Chapter  23:  Criteria for Weaning from Mechanical Ventilation: Evidence Report/Technology Assessment Number 23

Criteria for Weaning from Mechanical Ventilation

Suggested Citation

Cook D, Meade M, Guyatt G, et al. Criteria for Weaning From Mechanical Ventilation. Evidence Report/Technology Assessment No. 23 (Prepared by McMaster University under Contract No. 290-97-0017). AHRQ Publication No. 01-E010. Rockville MD: Agency for Healthcare Research and Quality. November 2000.

Overview

The majority of critically ill patients in most modern intensive care units (ICUs) require a period of mechanical ventilation. Prolonged mechanical ventilation is associated with nosocomial pneumonia, cardiac-associated morbidity, and death. Prematurely discontinuing mechanical ventilation may result in reintubation which is associated with complications similar to prolonged ventilation. Thus, optimal weaning-minimizing the duration of mechanical ventilation without incurring substantial risk of reintubation and thus preventing important complications-is a crucial part of the management of critically ill patients. Therefore, the Agency for Healthcare Research and Quality (AHRQ) asked us to address the following questions:

• 1

  When should weaning be initiated?

• 2

  What criteria should be used to initiate the weaning process?

• 3

  What are the most effective methods of weaning from mechanical ventilation?

• 4

  What are the optimal roles of nonphysician health care professionals in facilitating safe and expeditious weaning?

• 5

  What is the value of clinical practice algorithms and computers in expediting weaning?

Reporting the Evidence

We resolved to retrieve all randomized trials and the most relevant clinical observational studies that addressed the AHRQ review questions. Conceptually, we were interested in any patients receiving mechanical ventilation, in any strategies designed to facilitate weaning and extubation, in predictors of weaning and extubation in all critically ill patients, and in predictors of the duration of weaning in patients with chronic obstructive pulmonary disease (COPD) or patients following cardiac surgery.

Methodology

To identify relevant studies, we searched MEDLINE, EMBASE, HealthSTAR, CINAHL, the Cochrane Controlled Trials Registry, and the Cochrane Data Base of Systematic Reviews from 1971 to 1998. We also examined reference lists and personal files and hand searched Respiratory Care. We did not explicitly search for unpublished literature. We retrieved all articles that either of two reviewers of the titles and abstracts considered possibly eligible. The same two reviewers examined the full text and made final decisions regarding eligibility based on the inclusion and exclusion criteria described above.

Five respiratory therapists and five intensivists participated in data abstraction and in rating the methodologic quality of all eligible randomized trials or nonrandomized controlled cohort studies addressing treatment issues, and all studies providing quantitative data concerning predictors of weaning and extubation. Two reviewers abstracted the data and assessed the methodologic quality of each study.

Methodologic features of randomized trials that we abstracted included the method of randomization and whether randomization was concealed; the extent to which groups were similar with respect to important prognostic factors; whether investigators conducted an intention to treat analysis; whether patients, clinicians, and those assessing outcome were blind to allocation; the extent to which the groups received similar cointerventions; and the reporting of the reasons for study withdrawal.

For nonrandomized controlled clinical trials, we considered the extent to which groups were similar with respect to important prognostic factors, whether the investigators adjusted for differences in prognostic factors, and the extent to which the groups received similar cointerventions.

For studies addressing predictors of weaning success, we considered whether investigators enrolled a representative sample of patients and whether those making weaning decisions or assessing outcomes were blind to predictor variables.

For qualitative studies, we considered whether the choice of participants was relevant to the research question and if their selection was well reasoned, whether the data collection methods were appropriate for the research objectives, whether the data collection was comprehensive enough to support rich and robust descriptions of the observed events, and whether the data were appropriately analyzed and the findings adequately corroborated.

To synthesize the data from randomized trials comparing weaning interventions we abstracted or, when necessary, calculated effect sizes in terms of relative risks and associated 95 percent confidence intervals (CIs) for binary outcomes and mean differences and 95 percent CIs for continuous variables. We reviewed the interventions and outcomes and decided when it was legitimate to pool across studies and when it was not. When pooling was not appropriate, we categorized studies according to similarity of interventions. All our pooled analyses are based on a random effects model that includes differences between studies in calculating the variance estimate provided the strategy for final estimates of all treatment effects. For nonrandomized studies that compared alternative weaning interventions, we used similar methodology for calculating point estimates and CIs for individual studies but made no attempt to pool data across studies.

For observational studies addressing prediction of successful weaning and duration of ventilation, we categorized studies according to the outcome of interest and, for each predictor in each study in which the data were available, we constructed a 2X2 table examining the presence or absence of the predictor in relation to the success or failure of the weaning process. This procedure allowed calculation of the sensitivity and specificity of the tests and their associated 95 percent CIs as well as odds ratios and their 95 percent CIs and the associated likelihood ratios. We then organized the observational studies according to predictors of interest. We defined predictors as relevant if they showed potential for differentiating success from failure and retained all predictors for which results were presented in 2X2 tables if there was an associated likelihood ratio (LR) of greater than 2 or lower than 0.5. When results were presented as means and standard deviations of the success and failure groups, we included predictors if the difference in means between the two groups was greater than one-half of the smaller of the standard deviations of the two groups. Where appropriate, we pooled the observational data to narrow the 95 percent CIs.

Findings

• We reviewed 154 articles.

• The issue of the optimal start of weaning is confounded by alternative definitions of weaning: one reasonable conceptualization is weaning beginning with the onset of mechanical ventilation. Research to date suggests the best answer to "when to start weaning" is to develop a protocol implemented by nurses and respiratory therapists that begins testing for the opportunity to reduce support very soon after intubation and reduces support at every opportunity.

• Differences in clinicians' intuitive threshold for reduction or discontinuation of ventilatory support have a greater impact on failure of spontaneous breathing trials, or on reintubation, than do modes of weaning. When clinicians set a high threshold, many patients who could tolerate weaning remain on mechanical support longer than is necessary.

• For stepwise reductions in mechanical support, pressure support mode or multiple daily T-piece trials may be superior to intermittent mandatory ventilation.

• For trials of unassisted breathing, low levels of pressure support may be beneficial.

• There may be substantial benefits to early extubation and institution of noninvasive positive pressure ventilation for patients who are alert, cooperative, and are ready to breathe without an artificial airway.

• Following cardiac surgery, early extubation is unequivocably achieved with a variety of anesthetic interventions and ICU protocols; however, the corresponding reduction in ICU stay is generally small and the impact on complications, though rare, remains unclear.

• The role of computerized weaning protocols has not been established.

• Although steroids can reduce postextubation stridor in children, their impact on reintubation in children and adults remains uncertain.

• Most theoretically plausible predictors of weaning and extubation success have no predictive power. Those with some predictive power include the rapid shallow breathing index, which has been most intensively studied, and occlusion pressure/maximum inspiratory pressure (P_0.1/MIP) and the compliance, rate, oxygenation, and pressure (CROP) index. However, these are relatively weak predictors of weaning success. Tests are rarely useful in increasing the probability of weaning success; on occasion, they can lead to moderate reductions in the probability of success. In general, weaning predictors were probably found to perform poorly because physicians have already considered the results when they select patients for study.

Future Research

• Examination of alternative weaning strategies should enroll homogeneous patient groups: those whose likely period of additional ventilation is a few hours, and those whose likely period is a few days. Patients after cardiac surgery constitute another population that should be considered separately.

• In the setting of a high threshold for extubation associated with low failure rates, investigators would require trials of thousands of patients to demonstrate differences between techniques and tens of thousands to demonstrate differences in complications of failed extubation. Investigators should establish plausible event rates before embarking on clinical trials.

• Investigators should attempt to elucidate the tradeoff between decreasing duration of time on a ventilator and the increase in reintubation rates associated with a low weaning threshold (e.g., what reduction in duration of time on a ventilator would warrant an increase in reintubation rates from 5 to 10 percent)? This work should involve attention to the important consequences of prolonged ventilation or reintubation, including nosocomial pneumonia, cardiac morbidity, and death.

• Investigators should launch trials examining the use of noninvasive positive pressure ventilation (NPPV) in reducing the duration of intubation and total mechanical support. Future research should also explore the optimal timing and management of NPPV for weaning purposes, its effect on morbidity (e.g., pneumonia), length of ICU stay, and mortality.

• Investigators should launch additional randomized trials of weaning protocols implemented by respiratory therapists and nurses. These trials should evaluate the differential impact of protocols in different types of patients and in ICUs with different organizational structures (e.g., open versus closed units, teaching versus community hospitals). The influence of different protocols and their impact on ICU and hospital length of stay and costs are important future considerations.

• A more fruitful line of investigation than further research seeking powerful predictors of successful weaning or extubation might be randomized trials of weaning protocols that decrease the duration of mechanical ventilation without substantially increasing rates of failed extubation.

Organization

We begin this report with background information regarding our perspective on the issues of weaning patients from mechanical ventilation. We then describe the methodology related to our definition of the study questions, our inclusion and exclusion criteria, our search, and our strategies for organizing and synthesizing our findings. Because the methodology of the individual studies and the types of questions they address are linked, we have organized the Results chapter of our report largely according to the types of studies. We address, in order, randomized controlled trials (RCTs) and nonrandomized controlled trials of weaning interventions, observational studies addressing predictors of weaning success, qualitative studies of the experience of health providers and patients involved in the weaning process, and studies using quantitative approaches to examine patient experience. Because the implications for future research are specific to each of these areas and within the controlled trials are specific to the interventions, we present our thoughts about future research as part of those sections of the conclusion. We deal with the strengths and limitations of our systematic review as the penultimate section of Chapter 4, Conclusions and Future Research. We end our report with a distillation of our most important inferences and thoughts about directions for future research in this field.

Mechanical Ventilation and Weaning from Mechanical Ventilation

Mechanical ventilation refers to the use of life support technology to perform the work of breathing for patients who are unable to breathe effectively on their own. Patients requiring mechanical ventilation include: (1) critically ill patients with advanced and potentially reversible respiratory failure due to pulmonary or non-pulmonary processes, (2) patients who are only temporarily unable to ventilate adequately on their own following general anesthesia, and (3) patients who have chronic respiratory or neuromuscular disorders that may prevent them from breathing effectively without mechanical support. Our report will address patients in all three groups.

Weaning from mechanical ventilation generally refers to the progressive reduction in mechanical support that is delivered to patients in the first two groups as they progressively increase their own contributions to breathing. Therefore, the settings relevant to this proposal are intensive care unit (ICUs), intermediate care units, stepdown units, postanesthetic recovery units, and other facilities in which the goal remains to discontinue mechanical support. Patients who are unable to be successfully liberated from mechanical ventilation in acute care settings and who are looked after in chronic ventilatory care settings are not the subject of this report.

According to conventional terminology, mechanical ventilation refers to the use of the ventilator to deliver inspired air through an artificial airway that is either the endotracheal tube or a tracheostomy tube. However, technology is now available that allows the provision of mechanical support without the use of an artificial airway. This technology is referred to as noninvasive positive pressure ventilation (NPPV). The advent of NPPV has, therefore, broadened the domain of mechanical ventilation and weaning from mechanical ventilation, as well as the scope of clinical research in these areas.

Questions On Weaning From Mechanical Ventilation

Our review addresses the five questions specified by AHRQ.

• 1

  When should weaning be initiated?

• 2

  What criteria should be used to initiate the weaning process?

• 3

  What are the most effective methods of weaning from mechanical ventilation?

• 4

  What are the optimal roles of nonphysician health care professionals in facilitating safe and expeditious weaning?

• 5

  What is the value of clinical practice algorithms and computers in expediting weaning?

This report summarizes the clinical literature that directly or indirectly addresses each of these questions. Some of these questions can be comprehensively addressed by the currently available literature (e.g., question 4 regarding multidisciplinary roles in facilitating weaning), whereas other questions are also well informed by physiologic studies outside the scope of this report (e.g., question 1 regarding when weaning should be initiated). Given that different ways of thinking about weaning could lead to different criteria for when weaning has started, the framing of the first two questions provides special challenges. We have dealt with this issue by reflecting on evidence that bears on the entire weaning process. We now provide some introductory comments about weaning from mechanical ventilation and our frame of reference for approaching these questions.

Importance of Optimizing the Weaning Process

The weaning process and definitions of weaning success and failure are variably defined by investigators in this field. According to the most liberal definition, attempts to reduce the level of support may begin as soon as mechanical ventilation begins, and virtually the whole period on the ventilator could be considered part of "weaning process." A much more conservative definition would reserve the term "weaning" for the final stages of mechanical ventilation in which the attending health care workers believe the possibility of the patient's breathing without assistance is near or imminent.

