Section II: Systematic Reviews of theEvidence Base for Ventilator Weaning

Introduction to a Series ofSystematic Reviews ofWeaning From MechanicalVentilation*

Maureen Meade, MD; Gordon Guyatt, MD;Lauren Griffith, MSc; Lynda Booker, BA; Jill Randall, RRT;and Deborah J. Cook, MD

(CHEST 2001; 120:396S–399S)

Key words: mechanical ventilation; meta-analysis; methodology;systematic reviews; weaning

Abbreviations: AHCPR � Agency for Health Care Policy andResearch; CINAHL � Cumulative Index to Nursing and AlliedHealth Literature; EMBASE � Excerpta Medica Database;NPPV � noninvasive positive-pressure ventilation

W hy is weaning important? Over 90% of critically illpatients require mechanical ventilation, and 40% of

the time the patient is receiving mechanical ventilation isspent in the process of weaning from it.1 Meanwhile, thereare several concerns associated with prolonged mechanicalventilation. For patients, these concerns include height-ened morbidity (including ventilator-associated pneumo-nia,2–4 ventilator-associated lung injury 5–7), and increasedmortality8,9). Additionally, even if patients are recoveringfrom their acute illness, as long as they remain dependenton mechanical ventilation, they generally remain in theICU. In the context of widespread and unceasing ICU bedshortages, this is a problematic situation. Finally, chal-lenges to health-care organizations include the additionalresource consumption incurred when patients receivemechanical ventilation, such as increased nursing, need fora respiratory therapist, and equipment costs.

It follows that weaning patients from mechanical ven-tilation should occur as quickly as possible. However,rapid weaning has its own potential problems. Reducingmechanical support too quickly may result in fatigue orcardiovascular instability, either of which may ultimatelydelay the weaning process. Premature extubation, leadingto reintubation, is associated with the increased risk ofpneumonia and with increased mortality.10

Because patients receiving mechanical ventilation incursignificant morbidity, mortality, and costs, and becauseboth premature weaning as well as delayed weaning cancause harm, weaning that is both expeditious and safe ishighly desirable. Our objectives were to determine whatwe can learn from clinical studies of when and howweaning should begin, proceed, and end, and to summa-rize this literature for critical-care clinicians.

Reviews of the Weaning LiteratureWe conducted the majority of this work under the

auspices of the Agency for Health Care Policy and Re-search (AHCPR [recently renamed the Agency forHealthcare Research and Quality]), a subsidiary of the USDepartment of Health and Human Services. Contributorsto this document include the members of the McMasterUniversity Evidence-Based Practice Center, members ofthe American College of Chest Physicians’ Expert Panelon Weaning from Mechanical Ventilation, and an assem-bly of international experts in the field of mechanicalventilation who served as peer reviewers for the finalreport to AHCPR.

Our task for this CHEST supplement was to review allrandomized trials and the clinically most applicable obser-vational studies that could guide clinicians in weaningpatients from mechanical ventilation. Conceptually, wewere interested in any critically ill patients receivingmechanical ventilation, in any strategies that were de-signed to facilitate weaning and extubation, in predictorsof weaning and extubation in heterogeneous ICU patients,in populations with COPD, and in patients who hadundergone cardiac surgery. Our target populations in-cluded adult and pediatric patients who were receivingmechanical ventilation and had either an endotrachealtube or a tracheostomy tube.

We excluded studies of highly specific populations (forexample, patients with spinal cord injury or obstructivesleep apnea) and studies in neonates (since many studiesin this population have been published as CochraneCollaboration reviews). The clinical settings relevant toour review include ICUs, intermediate-care units, andpostanesthesia recovery rooms. We excluded studies ofhome ventilation for children or adults and those usingchronic ventilation settings. With respect to weaninginterventions, we included any ventilation, or weaningstrategy or intervention (eg, mode, method, procedure,protocol, timing, operator, computer, tracheostomy, non-invasive ventilation modes, adjunctive holistic aids, andother miscellaneous approaches), that were geared tofacilitate weaning and/or extubation. We excluded articleswith a focus on mechanical ventilation strategies forshort-term care (eg, lung protective ventilation strategies)

