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Abstract
The Centers for Disease Control and Prevention (CDC) released ventilator-associated event (VAE) definitions in 2013. The new definitions were designed to track episodes of sustained respiratory deterioration in mechanically ventilated patients after a period of stability or improvement. More than 2,000 U.S. hospitals have reported their VAE rates to the CDC, but there has been little guidance to date on how to prevent VAEs. Existing ventilator-associated pneumonia prevention bundles are unlikely to be optimal insofar as pneumonia accounts for only a minority of VAEs. This review proposes a framework and potential intervention set to prevent VAEs on the basis of studies of VAE epidemiology, risk factors, and prevention. Work to date suggests that the majority of VAEs are caused by four conditions: pneumonia, fluid overload, atelectasis, and acute respiratory distress syndrome. Interventions that minimize ventilator exposure and target one or more of these conditions may therefore prevent VAEs. Potential strategies include avoiding intubation, minimizing sedation, paired daily spontaneous awakening and breathing trials, early exercise and mobility, low tidal volume ventilation, conservative fluid management, and conservative blood transfusion thresholds. Interventional studies have thus far affirmed that minimized sedation, paired daily spontaneous awakening and breathing trials, and conservative fluid management can reduce VAE rates and improve patient-centered outcomes. Further studies are needed to evaluate the impact of the other proposed interventions, to identify additional modifiable risk factors for VAEs, and to measure whether combining strategies into VAE prevention bundles confers additional benefits over implementing one or more of these interventions in isolation.
The U.S. Centers for Disease Control and Prevention (CDC) released a new surveillance paradigm for complications of mechanical ventilation in 2013 (1). The new paradigm, called ventilator-associated events (VAEs), was designed to overcome many of the limitations of ventilator-associated pneumonia (VAP) as a quality metric including its complexity, subjectivity, low frequency, and marginal attributable mortality (2–9). VAE definitions shift the focus of surveillance away from pneumonia in particular to complications in mechanically ventilated patients in general (10). The proposed advantages of this shift are twofold: (1) it broadens the focus of surveillance to include additional potentially preventable morbid complications of mechanical ventilation such as acute respiratory distress syndrome (ARDS), fluid overload, and atelectasis; and (2) it allows for simple, objective, and potentially automatable surveillance definitions based on trajectory changes in patients’ ventilator settings. Whether VAE will ultimately prove to be a more robust and impactful quality metric than VAP remains to be seen.
A VAE is defined as at least 2 days of stable or decreasing ventilator settings followed by at least 2 days of increased ventilator settings. In particular, the definition requires an increase in the daily minimum positive end-expiratory pressure (PEEP) of at least 3 cm H2O for at least 2 days or an increase in the daily minimum fraction of inspired oxygen (FiO2) of at least 20 points for at least 2 days relative to the preceding 2 days (Figure 1). Additional criteria allow for the subclassification of VAEs into infection-related ventilator-associated complications (IVACs) and/or possible ventilator-associated pneumonias (10).
Figure 1. Ventilator-associated events (VAEs). VAEs are defined by trajectory changes in patients’ ventilator settings, using either positive end-expiratory pressure (PEEP) or fraction of inspired oxygen (FiO2) criteria: (1) at least 2 days of stable or decreasing daily minimum PEEP followed by an increase of at least 3 cm H2O sustained for at least 2 days or (2) at least 2 days of stable or decreasing daily minimum FiO2 followed by an increase of at least 20 points sustained for at least 2 days.
[More] [Minimize]VAE definitions were designed for the purposes of population surveillance and quality improvement. They were not designed to inform the immediate clinical management of deteriorating patients (indeed, by definition, a VAE is only apparent 2 days after the onset of deterioration). Instead, VAE surveillance is intended to provide hospitals with a big-picture view of complication rates, a more objective basis for comparison with other hospitals, and an anchor around which to explore the reasons why some patients deteriorate in their institution and thereby inform possible system-level improvements in care that can be applied to future patients.
Multiple studies have characterized the incidence and attributable mortality of VAEs. Incidence rates vary by intensive care unit (ICU) type but generally range from 10–15 events per 1,000 ventilator-days or 4–7 events per 100 episodes of mechanical ventilation (11–14). Most studies report that patients with VAEs are approximately twice as likely to die as matched patients without VAEs (11–19). VAEs are also associated with more time on mechanical ventilation, longer ICU stays, and higher rates of antimicrobial use (11, 12, 17, 19).
The relative frequency of VAEs, their high attributable morbidity and mortality, and their strong association with antibiotic use make them potentially useful targets for prevention and quality improvement programs. A number of articles have been published on risk factors and interventions to prevent VAEs, but as yet there is no single, comprehensive guide to preventing VAEs. This review proposes a framework and bundle of interventions to prevent VAEs on the basis of studies to date of clinical correlates, risk factors, and prevention strategies for VAEs.
Five case series enumerate the clinical events that most commonly trigger VAEs. Four of the five case series were based on open-ended chart reviews designed to elicit any possible causes for patient VAEs. In these series, the majority of VAEs were caused by one of four conditions: pneumonia, fluid overload, atelectasis, and ARDS (Table 1). Depending on the series, pneumonia accounted for about 25–40% of VAEs, fluid overload (including pulmonary edema) for 20–40%, atelectasis for 10–15%, and ARDS for 10–20% (12, 15, 17, 20). The fifth case series retrospectively applied a variant definition for VAE to a multicenter cohort of 13,702 patients (19). The variant definition included higher thresholds for significant changes in PEEP and the option of using changes in PaO2:FiO2 ratios to trigger VAEs. These investigators identified 2,331 VAEs and attributed 27% to nosocomial infections (mainly pneumonia), 14% to iatrogenic complications (atelectasis, pneumothorax, thromboembolism, failed extubations, etc.), 17% to transport, and 5% to fluid resuscitation. Attributions were restricted, however, to a limited list of complications that have been predefined in 1997. Across all series, investigators have been unable to identify the clinical precipitants for rising ventilator settings in 10–40% of cases (12, 15, 17, 19, 20).
| Klompas et al. (15)* (n = 44) | Hayashi et al. (17) (n = 153) | Klein Klouwenberg et al. (12)* (n = 81) | Boyer et al. (20) (n = 67) | All Studies Combined* (n = 345) | |
|---|---|---|---|---|---|
| Pneumonia and/or aspiration | 10 (23%) | 66 (43%) | 28 (35%) | 21 (31%) | 125 (36%) |
| Pulmonary edema, pleural effusion, and/or heart failure | 8 (18%) | 40 (26%) | 39 (48%) | 10 (15%) | 97 (28%) |
| Atelectasis | 5 (11%) | 25 (16%) | 12 (15%) | 6 (9.0%) | 48 (14%) |
| Acute respiratory distress syndrome | 7 (16%) | 10 (6.5%) | — | 14 (21%) | 31 (9.0%) |
| Mucous plugging | 1 (2%) | — | — | — | 1 (0.3%) |
| Abdominal distension/compartment syndrome | 1 (2%) | 2 (1.3%) | 9 (11%) | — | 12 (3.5%) |
| Pulmonary embolus | 1 (2%) | 3 (2.0%) | — | — | 4 (1.2%) |
| Pneumothorax | — | — | 2 (2.5%) | 2 (3.0%) | 4 (1.2%) |
| Radiation pneumonitis | 1 (2%) | — | — | — | 1 (0.3%) |
| Sepsis syndrome/extrapulmonary infection | 1 (2%) | — | 9 (11%) | 3 (4.5%) | 13 (3.8%) |
| Poor pulmonary toilet | 1 (2%) | — | — | 1 (0.3%) | |
| Acute neurological event | — | — | 10 (12%) | 10 (2.9%) | |
| Transfusion-associated lung injury | — | — | — | 2 (3.0%) | 2 (0.6%) |
| Other | — | — | — | 9 (13%) | 9 (2.6%) |
| No apparent pulmonary complication | 18 (41%) | 17 (11%) | 10 (12%) | — | 45 (13%) |
There are three major approaches to prevent VAEs: (1) avoid intubation, (2) minimize duration of mechanical ventilation, and (3) target the specific conditions that most frequently trigger VAEs. In practice, these approaches are often highly congruent. Many of the most effective strategies to avoid intubation and minimize ventilator time have also been associated with lower rates of infection, fluid overload, atelectasis, and/or ARDS. Likewise, the most reliable strategies to prevent these complications are arguably those that have been shown also to decrease duration of mechanical ventilation, length of stay, and/or mortality.