Weaning can be considered a gradual decrease in mechanical support, effected by: (1) increasing periods of unassisted breathing, (2) unassisted breaths alternating with progressively fewer ventilator breaths, or (3) reductions of ventilatory support in breaths triggered by patient effort. Unassisted breathing can be: (1) for short periods as part of a process designed to gradually decrease ventilatory support, (2) for periods typically up to 2 hours for assessing discontinuation readiness, or (3) as termination to the weaning process. Since many patients can be successfully liberated from mechanical ventilation after a brief spontaneous breathing trial, the term "weaning" might not be suitable in this instance. For some investigators, "weaning success" is defined as sustained spontaneous, unassisted breathing with or without an artificial airway, and for others it is defined as sustained extubation. Since our remit was neither to develop a new weaning definition nor select one particular definition, we considered weaning as broadly described by investigators in this field. Therefore, from the studies included in this systematic review, we recorded the weaning processes and outcomes that evaluated how best to predict and maintain liberation from mechanical ventilation.

By one estimate, patients spend, on average, approximately 41 percent of their time receiving mechanical ventilation in the weaning process (Esteban, Alia, Ibanez, et al., 1994). Efforts to reduce the duration of weaning are important because mechanical ventilation is associated with considerable morbidity, pulmonary barotrauma (Meade and Cook, 1995; Meade, Cook, Kernerman, et al., 1997; Slutsky and Trembly, 1998), ventilator-associated pneumonia (Cook, Walters, Brun-Buisson, et al., 1998; Papazian, Bregeon, Thirion, et al., 1996; Vincent, Bihari, Suter, et al., 1995), and mortality (Ely, Baker, Evans, et al., 1999; Fagon, Chastre, Vuagnat, et al., 1996). In addition to increasing morbidity and mortality, a long duration of mechanical ventilation is associated with increased health care costs, both because of a longer stay in the ICU and because of the costs associated with mechanical ventilation itself (e.g., more nursing and respiratory therapy time and more ventilator management interventions).

At the same time, premature discontinuation of mechanical ventilation can also contribute to failed extubation (a failed extubation is typically characterized by the need for reintubation within a short period of time) and thus contribute to ongoing risk of morbidity and ICU complications in critically ill patients. Failed trials of extubation can contribute to respiratory muscle fatigue or injury, which may in turn delay future weaning attempts and therefore prolong mechanical ventilation even further, possibly incurring the need for more sedation and potentiating cardiac ischemia. Aside from patients' distress if they must breathe unassisted before they are ready, reintubation is associated with airway trauma, oropharyngeal or gastric aspiration, acute lung injury, risk of cardiovascular compromise, and the adverse sequelae of episodic hypoxemia. Reintubation has also been associated with increased risk of mortality after controlling for severity of illness and comorbid conditions (Epstein and Ciubotaru, 1997; Esteban, Alia, Ibanez, et al., 1994).

In considering these issues, it is worthwhile to note that the goals of shortening the duration of weaning and avoiding premature termination of mechanical ventilation will always, to some extent, compete. We can think of alternative thresholds for decreasing and discontinuing ventilatory support. Clinicians choosing a low threshold will reduce support whenever patients might tolerate it and will therefore minimize the duration of mechanical ventilation. Clinicians who choose a high threshold will not reduce support unless they are confident patients will tolerate support reduction and may seldom need to reintubate patients.

In choosing thresholds for reducing mechanical support, clinicians thus face a tradeoff between decreasing the duration of ventilation at the risk of a larger number of weaning failures and reintubations or minimizing weaning failures at the risk of unnecessary prolonged ventilation. Defining the optimal tradeoff between shortening average times on the ventilator and minimizing the rate of reintubation presents a challenge for health care workers managing critically ill patients, particularly since clinicians currently disagree on what constitutes an "acceptable" rate of failed extubation.

This disagreement flows in part from a lack of clinical data. Both extending the duration of ventilation and the necessity for reintubation have direct consequences important to patients and the health care system. At the same time, both (and particularly the latter) constitute to some extent surrogate endpoints. Clinicians place a priority in avoiding reintubation because of concern that it may increase the frequency of pneumonia, myocardial infarction, and death. Prolonged ventilation prior to extubation may have an impact on the rate of these same outcomes. Thus, the immediate effect of alternative weaning strategies on duration of ventilation before extubation and on reintubation rates is poorly understood. Only knowledge of their effects on the putative complications of prolonged ventilation or intubation can fully inform tradeoffs between alternative weaning strategies.

How Can Clinicians Conduct an Optimal Wean?

One strategy for optimizing the duration of mechanical ventilation relies on optimal recognition of when patients would tolerate reduction in mechanical support and when, ultimately, they would tolerate discontinuation. Research in this area examines patient characteristics that might predict their ability to tolerate reductions or discontinuation of mechanical support.

As noted above, clinicians need to trade off goals of reducing mean time on the ventilator with minimizing rates of reintubation and, thus, defining the optimal threshold is an important goal for weaning research. At the same time, it would be highly desirable to find an approach that simultaneously minimizes both the duration of ventilation and the need for reintubation. Currently, clinicians use a variety of indicators including some assessed qualitatively (e.g., diaphoresis, anxiety) and some assessed quantitatively (e.g., vital signs, such as heart rate, respiratory rate, blood pressure, and pulmonary mechanics, such as tidal volume, airway occlusion pressure, work of breathing, rapid shallow breathing index), or scores that combine two or more of these variables to guide weaning. Clinicians may not only have different thresholds, they may also choose different patient characteristics to determine whether a patient has a decreased need, or no further need, of the support of a ventilator. Whatever patient characteristics they use, in making the final decision about reducing or discontinuing mechanical support, they intuitively weigh these factors.

It is therefore no surprise that a physician's judgment of a patient's readiness for weaning is often inaccurate. In one study, one-half of the patients whom physicians considered to be incapable of sustaining spontaneous ventilation subsequently tolerated a weaning trial (Stroetz and Nubmayr, 1995). All this raises the possibility that different health care workers may do a better job of rapid detection of problems with reductions in ventilatory support.

Perhaps a deeper quantitative understanding of the results of tests that may predict weaning success would improve clinicians' accuracy. Traditional indices of diagnostic test power include sensitivity (the proportion of those who successfully wean who have "positive" test results) and specificity (the proportion of those who do not successfully wean who have "negative" test results). Sensitivity and specificity are limited in that they rely on a single cutpoint or threshold and they do not provide an easy way to go from the pretest likelihood or probability of successful weaning, through the tests results, to the posttest probability. Likelihood ratios (the ratio of the proportion of patients with a test result who successfully wean to the proportion of patients with the same test result who do not successfully wean) allow consideration of multiple cutpoints or thresholds. Furthermore, a simple nomogram allows the transition from the pretest probability of success, through the test result, to the posttest probability.

Algorithms present an alternative approach that does not rely on clinicians' sophisticated use of information from diagnostic tests. Ventilation researchers have suggested standardized algorithms for advancing the wean which include criteria for cutting the rate of reduction of support or returning to a previous greater level of support (Ely, Baker, Dunagan, et al., 1996; Kollef, Shapiro, Silver, et al., 1997). Recently, computer technology for implementing these algorithms has become available (Strickland and Hasson, 1993). Clinician-guided or computer-guided protocols could, in theory, increase the rate at which patients wean without a consequent increase in premature reduction of support. On the other hand, protocols could, in theory, also make the weaning process formulaic in a manner that decreases caregiver sensitivity to subtle clinical findings that might predict adverse effects and attendant weaning failure. In one protocol-guided study, one-third of patients who failed to pass the daily screen were still successfully extubated, highlighting that rigid adherence to the protocol may not be ideal, since, in this case, it would have unnecessarily committed these patients to prolonged ventilation (Ely, Baker, Dunagan, et al., 1996).

A second fundamental strategy for optimizing the weaning process follows the decision that a patient can tolerate reduction of mechanical support and focuses on the choice of the method of reduction. Implicit in these options is the hypothesis that some methods of gradual support are better than others because of differential mechanics or respiratory muscle conditioning that might favor a patient's capacity to breath unassisted. Clinicians have a menu of ventilation modes from which they can choose. These include, but are not restricted to, T-piece trials, synchronized intermittent mandatory ventilation (SIMV), pressure support (PS), continuous positive airway pressure (CPAP), combinations of the foregoing, and newer approaches to weaning such as volume support, proportional assist ventilation (PAV), and NPPV. One of these methods, T-piece trials, can be used in two different ways, one of which is aligned with a traditional description of weaning (conceptualized as a gradual reduction in support) and one of which is not. For example, multiple periods of breathing through a T-piece that are gradually increased in length is more consistent with the former approach (Esteban, Alia, Ibanez, et al, 1994), whereas once or twice a day discontinuation assessments with the specific goal of achieving discontinuation from mechanical ventilation is more consistent with the latter approach (Brochard, Rauss, Benito, et al., 1994). Most clinicians are familiar with each of these strategies and use a subset of them to various degrees in practice.

It may be that some approaches to weaning work better than others in reducing the duration of weaning. Ascertaining the best approaches, and disseminating such information, could improve the quality of care of mechanically ventilated patients, and reduce morbidity and costs.

Eligibility Criteria

We resolved to retrieve all randomized trials that addressed the AHRQ review questions. Conceptually, we were interested in any patients receiving mechanical ventilation in an intensive care setting, any strategies designed to facilitate weaning and extubation, any predictors of weaning and extubation in all critically ill patients, and predictors of the duration of weaning in patients with chronic obstructive pulmonary disease (COPD) or patients following cardiac surgery. Appendix G shows our relevance form and Appendix H provides a list summarizing our inclusion and exclusion criteria.

Search for Relevant Studies

To identify relevant studies, we searched MEDLINE, EMBASE, HealthSTAR, CINAHL, the Cochrane Controlled Trials Registry, the Cochrane Data Base of Systematic Reviews from 1971 to 1998, and personal files. We examined the reference lists of all included articles for other potentially relevant citations. In addition, we hand searched the respiratory therapy journal Respiratory Care from 1997 to 1999. We did not explicitly search for unpublished literature. Appendixes A to F summarize our search strategies.

Two reviewers examined each title and abstract. Reviewers included either two of the investigators or one investigator and one senior respiratory therapist. We took a comprehensive approach and retrieved all articles that either reviewer considered possibly eligible. The same two reviewers examined the full text and made final decisions regarding eligibility based on the inclusion and exclusion criteria described above. These decisions were made unblinded to the source, authors, and conclusions of each study. Disagreements were resolved by consensus.

Data Abstraction and Assessment of Methodologic Quality

Five respiratory therapists and five intensivists participated in data abstraction and in rating the methodologic quality of all eligible randomized trials or nonrandomized controlled cohort studies addressing treatment issues and all studies providing quantitative data concerning predictors of weaning and extubation. We trained each of the abstractors and constructed manuals to help them with their task. Two reviewers abstracted the data and assessed the methodologic quality of each study. Reviewers resolved disagreement through discussion or consultation with one of the investigators. Final data abstraction was rechecked by one of the investigators.

We developed a generic data collection form applicable to both randomized trials and observational studies (Appendix I), a form particular to the randomized trials (Appendix J), a form particular to nonrandomized controlled studies of weaning interventions (Appendix K), and a form particular to observational articles providing quantitative information about weaning predictors (Appendix L).

Methodologic features of randomized trials that we abstracted included the method of randomization and whether randomization was concealed; the extent to which groups were similar with respect to important prognostic factors; whether investigators conducted an intention to treat analysis; whether patients, clinicians, and those assessing outcome were blind to allocation; the extent to which the groups received similar cointerventions; and reporting of the reasons for study withdrawal.

Because it is a relatively new methodologic term, the issue of concealment deserves further comment. A study is concealed if those making the judgment about whether a patient is eligible to be enrolled is unaware, at the time they are making this decision, whether a patient will be allocated to the experimental or control group. Lack of concealment may theoretically destroy the balance in prognostic factors that investigators strive to achieve through randomization. For instance, those making decisions about eligibility and enrollment may systematically exclude sicker patients if they know these patients are going to be allocated to the treatment group. Some empirical data suggest that unconcealed studies yield systematically larger treatment effects than do concealed studies (Moher, Pham, Jones, et al., 1998; Schulz, Chalmers, Hayes, et al., 1995).

For nonrandomized controlled clinical trials, we considered the extent to which groups were similar with respect to important prognostic factors, whether the investigators adjusted for differences in prognostic factors, and the extent to which the groups received similar cointerventions.

For studies addressing predictors of weaning success, we considered whether investigators enrolled a representative sample of patients and whether those making weaning decisions or assessing outcomes were blind to predictor variables (Jaeschke, 1994a).

For qualitative studies, we considered whether the choice of participants was relevant to the research question and if their selection well reasoned, whether the data collection methods were appropriate for the research objectives, whether the data collection was comprehensive enough to support rich and robust descriptions of the observed events, and whether the data were appropriately analyzed and the findings adequately corroborated (Giacomini, work in progress).

