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Ventilator-Associated Eventsandtheir Prevention: Noelle M. Cocoros,, Michael Klompas
Ventilator-Associated Eventsandtheir Prevention: Noelle M. Cocoros,, Michael Klompas
KEYWORDS
Ventilator-associated events Ventilator-associated pneumonia
Mechanical ventilation Quality improvement Infection control Prevention
KEY POINTS
Surveillance definitions for ventilator-associated events (VAEs) were designed to increase
the objectivity, breadth, and reproducibility of adverse event surveillance in mechanically
ventilated patients.
The most common conditions that trigger VAEs include pneumonia, fluid overload, acute
respiratory distress syndrome (ARDS), and atelectasis.
Promising strategies to prevent VAEs include minimizing sedation, enhancing the perfor-
mance of paired daily spontaneous awakening trials (SATs) and spontaneous breathing
trials (SBTs), promoting early mobility, setting low tidal volume ventilation, using intrave-
nous fluids conservatively after resuscitation, and implementing restrictive transfusion
thresholds.
INTRODUCTION
Up to 800,000 patients per year receive mechanical ventilation in the United States.1,2
This procedure can be lifesaving for patients with acute respiratory failure but also in-
creases risk for multiple adverse events, some of which can culminate in death. Some
of these complications are directly caused by mechanical ventilation, others only indi-
rectly. The objective of this article is to review current literature on the epidemiology,
outcomes, risk factors, and prevention strategies for VAEs, including pneumonia. This
article focuses on the adult patient population but also briefly describes relevant work
in pediatric and neonatal populations.
Conflicts of Interest: N. Cocoros and M. Klompas have received grant funding from the Agency
for Healthcare Research and Quality (Grant # 1R18HS021636) and the Centers for Disease Con-
trol and Prevention (Grant # 1U54CK000172) for research on ventilator-associated events.
a
Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical
School, 401 Park Street, Suite 401, Boston, MA 02215, USA; b Department of Medicine, Brigham
and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
* Corresponding author. Department of Population Medicine, 401 Park Street, Suite 401, Bos-
ton, MA 02215.
E-mail address: mklompas@partners.org
Mechanically ven lated pa ent with ≥2 d of stable or improving daily minimum PEEP or FiO2
followed by Criterion 1 or 2 for ≥2 d
Within 2 d of mee ng the criteria for IVAC, pa ent meets one of the
following criteria are met
adult VAE surveillance definitions. The core definition in the VAE set is called a
ventilator-associated condition (VAC). VAC is designed to detect respiratory deterio-
ration after a period of stability or improvement. To be eligible for a VAE, a patient
must first demonstrate at least 2 days of stable or improving ventilator settings,
namely the daily minimum fraction of inspired oxygen (FIO2) or positive end-
expiratory pressure (PEEP). If a patient subsequently requires an increase in the daily
minimum FIO2 by greater than or equal to 0.20 or an increase in the daily minimum
PEEP by greater than or equal to 3 cm H2O, and the increase is sustained for at least
2 calendar days relative to both baseline days, then the patient meets VAC criteria
and has a VAE. There are then additional criteria to identify the subset of VACs
that may be attributable to infection and the subset of those that might be due to
pneumonia. An infection-related ventilator-associated complication (IVAC) occurs
in a patient with VAC who has concurrent inflammatory changes (abnormal white
blood cell count or temperature) and a treatment course adjustment (at least
4 days of new antimicrobials starting within 2 days of the VAC). Both VAC and
IVAC intentionally capture pulmonary and nonpulmonary complications.5 The last
surveillance tier of the VAE definition set identifies the subset of IVACs that are
possible VAPs (PVAPs). This final tier is flagged by a case of IVAC with positive res-
piratory cultures.
overload, ARDS, and atelectasis were the most common conditions that triggered
VAEs.13,20,24,27,28,31 Pneumonia and respiratory infections accounted for approxi-
mately 25% to 40% of cases, pulmonary edema and/or fluid overload for 20% to
40% of cases, atelectasis for 10% to 15%, and ARDS for 10% to 20%. The proportion
of cases with no identified trigger ranged from 6% to 41%.13,20,27 Prospective studies
were more apt to identify causes for VAEs compared with retrospective studies. Hay-
ashi and colleagues27 found that although more than 30% of VAC patients did not
have a particular diagnosis documented in the chart at the time of VAE, many of these
were functionally treated for presumed respiratory infections and/or pulmonary edema
with antibiotics and/or furosemide.