Using this framework, potential strategies to prevent VAEs include avoiding intubation, minimizing sedation, improving performance of coordinated daily spontaneous awakening and breathing trials (SATs and SBTs), early mobility, low tidal volume ventilation, conservative fluid management, and conservative blood transfusion thresholds. These interventions were selected because trial data suggest these strategies can decrease the duration of mechanical ventilation, and in most cases, lower the incidence of one or more of the four conditions most frequently associated with VAEs (pneumonia, excess fluid, atelectasis, and/or ARDS). The interplay between these effects is shown in Figure 2. The rationale, general evidence, and VAE-specific evidence supporting each of these interventions are described below.
Figure 2. Potential strategies to prevent ventilator-associated events (VAEs). The framework to prevent VAEs reported in this review favors interventions that (1) shorten the average duration of mechanical ventilation and (2) target one or more of the four conditions that most frequently trigger VAEs. Demonstrated here is the interplay between these two objectives. ARDS = acute respiratory distress syndrome; SATs = spontaneous awakening trials; SBTs = spontaneous breathing trials.
[More] [Minimize]Avoiding intubation through noninvasive positive pressure ventilation or high-flow oxygen via nasal cannula is associated with better outcomes in selected populations (21–24). These strategies can be used to avoid intubation and/or to facilitate earlier extubation. Neither intervention, however, has been studied regarding VAEs. In addition, VAE surveillance is currently limited to patients receiving invasive mechanical ventilation. The CDC recommends ventilator-days or ventilator episodes as denominators when reporting VAE rates, and hence the metric is likely blind to systematic efforts to avoid intubations. This gap could be corrected by developing parallel VAE criteria for patients receiving noninvasive positive pressure ventilation and/or by reporting VAE rates relative to all ICU admissions, but the value of these approaches has not been studied. This review therefore focuses on strategies to prevent VAEs among patients receiving invasive mechanical ventilation.
An increasing body of evidence associates choice, depth, and duration of sedation with increased risk for a range of adverse effects including delirium, immobility, infection, VAEs, prolonged mechanical ventilation, increased length of stay, and death (25–31). Deep and/or sustained sedation likely increases VAE risk in two ways: (1) by prolonging the duration of mechanical ventilation and hence time at risk for VAEs, and (2) by increasing the risk for specific complications that may be associated with VAEs. For example, deep sedation may increase the risk for atelectasis, aspiration, and impaired clearance of respiratory secretions that in turn may increase the risk for pneumonia (32). A case–control study of risk factors for VAEs found that benzodiazepine and opioid exposures were independent risk factors for IVACs (30). Another analysis found that benzodiazepines and propofol were associated with increased risk for VAEs whereas dexmedetomidine was not (33).
Minimizing the depth and duration of sedation is associated with less time to extubation and possibly lower mortality rates (34). Most strikingly, a randomized controlled trial comparing routine sedation with propofol and midazolam versus a strategy of no sedation reported that mechanical ventilation without sedation was associated with 4.2 more ventilator-free days compared with management with sedation (35).
Some of the success of this investigation may have been attributable to their use of 1:1 nursing insofar as patients randomized to no sedation had significantly more episodes of agitation compared with patients on sedation. It is therefore not clear whether a strategy of no sedation is generalizable to routine practice in U.S. hospitals, where 1:1 nursing is not routinely possible and where ICU culture still favors at least some degree of sedation (36, 37). Nonetheless, this trial at the very least challenges our assumptions about the minimum amount of sedation that patients require to tolerate mechanical ventilation and critical illness.
In addition, a series of studies over the past decade suggest that benzodiazepines are associated with poorer outcomes compared with nonbenzodiazepines such as propofol and dexmedetomidine (31). Minimizing sedation may increase the incidence of agitated delirium and self-extubations, which in turn may require higher staffing levels, emergency reintubations, and more patient contact time. On balance, though, protocols to reduce sedation and avoid benzodiazepines appear to lower pneumonia risk and decrease time to extubation without long-term adverse consequences (38–45).
Two of the most potent strategies to diminish duration of mechanical ventilation and hence time at risk for VAEs are daily SATs and SBTs. At least three studies have found that SATs and/or SBTs are protective against VAEs (18, 46, 47). There are rich randomized controlled trial data establishing that SATs and SBTs can decrease time to extubation by 1.5–2.5 days compared with usual care (48–50). Coordinating these two interventions together appears to be synergistic, presumably because patients are more likely to pass SBTs if they are awake for the trial. Pairing SATs and SBTs together has been associated with 3.1 more ventilator-free days compared with daily SBTs alone (34).
A subsequent trial reported that sedative interruptions conferred no additional benefit in patients already being managed with a sedation protocol (51). However, patients randomized to sedative interruptions in this study received higher average daily doses of midazolam and fentanyl compared with patients being managed by protocol alone. This paradoxical result is an important reminder that SATs are means, not ends. The intent of both SATs and sedation protocols is to facilitate minimizing sedation. Their success is contingent on them driving less sedative use, not simply on their institution alone.
Enhancing the frequency and reliability of paired daily SATs and SBTs can reduce VAE rates. The CDC Prevention Epicenters Wake Up and Breathe Collaborative brought together 12 ICUs affiliated with 7 hospitals to increase the frequency of paired daily SATs and SBTs (46). Over a 19-month period, the collaborative increased the frequency of SATs from 14 to 77% of days where indicated, SBTs from 49 to 75% of days where indicated, and the fraction of SBTs done off sedation from 6.1 to 87%. These improvements were associated with a decrease in VAEs from 9.7 to 5.2 events per 100 episodes of mechanical ventilation (adjusted odds ratio [OR], 0.63; 95% confidence interval [CI], 0.42–0.97) and a decrease in IVACs from 3.5 to 0.52 events per 100 episodes of mechanical ventilation (adjusted OR, 0.35; 95% CI, 0.17–71). These were further accompanied by a 2.4-day decrease in mean duration of mechanical ventilation, a 3.0-day decrease in ICU length of stay, and a 6.3-day decrease in hospital length of stay. There was no change in mortality rates.
Immobility has long been recognized as a risk factor for prolonged length of stay, pneumonia, atelectasis, delirium, and other complications of critical illness (52). Mobilizing patients while still on mechanical ventilation is increasingly recognized as a potent strategy to decrease duration of mechanical ventilation, prevent delirium, and enhance patients’ sense of well-being. One randomized controlled trial found that early physical and occupational therapy in mechanically ventilated patients who were functionally independent at baseline was associated with 2.4 more ventilator-free days and 2.0 fewer days of delirium compared with daily interruption of sedation alone (53). Other investigators have reported similar improvements after implementing early mobility programs (54–59). In practice, early mobility programs can be difficult to implement given the complexity of safely mobilizing a patient while still on a ventilator. Surveys suggest that most ICUs are still struggling to provide this intervention to most patients (60, 61).