Statistical Synthesis

When we found duplicate reports of the same study in preliminary abstracts and articles (Chaney, Nikolov, Blakeman, et al., 1999; Chatila, Ani, Guaglianone, et al. 1996a; Cheng, 1996b; Goodnough-Hanneman, 1992; Nava, Zanotti, Rubini, et al 1994a; Zanotti, Rubini, Iotti, et al., 1995), we used the most complete information (Chaney, Nikolov, Blakeman, et al., 1998; Chatila, Jacob, Guaglianone, et al.,1996b; Cheng, 1996b; Goodnough, 1994; Nava, Rubini, Zanotti, et al. 1994b). We divided our approaches to synthesis (and subsequently our results) into studies dealing with randomized and nonrandomized controlled comparisons of alternative weaning interventions and observational studies addressing the prediction of successful weaning and duration of mechanical ventilation.

Controlled Comparisons of Alternative Treatments

We began by identifying all the interventions and outcomes addressed by randomized trials. We abstracted or, when necessary, calculated effect sizes in terms of relative risks and associated 95 percent confidence intervals (CIs) for binary outcomes and mean differences and 95 percent CIs for continuous variables. We transformed interquartile ranges into standard deviations when necessary to obtain variance estimates for testing differences between groups. Confidence intervals are not reported when variance data were either not provided by authors or were not estimable using either a precise p value or an interquartile range.

We reviewed the interventions and outcomes and decided when it was legitimate to pool across studies and when it was not. When pooling was not appropriate, we divided studies into categories according to similarity of interventions.

We pooled when, in our judgment, the underlying pathophysiology was such that across the range of populations, management strategies in treatment and control groups, and key outcomes studied, we would expect more or less the same treatment effect. In general, we did not see differences in distributions of characteristics of populations between studies as an impediment to pooling. For instance, consider two studies of the same weaning strategy. One enrolls patients 8 days after the onset of mechanical ventilation, and another, 14 days after. However, both studies enroll some patients after 3 days of ventilation, and others, after 3 months. Thus, the individual studies are themselves pooling data from patients with the full spectrum of duration. When interventions, outcomes, and trial methodology are similar, we do not see serious impediments to pooling in this sort of situation.

For instances in which we could pool data, for continuous variables we considered the mean in each group and an estimate of variability from each group that determined the weight given to the study in the pooled analysis. For pooling binary data, we calculated risk ratios using methods described by Fleiss (Fleiss, 1993). We constructed 2X2 tables in each study for which the data were available and calculated the associated risk ratios. For both continuous and binary variables, we tested for heterogeneity using a test based on the chi-squared distribution with N1 degrees of freedom where N is the number of studies. When we found clinically important heterogeneity that could not be explained by the play of chance, we reviewed the methodology of the original studies in search of explanations of the differences in outcome. All our analyses are based on a random effects model that incorporates differences between studies in the calculation of the the variance estimate for all treatment effects.

For nonrandomized studies that compared alternative weaning interventions, we used similar methodology for calculating point estimates and CIs for individual studies but made no attempt to pool data across studies.

Observational Studies Addressing Prediction of Successful Weaning and Duration of Ventilation

When results were presented as means and standard deviations of the success and failure groups, we included predictors if the difference in means between the two groups was greater than one-half of the smaller of the standard deviations of the two groups. Finally, we included predictors with a statistically significant association with the outcome of interest when there was no information about the power of the predictor in terms of either LRs or differences in distributions of success and failure groups.

When the results differed across studies, we included the predictor unless it was not predictive in a substantial majority of the studies that included a substantial majority of the patients. For example if only one of many studies found a predictor to be of value, we included this study unless the sample size was less than 50 percent of the total sample size of all studies that examined that predictor.

Methodology For Pooling Study Results

Where appropriate, we pooled the observational data to narrow the 95 percent CIs. We did not pool results unless it was clinically sensible.

The results of the predictor studies were reported in various ways (e.g., means and proportions in patients who were successfully and unsuccessfully extubated). The investigators presented varying analyses (e.g., sensitivity and specificity, Pearson correlation coefficients, chi-square tests, student's t tests, analysis of variance, and regression). To facilitate meta-analyses, we summarized data in a common form when possible (Irwig, Tosteson, Gatsonis, et al., 1994).

Some observational studies examined predictors of successful outcome and presented these data in a manner allowing creation of a 2X2 table. Using these data, we calculated the pooled LR of a positive test result, the pooled LR of a negative test result, the pooled sensitivity and specificity of a given predictor threshold, and an associated pooled odds ratio (OR). If there were more than three studies examining a predictor with plausible and clinically important test properties, we constructed summary receiver operator characteristics (ROC) curve.

Other observational studies examined predictors of successful outcome and presented these data in using means and standard deviations in the successful and unsuccessful group. The majority of studies presented data in this manner. We tested the assumption of normality for predictors presented in this manner in several ways. First, when we had individual patient data from the original reports, we inspected this directly. Second, when we did not have individual patient data, we inspected the mean and standard deviation for skewness, noting when the value obtained by adding two standard deviations to, and subtracting two standard deviations from, the mean yielded clinically implausible values. If we could assume normality, knowing the total sample size and the number of patients in the successful and unsuccessful groups, we estimated the number of patients in each cell of a 2X2 table. Thus, we were able to compute the summary statistics as listed above for data presented in binary fashion. We used the predictor threshold most often provided by the investigators to create these LRs. We calculated CIs for all summary measures (Littenberg and Moses, 1993). We did not pool predictor data across studies in which some investigators presented their results as binary variables and others presented their results as continuous variables. Rather, we juxtapose the results, giving an indication of their consistency.

Other Types of Studies

We classified other types of studies according to their study design and the topic areas they addressed and provide narrative descriptions of the individual study methodology and results. These include qualitative studies examining the experience of health workers involved in the care of patients being weaned from mechanical ventilation and studies using qualitative and/or quantitative methods to examine patients' experience of weaning.

Randomized and Nonrandomized Controlled Trials

In the second clinical context we identified, the clinician faces a patient who is improving but who is unlikely to tolerate unassisted ventilation for at least 24 hours and perhaps up to several days. The clinician wishes to progressively decrease the level of mechanical support and has a number of modes available to achieve this goal. We refer to this group of trials as "studies comparing alternative ventilation modes for stepwise reductions in mechanical support."

We identified three studies that addressed related issues but did not fit clearly into either one of these categories. These studies examined the impact of stepwise reductions in mechanical support in patients over periods of up to 48 hours.

We identified three RCTs that compared physician-directed weaning with weaning directed by a protocol with major involvement from respiratory therapists and nurses or a computer-driven protocol.

Another set of randomized trials dealt with the timing of extubation in patients who had undergone cardiac surgery. The management issue is whether clinicians can achieve early extubation without deleterious consequences for patients. Investigators have addressed two approaches to early extubation in such patients: alternative anesthesia regimens and alternative strategies once the patient reaches the ICU.

Investigators have tested, in both children and adults, whether parenteral steroid administration could reduce postextubation edema and thus prevent stridor or distress requiring reintubation.

The balance of fat and carbohydrate that patients receive determines their respiratory quotient and the amount of carbon dioxide they produce. Theoretically, this may influence the burden on their respiratory system during the weaning process. Two RCTs have tested the hypothesis that weaning could be expedited by use of low carbohydrate feeds.

Controlled Trials of Discontinuation Assessment Strategies

The second Esteban study (Esteban, Alia, Tobin, et al., 1999) compared a 30-minute with a 120-minute T-piece trial of spontaneous breathing prior to extubation. There was no reported difference in the rate of reintubation between groups, and patients randomized to the shorter T-piece trial benefited from statistically significant reductions in ICU and hospital length of stay (2 days and 5 days shorter, respectively).

There were no nonrandomized trials in this category of weaning interventions.

Controlled Trials of Progressive Reduction in Mechanical Support

In both studies, the investigators recruited patients who had failed a T-piece trial. Esteban, Frutos, Tobin, et al. (1995) conducted their T-piece trial in 546 patients, only 130 of whom had respiratory distress during a 2-hour T-piece trial. Brochard, Rauss, Benito, et al. (1994) found a similar strikingly high proportion of patients who tolerated their 2-hour T-piece trial: of 456 patients in who underwent the T-piece trial, only 109 were unable to tolerate spontaneous breathing and were therefore randomized.

Of those randomized, patients in the Esteban trial had a prior mean duration of mechanical ventilation of approximately 9.3 days, with a minimum of 24 hours. Brochard's patients also had a minimum duration of ventilation of 24 hours. The approximate mean duration of ventilation in the Brochard patients was 14 days.

In the comparison of pressure support to SIMV on duration of weaning, both studies found trends in favor of pressure support; the effect in the Brochard, Rauss, Benito, et al. (1994) study was much larger. The magnitude of the trend in the pooled result of duration of ventilation is over 60 hours, and the CI comes close to excluding no effect. The pooled results of pressure support versus SIMV on the combined endpoint show an extremely wide CI.

Two additional nonrandomized trials evaluated the use of NPPV in weaning. Patel, Petrini, and Dwyer (1999) compared 24 hours of intermittent nasal CPAP with 24 hours of invasive CPAP in patients who were weaned for 24 hours to PS 5 cm H₂O plus positive end-expiratory pressure (PEEP) 5 cm H₂O following prolonged ventilation. There was a marginal increase in the reintubation rate in the patients receiving invasive CPAP versus noninvasive CPAP. Hilbert, Gruson, Portel, et al. (1998a) evaluated NPPV in COPD patients who developed hypercapnic respiratory insufficiency after extubation. Comparing patients managed with NPPV with historical controls, there was a statistically significant reduction in the rate of reintubation with NPPV and a nonsignificant survival benefit.

Controlled Trials Comparing Alternative Ventilation Modes for Weans Lasting Less Than 48 Hours

Controlled Trials Comparing Weaning Protocols to Physician-Directed Weaning

Ely, Baker, Dunagan, et al. (1996) studied a different group of patients: median durations of mechanical ventilation were 4.5 and 6 days in the protocol- and physician-directed groups respectively. The relative risk of successful extubation in the protocol-directed group was 2.13 (95 percent CI 1.55 to 2.92, p<0.001), indicating that mechanical ventilation was discontinued sooner than in the control group. The largest separation between groups was at approximately 5 days and differences disappeared by about 15 days. Patients in the physician-directed group spent a day longer in the intensive care unit and 1.5 days longer in the hospital; neither of these differences reached statistical significance.

In addition to these RCTs, 11 nonrandomized controlled clinical trials have examined the impact of, largely, respiratory therapist- or nursing-directed weans, compared with physician-directed weans, on weaning outcomes in critically ill patients (Evidence Tables 9 and 10). These studies, conducted in a variety of patient populations, are generally much larger than the corresponding RCTs but are more prone to biased results (Evidence Table 9d). Their results are generally consistent with the results of the RCTs, demonstrating statistically significant reductions (Foster, Conway, Pamulkov, et al., 1984; Horst, Mouro, Hall, et al., 1998; Rotello, Warren, Jastremski, et al., 1992) or trends toward reductions (Burns, Marshall, Burns, et al., 1998; Kollef, Horst, Prang, et al., 1998; Saura, Blanch, Mestre, et al., 1996a; Wood, MacLeod, and Moffatt, 1995) in the duration of mechanical ventilation and ICU length of stay, as well as benefits to protocolized weans with respect to a variety of other study outcomes (number of arterial blood gases required). Mortality and reintubation rates did not appear to differ between experimental and control groups among these nonrandomized studies, nor were other complications associated with protocolized weaning reported.

Controlled Trials of Early Versus Late Extubation Following Cardiac Surgery

Five RCTs that used other approaches to achieve early extubation included more varied populations: one trial in elderly patients undergoing elective abdominal aortic reconstruction (Shackford, Virgilio, and Peters, 1981), one trial in patients undergoing mitral valvulotomy (Tempe, Cooper, Mohan, et al., 1995), and three trials in patients undergoing coronary artery bypass surgery (Dumas, Dupuis, Searle, et al., 1999; Quasha, Loeber, Feeley, et al., 1980; Reyes, Vega, Blancas, et al., 1997). Two RCTs reversed neuromuscular blockade to achieve early extubation (Tempe, Cooper, Mohan, et al., 1995; Quasha, Loeber, Feeley, et al., 1980); one discontinued sedation at an earlier point (Dumas, Dupuis, Searle, et al., 1999) whereas two simply instituted early efforts at extubation (Shackford, Virgilio, and Peters, 1981; Reyes, Vega, Blancas, et al., 1997). Sample sizes varied from 35 to 404; only Reyes, Vega, Blancas, et al. (1997) recruited more than 100 patients.

