respir Crit Care Med. 2012;185(4):349-350.
  29. Thille AW, Richard JC, Brochard L. The decision to extubate in the intensive care unit. Am J Respir Crit Care Med. 2013;187(12):1294-1302. doi:10.1164/rccm.201208-1523CI
  30. Pellegrini JAS, Moraes RB, Maccari JG, et al. Spontaneous breathing trials with t-piece or pressure support ventilation. Respir Care. September 2016:respcare.04816. doi:10.4187/respcare.04816.
  31. Teixeira SN, Osaku EF, Costa CRL de M, et al. Comparison of proportional assist ventilation plus, t-tube ventilation, and pressure support ventilation as spontaneous breathing trials for extubation: a randomized study. Respir Care. 2015;60(11):1527-1535.
  32. Esteban A, Alía I, Tobin MJ, et al. Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med. 1999;159(2):512-518.
  33. Perren A, Domenighetti G, Mauri S, Genini F, Vizzardi N. Protocol-directed weaning from mechanical ventilation: clinical outcome in patients randomized for a 30-min or 120-min trial with pressure support ventilation. Intensive Care Med. 2002;28(8):1058-1063.
  34. Boles J-M, Bion J, Connors A, et al. Weaning from mechanical ventilation. In: Vol 29. European Respiratory Society; 2007:1033-1056.
  35. Salam A, Smina M, Gada P, et al. The effect of arterial blood gas values on extubation decisions. Respir Care. 2003;48(11):1033-1037.
  36. Fernandez MM, Gonzoalez-Castro A, et al. Reconnection to mechanical ventilation for 1 hour after a successful spontaneous breathing trial reduces reintubation in critically ill patients: a multicenter randomized controlled trial. Intensive Care Med (2017) 43:1660-1667.
  37. Choi J, Tasota FJ, Hoffman LA. Mobility interventions to improve outcomes in patients undergoing prolonged mechanical ventilation: a review of the literature. Biological Research For Nursing. 2008;10(1):21-33.
  38. Tipping CJ, Harrold M, Holland A, Romero L, Nisbet T, Hodgson CL. The effects of active mobilization and rehabilitation in ICU on mortality and function: a systematic review. Intensive Care Med. 2017;43(2):171-183.
  39. Lai C-C, Chou W, Chan K-S, et al. Early mobilization reduces duration of mechanical ventilation and intensive care unit stay in patients with acute respiratory failure. Arch Phys Med Rehabil. 2017;98(5):931-939
  40. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. The Lancet. 2009;373(9678):1874-1882.
  41. Treggiari MM, Romand J-A, Yanez ND, et al. Randomized trial of light versus deep sedation on mental health after critical illness. Crit Care Med. 2009;37(9):2527-2534.
  42. Shehabi Y, Bellomo R, Reade MC, et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186(8):724-731.
  43. Tanaka LMS, Azevedo LCP, Park M, et al. Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study. Crit Care. 2014;18(4):R156.
  44. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301(5):489-499.
  45. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007;298(22):2644-2653.
  46. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012;307(11):1151-1160.
  47. Resar R, Pronovost P, Haraden C, Simmonds T, Rainey T, Nolan T. Using a bundle approach to improve ventilator care processes and reduce ventilator-associated pneumonia. J Comm J Qual Patient Saf. 2005;31(5):243-248.
  48. Berenholtz SM, Pham JC, Thompson DA, et al. Collaborative cohort study of an intervention to reduce ventilator-associated pneumonia in the intensive care unit. Infect Control Hosp Epidemiol. 2011;32(4):305-314.
  49. Sen S, Johnston C, Greenhalgh D, Palmieri T. Ventilator-associated pneumonia prevention bundle significantly reduces the risk of ventilator-associated pneumonia in critically ill burn patients. J Burn Care Res. 2016;37(3):166-171.
  50. Morris AC, Hay AW, Swann DG, et al. Reducing ventilator-associated pneumonia in intensive care: impact of implementing a care bundle. Crit Care Med. 2011;39(10):2218-2224.