There are no studies to date directly assessing the impact of early mobility on VAE risk. However, to the extent that early mobility can decrease patients’ time on mechanical ventilation, it is also likely to decrease their risk for VAEs. Early mobility may also decrease the incidence of atelectasis (which accounts for about 10–15% of VAEs) and pneumonia (which accounts for 25–40% of VAEs) (54, 62, 63).
There may be important synergies between minimizing sedation, performing daily SATs and SBTs, and early mobility. Less sedation decreases ventilator dependence and risk of delirium. Coordinating SBTs and early mobility with sedative interruptions increases patients’ chances of success. Preventing delirium and encouraging physical activity decreases the need to use sedatives to calm patients. Quality advocates suggest combining these five interventions into the so-called ABCDE package (Awakening and Breathing Coordination, Delirium monitoring and management, Early exercise and mobility). A before–after study of the ABCDE bundle in seven different units of one hospital reported that patients in the postimplementation period had three more ventilator-free days and nearly half the frequency of delirium compared with patients in the preimplementation period (57). On the other hand, a randomized controlled trial of early tracheotomy versus prolonged intubation in cardiac surgery patients found no difference in ventilator-free days, ICU length of stay, or mortality rates despite significantly less sedation and higher levels of mobility among patients randomized to early tracheotomy (64). Randomized controlled trials assessing the impact of ABCDE on VAE are needed.
High-quality randomized controlled trials suggest that low tidal volumes are associated with lower mortality rates in patients with ARDS, and a growing number of studies suggest that low tidal volume ventilation may help prevent ARDS, atelectasis, and lung infections in patients without ARDS (65–69). Given that these three conditions collectively account for the majority of VAEs, there is a reasonable likelihood that low tidal volume ventilation will also prevent VAEs. A case–control study affirmed that high tidal volumes are independently associated with higher risk for VAEs: each milliliter increase above 6 ml/kg predicted body weight increased the odds of VAE by 21% (70).
The most robust evidence to date that low tidal volume ventilation is helpful in patients without ARDS comes from a meta-analysis of 20 studies (68). Low tidal volume ventilation was associated with significantly lower rates of lung injury, pulmonary infection, and atelectasis, as well as shorter hospital length of stay and lower mortality rates. The majority of studies included in the meta-analysis, however, were short-term evaluations of surgical patients (median time of per-protocol protective ventilation, 6.9 h; median duration of follow-up, 21 h), and hence the applicability of these studies to longer periods of mechanical ventilation in critically ill patients is unclear. Nonetheless, at least one randomized controlled trial suggests that low tidal volume ventilation may indeed be beneficial in critically ill patients without ARDS. Determann and colleagues randomized 150 patients expected to require more than 72 hours of mechanical ventilation to tidal volumes of 6 versus 10 ml/kg predicted body weight (66). Patients randomized to low tidal volumes had significantly lower rates of acute lung injury (2.6 vs.13.5%; P = 0.01). There were no differences between groups in ventilator-free days or mortality, but the trial was not powered to assess these outcomes and the study predated the development of VAE definitions. A patient-level analysis of data from this trial combined with mainly observational data from other trials affirmed lower rates of ARDS, but only trends toward less pneumonia and lower mortality rates (69). Further data are therefore required to confirm whether low tidal ventilation can shorten time to extubation, prevent VAEs, and lower mortality in critically ill patients without ARDS.
Qualitative analyses suggest that 20–40% of VAEs are attributable to fluid overload including congestive heart failure, pulmonary edema, and new pleural effusions (12, 15, 17, 20). A case–control study found positive fluid balance to be an independent risk factor for VAEs (30) and a randomized controlled trial has demonstrated that conservative fluid management can significantly decrease the incidence of VAEs (71). These observations mirror the increasing recognition in the critical care community that excess fluids may increase morbidity and mortality, particularly in the postresuscitation phase of severe sepsis and/or during ventilator weaning (72–76). Positive fluid balance is also a risk factor for ARDS and may potentiate risk for pneumonia (71, 77, 78).
The Fluid and Catheter Treatment Trial (FACTT) showed that conservative fluid management is associated with more ventilator-free days in patients with ARDS (79). Emerging studies suggest that conservative fluid management during ventilator weaning can also increase ventilator-free days in patients without ARDS (80). Mekontso Dessap and colleagues, for example, randomized patients to daily B-type natriuretic peptide (BNP) level measurements versus usual care to guide fluid management during weaning from mechanical ventilation (80). Patients randomized to daily BNP levels were given more diuretics and achieved greater median negative fluid balances (–2,320 vs. –180 ml). This was associated with less time to extubation and more ventilator-free days. The investigators subsequently applied VAE criteria to their data set and found that the incidence of VAEs was 50% lower among patients randomized to daily BNP levels (71).
It is not clear how best to operationalize conservative fluid management into routine care. The FACTT used a complicated protocol that specified different management strategies for 20 different permutations of central venous pressure, pulmonary artery occlusion pressure, mean arterial pressure, urinary output, and cardiac index or clinical examination findings (79). The complexity of this protocol limits its generalizability to routine practice for all patients. Daily BNP levels are attractively simple by comparison; however, BNP levels can be difficult to interpret in patients with renal impairment, a common condition in critically ill patients. The FACTT investigators published a simplified protocol that may prove easier to implement (FACTT Lite; Table 2) (81). Although the simplified protocol appears promising, it has not yet been tested in patients without ARDS and its impact on VAEs is unknown. In addition, the original FACTT protocol was associated with higher rates of long-term cognitive impairment among survivors of ARDS (82). It will be important to assess whether this risk extends to patients without ARDS as well.
| Central Venous Pressure (mm Hg) | Urine Output < 0.5 ml/kg/h | Urine Output ≥ 0.5 ml/kg/h |
|---|---|---|
| >8 | Furosemide, reassess in 1 h | Furosemide, reassess in 4 h |
| 4–8 | Give fluid bolus, reassess in 1 h | Furosemide, reassess in 4 h |
| <4 | Give fluid bolus, reassess in 1 h | No intervention, reassess in 4 h |
Blood transfusions are associated with increased risks for both pulmonary edema and ARDS (66, 77, 83–85), two of the four conditions responsible for most VAEs. Blood transfusions can also lower immunity and increase risk for serious infections, including pneumonia, a third condition responsible for many VAEs (86). First principles therefore suggest that conservative transfusion strategies may lower VAE rates. There have not been any interventional trials thus far specifically evaluating the association between blood transfusions and VAE risk; however, there are ample trial data suggesting that conservative transfusion thresholds are safe (85–91) and potentially beneficial for many patients with the possible exception of those convalescing after cardiac surgery (92). Studies specifically evaluating the impact of conservative transfusion thresholds on VAEs are needed.