Note that some of the studies reported here did not apply the current specific VAE definitions (CDC, 2016).
Abbreviations: HR, hazard ratio; LOS, length of stay; vent, ventilator.
a
Outcomes are among those with a VAC compared with matched patients without a VAC; ventilator duration and hospital/ICU LOS results are among survivors
only.13
b
Outcomes are among those with a VAC compared with matched patients without a VAC.9
c
Comparisons are among patients with and without a VAE.26
d
Outcomes are among those with a VAC compared with matched patients without a VAC.27
e
Multivariable time-averaged subdistribution HR, taking into account competing events.20
f
Cause-specific HR, taking into account competing events.20
g
Outcomes are among those with a VAE compared with matched patients without a VAE.25
h
Outcomes are among those with a VAE compared with patients without a VAE.11,24
i
Outcomes are among those with a VAE compared with patients without VAC or NHSN VAP.106
j
VAE compared with patients without VAC or NHSN VAP, adjusted for acuity and ICU type.106
893
894
Cocoros & Klompas
Table 2
Clinical triggers identified among adult patients with ventilator-associated events
Totals per study do not equal 100% because multiple triggers could be identified and reported per VAC event.
Abbreviations: TACO, transfusion-associated circulatory overload; TRALI, transfusion-related acute lung injury.
Ventilator-Associated Events and Their Prevention 895
association between higher tidal volumes and VAEs observed in this study is consis-
tent with the observation that approximately 10% to 20% of VAEs are caused by
ARDS; higher tidal volumes have previously been shown to be an independent risk
factor for acute lung injury risk and ARDS.33,34
Klompas and colleagues35 analyzed 9603 consecutive episodes of mechanical
ventilation in one large academic hospital to measure associations between different
kinds of sedatives and VAEs. The analysis took into account the day-to-day patterns
of sedative exposures for each patient. The investigators found that benzodiazepines
and propofol were associated with an increased risk for VAEs whereas dexmedetomi-
dine was not. They also found that propofol and dexmedetomidine were associated
with less time to extubation compared with benzodiazepines and that dexmedetomi-
dine was associated with less time to extubation compared with propofol.
Bouadma and colleagues30 noted that patient transport was associated with 17% of
VAEs in their multicenter retrospective dataset of 2331 cases. Nakahashi and col-
leagues28 identified 4 care-related variables (as opposed to host-related variables)
associated with VAEs among 3122 patients admitted to a Japanese ICU: absence
of intensivist participation in managing ventilated patients, the use of higher ventilator
driving pressures, development of edema, and higher body weight increases.
Because only a small proportion of VAEs are attributable to pneumonia, standard VAP
prevention bundles may not be the optimal strategy to reduce VAE rates. A logical
framework for preventing VAEs is to select interventions that decrease duration of me-
chanical ventilation (and hence time at risk for VAEs) and/or prevent 1 or more of the ma-
jor conditions associated with VAEs (pneumonia, fluid overload, atelectasis, and
ARDS).36 Using this framework, 6 interventions have been proposed to prevent
VAEs: minimize sedation, enhance the performance of daily paired SATs and SABs,
mobilize patients, use conservative fluid management, ventilate patients with low tidal
volumes, and set restrictive thresholds for blood transfusions (Fig. 2).37 There are likely
additional institution-specific strategies to improve care for ventilated patients that
could be identified by conducting root cause analyses of individual VAEs.24,30 The
following discussion focuses, however, on the evidence in favor of these 6 core
interventions.