There are an additional eight nonrandomized controlled studies of early versus late extubation following cardiac surgery (Evidence Tables 9 and 10). These were large studies conducted primarily in adults, and all studies evaluated a combination of altered anesthetic techniques and altered ICU care to achieve early extubation. The results were very similar to the RCT results. Duration of intubation was reduced with the implementation of early extubation strategies by 1 to 28 hours, though associated reductions in ICU and hospital lengths of stay were relatively small (though inconsistent), ranging from 1 to 53 hours, and 0.3 to 2.6 days, respectively. Complication rates varied across studies in early versus late extubation groups, and these event rates were rather small.

Controlled Trials of Corticosteroids to Prevent Post-Extubation Airway Complications

Three RCTs have addressed whether preextubation steroid administration can reduce postextubation stridor and the necessity for reintubation in children (Anene, Meert, Uy, et al., 1996; Harel, Vardi, Quigley, et al. 1997; Tellez, Galvis, Storgion, et al., 1991). In all three studies, patients, caregivers, and those assessing outcome were blind to allocation, patients having received dexamethasone or a matched placebo. Two trials (sample sizes of 66 and 153 children) enrolled patients who had not previously been extubated (Anene, Meert, Uy, et al., 1996; Tellez, Galvis, Storgion, et al., 1991). A smaller trial enrolled 23 children who had been reintubated for postextubation stridor, who received two doses of dexamethasone or placebo over 6 hours and were then extubated.

One nonrandomized controlled study evaluated corticosteroids to prevent postextubation airway complications in children. In a study evaluating steroids in patients who had failed extubation the first time, Freezer, Butt, and Phelan (1990) reported a statistically significant reduction in prolonged reintubation (>6 days) and in failed reextubations.

Controlled Trials of Enteral Nutrition

High carbohydrate loads can markedly increase carbon dioxide production, resulting in a respiratory quotient of >1.0. The biologic rationale for the high fat, low carbohydrate intervention tested in the following two trials is that the lower respiratory quotient might improve gas exchange and facilitate weaning from mechanical ventilation in patients with limited ventilatory reserve.

In a randomized, double-blind trial (al-Saady, Blackmore, and Bennett, 1989), 20 medical ICU patients were allocated to: (1) a high fat, low carbohydrate enteral feeding solution (Pulmocare: 17 percent protein, 55 percent fat, 28 percent carbohydrates) or (2) isocaloric feeds (Ensure Plus: 17 percent protein, 30 percent fat, 53 percent carbohydrates). Nutritional requirements were calculated at 1.5 times basal metabolic rate, delivered through a nasogastric tube. Patients were eligible if they had either COPD, asthma, pneumonia, or neurologic disease and if they could tolerate enteral nutrition. Exclusion criteria were nephrotic syndrome, hepatic failure, or diabetes mellitus. Patients were mechanically ventilated using intermittent positive pressure ventilation. Weaning was started when patients had a respiratory rate <30 breaths/minute, minute ventilation was <12 L/minute, if arterial partial pressure of oxygen (PaO₂) at fractional inspired concentration of oxygen (FiO₂ ) was >60 mmHg, when arterial partial pressure of carbon dioxide (PaCO₂) was 38-45 mmHg, and when pH was >7.3. T-piece weaning continued and was considered successful at 24 hours if the following were maintained: clinically and hemodynamically stable, respiratory rate <30 breaths/minute, minute ventilation <10 L/minute, if PaO₂ at FiO₂ was >60 mmHg, when PaCO₂ was 38-45 mmHg, and when pH was >7.3. The study was terminated as soon as patients were able to tolerate 3 hours of spontaneous breathing.

Randomization methods and concealment of allocation were not reported. The study was doubleblinded. Patients were comparable at baseline with respect to basic demographics, and preintervention duration of ventilation (approximately 64 and 70 hours, respectively). Cointervening carbohydrate loading in intravenous dextrose or oral medication was avoided.

Only one patient developed delayed gastric emptying in the high fat group; feeds were held for 2 hours but recommenced with no further problem. The PaCO₂ decreased significantly in the high fat feeding group just prior to weaning but increased slightly in patients receiving the isocaloric feed (p=0.003), whereas there was no difference in PaO₂ and tidal volume or respiratory rate. The time from feeding commencement to successful weaning was significantly shorter in the high fat group than in the isocaloric feeding group (86.1±17.8 versus 148.7±36.7 hours).

In a second randomized unblinded enteral nutrition trial (van den Berg, Bogaard, and Hop, 1994), 32 medical ICU patients were allocated to: (1) a high fat, low carbohydrate enteral feeding solution (Pulmocare: 17 percent protein, 55 percent fat, 28 percent carbohydrates) or (2) isocaloric feeds (Ensure Plus: 17 percent protein, 30 percent fat, 53 percent carbohydrates). Nutritional requirements were calculated at 1.5 times basal metabolic rate, delivered through a nasogastric tube. Patients were eligible if they had either COPD, neurologic disease, or pneumonia without COPD and if they could tolerate enteral nutrition. Exclusion criteria were renal failure, hepatic failure, diabetes mellitus, or respiratory failure "without a prospect of weaning from the ventilator." Patients were mechanically ventilated with a volume controlled mode. Weaning was started using CPAP when patients were afebrile, hemodynamically stable, required PEEP <10 cm H₂O on FiO₂ and when serum bicarbonate was <28 mmol/L. CPAP continued for a maximum of 3 hours until patients were too dyspneic or tired too continue; specific failure criteria were not reported. Rest periods lasted 4 to 6 hours and CPAP weaning trials occurred between rest periods. The study was terminated as soon as patients were able to tolerate 3 hours of spontaneous breathing.

Randomization was stratified based on the presence or absence of COPD. Concealment and allocation methods were not reported. Adherence to the feeding regimens was successful in all but one patient in each group, whose feeding was discontinued because of gastric distension; the outcome of these patients is not reported. Patients were comparable at baseline with respect to illness severity and nutritional status. Although the stratification of randomization based on COPD resulted in similar numbers of COPD patients in each arm, the distribution of cases of acute or chronic COPD as a reason for respiratory failure was not similar. In the high fat group, 10/11 patients with COPD were ventilated for acute or chronic respiratory failure versus 5/13 in the isocaloric feeding group. The former group also had severe hypercapnia during ventilation and during the weaning process; since this imbalance affected interpretation of the trial, two-way analysis of variance was used to evaluate whether the results obtained were related to the respiratory failure rather than the nutritional intervention.

The respiratory quotient was significantly lower in patients receiving the high fat, low carbohydrate feed compared with the isocaloric feed (0.72±0.02 versus 0.86±0.02, p<0.01). The minute ventilation during weaning was also lower (8.8±0.9 versus 10.5±0.8, p<0.01). A similar proportion of patients in both arms had a successful 3-hour trial of spontaneous breathing on CPAP (12/14 versus 13/16, p=0.74).

In a related nonrandomized controlled trial, Bassili and Dietel (1981) evaluated the effect of any (enteral or parenteral) nutritional support on weaning patients from mechanical ventilation. Patients comprising the control group received intravenous D5W (glucose solution), only. Though there was no difference in duration of mechanical ventilation between the two groups, there was a very large excess of nonextubations in the control patients. Possible causes of nonextubation are not reported (e.g., death, need for permanent tracheostomy, etc.).

Randomized Trials of Miscellaneous Studies

(1) The rationale for the first study (Niehoff, DelGuercio, LaMorte, et al., 1988) is that arterial blood gas analysis may not be needed as often if continuous monitoring of oxygenation and ventilation is provided during weaning. This trial was not designed to test the accuracy or utility of oximetry and capnography (which has been evaluated in technology assessment literature) but to evaluate its utility as a weaning adjunct.

In a randomized, unblinded trial, 24 postoperative cardiac patients were allocated to pulse oximetry and capnography or periodic arterial blood gases. IMV was used for weaning but stepwise decrements were not specified. The oximetry and capnography group had arterial blood gases on ICU admission, just before extubation, and if SaO₂ <95 percent or end-tidal CO₂ (PetCO₂) <26 or >40 mmHg, and as clinically indicated. The blood gas group was weaned if PaCO₂ was 35 to 45 mmHg and pH was 7.35 to 7.45, PaO₂>70 mmHg and respiratory rate <30 breaths/minute.

There were fewer blood gases performed in the oximetry and capnography group (5.9±2.7 versus 10.1±1.8, p<0.01). The duration of ventilation was similar (18.8±2.0 versus 19.7±1.9 hours). One patient in the blood gas group did not get extubated and was excluded from analysis. No patients required reintubation.

(2) To induce anxiolysis and minimize muscle fatigue, the effect of relaxation biofeedback on respiratory mechanics and weaning was tested (Holliday and Hyers, 1990).

In an unblinded randomized trial, 40 patients ventilated for >7 days were allocated to relaxation biofeedback or a control group. The biofeedback group received a multifaceted intervention for 30 to 50 minutes per day on CPAP 5 cm H₂O for 5 days per week until study termination, consisting of of communication (the patient was asked about feelings, breathing, and sleeping and was encouraged), tidal volume (V_t) feedback (auditory and visual feedback on a computer screen of the patients V_t compared with a threshold V_t) and computerized visual feedback of frontalis muscle tension by electromyography (EMG).

Cointerventions were not well described during the weaning process. Four patients randomized to the control group died and were not included in the analysis. Within-group changes in maximum inspiratory pressure (MIP), tidal volume, and minute ventilation were no different. The duration of ventilation was 12 days shorter in the biofeedback group (20.6±8.9 days versus 32.6±17.6 days, p=0.01). Nonextubation rates were the same. The undisclosed weaning using T-piece or IMV in this unblinded study that found a 12-day difference in duration of ventilation makes interpretation difficult; moreover, the generalizability of this technologically complex intervention is also limited.

(3) Functional residual capacity postspontaneous breathing on T-piece may be better restored with NPPV and CPAP than with spontaneous breathing and physiotherapy, thereby minimizing pulmonary edema and extubation failure.

In a randomized, unblinded trial of 75 cardiac surgery patients (Gust, Gottschalk, Schmidt, et al., 1996), three postextubation interventions were evaluated after 10 to 14 hours of controlled ventilation and 30 minutes of T-piece breathing. Patients were extubated, then randomized to either NPPV (n=25) involving BiPAP using the spontaneous timed mode (S/T) via nasal mask with an inspiratory positive airway pressure (IPAP) of 10 cm H₂O and an expiratory positive airway pressure (EPAP) of 5 cm H₂O and 10 L/minute of oxygen via nasal mask for 30 minutes; CPAP 7.5 cm H₂O and FiO₂ 0.5 for 30 minutes (n=25); or chest physiotherapy for 10 minutes and oxygen via nasal mask at 6 L/minute for 30 minutes (n=25).

Left ventricular function and inotropic support were comparable across groups. Cardiac surgical, anesthetic, and preextubation ICU management for the entire cohort are well described. No patients were lost to followup, and the analysis was intention-to-treat. All three groups had an increase in pulmonary blood volume index (PBVI) over time: 17 ml/m², 9 ml/m², and 17 ml/m² for BiPAP, CPAP, and chest physiotherapy, respectively. Following 30 minutes of each intervention, however, PBVI in the BiPAP group was significantly lower than the other two groups (p<0.05). Extravascular lung water (EVLW) increased significantly from extubation through the 30-minute intervention to 90 minutes following extubation in the chest physiotherapy group, compared with the other two groups (p<0.05). All patients in each group had sustained extubation.

(4) The rationale for this intervention is the catabolism of critical illness and functional and structural neuromuscular abnormalities in ventilated patients. Peripheral skeletal muscle function may improve following 1 week of postoperative growth hormone; however, a recent multicenter randomized trial showed that growth hormone was associated with increased ICU mortality (Takala, Ruokonen, Webster, et al., 1999). Nevertheless, this study of 12 days of growth hormone evaluated the duration of ventilation (Pichard, Kyle, Chevrolet, et al., 1996).

In a randomized, double-blinded trial, 20 patients requiring ventilation for >7 days were allocated to either 0.43 IU of recombinant growth hormone/kg/day administered subcutaneously for 12 days or normal saline. Patients were excluded if they had known myopathy, neuropathy, or a risk factor for neuromuscular abnormalities. Weaning began for all patients when: minute ventilation <10 L/minute, vital capacity >1 L, PaO₂>60 with FiO₂<0.4, or if a T-piece trial was tolerated for 30 minutes. Weaning began with SIMV; PS was added when spontaneous breathing developed and was gradually lowered. At PS of 10 cm H₂O, patients underwent a T-piece trial; after 12 hours of spontaneous breathing, patients were extubated. Parenteral nutrition was provided for the first 48 hours, and enteral nutrition was instituted.