Two interventions frequently included in ventilator bundles are unlikely to prevent VAEs: oral care with chlorhexidine and subglottic secretion drainage. Both of these strategies have been associated with lower VAP rates, but the balance of evidence suggests that these interventions primarily lower the frequency of false positive VAP diagnoses attributable to oropharyngeal colonization and/or high volumes of secretions. A meta-analysis of oral care with chlorhexidine reported lower VAP rates in open-label studies but not in double-blind studies (93). Furthermore, oral care with chlorhexidine did not decrease ventilator days, ICU length of stay, or mortality. Indeed, oral care with chlorhexidine has been associated with possible increases in mortality (93, 94). Likewise, two meta-analyses of subglottic secretion drainage failed to demonstrate any decreases in ventilator days, ICU days, or mortality (95, 96). One randomized controlled trial of subglottic secretion drainage included both VAP and VAE as outcomes: there was a significant decrease in VAPs but no change in VAEs, ventilator days, or ICU days, suggesting that the drop in VAPs may have been cosmetic (97).
Elevating the head of bed of critically ill patients is now ubiquitous in U.S. practice. Almost 99% of hospitals report routinely using semirecumbent positioning to prevent VAP (98). Notwithstanding the very high adoption rate for this intervention, the evidence base supporting head-of-bed elevation is sparse. Observational studies suggest that the supine position may be a risk factor for VAP (99). Randomized controlled trial data are more limited; only 3 trials with a collective enrollment of 337 patients have been published (100–102). One of the three trials reported a significant decrease in VAP rates, and the other two did not. Multiple studies attest to the practical challenge of continually maintaining patients in a semirecumbent position (102–105). Some investigators hypothesize that the lateral recumbent position may be a more effective strategy to prevent VAP (106, 107). To the extent that head-of-bed elevation may protect against VAP it may also protect against VAEs. Indeed, investigators from Japan found an association between head-of-bed elevation and fewer VAEs (OR, 0.26; 95% CI, 0.07–0.91) after adjusting for age, sex, chronic disease, sedative interruptions, and duration of intubation (personal communication, K. Tajimi, Akita University Hospital, Akita, Japan). There is little basis from currently available data to prioritize elevating the head of the bed to prevent VAP or VAE but neither is there any urgency to disrupt current practice given possible benefit, no cost, and minimal evidence of harm. Further study is warranted.
Hospital safety monitoring programs have traditionally reported VAPs per 1,000 ventilator-days. Ventilator-days may not be the best denominator to track VAE rates, however, because the most effective strategies to prevent VAEs likely also decrease mean duration of mechanical ventilation. If VAE rates are tracked using ventilator-days as the denominator, these interventions are liable to shrink the denominator and precipitate a paradoxical increase in observed VAE rates. Tracking VAEs using episodes rather than ventilator-days as the denominator can help avert this problem. The CDC Prevention Epicenters Wake Up and Breathe Collaborative highlighted this issue insofar as they observed no change in the risk of VAEs per ventilator-day but a significant decrease in VAEs per episode of mechanical ventilation (46). The CDC recently modified their VAE reporting rules to allow hospitals to use episodes in addition to ventilator-days as denominators.
All of the VAE prevention strategies proposed in this review are congruent with widely accepted best practice initiatives including the ABCDE bundle, the Choosing Wisely Campaign, the Society of Critical Care Medicine guidelines for the management of pain, agitation, and delirium, the Surviving Sepsis Campaign, and the Society for Healthcare Epidemiology of America's strategies to prevent ventilator-associated pneumonia (Table 3) (108–112). The congruence between practices likely to prevent VAEs and the practices recommended by these initiatives suggests that VAE surveillance may be able to serve as an objective metric to monitor the progress and impact of quality improvement efforts inspired by these campaigns.
| ABCDE (108) | Choosing Wisely Campaign (109) | Guidelines for the Management of Pain, Agitation, and Delirium (110) | Surviving Sepsis Campaign (111) | Strategies to Prevent Ventilator-associated Pneumonia (112) | |
|---|---|---|---|---|---|
| Minimize sedation | ✓ | ✓ | ✓ | ✓ | ✓ |
| Paired daily SATs and SBTs | ✓ | ✓ | ✓ | ✓* | ✓ |
| Early exercise and mobility | ✓ | ✓ | ✓† | ✓ | |
| Low tidal volume ventilation | ✓‡ | ||||
| Conservative fluid management | ✓‡ | ||||
| Conservative transfusion thresholds | ✓ | ✓ |
VAE surveillance may also help hospitals identify further opportunities to improve practice beyond the strategies included in current best practice guidelines. VAE surveillance identifies a specific event that providers can analyze to identify additional institution-specific risk factors for deterioration that are not included in current bundles. For example, root cause analyses of VAEs may identify intrahospital transportation, use of portable ventilators, inadequate PEEP for obese patients, poor endotracheal tube cuff pressure monitoring, failure to stop tube feeds during bed position changes, poor intraoperative ventilator management, low hand hygiene rates, and/or failure to create and adhere to institutional guidelines to manage ventilators as underappreciated areas for additional improvement. Some VAEs may paradoxically be caused by mid-course improvements in care (e.g., a new provider on service may elect to increase PEEP to decrease FiO2) but in that case it may allow for review of institutional practices and protocols governing ventilator management. Not every VAE will yield lessons to be learned—indeed, it is likely that some VAEs are unavoidable manifestations of respiratory deterioration and not preventable—but in aggregate they appear to offer a focus and a pathway to identify opportunities to improve care.
Concerns have been raised about the potential usefulness of VAE definitions for hospital quality and safety programs (113–116). The concerns fall into four categories: (1) most VAEs are not pneumonias; (2) VAE surveillance misses many pneumonias; (3) VAE surveillance is susceptible to gaming and variable case finding; and (4) there is scant evidence that VAEs are preventable.
The observation that most VAEs are not pneumonias is consistent with the CDC intent to expand the focus of surveillance to include additional potentially preventable complications in mechanically ventilated patients. Whether this broader focus will lead to broader prevention efforts and hence better outcomes for ventilated populations remains to be determined. Nonetheless, work to date on VAE risk factors and prevention has affirmed ARDS and fluid overload as important causes of morbidity that are not well addressed by most current ventilator bundles and therefore suggest the wisdom of expanding ventilator bundles to include low tidal volume ventilation, early mobility, conservative fluid management, and conservative transfusion thresholds.
The concern that VAE surveillance misses many pneumonias highlights the tension between surveillance versus clinical diagnosis. The emphasis in clinical care is on sensitivity. Clinicians cannot afford to miss serious diagnoses, even if this comes at the cost of initially overdiagnosing and overtreating some patients (117). Surveillance metrics, by contrast, are designed to give population-level insights into major sources of morbidity that can then be used to inform population-level interventions to be applied to all patients. The emphasis in surveillance is on objectivity, reproducibility, efficiency, and morbidity. VAE surveillance follows this paradigm insofar as the requirement for sustained increases in ventilator settings simultaneously facilitates the possibility of objective surveillance and sets a threshold effect for severity of illness. Only the most severe pneumonias that lead to sustained increases in ventilator settings qualify as VAEs. Nonetheless, pneumonias consistently constitute 25–40% of VAEs, and hence quality improvement initiatives designed to prevent VAEs must necessarily include strategies to prevent pneumonias. These strategies will be applied to all future patients, and hence they are as likely to protect patients against mild pneumonias that might never have triggered VAE criteria as they are to protect against more severe pneumonias that could trigger VAEs.