Minimize Sedation
Deep and prolonged sedation is associated with numerous adverse events, including
increased mortality, prolonged mechanical ventilation, and higher risk for VAEs.38–40
Deep and/or sustained sedation may trigger VAEs by prolonging time on mechanical
ventilation, increasing the need for mandatory modes of mechanical ventilation (which
in turn may increase the risk of lung injury), decreasing clearance of respiratory secre-
tions, and increasing the risk of atelectasis and aspiration.41 Collectively, these effects
predispose patients to pneumonia, atelectasis, and/or ARDS, 3 of the 4 clinical condi-
tions most commonly associated with VAEs.
Because sedation is associated with ICU-acquired infection — via several potential
mechanisms —short-acting sedatives and opioids have been recommended to
decrease time on the ventilator and time in the ICU.42,43 The short-acting sedatives
propofol and dexmedetomidine have been associated with less time to extubation
compared with benzodiazepines, and dexmedetomidine has been associated with
lower risk for VAEs. Conversely benzodiazepines, opioids, and paralytics have been
associated with increased risk for IVACs.32,35
896 Cocoros & Klompas
Pneumonia
DuraƟon of
VenƟlaƟon
Atelectasis
studies alone and/or inconsistent evidence
Overload
ARDS
from randomized controlled trials)
Fluid
Probable (evidence from randomized
controlled trials and/or meta-analyses)
Minimize sedaƟon
Early mobility
Fig. 2. Potential strategies to prevent VAEs. Interventions that decrease duration of me-
chanical ventilation and target 1 or more of the conditions that most commonly trigger
VAEs are highlighted. (Reprinted from Klompas M. Potential strategies to prevent
ventilator-associated events. Am J Respir Crit Care Med 2015;192(12):1420–30; with permis-
sionof the American Thoracic Society.)
The patients randomized to sedative interruptions in this trial, however, were paradox-
ically given more boluses and higher daily doses of midazolam and fentanyl compared
with patients managed by protocol alone. Presumably this reflected a persistent cul-
ture of sedation wherein patients who became agitated during sedative interruptions
were reflexively managed with more sedation rather than trying to manage their agita-
tion using nonsedating strategies.
management versus usual practice during the weaning phase of mechanical ventila-
tion. Conservative fluid management in this trial was driven by daily measurements
of B-type natriuretic peptide (BNP). Patients randomized to daily BNP levels were
administered less fluids and more diuretics and had greater negative fluid balances
compared with patients in the usual practice arm. Conservative fluid management
was associated with more ventilator-free days and substantially lower VAE rates.
There were 52% fewer VAEs in the intervention group compared with usual care
group.
What remains to be seen is how conservative fluid management is best operation-
alized. Wiedemann and colleagues67 used a complex protocol that included invasive
monitoring devices and a complicated management algorithm whereas Mekontso
Dessap and colleagues65 used daily BNP levels. Neither of these approaches is
optimal: invasive monitoring devices can be harmful, overly complex protocols are
difficult to generalize and error-prone, and daily BNP levels can be expensive and
challenging to interpret in patients with renal impairment. Additional approaches are
required. Possibilities include daily weight monitoring, noninvasive ultrasound mea-
surements, or simplified protocols for interpreting common physiologic data.69
Work in this area is ongoing.
with chlorhexidine and lower VAP rates in non–cardiac surgery patients and note that
there may be a signal toward higher mortality rates in patients randomized to chlorhex-
idine.77,78 The mechanism of increased mortality risk is unknown but 1 possible expla-
nation may be occasional episodes of aspiration of antiseptic precipitating ARDS.79–82
Note that the concern with oral care with chlorhexidine is specifically with the chlor-
hexidine component of the regimen. Oral care alone still seems reasonable for patient
hygiene and comfort. Few studies have rigorously assessed the impact of oral care
alone without an antiseptic on VAP and other outcomes but in contrast to chlorhexi-
dine there is no suggestion of a safety signal.83–85
An area of ongoing controversy is whether selective digestive decontamination with
a combination of oral and parenteral antibiotics can be helpful for patients. A series of
large randomized controlled trials have suggested that this strategy may not only pre-
vent VAP but also lower mortality rates.86–88 The practice is controversial, however,
due to fear that prescribing antibiotics for all ICU patients or all ventilated patients
may cultivate and promote multidrug resistant organisms that might ultimately
compromise the care of future ICU patients.89 The literature on the long-term impact
of selective digestive decontamination on ICU resistance rates and patient outcomes
is still in its infancy but studies thus far have not clearly confirmed enhanced risk.90–92
Some studies suggest that digestive decontamination may paradoxically lower overall
antibiotic dispensing, presumably by averting some infections. More data are needed,
particularly in settings with high baseline antibiotic resistance rates. Many hospitals in
Europe routinely practice selective digestive decontamination but it is almost never
practiced in North America.