After 12 days, the growth hormone group had higher growth hormone, insulin-like growth hormone factor-1, and insulin levels. Fat-free mass was increased in the treated compared with the untreated group. The cumulative duration of weaning over 12 days was similar (235.6±17.6 versus 245.4±14.7 hours). Patients similarly remained mechanically ventilated at 12 days (7/10 and 7/10, respectively).

(5) In 21 patients requiring ventilation for at least 3 days, SIMV was compared with pressure support for patient comfort. Patients were randomized to SIMV or PS and underwent a sequential 20 percent reduction in support at timed intervals. Then patients crossed over to the other arm after a 1- to 3-hour rest. Dyspnea and anxiety remained stable over time in each mode and were no different between groups. Of the 21 patients, 10 were weaned; the attribution of success to one or the other modes is not possible given the crossover design of the study. Potentially important cointerventions such as verbal feedback and touch are not described.

(6) Acupuncture has been found to relieve sore throats; its potential benefit averting largyngospasm was tested in 76 postoperative children randomized to receive either acupuncture with bloodletting at the Shao Shang acupoint on both thumbs just prior to extubation, or to a control group (Lee, Chien, Hsu, et al., 1998). Patients undergoing oropharyngeal surgery were not enrolled. Laryngospasm was defined as occuring within 2 minutes of extubation, characterized by stridor, silence resulting from total closure of the vocal cords, and cyanosis. In patients in the acupuncture group, 2/38 (5.3 percent) developed laryngospasm, whereas 9/38 (23.7 percent) did in the control group. No patients required reintubation.

(7) This study (Jiang, Kao, and Wang, 1999) tested the use of NIPPV postextubation. Enrolled patients were 93 extubated individuals, 56 of whom were electively extubated and 37 of whom had unplanned extubations. Patients were randomized to either BiPAP delivering IPAP 12 cm H₂O and EPAP 4 cm H₂O, by face mask for up to 72 hours, temporarily removed for suctioning and eating, or to oxygen therapy. Patients in both arms had arterial blood gases measured 1 to 3 hours postextubation. BiPAP was terminated and patients were intubated if arterial blood gases deteriorated, or if labored breathing or hemodynamic stability developed. Extubation failure was defined as the need for reintubation as judged by the attending physician. Patients had similar preextubation blood gases. The oxygen group had 7/46 reintubations, whereas the BiPAP group had 13/47 reintubations (not significantly different). The postextubation management with or without NIPPV therefore did not influence outcome, however, compared with the elective extubation patients (6/56), the unplanned extubation patients were more likely to be reintubated (14/37).

Observational Studies Addressing Prediction of Successful Weaning and Duration of Ventilation

Summary ROC Curves (Figures 1-8)

Figure 3. Weaning predictor analysis: summary receiver (more...)

   Figure 3. Weaning predictor analysis: summary receiver operating characteristics curve Predictor: rapid shallow breathing index (RSBI); outcome: successful extubation

Figure 4. Weaning predictor analysis: summary receiver (more...)

   Figure 4. Weaning predictor analysis: summary receiver operating characteristics curve Predictor: minute ventilation; outcome: successful discontinuation assessment and extubation

Summary ROC curves deal with the problem of different thresholds among studies. We show the summary ROC curves for several predictors of two main outcomes: successful extubation (Figures 1-3) and successful discontinuation assessment and extubation (Figures 4-8).

Figure 2. Weaning predictor analysis: summary receiver (more...)

   Figure 2. Weaning predictor analysis: summary receiver operating characteristics curve Predictor: respiratory rate; outcome: successful extubation

Figure 1 displays the summary ROC curve for minute ventilation as a predictor of successful extubation. Figure 2 displays the ROC curve for respiratory rate as a predictor of successful extubation. Figure 3 displays the summary ROC curve for the rapid shallow breathing index as a predictor of successful extubation.

Figure 5. Weaning predictor analysis: summary receiver (more...)

   Figure 5. Weaning predictor analysis: summary receiver operating characteristics curve Predictor: respiratory rate; outcome: successful discontinuation assessment and extubation

Figure 6. Weaning predictor analysis: summary receiver (more...)

   Figure 6. Weaning predictor analysis: summary receiver operating characteristics curve Predictor: tidal volume; outcome: successful discontinuation assessment and extubation

Figure 7. Weaning predictor analysis: summary receiver (more...)

   Figure 7. Weaning predictor analysis: summary receiver operating characteristics curve Predictor: rapid shallow breathing index (RSBI); outcome: successful discontinuation assessment and extubation

Figures 4-8 show the strength of several variables predicting successful discontinuation assessment: minute ventilation (Figure 4), respiratory rate (Figure 5), tidal volume (Figure 6), rapid shallow breathing index (Figure 7), and PI_max (Figure 8).

Testing for the presence of a threshold for Figure 1, the regression coefficient is 0.23 (p value 0.38), indicateing that there is no evidence of a threshold effect for minute ventilation as a predictor of successful extubation. Similarly, testing for a threshold effect for Figure 2, the regression coefficient is 0.45 (p value 0.19), indicating that there is no evidence of a threshold effect for respiratory rate. The same holds for rapid shallow breathing index, for which the coefficient is -0.30 (p value 0.29).

There is no evidence of a threshold effect for any of the predictors of successful discontinuation assessment and extubation: minute ventilation (coefficient 0.09, p value 0.89), respiratory rate (coefficient 0.11, p value 0.66), tidal volume (coefficient 0.30, p value 0.38), rapid shallow breathing index (coefficient 0.18, p value 0.48), and PI_max (coefficient 0.02, p value 0.93).

ROC curves can be used to compare two or more different signs or tests. The one lying furthest to the top left corner is the most accurate; this value is where sensitivity and specificity are highest. Of these eight summary ROC curves, none appears to be much more powerful than the others. For the three predictors that are graphed twice (minute ventilation, respiratory rate, and rapid shallow breathing index, which predict both successful extubation and predict successful spontaneous breathing discontinuation and extubation), we did not test for significant differences between the summary ROC curves, since we did not have the recommended 10 studies represented in each ROC curve (Moses, Shapiro, and Littenberg, 1993). This rationale precluded our testing for significant differences across all summary ROC curves.

Qualitative Studies of Weaning From Mechanical Ventilation

In this section, we describe the results of the qualitative studies in this field, which offer insight into social, emotional, and experiential phenomena. In contrast, quantitative studies (such as epidemiologic investigations and clinical trials) aim to test well-specified hypotheses concerning a few predetermined variables. The first study in this section on qualitative research will be described in detail to explain how specific critical appraisal criteria can be used to interpret and understand qualitative research reports.

Observational Studies Describing Patient Experience During Weaning

We identified four observational studies of patient experience during weaning that did not directly address our research questions and did not allow data extraction in tables. However, given the importance of understanding patient experience during weaning, we summarize them in narrative form here. These studies provide quantitative information; in the prior section on qualitative studies, we have described complementary results from studies of patient experience conducted using qualitative methodology.

(1) The objective of the first study (Bouley, Froman, and Shah, 1992) was to compare patient experience during SIMV, T-piece, and pressure support weaning and relate these to physiologic variables. Nine COPD patients ventilated for 4 to 18 days were included in a nonrandomized crossover study; all patients were observed for four weaning trials using two weaning modes. Dyspnea was measured on a visual analog scale; and its properties of sensitivity, validity, and reliability in ventilated patients were reported. In addition, 20 observations each of heart rate, respiratory rate, minute ventilation, and oxygen saturation were made. Patients had both SIMV 4 and T-piece (N=6) or SIMV 8 and pressure support (N=3) periods.

Dyspnea was no different between modes. Physiologic measures and type of weaning did not predict dyspnea ratings using regression analysis. Individual patient regression analyses differed, however, such that different variables predicted the dyspnea ratings in different patients. Physiologic responses and subjective experience of dyspnea therefore appear to have distinct patterns across patients in this small study.

(2) The objective of the second study (Lowry and Anderson, 1993) was to learn about patients' feelings, their perceptions of hope and social support, and their notion of the locus of control during weaning, including how these change over the weaning process. Ten alert and oriented mechanically ventilated patients who were physiologically ready to wean and who had undergone two to five failed weaning attempts underwent extensive testing using several instruments. The instruments used included the Multidimensional Health Locus of Control Scales Form which uses Likert scales to measure issues of power and control, a Hope Scale measured using a visual analog scale, the Norbeck Social Support Questionnaire which contains a 9-item 5-point scale about support structures, and the Anderson-Lowry Ventilation Scale with 10 items about fear and other responses to mechanical ventilation. The validity and reliability data for each instrument were provided when possible. There were 2 interviews per patient, but only 4 of 10 patients completed both.

Mechanical ventilation was reported as a moderately fearful experience, and fear decreased over time. During ventilation, patients felt as though the locus of control was external to themselves, reflecting the intense dependence they have on the ICU team and family members. Hope increased as time passed since successful weaning, and hopelessness predominated for patients who continued to require mechanical ventilation. This study reported properties of the instruments used and captured some important experiences of patients while weaning-lack of a sense of mastery, hopelessness, and fear. As time passed and patients were weaned, the locus of control was internalized, and patients were more hopeful and less fearful.

(3) The objective of the third study (Pochard, Lanore, Bellivier, et al., 1995) was to evaluate psychological status in 43 consecutive patients who had undergone successful weaning 48 to 96 hours earlier using an interviewer-administered 32-item questionnaire with visual analog scales. Almost all patients had received opiates, benzodiazepines, or neuromuscular blockers during their ICU stay but had none for 48 hours before the interview. Of the 43 patients, 9 had suffered a cardiac arrest during their ICU stay and 9 had a prior psychiatric history. Interviewer training, validation, and technique are not reported. Results are reported in text format without means or standard deviations. Myriad difficult experiences were recorded, including an inability to communicate, sleep disorders, dreaming, diffuse anxiety, fear of abandonment by staff, and depression. Patients could not recall distinguishing between night and day (N=23), reported being confused during weaning (N=15), and had hallucinations (N=9).

(4) The objective of this study (Menzel, 1997) was to examine patients' responses to communication during intubation and 7 days afterwards, following extubation, and to relate these to situational and demographic variables. Among 29 oriented patients from 4 ICUs who were intubated for at least 24 hours, questions were asked using the Emotion Scale and the Ease of Communication Scale, for a total of 23 items each using a Likert scale. Validity and reliability data are reported on these scales when possible.

There were no significant differences between the intubation and postextubation data overall, but one-third of patients reported differences of 20 percent or more between time periods. There were no correlations with situational and demographic variables. Women tended to report more fear of being unable to speak postextubation than during intubation; men reported less fear. Patients recalling less difficulty with communication had shorter periods of intubation. The emphasis on this report was on correlations and pre-post comparisons; relatively sparse data describe patients' perceptions.

Controlled Trials of Unassisted Ventilation

Because of small sample sizes and low event rates, most of the randomized trials provide little information about the relative impact of different modes of weaning. The second largest trial (Esteban, Alia, Gordo, et al., 1997) suggests a possible advantage of pressure support over a T-piece trial of spontaneous breathing. The largest trial (Esteban, Alia, Tobin, et al., 1999) suggests a possible advantage to 30-minute T-piece trials over 2-hour T-piece trials with respect to ICU and hospital lengths of stay.

A major theme found in other areas of weaning research emerges from review of the RCTs of unassisted ventilation in patients whom the clinician anticipates are ready for extubation. Irrespective of the interventions being compared, studies examining the impact of short periods of spontaneous breathing with or without some form of support show very different rates of failure of extubation, or reintubation. For instance, the two largest trials (Esteban, Alia, Gordo, et al., 1997; Esteban, Alia, Tobin, et al., 1999) found that 22 percent of 246 patients failed a T-piece weaning trial and of the 192 who were extubated 19 percent required reintubation. In contrast, Jones, Byrne, Morgan, et al. (1991) reported that only 4 percent of 52 patients on a T-piece wean were not extubated and, of those extubated, only 4 percent of 50 required reintubation. These discrepancies suggest that investigators are using quite different criteria when judging if a patient is ready for a trial of spontaneous breathing and different criteria for judging when the trial is a success and extubation is appropriate. When investigators explicitly described their criteria, obvious differences do not emerge. Nevertheless, differences in criteria must partially explain these differences in failure rates. We find the other explanation, that differences in patients leads to discrepancies in success rates, less plausible. This is particularly the case, since studies of predictors of weaning have demonstrated that a wide variety of readily identifiable patient characteristics have minimal or no association with weaning success.

These varying criteria have a number of implications. First, because a particular weaning strategy is superior in a setting where the threshold for a weaning trial, or for extubation, is low does not mean it will be superior in a setting where the threshold is much higher. In fact, where the threshold is high, and failure rates are less than 5 percent, the absolute superiority of one approach over another will be small and perhaps negligible. The other implications have to do with future research.