Other observers have noted that VAE surveillance is susceptible to variability and gaming. Klein Klouwenberg and colleagues demonstrated that VAE case finding varies depending on whether one defines daily minimum PEEP and FiO2 on the basis of minute-to-minute ventilator settings, hourly values abstracted from patient flowsheets, or 10th percentile values (12). The CDC subsequently clarified, however, that if one uses minute-to-minute ventilator settings for VAE surveillance, then the daily minimum PEEP and FiO2 are defined as the lowest values the patient was able to sustain for at least 1 hour. Mann and colleagues compared manual versus computer-based VAE surveillance in four hospitals. The three manual surveyors in the study missed between 18 and 54% of VAEs relative to the automated surveillance system (118). Lilly and colleagues suggested that one can game away the majority of VAEs by alternately raising and lowering patients’ PEEP by 1 cm H2O each day (13). This will preclude a stable baseline and thereby eliminate the possibility of VAEs, using PEEP criteria. There is no clinical rationale, however, for alternately raising and lowering PEEP by 1 cm H2O each day and hence it is clear that anyone applying this strategy is only interested in avoiding VAE detection. Setting aside the lost opportunity to analyze individual VAEs to discover possible opportunities to improve care, if VAE ever becomes a formal quality metric then manipulation of this sort could risk audit and sanction.
Finally, some authors have wondered what fraction of VAEs is preventable. Boyer and colleagues, for example, audited all VAEs in their facility for 1 year and estimated that only 37% were potentially preventable (20). Retrospectively estimating preventability, however, is difficult. A better guide to preventability is prospective interventional studies. More data on this question are needed, but the few intervention studies to date are encouraging. The Canadian Critical Care Trials Group reported a 29% decrease in VAEs by increasing concordance with ventilator guidelines, the CDC Prevention Epicenters Wake Up and Breathe Collaborative reported a 37% decrease in VAEs through enhanced adoption and performance of SATs and SBTs, Drees and colleagues reported a 42% decrease in VAEs through optimization of PEEP, and Mekontso Dessap and colleagues found that depletive fluid management during ventilator weaning was associated with a 50% decrease in VAEs (18, 46, 71, 119). It remains to be seen whether bundling multiple strategies together could lead to even greater decreases.
There are too few data at present to be confident that VAE surveillance will be a net benefit to hospitals and to patients. Unless and until we have such evidence it will be premature to designate VAE as a formal quality metric in pay-for-performance programs. Nonetheless, the data thus far are promising. VAE surveillance brings to light a broad set of patients suffering morbid events while on mechanical ventilation including many complications aside from pneumonia. VAE surveillance therefore invites hospitals to expand their prevention programs to address the broader array of complications identified through VAE surveillance. Potential strategies to prevent VAEs include avoiding intubation, minimizing sedation, coordinated daily SATs and SBTs, early mobility, low tidal volume ventilation, conservative fluid management, and conservative transfusion thresholds. Root cause analyses may suggest additional approaches to improve care for specific hospitals or populations. Ultimately, the success or failure of VAE definitions hinges on the extent to which they are able to catalyze better care and outcomes. There is consequently a pressing need for further interventional studies to better define how best to prevent VAEs and the extent to which VAE surveillance and prevention programs can improve patient-centered outcomes.
| 1. | Klompas M. Complications of mechanical ventilation—the CDC’s new surveillance paradigm. N Engl J Med 2013;368:1472–1475. |
| 2. | Tejerina E, Esteban A, Fernández-Segoviano P, Frutos-Vivar F, Aramburu J, Ballesteros D, Rodríguez-Barbero JM. Accuracy of clinical definitions of ventilator-associated pneumonia: comparison with autopsy findings. J Crit Care 2010;25:62–68. |
| 3. | Stevens JP, Kachniarz B, Wright SB, Gillis J, Talmor D, Clardy P, Howell MD. When policy gets it right: variability in U.S. hospitals’ diagnosis of ventilator-associated pneumonia. Crit Care Med 2014;42:497–503. |
| 4. | Klein Klouwenberg PM, Ong DS, Bos LD, de Beer FM, van Hooijdonk RT, Huson MA, Straat M, van Vught LA, Wieske L, Horn J, et al. Interobserver agreement of Centers for Disease Control and Prevention criteria for classifying infections in critically ill patients. Crit Care Med 2013;41:2373–2378. |
| 5. | Melsen WG, Rovers MM, Koeman M, Bonten MJ. Estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies. Crit Care Med 2011;39:2736–2742. |
| 6. | Melsen WG, Rovers MM, Groenwold RH, Bergmans DC, Camus C, Bauer TT, Hanisch EW, Klarin B, Koeman M, Krueger WA, et al. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis 2013;13:665–671. |
| 7. | Klompas M. Interobserver variability in ventilator-associated pneumonia surveillance. Am J Infect Control 2010;38:237–239. |
| 8. | Klompas M, Platt R. Ventilator-associated pneumonia—the wrong quality measure for benchmarking. Ann Intern Med 2007;147:803–805. |
| 9. | Bekaert M, Timsit JF, Vansteelandt S, Depuydt P, Vésin A, Garrouste-Orgeas M, Decruyenaere J, Clec’h C, Azoulay E, Benoit D; Outcomerea Study Group. Attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis. Am J Respir Crit Care Med 2011;184:1133–1139. |
| 10. | Magill SS, Klompas M, Balk R, Burns SM, Deutschman CS, Diekema D, Fridkin S, Greene L, Guh A, Gutterman D, et al. Developing a new, national approach to surveillance for ventilator-associated events. Crit Care Med 2013;41:2467–2475. |
| 11. | Klompas M, Kleinman K, Murphy MV. Descriptive epidemiology and attributable morbidity of ventilator-associated events. Infect Control Hosp Epidemiol 2014;35:502–510. |
| 12. | Klein Klouwenberg PM, van Mourik MS, Ong DS, Horn J, Schultz MJ, Cremer OL, Bonten MJ; MARS Consortium. Electronic implementation of a novel surveillance paradigm for ventilator-associated events: feasibility and validation. Am J Respir Crit Care Med 2014;189:947–955. |
| 13. | Lilly CM, Landry KE, Sood RN, Dunnington CH, Ellison RT III, Bagley PH, Baker SP, Cody S, Irwin RS; UMass Memorial Critical Care Operations Group; UMass Memorial Critical Care Operations Group. Prevalence and test characteristics of National Health Safety Network ventilator-associated events. Crit Care Med 2014;42:2019–2028. |
| 14. | Stevens JP, Silva G, Gillis J, Novack V, Talmor D, Klompas M, Howell MD. Automated surveillance for ventilator-associated events. Chest 2014;146:1612–1618. |
| 15. | Klompas M, Khan Y, Kleinman K, Evans RS, Lloyd JF, Stevenson K, Samore M, Platt R; CDC Prevention Epicenters Program. Multicenter evaluation of a novel surveillance paradigm for complications of mechanical ventilation. PLoS One 2011;6:e18062. |
| 16. | Klompas M, Magill S, Robicsek A, Strymish JM, Kleinman K, Evans RS, Lloyd JF, Khan Y, Yokoe DS, Stevenson K, et al.; CDC Prevention Epicenters Program. Objective surveillance definitions for ventilator-associated pneumonia. Crit Care Med 2012;40:3154–3161. |