*From the Departments of Medicine (Drs. Meade, Guyatt, andCook) and Clinical Epidemiology & Biostatistics (Mss. Griffithand Booker), McMaster University, Hamilton, Ontario, Canada;and the Department of Respiratory Therapy (Ms. Randall), St.Joseph’s Hospital, Hamilton, Ontario Canada.This article is based on work performed by the McMasterUniversity Evidence-based Practice Center, under contract tothe Agency for Healthcare Research and Quality (Contract No.290-97-0017), Rockville, MD.Correspondence to: D.J. Cook, MD, McMaster University, Fac-ulty of Health Sciences Center, Department of Clinical Epidemi-ology & Biostatistics, 1200 Main St West, Hamilton L8N 3Z5,Ontario, Canada; e-mail: debcook@mcmaster.ca

396S Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support

and interventions the influence of which on the durationof ventilation has already been summarized in a recentsystematic review (eg, sedation in the ICU or optimaltiming of tracheotomy). Trials in which at least 20% ofpatients were eliminated from the analysis after random-ization were excluded. We excluded costs due to insuffi-cient reporting of economic outcomes and their poorgeneralizability. In addition, we reviewed predictors ofweaning and/or extubation success, and predictors of theduration of mechanical ventilation in cardiac surgery andCOPD patients. We omitted studies predicting terminalweaning for the purposes of the withdrawal of life support.Finally, we analyzed a broad range of clinical outcomes,although we excluded studies that reported only physio-logic outcomes.

Identifying Relevant StudiesTo identify relevant studies, we searched MEDLINE,

Excerpta Medica Database (EMBASE), Health ServicesTechnology Administration and Research, Cumulative In-dex to Nursing and Allied Health Literature (CINAHL),the Cochrane Controlled Trials Registry, and the Co-chrane Data Base of Systematic Reviews from 1971 to1998. We also examined reference lists and personal files,and we hand searched the journal Respiratory Care. Wedid not explicitly search for unpublished literature. Weretrieved all articles that either of two reviewers of thetitles and abstracts considered to be possibly eligible. Thesame two reviewers examined the full text and made finaldecisions regarding eligibility based on the inclusion andexclusion criteria described above.

Our database search for relevant articles yielded a totalof 5,653 citations of which 927 proved potentially eligibleon the basis of reviewing the title and abstract. We wereable to obtain hard copies of 924 of these articles. Weincluded a total of 154 studies after comprehensive reviewof the full article. The absolute agreement between thetwo observers for determining eligibility for articles was0.89, and the � for agreement was 0.68.

Abstracting and Summarizing DataOur goal was to be as systematic as possible, not only in

the identification and selection of studies, but in theabstraction and summarization of the data. To achieve thisgoal, we developed general forms to abstract data from allstudies and forms that were specific to randomized trials,nonrandomized controlled studies, and studies of weaningpredictors. We developed an implementation manual andtrained five respiratory therapists and five intensivists toabstract data related to study characteristics, methodolog-ical quality, and results using duplicate independent re-views. Quantitative data were abstracted using severalmetrics. We pooled results across randomized trials andacross studies of weaning predictors only when our assess-ment of the patients, interventions, and outcomes sug-gested that pooling was legitimate. Additional detailsspecific to each clinical question are reported in brief insubsequent reviews in this series.

Strengths and Weaknesses of OurSystematic Reviews

The limitations of any review can be categorized intothose relating to the review methods themselves and thoserelated to the primary studies included in the review. Weaddressed the strengths and limitations of the primarystudies (ie, randomized trials, nonrandomized controlledtrials, observational studies, and qualitative studies) in theindividual sections of this supplement. We will now criti-cally appraise this report according to the review method-ology we employed.