Controlled Trials of Progressive Reduction in Mechanical Support

The issue of different thresholds that was so evident in the RCTs of unassisted ventilation is also relevant in randomized trials of various modes for progressive reduction in mechanical support. For instance, the mean duration of weaning in the T-piece group in the Brochard trial (Brochard, Rauss, Benito, et al., 1994) was 8.5 days and in the Esteban, Frutos, Tobin, et al. (1995) study, 3 days. Here, the major focus of judgment may be issues of patient selection (although the reasons for differences are not apparent from descriptions of the recruiting process) and the judgment as to when the weaning process begins.

The results of these studies suggest the possibility that a multiple daily T-piece wean, or pressure support, may be superior to SIMV. Even for this comparison, however, the CIs on pooled estimates approach no effect. Further, these trials compared particular SIMV weaning regimens. Other weaning regimens using SIMV may produce different results. This is also true of the other weaning modes studied. For instance, the Esteban, Frutos, Tobin, et al. (1995) criteria for weaning may have made it more difficult for patients in the pressure support group to meet extubation criteria than for those in the other groups.

The Jounieaux study (Jounieaux, Duran, and Levi-Valensi, 1994) of synchronized IMV and pressure support versus synchronized IMV suggests the superiority of a regimen that includes pressure support by its finding of a shorter weaning time in the pressure support group. Because of the small sample size and low event rates, the study provides very little information about effects on outcomes of nonextubation or reintubation.

The most dramatic finding in studies of progressive reduction in ventilatory support comes from two small but sound RCTs comparing NPPV with pressure support with or without CPAP. In the larger of these studies (N=50), patients spent a mean of 9 days less in the ICU, and the lower limit of the 95 percent CI, representing the minimal effect of the interventions, was approximately 3 days. The smaller study also reported trends in favor of NPPV. Furthermore, strong trends in mortality and nosocomial pneumonia in these studies favored the NPPV group. The results of two nonrandomized controlled trials are also consistent with these findings.

Controlled Trials Comparing Alternative Ventilation Modes for Weans Lasting Less Than 48 Hours

Two of the three randomized studies in this category provide further evidence that IMV may be a less advantageous than other methods of decreasing mechanical support (Chopin, Chambrin, Mangalaboyi, et al., 1989; Esen, Denkel, Telci, et al., 1992), and so do the nonrandomized studies (Rathgeber, Schorn, Falk, et al., 1997; Tomlinson, Miller, Lorch, et al., 1989). One RCT provides preliminary data on an innovative technique of reducing support (mimum minute ventilation).

Controlled Trials Comparing Weaning Protocols to Physician-Directed Weaning

One study of a computer-directed weaning protocol was too small to provide useful information (Strickland and Hasson, 1993).

Two large RCTs and 11 nonrandomized controlled studies suggest that the duration of weaning can be decreased by putting the direction of the wean in the hands of respiratory therapists and nurses who are guided by a protocol. If this is so, one might expect benefits in other important outcomes: reduced stay in the ICU and in the hospital and consequent reduction in costs. Inferences about the effect of these protocolized interventions on these outcomes are not strong, given the imprecision of these estimates.

Large effects were seen in the RCT (Ely, Baker, Dunagan, et al., 1996) in which patients required longer periods of ventilation. In the randomized trial in which patients required shorter periods of ventilation (Kollef, Shapiro, Silver, et al., 1997), benefits appeared larger in the patients within the study who required longer periods of ventilation. Thus, benefits of protocol-driven weaning are likely to be greatest in patients destined to spend longer periods on the ventilator.

Even if protocol-directed weaning has a favorable effect on duration of ICU stay, the generalizability of these findings is not likely universal; protocol-directed weaning may be superior in some circumstances for some patients, but probably not for all protocols and all physicians in all settings.

Controlled Trials of Early Versus Late Extubation Following Cardiac Surgery

These randomized trials were consistently limited by failure to do an intention-to-treat analysis, a potentially serious problem. Even considering this limitation, they unequivocally demonstrate that extubation can be achieved a few hours earlier than was the case with previous conventional practice and that this reduction likely leads to patients spending fewer hours in the ICU, and possibly less time in hospital. Significant morbidity occurs infrequently enough that CIs around relative risks with early versus late extubation are very wide. In fact, the CIs are so wide that they are consistent both with a substantial increase or a substantial decrease in relative risk with early extubation. Another way to look at this result, however, is that event rates remain low in patients receiving early extubation. These low event rates, and the safety of early extubation, may well be restricted to relatively low risk CABG patients. Results of nonrandomized controlled trials corroborated these findings.

Controlled Trials of Corticosteroids to Prevent Postextubation Airway Complications

Two well-designed trials of dexamethasone in which patients, caregivers, and those assessing outcome were blind to allocation have unequivocally demonstrated that steroids reduce postextubation stridor (Anene, Meert, Uy, et al., 1996; Telez, Galvis, Storgion, et al., 1991). In contrast to the effect on stridor, the effect on reintubation is far from clear. In one of the two studies, 7 of 32 patients not receiving steroids required reintubation in contrast to 0 of 31 receiving steroids. The trend in the other study was in the opposite direction, with 4 of 77 and 9 of 76 children requiring reintubation. We found no adequate explanation for this difference.

The four trials of steroids in adults observed so few events that even the results of the pooled analysis are essentially uninformative (Chaney, Nikolov, Blakeman, et al., 1998; Darmon, Rauss, Dreyfuss, et al., 1992; Gaussorgues, Boyer, Piperno, et al.,1987; Ho, Harn, Lien, et al., 1996): they are consistent with a reduction in relative risk of reintubation of 86 percent and also with an increase in relative risk of reintubation of 58 percent.

Controlled Trials of Enteral Nutrition

Two randomized trials of high fat, low carbohydrate enteral nutrition enrolled a total of 52 patients. One study (al Saady, Blackmore, and Bennett, 1989) found a significant decrease in PaCO₂ whereas the other (van den Berg, Bogaard, and Hop, 1994) found a significantly lower respiratory quotient and minute ventilation in patients receiving the high fat feeds. The time from feeding commencement to successful weaning was significantly shorter in the high fat group than in the isocaloric feeding group (al Saady, Blackmore, and Bennett, 1989), but in the unblinded study (van den Berg, Bogaard, and Hop, 1994), the rate of successful 3-hour spontaneous breathing trials was the same. High fat feeds appear to have favorable physiologic effects on carbon dioxide production and may be useful in patients with impaired ventilatory reserve. These two studies were underpowered for clinically important outcomes, and their results require confirmation or refutation.

Controlled Trials: Miscellaneous Studies

In terms of pharmacologic interventions, the ventilation and weaning outcomes were similar in the small double-blind trial of 12 days of recombinant growth hormone (Pichard, Kyle, Chevrolet, et al., 1996). Future research with this agent is unlikely given the recent multicenter RCT showing increased mortality in ICU patients receiving growth hormone (Takala J, Ruokonen E, Webster N, et al., 1999).

In terms of technologic interventions, in the randomized trial of oximetry and capnography to monitor patients during weaning (Niehoff, DelGuercio, LaMorte, et al., 1988), approximately one-half as many blood gases were performed compared with the number in the control arm. However, the control patients were already getting approximately one blood gas every 2 hours; such a dramatic benefit is unlikely today, since this baseline blood gas frequency is highly atypical except for very difficult to wean patients.

Intensive biofeedback intervention (Holliday and Hyers, 1990) showed a dramatic difference of 12 days in duration of ventilation; however, the weaning methods were not described in this unblinded study and this estimate of the treatment effect could be inflated. This intervention is unlikely to be used in practice; perhaps a simpler version will be tested in future trials, since the principle of positive reinforcement and feedback has been shown to be effective for other health outcomes.

In terms of postextubation interventions, following CABG, three strategies were tested: NPPV, CPAP, or chest physiotherapy (Gust, Gottschalk, Schmidt, et al., 1996). All three groups had an increase in PBVI over time but PBVI was lower in the NPPV group after 30 minutes and EVLW was higher following extubation in the chest physiotherapy group. All patients sustained successful extubation. These outcomes tell us useful information about physiologic responses postextubation that can be considered in patients with high fillings pressures.

Observational Studies Addressing Prediction of Successful Weaning and Duration of Ventilation

Investigators have assessed an extraordinarily diverse collection of potential predictors of successful weaning and duration of mechanical ventilation; we found 462 predictors. However, the results lead to a number of clear conclusions.

The next important observation corresponds to the finding that specificities are seldom over 50 percent. LRs of positive tests are most frequently close to 1. Thus, a positive result does virtually nothing to increase the probability of success.

A negative result sometimes leads to appreciable decreases in the probability of successful wean. In interpreting these results, we will assume a pretest probability of success of 50 percent. A high respiratory rate (LR 0.32) will decrease the probability of success in reducing mechanical support from 50 percent to approximately 25 percent, the probability of success in a trial of unassisted breathing (LR 0.25) to approximately 20 percent, and the probability of success in a trial of extubation (LR about 0.5) to approximately 33 percent.

The most frequently studied and one of the most powerful tests is the rapid shallow breathing index. Pooled results for this test consistently show that a positive result (breathing pattern is neither rapid nor shallow) is moderately helpful in increasing the probability of a successful wean: individual study LRs are usually lower than 2, meaning the pretest probability of 50 percent will rise no higher than 66 percent. A negative result (breathing tends to be rapid and shallow) decreases the probability of a successful weaning trial alone or in combination with extubation from 50 percent to about 17 percent. Considering pooled data, the LR for the rapid shallow breathing index at predicting successful discontinuation assessment was 1.7, at predicting successful extubation was between 1.3 and 1.8 (the latter occurs when the variable is indexed to body weight), and at predicting successful discontinuation assessment and extubation was as high as 2.8. The power of the rapid shallow breathing index for the outcome of successful extubation alone is moderate (LR of approximately 0.4 corresponding to a change in probability from 50 percent to about 30 percent).

Why do these tests perform so poorly? The likely explanation is that physicians have already considered the results when they choose patients for trials of weaning. For instance, clinicians may seldom test patients with very high respiratory rates, who are capable of generating only very low pressures, or whose tidal volumes are very low for their ability to wean. Similarly, clinicians may not wait until the respiratory rate, tidal volume, or pressure generation is normal before they wean, for this would lead to excessive time on the ventilator. This means that the range of results in patients who are tested is relatively narrow.

Furthermore, when results of a single test are more extreme, it is likely that physicians are attempting a wean only because other observations suggest the limited impact of an isolated aberrant finding. For instance, adequate tidal volume and pressure generation may indicate to a clinician that an elevated respiratory rate is due largely to patient anxiety and does not indicate that the patient will be unable to wean. These considerations suggest that it is unrealistic to expect physiologic tests to be highly predictive in patients who clinicians judge have an intermediate probability of weaning success.

Observational Studies Describing Patient Experience During Weaning

Patients in the ICU can have a range of difficult experiences. These may be particularly acute when they are moving toward liberation from mechanical ventilation. In two of these studies (Bouley, Froman, and Shah, 1992; Lowry and Anderson, 1993), data were collected while patients were ventilated. These studies are limited by small sample sizes. Some of the studies provide details of the properties of the instruments they used whereas some studies used simple visual analog scales. Dyspnea was not found to be subjectively different across different modes of weaning. Lack of mastery, hopelessness and fear were found in one study (Lowry and Anderson, 1993) while another found depression, anxiety, fear of abandonment by staff (Pochard, Lanore, Bellivier, et al., 1995) and fear of inability to speak (Menzel, 1997). Stronger research methods would be welcome in this field, including explicit assessments of competency, reporting of cognitive status and recording recent drug exposure in patients. Some of these studies were very rigorous in reporting the properties of the instruments they used; validity and reliability in future studies should ideally be determined in the same population of patients as the ones under study. Awareness of these adverse experiences is important for all clinicians, and provision of support to attend to them is part of holistic critical care.

Strengths and Limitations of This Review

The limitations of any review can be categorized into those relating to the review methods themselves and those related to the primary studies included in the review. We addressed strengths and limitations of the primary studies (randomized trials, nonrandomized controlled trials, observational studies and qualitative studies) in previous sections of this report. We will now critically appraise this report according to the review methodology we employed.

Summary of Inferences From This Review

• Differences in clinicians' intuitive threshold for reduction or discontinuation of ventilatory support have a far greater impact on failure of spontaneous breathing trials, or on reintubation, than do modes of weaning. When clinicians set a high threshold, many patients who could tolerate weaning remain on mechanical support longer than is necessary.

• There may be an interaction between threshold and mode of weaning; that is, one mode may be superior when the threshold is high and another when the threshold is low.