| 17. | Hayashi Y, Morisawa K, Klompas M, Jones M, Bandeshe H, Boots R, Lipman J, Paterson DL. Toward improved surveillance: the impact of ventilator-associated complications on length of stay and antibiotic use in patients in intensive care units. Clin Infect Dis 2013;56:471–477. |
| 18. | Muscedere J, Sinuff T, Heyland DK, Dodek PM, Keenan SP, Wood G, Jiang X, Day AG, Laporta D, Klompas M; Canadian Critical Care Trials Group. The clinical impact and preventability of ventilator-associated conditions in critically ill patients who are mechanically ventilated. Chest 2013;144:1453–1460. |
| 19. | Bouadma L, Sonneville R, Garrouste-Orgeas M, Darmon M, Souweine B, Voiriot G, Kallel H, Schwebel C, Goldgran-Toledano D, Dumenil AS, et al.; OUTCOMEREA Study Group. Ventilator-associated events: prevalence, outcome, and relationship with ventilator-associated pneumonia. Crit Care Med 2015;43:1798–1806. |
| 20. | Boyer AF, Schoenberg N, Babcock H, McMullen KM, Micek ST, Kollef MH. A prospective evaluation of ventilator-associated conditions and infection-related ventilator-associated conditions. Chest 2015;147:68–81. |
| 21. | Burns KE, Meade MO, Premji A, Adhikari NK. Noninvasive ventilation as a weaning strategy for mechanical ventilation in adults with respiratory failure: a Cochrane systematic review. CMAJ 2014;186:E112–E122. |
| 22. | Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, Prat G, Boulain T, Morawiec E, Cottereau A, et al.; FLORALI Study Group; REVA Network. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med 2015;372:2185–2196. |
| 23. | Girou E, Schortgen F, Delclaux C, Brun-Buisson C, Blot F, Lefort Y, Lemaire F, Brochard L. Association of noninvasive ventilation with nosocomial infections and survival in critically ill patients. JAMA 2000;284:2361–2367. |
| 24. | Girou E, Brun-Buisson C, Taillé S, Lemaire F, Brochard L. Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA 2003;290:2985–2991. |
| 25. | Shehabi Y, Chan L, Kadiman S, Alias A, Ismail WN, Tan MA, Khoo TM, Ali SB, Saman MA, Shaltut A, et al.; Sedation Practice in Intensive Care Evaluation (SPICE) Study Group Investigators. Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study. Intensive Care Med 2013;39:910–918. |
| 26. | Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, McArthur C, Seppelt IM, Webb S, Weisbrodt L; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Group. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med 2012;186:724–731. |
| 27. | Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, Shintani AK, Thompson JL, Jackson JC, Deppen SA, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007;298:2644–2653. |
| 28. | Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, et al.; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301:489–499. |
| 29. | Nseir S, Makris D, Mathieu D, Durocher A, Marquette CH. Intensive care unit–acquired infection as a side effect of sedation. Crit Care 2010;14:R30. |
| 30. | Lewis SC, Li L, Murphy MV, Klompas M; CDC Prevention Epicenters. Risk factors for ventilator-associated events: a case–control multivariable analysis. Crit Care Med 2014;42:1839–1848. |
| 31. | Fraser GL, Devlin JW, Worby CP, Alhazzani W, Barr J, Dasta JF, Kress JP, Davidson JE, Spencer FA. Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated, critically ill adults: a systematic review and meta-analysis of randomized trials. Crit Care Med 2013;41(9 Suppl 1):S30–S38. |
| 32. | Metheny NA, Clouse RE, Chang YH, Stewart BJ, Oliver DA, Kollef MH. Tracheobronchial aspiration of gastric contents in critically ill tube-fed patients: frequency, outcomes, and risk factors. Crit Care Med 2006;34:1007–1015. |
| 33. | Klompas M, Li L, Kleinman K, Szumita PM, Murphy MV. Associations between different sedatives and ventilator-associated events, length of stay, and mortality in mechanically ventilated patients. Chest [online ahead of print] 22 Oct 2015; DOI: 10.1378/chest.15-1389. |
| 34. | Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, Taichman DB, Dunn JG, Pohlman AS, Kinniry PA, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008;371:126–134. |
| 35. | Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet 2010;375:475–480. |
| 36. | Tanios MA, de Wit M, Epstein SK, Devlin JW. Perceived barriers to the use of sedation protocols and daily sedation interruption: a multidisciplinary survey. J Crit Care 2009;24:66–73. |
| 37. | Burns SM. Adherence to sedation withdrawal protocols and guidelines in ventilated patients. Clin Nurse Spec 2012;26:22–28. |
| 38. | Kollef MH, Shapiro SD, Silver P, St John RE, Prentice D, Sauer S, Ahrens TS, Shannon W, Baker-Clinkscale D. A randomized, controlled trial of protocol-directed versus physician-directed weaning from mechanical ventilation. Crit Care Med 1997;25:567–574. |
| 39. | Brook AD, Ahrens TS, Schaiff R, Prentice D, Sherman G, Shannon W, Kollef MH. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med 1999;27:2609–2615. |
| 40. | Marelich GP, Murin S, Battistella F, Inciardi J, Vierra T, Roby M. Protocol weaning of mechanical ventilation in medical and surgical patients by respiratory care practitioners and nurses: effect on weaning time and incidence of ventilator-associated pneumonia. Chest 2000;118:459–467. |
| 41. | Dries DJ, McGonigal MD, Malian MS, Bor BJ, Sullivan C. Protocol-driven ventilator weaning reduces use of mechanical ventilation, rate of early reintubation, and ventilator-associated pneumonia. J Trauma 2004;56:943–951, discussion 951–952. |
| 42. | Lellouche F, Mancebo J, Jolliet P, Roeseler J, Schortgen F, Dojat M, Cabello B, Bouadma L, Rodriguez P, Maggiore S, et al. A multicenter randomized trial of computer-driven protocolized weaning from mechanical ventilation. Am J Respir Crit Care Med 2006;174:894–900. |
| 43. | Quenot JP, Ladoire S, Devoucoux F, Doise JM, Cailliod R, Cunin N, Aubé H, Blettery B, Charles PE. Effect of a nurse-implemented sedation protocol on the incidence of ventilator-associated pneumonia. Crit Care Med 2007;35:2031–2036. |
| 44. | Marshall J, Finn CA, Theodore AC. Impact of a clinical pharmacist-enforced intensive care unit sedation protocol on duration of mechanical ventilation and hospital stay. Crit Care Med 2008;36:427–433. |
| 45. | Strøm T, Stylsvig M, Toft P. Long-term psychological effects of a no-sedation protocol in critically ill patients. Crit Care 2011;15:R293. |
| 46. | Klompas M, Anderson D, Trick W, Babcock H, Kerlin MP, Li L, Sinkowitz-Cochran R, Ely EW, Jernigan J, Magill S, et al.; CDC Prevention Epicenters. The preventability of ventilator-associated events. Am J Respir Crit Care Med 2015;191:292–301. |
| 47. | Posa P, Barnes D, Bogan B, DiGiovine B, Dammeyer J, Hyzy R, Miller M, Melville A. Compliance with spontaneous breathing trial protocol associated with lower VAE rates. Crit Care Med 2014;42:A1547. |
| 48. | Esteban A, Frutos F, Tobin MJ, Alía I, Solsona JF, Valverdú I, Fernández R, de la Cal MA, Benito S, Tomás R, et al.; Spanish Lung Failure Collaborative Group. A comparison of four methods of weaning patients from mechanical ventilation. N Engl J Med 1995;332:345–350. |
| 49. | Ely EW, Baker AM, Dunagan DP, Burke HL, Smith AC, Kelly PT, Johnson MM, Browder RW, Bowton DL, Haponik EF. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996;335:1864–1869. |