The strengths of our systematic reviews include effortsto define focused clinical questions and to identify expliciteligibility criteria for each question. Our eligibility criteriainvariably specified the population of interest, the inter-vention or exposure, the outcome, and the methodology.As we have described, the scope of our searching wasbroad and involved five large databases. The use ofEMBASE maximized the possibility of identifying relevantEuropean literature to avoid a language bias in this review,and we included French, Italian, Spanish, Japanese, andRussian studies. Searching EMBASE, Health ServicesTechnology Administration and Research, and CINAHLmaximized the chances of finding relevant studies innursing and respiratory therapy journals to avoid a biasedselection of research in medical journals. We also hand-searched Respiratory Care, even though that journal isindexed on CINAHL, since we have previously found thatmany research reports are poorly indexed in bibliographicdatabases. We used the most current randomized trialregistry from the Cochrane Library, as well as citationreviews, our personal files, and author contacts. Thus, oursearching strategy was comprehensive and minimizedlanguage bias and discipline bias. We did not, however,search extensively for unpublished studies, and our resultsmay therefore be subject to publication bias.

We critiqued each study in this report, providing clini-cal characteristics and methodological details in the textand associated tables. Given the diversity of the objectives,designs, populations, interventions, predictors, and out-comes of these studies, we did not use a universalquantitative scoring system to assess validity but choseinstead a more explicit component approach to qualityassessment that was adapted to each research question andstudy design. We used critical appraisal questions for moststudies taken from the Users’ Guides to the MedicalLiterature series published in the Journal of the AmericanMedical Association. Due to space constraints, some de-sign features of the studies that we reviewed are notreported in these systematic reviews but are available onrequest.

Because reviews are retrospective exercises and areprone to systematic and random error, we conductedseveral steps in this systematic review in duplicate, includ-ing the following: (1) citation review from the biblio-graphic databases; (2) assessment of relevance based onthe full text of each article; (3) assessment of methodolog-ical quality; (4) abstraction of clinical characteristics andresults; and (5) statistical analysis. Steps 3 and 4 involvedcritical-care physicians and respiratory therapists trained

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in research methods. Our core research team membersinterpreted and synthesized the findings in duplicate. Wewere as careful as possible conducting the review, but weidentified and remediated errors at each step in ourprocess. Since our reviews were completed, several addi-tional relevant studies have been published, which are notincluded in the ensuing articles for this CHEST supple-ment.

Our ResultsOur key findings may confirm many clinical impres-

sions, but may challenge others. We have tried to beexplicit about the evidence and to separate the evidencefrom our inferences. We trust that our summaries of theevidence will allow others, with different perspectives, todraw their own inferences.

The issue of the optimal start of weaning is confoundedby alternative definitions of weaning. One reasonableconceptualization is weaning beginning with the onset ofmechanical ventilation. The research to date suggests thatthe best answer to “when to start weaning” is to develop aprotocol implemented by nurses and respiratory therapiststhat begins testing for the opportunity to reduce supportvery soon after intubation and reduces support at everyopportunity. Differences in clinicians’ intuitive thresholdfor the reduction or discontinuation of ventilatory supportappear to have a greater impact on the failure of sponta-neous breathing trials, or on reintubation, than do modesof weaning. When clinicians set a high threshold, manypatients who could tolerate weaning continue to receivemechanical ventilatory support longer than is necessary.

As to the modes and methods of weaning, for stepwisereductions in mechanical ventilatory support, pressuresupport mode or multiple daily t-piece trials may besuperior to intermittent mandatory ventilation. For trialsof unassisted breathing, low levels of pressure support maybe beneficial to overcome the resistance of the ventilatorcircuit. There may be substantial benefits to early extuba-tion and the institution of noninvasive positive-pressureventilation (NPPV) for patients who are alert, cooperative,and ready to breathe without an artificial airway. However,like others,11 we conclude that the manner in which themode of weaning is applied may have a greater effect onthe likelihood of weaning than the mode itself.

Following cardiac surgery, a variety of anesthetic inter-ventions and ICU protocols facilitate early extubation. Theattendant reduction in ICU stay is generally modest,complications are very rare, and thus, a substantial benefitis not well-established.