• IMV may be less advantageous than other modes of reducing support.

• The issue of the optimal start of weaning is confounded by alternative definitions of weaning: one reasonable conceptualization is that weaning begins with the onset of mechanical ventilation. Research to date suggests the best answer to "when to start weaning" is to develop a protocol implemented by nurses and respiratory therapists that begins testing for the opportunity to reduce support very soon after intubation and reduces support at every opportunity.

• Failure of extubation is to an extent a surrogate outcome for the putative adverse consequences of failure to extubate: prolonged ventilation, oropharyngeal or gastric aspiration, acute lung injury, and cardiovascular compromise. Prolonged ventilation prior to extubation may also increase the likelihood of each of the measurable endpoints that flow from these processes: pneumonia, myocardial infarction, and death. Most trials to date are not powered to examine the frequency of these events and can thus provide little information on the tradeoff between reducing the length of ventilation prior to extubation and decreasing the rate of reintubation.

• The most promising mode of ventilatory support is NPPV, which may shorten the duration of ventilation, avoid reintubation, and reduce mortality.

• In low-risk cardiac patients, strategies to shorten duration of ventilation through early extubation can be successfully implemented while maintaining very low complication rates.

• Although steroids can reduce postextubation stridor in children, their impact on reintubation in children and adults remains uncertain.

• Most theoretically plausible predictors of weaning and extubation success have no predictive power, and even those with some predictive power are relatively weak. Tests are rarely useful in increasing the probability of success; on occasion, they can lead to moderate reductions in the probability of success.

We can reframe these conclusions in terms of the original AHRQ questions as follows:

1. When should weaning be initiated?

2. What criteria should be used to initiate the weaning process?

Explicit protocols that begin testing for the opportunity to reduce support very soon after intubation and reduce support at every opportunity have consistently done as well or better than intuitive approaches when formally tested in appropriate patients. Details of these protocols differ; any provides reasonable guidance.

3. What are the most effective methods of weaning from mechanical ventilation?

For most methods of weaning, the impact may be small in relation to criteria used for the reduction and discontinuation of support. The use of NPPV may be an exception.

4. What are the optimal roles of nonphysician health care professionals in facilitating safe and expeditious weaning?

Weaning protocols implemented by respiratory therapists and nurses are likely to reduce the duration of mechanical ventilation and may reduce length of ICU stay, and thus health care resource consumption.

5. What is the value of clinical practice algorithms and computers in expediting weaning?

Computer algorithms have received minimal study and have attendant logistic barriers; they have not been compared with weaning protocols.

Summary of Recommendations for Future Research

Examination of alternative weaning strategies should enroll homogeneous patient groups: those whose likely period of additional ventilation is a few hours, and those whose likely period is a few days. Patients after cardiac surgery constitute another relevant patient population that should be considered separately. In this group, the success of strategies to decrease ventilation time in low risk patients can be considered established.

In the setting of a high threshold for extubation associated with low failure rates, investigators would require trials of thousands of patients to demonstrate differences between techniques and tens of thousands to demonstrate differences in complications of failed extubation. Investigators should establish plausible event rates before embarking on clinical trials.

Investigators should attempt to elucidate the tradeoff between decreasing duration of time on a ventilator and the increase in reintubation rates associated with a low weaning threshold (e.g., what reduction in duration of time on a ventilator would warrant an increase in reintubation rates from 5 to 10 percent)? This work should consider the important consequences of prolonged ventilation or reintubation, including nosocomial pneumonia, cardiac morbidity, and death.

Investigators should launch trials examining the use of NPPV in reducing the duration of intubation and total mechanical support. Future research should also explore the optimal target population, timing and management of NPPV for weaning purposes, its effect on morbidity, length of ICU stay, and mortality.

Investigators should launch randomized trials of weaning protocols implemented by respiratory therapists and nurses. These trials should evaluate the differential impact of protocols in different types of patients and in ICUs with different organizational structures (e.g., openversus closed units, teaching versus community hospitals). The influence of different protocols and their impact on ICU and hospital length of stay and costs are important future considerations.

A more fruitful line of investigation than further research seeking powerful predictors of successful weaning or extubation might be randomized trials of weaning protocols that decrease the duration of mechanical ventilation without substantially increasing rates of failed extubation.

Appendix A. Search Strategy: MEDLINE and HealthSTAR for Intervention Studies

Set Search

• 001 ventilator weaning/

• 002 trial$ of spontaneous breathing.ti,ab.

• 003 exp respiration, artificial/

• 004 exp intubation, intratracheal/

• 005 patient triggered ventilation.ti,ab.

• 006 (intermittent manditory ventilation or simv or imv).ti,ab.

• 007 positive pressure ventilation.ti,ab.

• 008 pressure support ventilation.ti,ab.

• 009 nippv.ti,ab.

• 010 mechanical ventilation.ti,ab.

• 011 (continuous positive airway pressure or cpap).ti,ab.

• 012 bipap.ti,ab.

• 013 wean$.ti,ab.

• 014 extubat$.ti,ab.

• 015 duration.ti,ab.

• 016 discontinu$.ti,ab.

• 017 or/3-12

• 018 or/13-16

• 019 17 and 18

• 020 1 or 2 or 19

• 021 randomized controlled trial.pt.

• 022 controlled clinical trial.pt.

• 023 randomized controlled trials.sh.

• 024 random allocation.sh.

• 025 double-blind method.sh.

• 026 single-blind method.sh.

• 027 or/21-26

• 028 (animal not human).sh.

• 029 27 not 28

• 030 clinical trial.pt.

• 031 exp clinical trials/

• 032 (clin$ adj25 trial:).ti,ab.

• 033 ((single$ or doubl$ or trebl$ or tripl$) adj25 (blind$))

• 034 placebos.sh.

• 035 placebo$.ti,ab.

• 036 random$.ti,ab.

• 037 research design.sh.

• 038 or/30-37

• 039 38 not 28

• 040 39 not 29

• 041 comparative study.sh.

• 042 exp evaluation studies/

• 043 follow-up studies.sh.

• 044 prospective studies.sh.

• 045 (control$ or prospectiv$ or vounteer$).ti,ab.

• 046 or/41-45

• 047 46 not 28

• 048 47 not (29 or 40)

• 049 29 or 40 or 48

• 050 20 and 49

• 051 50 not letter.pt.

• 052 51 not editorial.pt.

• 053 52 not news.pt.

• 054 53

Appendix B. Search Strategy: MEDLINE AND HealthSTAR for Observational Studies

• Set Search

• 001 ventilator weaning/

• 002 trial$ of spontaneous breathing.ti,ab.

• 003 exp respiration, artificial/

• 004 exp intubation, intratracheal/

• 005 patient triggered ventilation.ti,ab.

• 006 (intermittent manditory ventilation or simv or imv).ti,ab.

• 007 positive pressure ventilation.ti,ab.

• 008 pressure support ventilation.ti,ab.

• 009 nippv.ti,ab.

• 010 mechanical ventilation.ti,ab.

• 011 (continuous positive airway pressure or cpap).ti,ab.

• 012 bipap.ti,ab.

• 013 wean$.ti,ab.

• 014 extubat$.ti,ab.

• 015 duration.ti,ab.

• 016 discontinu$.ti,ab.

• 017 or/3-12

• 018 or/13-16

• 019 17 and 18

• 020 1 or 2 or 19

• 021 exp sensitivity/

• 022 exp diagnostic errors/

• 023 likelihood functions/

• 024 reproducibility of results/

• 025 area under curve/

• 026 (sensitivit: or specificit: or predictive value:).tw.

• 027 (false positive or false negative or false rate:).tw.

• 028 (likelihood ratio: or receiver operat: curve:).tw.

• 029 (pretest likelihood or pre test likelihood or posttest likel

• 030 (ppv or npv or roc or diagnostic standard: or accura:).tw.

• 031 (pretest probability or pre test probability or posttest pro

• 032 or/21-31

• 033 (predict: or index:).tw.

• 034 32 or 33

• 035 20 and 34

• 036 35 not letter.pt.

• 037 36 not editorial.pt.

• 038 37

Appendix C. Search Strategy: CINAHL for Intervention Studies

• Set Search

• 001 ventilator weaning/

• 002 trial$ of spontaneous breathing.ti,ab.

• 003 exp respiration, artificial/

• 004 exp intubation, intratracheal/

• 005 patient triggered ventilation.ti,ab.

• 006 (intermittent manditory ventilation or simv or imv).ti,ab.

• 007 positive pressure ventilation.ti,ab.

• 008 pressure support ventilation.ti,ab.

• 009 nippv.ti,ab.

• 010 mechanical ventilation.ti,ab.

• 011 (continuous positive airway pressure or cpap).ti,ab.

• 012 bipap.ti,ab.

• 013 wean$.ti,ab.

• 014 extubat$.ti,ab.

• 015 duration.ti,ab.

• 016 discontinu$.ti,ab.

• 017 or/3-12

• 018 or/13-16

• 019 17 and 18

• 020 1 or 2 or 19

• 021 exp ventilation, mechanical/

• 022 21 and 18

• 023 20 or 22

• 024 randomized controlled trial.pt.

• 025 controlled clinical trial.pt.

• 026 randomized controlled trials.sh.

• 027 random allocation.sh.

• 028 double-blind method.sh.

• 029 single-blind method.sh.

• 030 or/24-29

• 031 (animal not human).sh.

• 032 30 not 31

• 033 clinical trial.pt.

• 034 exp clinical trials/

• 035 (clin$ adj25 trial:).ti,ab.

• 036 ((single$ or doubl$ or trebl$ or tripl$) adj25 (blind$))

• 037 placebos.sh.

• 038 placebo$.ti,ab.

• 039 random$.ti,ab.

• 040 research design.sh.

• 041 or/33-40

• 042 41 not 31

• 043 42 not 32

• 044 comparative study.sh.

• 045 exp evaluation studies/

• 046 follow-up studies.sh.

• 047 prospective studies.sh.

• 048 (control$ or prospectiv$ or vounteer$).ti,ab.

• 049 or/44-48

• 050 49 not 31

• 051 50 not (32 or 43)

• 052 32 or 43 or 51

• 053 exp clinical trials/

• 054 exp clinical research/

• 055 random assignment/

• 056 research.pt.

• 057 30 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 45 or 47

• 058 57 and 23

• 059 58 not letter.pt.

• 060 59 not editorial.pt.

• 061 60

Appendix D. Search Strategy: CINAHL for Observational Studies

• Set Search

• 001 ventilator weaning/

• 002 trial$ of spontaneous breathing.ti,ab.

• 003 exp respiration, artificial/

• 004 exp intubation, intratracheal/

• 005 patient triggered ventilation.ti,ab.

• 006 (intermittent manditory ventilation or simv or imv).ti,ab.

• 007 positive pressure ventilation.ti,ab.

• 008 pressure support ventilation.ti,ab.

• 009 nippv.ti,ab.

• 010 mechanical ventilation.ti,ab.

• 011 (continuous positive airway pressure or cpap).ti,ab.

• 012 bipap.ti,ab.

• 013 wean$.ti,ab.

• 014 extubat$.ti,ab.

• 015 duration.ti,ab.

• 016 discontinu$.ti,ab.

• 017 or/3-12

• 018 or/13-16

• 019 17 and 18

• 020 1 or 2 or 19

• 021 exp sensitivity/

• 022 exp diagnostic errors/

• 023 reproducibility of results/

• 024 (sensitivit: or specificit: or predictive value:).tw.

• 025 (false positive or false negative or false rate:).tw.

• 026 (likelihood ratio: or receiver operat: curve:).tw.

• 027 (pretest likelihood or pre test likelihood or posttest likel

• 028 (ppv or npv or roc or diagnostic standard: or accura:).tw.

• 029 (pretest probability or pre test probability or posttest pro

• 030 (predict: or index:).tw.

• 031 exp ventilation, mechanical/

• 032 18 and 31

• 033 32 or 20

• 034 false negative reactions/

• 035 false positive reactions/

• 036 exp clinical assessment tools/

• 037 (measurement issues and assessments).ti,sh,ab,it.

• 038 (reliability and validity).ti,sh,ab,it.