| 50. | Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000;342:1471–1477. |
| 51. | Mehta S, Burry L, Cook D, Fergusson D, Steinberg M, Granton J, Herridge M, Ferguson N, Devlin J, Tanios M, et al.; SLEAP Investigators; Canadian Critical Care Trials Group. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA 2012;308:1985–1992. |
| 52. | Morris PE. Moving our critically ill patients: mobility barriers and benefits. Crit Care Clin 2007;23:1–20. |
| 53. | Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, Spears L, Miller M, Franczyk M, Deprizio D, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009;373:1874–1882. |
| 54. | Titsworth WL, Hester J, Correia T, Reed R, Guin P, Archibald L, Layon AJ, Mocco J. The effect of increased mobility on morbidity in the neurointensive care unit. J Neurosurg 2012;116:1379–1388. |
| 55. | Needham DM, Korupolu R, Zanni JM, Pradhan P, Colantuoni E, Palmer JB, Brower RG, Fan E. Early physical medicine and rehabilitation for patients with acute respiratory failure: a quality improvement project. Arch Phys Med Rehabil 2010;91:536–542. |
| 56. | Morris PE, Goad A, Thompson C, Taylor K, Harry B, Passmore L, Ross A, Anderson L, Baker S, Sanchez M, et al. Early intensive care unit mobility therapy in the treatment of acute respiratory failure. Crit Care Med 2008;36:2238–2243. |
| 57. | Balas MC, Vasilevskis EE, Olsen KM, Schmid KK, Shostrom V, Cohen MZ, Peitz G, Gannon DE, Sisson J, Sullivan J, et al. Effectiveness and safety of the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle. Crit Care Med 2014;42:1024–1036. |
| 58. | Klein K, Mulkey M, Bena JF, Albert NM. Clinical and psychological effects of early mobilization in patients treated in a neurologic ICU: a comparative study. Crit Care Med 2015;43:865–873. |
| 59. | Engel HJ, Tatebe S, Alonzo PB, Mustille RL, Rivera MJ. Physical therapist–established intensive care unit early mobilization program: quality improvement project for critical care at the University of California San Francisco Medical Center. Phys Ther 2013;93:975–985. |
| 60. | Nydahl P, Ruhl AP, Bartoszek G, Dubb R, Filipovic S, Flohr HJ, Kaltwasser A, Mende H, Rothaug O, Schuchhardt D, et al. Early mobilization of mechanically ventilated patients: a 1-day point-prevalence study in Germany. Crit Care Med 2014;42:1178–1186. |
| 61. | Hodgson C, Bellomo R, Berney S, Bailey M, Buhr H, Denehy L, Harrold M, Higgins A, Presneill J, Saxena M, et al.; TEAM Study Investigators. Early mobilization and recovery in mechanically ventilated patients in the ICU: a bi-national, multi-centre, prospective cohort study. Crit Care 2015;19:81. |
| 62. | Scheidegger D, Bentz L, Piolino G, Pusterla C, Gigon JP. Influence of early mobilisation of pulmonary function in surgical patients. Eur J Intensive Care Med 1976;2:35–40. |
| 63. | Clark DE, Lowman JD, Griffin RL, Matthews HM, Reiff DA. Effectiveness of an early mobilization protocol in a trauma and burns intensive care unit: a retrospective cohort study. Phys Ther 2013;93:186–196. |
| 64. | Trouillet JL, Luyt CE, Guiguet M, Ouattara A, Vaissier E, Makri R, Nieszkowska A, Leprince P, Pavie A, Chastre J, et al. Early percutaneous tracheotomy versus prolonged intubation of mechanically ventilated patients after cardiac surgery: a randomized trial. Ann Intern Med 2011;154:373–383. |
| 65. | Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347–354. |
| 66. | Determann RM, Royakkers A, Wolthuis EK, Vlaar AP, Choi G, Paulus F, Hofstra JJ, de Graaff MJ, Korevaar JC, Schultz MJ. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care 2010;14:R1. |
| 67. | Li G, Malinchoc M, Cartin-Ceba R, Venkata CV, Kor DJ, Peters SG, Hubmayr RD, Gajic O. Eight-year trend of acute respiratory distress syndrome: a population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med 2011;183:59–66. |
| 68. | Serpa Neto A, Cardoso SO, Manetta JA, Pereira VG, Espósito DC, Pasqualucci MdeO, Damasceno MC, Schultz MJ. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA 2012;308:1651–1659. |
| 69. | Neto AS, Simonis FD, Barbas CS, Biehl M, Determann RM, Elmer J, Friedman G, Gajic O, Goldstein JN, Linko R, et al.; PROtective Ventilation Network Investigators. Lung-protective ventilation with low tidal volumes and the occurrence of pulmonary complications in patients without acute respiratory distress syndrome: a systematic review and individual patient data analysis. Crit Care Med 2015;43:2155–2163. |
| 70. | Ogbu OC, Martin GS, Sevransky JE, Murphy DJ. High tidal volumes are independently associated with development of a ventilator-associated condition in the ICU [abstract]. Am J Respir Crit Care Med 2015;191:A3117. |
| 71. | Mekontso Dessap A, Katsahian S, Roche-Campo F, Varet H, Kouatchet A, Tomicic V, Beduneau G, Sonneville R, Jaber S, Darmon M, et al. Ventilator-associated pneumonia during weaning from mechanical ventilation: role of fluid management. Chest 2014;146:58–65. |
| 72. | Schuller D, Mitchell JP, Calandrino FS, Schuster DP. Fluid balance during pulmonary edema: is fluid gain a marker or a cause of poor outcome? Chest 1991;100:1068–1075. |
| 73. | Murphy CV, Schramm GE, Doherty JA, Reichley RM, Gajic O, Afessa B, Micek ST, Kollef MH. The importance of fluid management in acute lung injury secondary to septic shock. Chest 2009;136:102–109. |
| 74. | Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011;39:259–265. |
| 75. | Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D; Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34:344–353. |
| 76. | Mitchell JP, Schuller D, Calandrino FS, Schuster DP. Improved outcome based on fluid management in critically ill patients requiring pulmonary artery catheterization. Am Rev Respir Dis 1992;145:990–998. |
| 77. | Jia X, Malhotra A, Saeed M, Mark RG, Talmor D. Risk factors for ARDS in patients receiving mechanical ventilation for > 48 h. Chest 2008;133:853–861. |
| 78. | Richardson JD, Woods D, Johanson WG Jr, Trinkle JK. Lung bacterial clearance following pulmonary contusion. Surgery 1979;86:730–735. |
| 79. | Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564–2575. |
| 80. | Mekontso Dessap A, Roche-Campo F, Kouatchet A, Tomicic V, Beduneau G, Sonneville R, Cabello B, Jaber S, Azoulay E, Castanares-Zapatero D, et al. Natriuretic peptide–driven fluid management during ventilator weaning: a randomized controlled trial. Am J Respir Crit Care Med 2012;186:1256–1263. |
| 81. | Grissom CK, Hirshberg EL, Dickerson JB, Brown SM, Lanspa MJ, Liu KD, Schoenfeld D, Tidswell M, Hite RD, Rock P, et al.; National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network. Fluid management with a simplified conservative protocol for the acute respiratory distress syndrome. Crit Care Med 2015;43:288–295. |
| 82. | Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, Localio AR, Demissie E, Hopkins RO, Angus DC. The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 2012;185:1307–1315. |
| 83. | Gajic O, Rana R, Mendez JL, Rickman OB, Lymp JF, Hubmayr RD, Moore SB. Acute lung injury after blood transfusion in mechanically ventilated patients. Transfusion 2004;44:1468–1474. |
| 84. | Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, Rana R, St Sauver JL, Lymp JF, Afessa B, et al. Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 2004;32:1817–1824. |
| 85. | Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes: a meta-analysis and systematic review. Am J Med 2014;127:124–131.e3. |