We found that most theoretically plausible predictors ofweaning and extubation success have no predictive power.Those with some predictive power include the rapidshallow breathing index, which has been most intensivelystudied, as well as the ratio of mouth occlusion pressuremeasured 0.1 s after the onset of inspiratory effort at P0.1impedance to maximal inspiratory pressure and the CROP(compliance, rate, oxygenation, and pressure) index. How-ever, these are relatively weak predictors of weaningsuccess. We found that tests are rarely useful in increasingthe probability of weaning success, although on occasion,

they can lead to moderate reductions in the probability ofsuccess. The reason that weaning predictors were found toperform poorly is probably because physicians have al-ready considered the results when they select patients forstudy.

Future Research DirectionsThese systematic reviews led to several suggestions for

future research directions in weaning patients from me-chanical ventilation.

1. Examination of alternative weaning strategies shouldenroll more homogeneous groups than in most priorstudies, clearly separating those patients whose likelyperiod of additional ventilation is a few hours fromthose whose likely period is a few days. Examples ofhomogeneous populations for targeting in futurestudies include patients with COPD exacerbationsand postoperative cardiac surgery patients.

2. In the setting of a high threshold for extubationassociated with low failure rates, randomized trials ofthousands of patients would be needed to demon-strate the differences between techniques, and sam-ple sizes of tens of thousands would be needed todemonstrate differences in the complications rates offailed extubation. Investigators should establish plau-sible event rates before embarking on randomizedclinical trials.

3. Studies are needed to elucidate the tradeoff betweendecreasing the duration of mechanical ventilationand increasing the reintubation rates associated witha low weaning threshold. For example, what reduc-tion in the duration of time on a ventilator wouldwarrant an increase in reintubation rates from 5 to10%? This work should attend to the importantconsequences of prolonged ventilation and reintuba-tion, including nosocomial pneumonia, cardiac mor-bidity, and death.

4. Future research should examine the potential forNPPV to reduce the duration of intubation and totalmechanical ventilation support. Useful studies wouldexplore the optimal timing and management ofNPPV for weaning purposes, including the postex-tubation application of NPPV targeted at patients athigh risk of extubation failure.

5. Additional randomized trials of weaning protocolsimplemented by respiratory therapists and nursesshould be launched. These trials should evaluate theimpact of different protocols in different types ofpatients and in ICUs with different organizationalstructures (eg, open vs closed units and teaching vscommunity hospitals). The impact of protocols onICU and hospital lengths of stay and costs areimportant considerations.

6. A more fruitful line of investigation than furtherresearch seeking powerful predictors of successfulweaning or extubation might be randomized trialsbuilding on the protocol studies already published.Such trials could test multifaceted, multidisciplinaryweaning programs addressing both pulmonary andnonpulmonary influences on weaning that may de-

398S Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support

crease the duration of mechanical ventilation with-out substantially increasing the rates of failed extu-bation and other complications.

7. Finally, health services research is needed to evalu-ate whether clinicians are applying the results of themost promising studies appropriately, and what theconsequences of this application are in the realworld. Individual practitioners, multidisciplinaryteams, and institutional infrastructures should betested to determine the best ways to put into practicewhat we already know about optimal methods to weanpatients from mechanical ventilation.

The data included in this systematic review and a morecomprehensive discussion of the original articles are in-cluded in an Evidence Report of the Agency for Health-care Research and Quality.12

ACKNOWLEDGMENTS: We thank Ann Mckibbon for herexpert librarian skills and database searching, and Bruce Weaver,Stephen Walter, and Robin Roberts for their statistical advice.The peer reviewers for this AHCPR Report provided insightfuladvice, and we thank Suzanne Burns, Wes Ely, Scott Epstein,Jesse Hall, John Heffner, Dean Hess, Rolf Hubmayer, RobertKacmarek, Neil McIntyre, Peter Pronovost, and Peer ReviewEditor Patricia Houston. Our appreciation is extended to HeinerBucher, Toshi Fukuoka, Luz Letelier, and Marco Ranieri for thetranslation of non-English-language articles. We are grateful toseveral individuals for their administrative help during the prep-aration of these reviews, including Anne Snider, Alejandro Jadad,Marlene Taylor, Deborah Maddock, Karen Burns, and LaurelRaftery. Finally, we would like to acknowledge our advisorsArthur Slutsky and Anne Perry, as well as Sydney Parker and EdDellert of the American College of Chest Physicians.

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