• 039 exp "reliability and validity"/

• 040 exp construct validity/

• 041 exp observer bias/

• 042 nursing assessment/

• 043 or/21-30

• 044 or/34-43

• 045 33 and 44

• 046 45

Appendix E. Search Strategy: EMBASE for Intervention Studies

• Set Search

• #1: ARTIFICIAL-VENTILATION

• #2: ARTIFICIAL-VENTILATION

• #3: explode ARTIFICIAL-VENTILATION / all subheadings

• #4: explode ASSISTED-VENTILATION / all subheadings

• #5: PATIENT

• #6: TRIGGERED

• #7: VENTILATION

• #8: PATIENT TRIGGERED VENTILATION

• #9: INTERMITTENT

• #10: MANDATORY

• #11: VENTILATION

• #12: INTERMITTENT MANDATORY VENTILATION

• #13: SIMV

• #14: IMB

• #15: IMV

• #16: POSITIVE

• #17: PRESSURE

• #18: VENTILATION

• #19: POSITIVE PRESSURE VENTILATION 1873

• #20: PRESSURE

• #21: SUPPORT

• #22: VENTILATION

• #23: PRESSURE SUPPORT VENTILATION

• #24: NIPPV

• #25: BIPAP

• #26: MECHANICAL

• #27: VENTILATION

• #28: MECHANICAL VENTILATION

• #29: #1 or #2 or #3 or #4 or #8 or #12 or #13 or #15 or #19 or #23 or #24 or #25 or #28

• #30: WEAN:

• #31: WEAN

• #32: WEANING

• #33: WEANED

• #34: WEANS

• #35: WEAN or WEANING or WEANED or WEANS

• #36: EXTUBATE

• #37: EXTUBATED

• #38: EXTUBATION

• #39: EXTUBATES

• #40: EXTUBATE or EXTUBATED or EXTUBATION or EXTUBATES

• #41: DISCONTINUE

• #42: DISCONTINUED

• #43: DISCONTINUATION

• #44: DISCONTINUE or DISCONTINUED or DISCONTINUATION #45: #35 or #40 or #44

• #46: #29 and #45

• #47: RANDOM

• #48: RANDOMIZED

• #49: RANDOMISED

• #50: RANDOM or RANDOMIZED or RANDOMISED

• #51: CLINICAL

• #52: TRIAL

• #53: CLINICAL TRIAL

• #54: DOUBLE

• #55: BLIND

• #56: SINGLE

• #57: BLIND

• #58: TRIPLE

• #59: BLIND

• #60: DOUBLE BLIND OR SINGLE BLIND OR TRIPLE BLIND

• #61: RANDOMIZED-CONTROLLED-TRIAL / all subheadings

• #62: explode CLINICAL-TRIAL / all subheadings

• #63: MAJOR-CLINICAL-STUDY / all subheadings

• #64: RANDOMIZATION / all subheadings

• #65: #50 or #53 or #60 or #61 or #62 or #63 or #64

• #66: #46 and #65

Appendix F. Search Strategy: EMBASE for Observational Studies

• Set Search

• #1: ARTIFICIAL-VENTILATION

• #2: ARTIFICIAL-VENTILATION

• #3: explode ARTIFICIAL-VENTILATION / all subheadings

• #4: explode ASSISTED-VENTILATION / all subheadings

• #5: PATIENT

• #6: TRIGGERED

• #7: VENTILATION

• #8: PATIENT TRIGGERED VENTILATION

• #9: INTERMITTENT

• #10: MANDATORY

• #11: VENTILATION

• #12: INTERMITTENT MANDATORY VENTILATION

• #13: SIMV

• #14: IMB

• #15: IMV

• #16: POSITIVE

• #17: PRESSURE

• #18: VENTILATION

• #19: POSITIVE PRESSURE VENTILATION

• #20: PRESSURE

• #21: SUPPORT

• #22: VENTILATION

• #23: PRESSURE SUPPORT VENTILATION

• #24: NIPPV

• #25: BIPAP

• #26: MECHANICAL

• #27: VENTILATION

• #28: MECHANICAL VENTILATION

• #29: #1 or #2 or #3 or #4 or #8 or #12 or #13 or #15 or #19 or #23 or #24 or #25 or #28

• #30: WEAN:

• #31: WEAN

• #32: WEANING

• #33: WEANED

• #34: WEANS

• #35: WEAN or WEANING or WEANED or WEANS

• #36: EXTUBATE

• #37: EXTUBATED

• #38: EXTUBATION

• #39: EXTUBATES

• #40: EXTUBATE or EXTUBATED or EXTUBATION or EXTUBATES

• #41: DISCONTINUE

• #42: DISCONTINUED

• #43: DISCONTINUATION

• #44: DISCONTINUE or DISCONTINUED or DISCONTINUATION

• #45: #35 or #40 or #44

• #46: #29 and #45

• #47: DIAGNOSTIC-ACCURACY / all subheadings

• #48: DIAGNOSTIC-ERROR / all subheadings

• #49: DIAGNOSTIC-VALUE / all subheadings

• #50: DIFFERENTIAL-DIAGNOSIS / all subheadings

• #51: RECEIVER-OPERATING-CHARACTERISTIC / all subheadings

• #52: AREA-UNDER-THE-CURVE / all subheadings

• #53: SENSITIVITY

• #54: SENSITIVITIES

• #55: SENSITIVITY or SENSITIVITIES

• #56: SPECIFICITY

• #57: SPECIFICITIES

• #58: SPECIFICITY or SPECIFICITIES

• #59: PREDICTIVE

• #60: VALUE

• #61: PREDICTIVE

• #62: VALUES

• #63: PREDICTIVE VALUE OR PREDICTIVE VALUES

• #64: FALSE

• #65: POSITIVE

• #66: FALSE

• #67: NEGATIVE

• #68: FALSE POSITIVE OR FALSE NEGATIVE

• #69: LIKELIHOOD

• #70: RATIO

• #71: LIKELIHOOD RATIO

• #72: LIKELIHOOD

• #73: RATIOS

• #74: LIKELIHOOD RATIOS

• #75: PPV

• #76: NPV

• #77: ROC

• #78: PPV or NPV or ROC

• #79: PREDICT

• #80: PREDICTION

• #81:PREDICTIVE

• #82: PREDICTS

• #83: PREDICTED

• #84: PREDICT or PREDICTION or PREDICTIVE or PREDICTS or PREDICTED

• #85: INDEX

• #86: #47 or #48 or #49 or #50 or #51 or #52 or #55 or #58 or #63 or #68 or #71 or #74 or #78 or #84 or #85

• #87: #46 and #86

Appendix G. Relevance Form: Weaning from Mechanical Ventilation

We Ref ID #

Person Screening DJC MOM

Include

Exclude because:

• 1

  Publication type

  1. Editorials

  2. Letters

  3. Consensus conference reports

  4. Position papers

• 2

  Population

  1. Neonates

  2. Highly specific populations (obstructive sleep apnea, Guillain Barre Syndrome, flail chest)

  3. Specific conditions (polyneuropathy of the critically ill)

  4. Ventilator associated pneumonia (prevention, diagnosis, treatment)

• 3

  Setting

  1. Home ventilation for adults

• 4

  Design

  1. Observational studies less than 20 patients

  2. Case reports

  3. Narrative reviews

• 5

  Outcomes

  1. Studies that examine only physiologic end points

• 6

  Intervention

  1. Studies of self-extubation

  2. Surgical and anaesthetic techniques

  3. Studies of sedation use, neuromuscular blockade, reversal of neuromuscular blockade

  4. Studies about fluid administration

  5. ECMO, NO, lung-protective ventilation strategies, HFO, HFJV, PLV

  6. Interventions initiated at the onset of mechanical ventilation except in CABG or COPD patients

Other ____________________________________________________________________
_________________________________________________________________________

Appendix H. Selection Criteria for Articles About Weaning

GENERIC INCLUSION CRITERIA

Design

1. Randomized controlled trials

2. Observational studies

3. Non-randomized Controlled Clinical Trials

4. Qualitative studies

Setting

1. Intensive care units

2. Post-anaesthetic care units

Population

1. Adults or

2. Children with and endotracheal tube (including tracheostomy) who are mechanically ventilated

Intervention

1. Any ventilation or weaning strategy (mode, method, protocol, procedure, operator, timing, computer use, non-invasive ventilation, tracheostomy, holistic care,) that is geared to facilitate weaning and/or extubation .

2. Measurement of predictors of weaning and extubation success.

3. Measurement of predictors of duration of ventilation (in cardiac surgery and COPD patients).

4. Miscellaneous interventions designed explicitly to facilitate weaning

EXCLUSION CRITERIA

Publication type

1. Editorials

2. Letters

3. Consensus conference reports

4. Position papers

5. arrative or systematic reviews

Design

1. Observational studies less than 20 patients

2. Case reports

Setting

1. Home ventilation for adults

2. Chronic ventilation facilities

Population

1. Neonates

2. Highly specific populations (obstructive sleep apnea, Guillain Barre Syndrome, flail chest)

3. Specific conditions (polyneuropathy of the critically ill)

4. Ventilator associated pneumonia (prevention, diagnosis, treatment)

Intervention

1. Studies of self-extubation

2. Studies of sedation use, neuromuscular blockade, reversal of neuromuscular blockade.

3. Studies about fluid administration.

4. ECMO, NO, lung-protective ventilation strategies, HFO, HFJV, PLV.

5. Interventions initiated at the onset of mechanical ventilation except in CABG or COPD patients

Outcomes

1. Studies that examine only physiologic end points

Appendix I. Extraction Form for General Characteristics fo All Studies

Appendix J. Extraction Form for Randomized Clinical Trials

Appendix K. Extraction Form for Nonrandomized Controlled Clinical Trials

Appendix L. Extraction Form for Observational Studies

Appendix M. Acronyms and Abbreviations

AaDO2: alveolar-arterial oxygen tension difference

ABG: arterial blood gas

AHCPR: Agency for Health Care and Policy Research

APACHE II: Acute Physiologic and Chronic Health Evaluation - II

APRV: airway pressure release ventilation

ARDS: acute respiratory distress syndrome

BiPAP: biphasic positive airway pressure

BP: blood pressure

CABG: coronary artery bypass graft

CaO2: arterial oxygen content

CCU: coronary care unit

Cdyn: dynamic lung compliance

CHF: congestive heart failure

CI: cardiac index

CINAHL: Cumulative Index to Nursing and Allied Health Literature

CK-MB: creatine kinase - MB fraction

COPD: chronic obstructive pulmonary disease

CPAP: continuous positive airway pressure

CPK: creatine phosphokinase

CROP: compliance, rate, oxygenation and pressure index (Cdyn x PImax x [PaO2/PAO2])/rate

CVA: cerebrovascular accident

CVICU: cardiovascular intensive care unit

CXR: chest X-ray

DLCO: diffusion capacity of the lung for carbon monoxide

ECMO: extracorporeal membrane oxygenation

EMG: electromyography

EPAP: expiratory positive airway pressure

EVLW: extravascular lung water

f/Vt: frequency/tidal volume

FeV1: forced expiratory volume at one second

FiO2: fractional inspired concentration of oxygen

FVC: forced vital capacity

HFJV: high frequency jet ventilation

HFO: high frequency oscillation

HR: heart rate

I:E: ratio of inspiratory time to expiratory time

ICU: intensive care unit

IEQ: inspiratory effort quotient = k(Vt/Cdyn)(Ti/Ttotal)/MIP

IMV: intermittent mandatory ventilation

IPAP: inspiratory positive airway pressure

LISS: Lung Injury Severity Score

LR: likelihood ratio

MIP: maximum inspiratory pressure

MMEF: maximum mid-expiratory flow

MMV: minimum minute ventilation

MPM: Mortality Prediction Model

NIF: negative inspiratory force

NIP: negative inspiratory pressure

NMD: neuromuscular disorder

NG: nasogastric tube

NO: nitric oxide

NPPV: noninvasive positive pressure ventilation

NYHA: New York Heart Association

OR: odds ratio

OR: operating room

P0.1: occlusion pressure

PaCO2: arterial partial pressure of carbon dioxide

PaO2: arterial partial pressure of oxygen

PAV: proportional assist ventilation

Pbreath: the pressure a patient must generate to take an unassisted breath

PBVI: pulmonary blood volume index

PEEP: positive end-expiratory pressure

PetCO2: end-tidal CO2

PI max: maximal inspiratory pressure

PIP: peak inspiratory pressure

PS: pressure support

PTI: modified inspiratory pressure-time index; reflects the force and duration ofinspiratory muscle contraction

PVR: pulmonary vascular resistance

Res: resistance

RCT: randomized controlled trial

RDS: respiratory distress syndrome

ROC curve: receiver operator characteristic curve

RR: respiratory rate

RSBI: rapid shallow breathing index

RT: respiratory therapist

SaO2: percentage of hemoglobin saturated with oxygen in arterial blood

SAPS: Simplified Acute Physiology Score

sd: standard deviation

se: standard error

sens: sensitivity

SICU: surgical intensive care unit

SIMV: synchromized intermittent mandatory ventilation

spec: specificity

SV: stroke volume

SVR: systemic vascular resistance

Ti: inspiratory time

TPN: total parenteral nutrition

VAP: ventilator-associated pneumonia

VC: vital capacity

VE: minute ventilation

Vt: tidal volume