| 86. | Rohde JM, Dimcheff DE, Blumberg N, Saint S, Langa KM, Kuhn L, Hickner A, Rogers MA. Health care–associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA 2014;311:1317–1326. |
| 87. | Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E; Transfusion Requirements in Critical Care Investigators; Canadian Critical Care Trials Group. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409–417. |
| 88. | Lacroix J, Hébert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, Gauvin F, Collet JP, Toledano BJ, Robillard P, et al.; TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators Network. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007;356:1609–1619. |
| 89. | Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, Fukushima J, Kalil Filho R, Sierra DB, Lopes NH, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA 2010;304:1559–1567. |
| 90. | Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil C, Graupera I, Poca M, Alvarez-Urturi C, Gordillo J, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368:11–21. |
| 91. | Walsh TS, Boyd JA, Watson D, Hope D, Lewis S, Krishan A, Forbes JF, Ramsay P, Pearse R, Wallis C, et al.; RELIEVE Investigators. Restrictive versus liberal transfusion strategies for older mechanically ventilated critically ill patients: a randomized pilot trial. Crit Care Med 2013;41:2354–2363. |
| 92. | Murphy GJ, Pike K, Rogers CA, Wordsworth S, Stokes EA, Angelini GD, Reeves BC; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015;372:997–1008. |
| 93. | Klompas M, Speck K, Howell MD, Greene LR, Berenholtz SM. Reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation: systematic review and meta-analysis. JAMA Intern Med 2014;174:751–761. |
| 94. | Price R, MacLennan G, Glen J; SuDDICU Collaboration. Selective digestive or oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of death in general intensive care: systematic review and network meta-analysis. BMJ 2014;348:g2197. |
| 95. | Roquilly A, Marret E, Abraham E, Asehnoune K. Pneumonia prevention to decrease mortality in intensive care unit: a systematic review and meta-analysis. Clin Infect Dis 2015;60:64–75. |
| 96. | Caroff DA, Li L, Muscedere J, Klompas M. Subglottic secretion drainage and objective outcomes: systematic review and meta-analysis. Crit Care Med (In press) |
| 97. | Damas P, Frippiat F, Ancion A, Canivet JL, Lambermont B, Layios N, Massion P, Morimont P, Nys M, Piret S, et al. Prevention of ventilator-associated pneumonia and ventilator-associated conditions: a randomized controlled trial with subglottic secretion suctioning. Crit Care Med 2015;43:22–30. |
| 98. | Krein SL, Fowler KE, Ratz D, Meddings J, Saint S. Preventing device-associated infections in US hospitals: national surveys from 2005 to 2013. BMJ Qual Saf 2015;24:385–392. |
| 99. | Kollef MH. Ventilator-associated pneumonia: a multivariate analysis. JAMA 1993;270:1965–1970. |
| 100. | Drakulovic MB, Torres A, Bauer TT, Nicolas JM, Nogué S, Ferrer M. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet 1999;354:1851–1858. |
| 101. | Keeley L. Reducing the risk of ventilator-acquired pneumonia through head of bed elevation. Nurs Crit Care 2007;12:287–294. |
| 102. | van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, Joore HC, van Schijndel RJ, van der Tweel I, Ramsay G, Bonten MJ. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit Care Med 2006;34:396–402. |
| 103. | Balonov K, Miller AD, Lisbon A, Kaynar AM. A novel method of continuous measurement of head of bed elevation in ventilated patients. Intensive Care Med 2007;33:1050–1054. |
| 104. | Grap MJ, Munro CL, Hummel RS III, Elswick RK Jr, McKinney JL, Sessler CN. Effect of backrest elevation on the development of ventilator-associated pneumonia. Am J Crit Care 2005;14:325–332, quiz 333. |
| 105. | Rose L, Baldwin I, Crawford T, Parke R. Semirecumbent positioning in ventilator-dependent patients: a multicenter, observational study. Am J Crit Care 2010;19:e100–e108. |
| 106. | Panigada M, Berra L, Greco G, Stylianou M, Kolobow T. Bacterial colonization of the respiratory tract following tracheal intubation-effect of gravity: an experimental study. Crit Care Med 2003;31:729–737. |
| 107. | Mauri T, Berra L, Kumwilaisak K, Pivi S, Ufberg JW, Kueppers F, Pesenti A, Bigatello LM. Lateral–horizontal patient position and horizontal orientation of the endotracheal tube to prevent aspiration in adult surgical intensive care unit patients: a feasibility study. Respir Care 2010;55:294–302. |
| 108. | Morandi A, Brummel NE, Ely EW. Sedation, delirium and mechanical ventilation: the “ABCDE” approach. Curr Opin Crit Care 2011;17:43–49. |
| 109. | Halpern SD, Becker D, Curtis JR, Fowler R, Hyzy R, Kaplan LJ, Rawat N, Sessler CN, Wunsch H, Kahn JM; Choosing Wisely Taskforce; American Thoracic Society; American Association of Critical-Care Nurses; Society of Critical Care Medicine. An official American Thoracic Society/American Association of Critical-Care Nurses/American College of Chest Physicians/Society of Critical Care Medicine policy statement: the Choosing Wisely top 5 list in critical care medicine. Am J Respir Crit Care Med 2014;190:818–826. |
| 110. | Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM, et al.; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263–306. |
| 111. | Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al.; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637. |
| 112. | Klompas M, Branson R, Eichenwald EC, Greene LR, Howell MD, Lee G, Magill SS, Maragakis LL, Priebe GP, Speck K, et al.; Society for Healthcare Epidemiology of America (SHEA). Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35:915–936. |
| 113. | Shorr AF, Zilberberg MD. Nature (and the ICU) abhors a VACuum. Chest 2012;142:1365–1366. |
| 114. | Lilly CM, Ellison RT III. Quality measures for critically ill patients: where does ventilator-associated condition fit in? Chest 2013;144:1429–1430. |
| 115. | Niederman MS, Nair GB. Managing ventilator complications in a “VACuum” of data. Chest 2015;147:5–6. |
| 116. | Wunderink RG. Ventilator-associated complications, ventilator-associated pneumonia, and Newton’s third law of mechanics. Am J Respir Crit Care Med 2014;189:882–883. |
| 117. | Nussenblatt V, Avdic E, Berenholtz S, Daugherty E, Hadhazy E, Lipsett PA, Maragakis LL, Perl TM, Speck K, Swoboda SM, et al. Ventilator-associated pneumonia: overdiagnosis and treatment are common in medical and surgical intensive care units. Infect Control Hosp Epidemiol 2014;35:278–284. |
| 118. | Mann T, Ellsworth J, Huda N, Neelakanta A, Chevalier T, Sims KL, Dhar S, Robinson ME, Kaye KS. Building and validating a computerized algorithm for surveillance of ventilator-associated events. Infect Control Hosp Epidemiol 2015;36:999–1003. |
| 119. | Drees M, Brown J, Gillin T, Protokowicz N, Fagraeus L, Pranchisin TL, Booker B, Domroski G, Emberger J, Maheshwari V, et al. Optimization of PEEP as a strategy to reduce ventilator-associated events. Presented at IDWeek 2014. October 8–12, 2014, Philadelphia, PA. Abstract 884. |
Supported by the Centers for Disease Control and Prevention.
CME will be available for this article at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201506-1161CI on September 23, 2015
Author disclosures are available with the text of this article at www.atsjournals.org.