One additional practice commonly advocated to prevent VAP is the use of endotra-
cheal tubes with subglottic secretion drainage. These devices are designed to mini-
mize the pooling of secretions above the endotracheal tube cuff and hence diminish
the volume of microbe-laden secretions seeping around the cuff and into the lungs.
Early meta-analyses of this strategy suggested both lower VAP rates and shorter du-
rations of mechanical ventilation leading to a recommendation in favor of subglottic
secretion drainage in VAP prevention guidelines.72,93–96 These analyses were based
on a possible misinterpretation of 1 key trial, however, that was responsible for
much of the signal toward better objective outcomes.97 An updated meta-analysis
that excluded this trial failed to find any improvements in duration of mechanical venti-
lation, ICU length of stay, or mortality.98
clinicians. They reported incidence rates of approximately 3 per 1000 ventilator days in
the PICU, neonatal ICU, and cardiac ICU (CICU). They also reported substantial
increased risk of hospital mortality, increased hospital and ICU lengths of stay, and
longer ventilation duration among children with a VAC compared with matched patients
without a VAC across all ICU types. The need for a VAC definition tailored to the “het-
erogeneous” pediatric population has received support, but validation and replication
in other studies is needed.101 It also remains to be seen whether the IVAC and PVAP
constructs for adult VAE surveillance are applicable to neonates and children, although
1 study suggests that the specific adult criteria, in particular reliance on temperature
and WBC count thresholds, are not appropriate in pediatric patients.100
Risk factors for VAEs in pediatric and adult populations may differ, requiring new an-
alyses and perhaps different approaches for prevention in neonates and children. Pre-
liminary work has indicated that weaning from sedation may have a protective
relationship with pediatric VAC occurrence across all ICU types and that excess fluid
balance in PICU/CICU patients, and use of neuromuscular blockade in all ICUs, may
be positively associated with pediatric VAC.102
The introduction of VAE definitions has been controversial among some stakeholders.
The most common criticisms of VAE definitions are as follows: (1) VAE surveillance is
neither sensitive nor specific for clinically defined VAP, (2) clinicians can avoid VAE
detection by manipulating ventilator settings, and (3) VAEs are simply markers of se-
vere underlying illness and not preventable complications.
Numerous studies have documented poor correlation between VAE and
VAP.13,20,26,103,104 The first study that proposed VAE criteria documented that only
23% of VAEs met NHSN’s then-current VAP criteria and only 56% of NHSN VAPs
met VAE criteria. Subsequent studies documented similar positive predictive values
(20%–40%) and sensitivities (40%–60%) for VAE relative to clinically defined VAP.
The poor correlation between VAE and VAP bespeaks 2 issues. The first is that VAE
definitions were intentionally designed to broaden the scope of surveillance to include
additional complications of mechanical ventilation over and above pneumonia.105 The
definitions are intended to flag any deleterious event that leads to respiratory deterio-
ration, including fluid overload, atelectasis, ARDS, pulmonary embolism, pneumo-
thorax, and so forth. It is, therefore, expected and arguably desirable that only a
fraction of VAEs are attributable to pneumonia. The second issue is that VAE defini-
tions were developed to support quality improvement at the population level rather
than to support real-time clinical diagnoses. VAE definitions, therefore, favor objectiv-
ity and morbidity over sensitivity. The VAE minimum change values for PEEP and FIO2
exert a threshold effect that simultaneously makes surveillance more objective
(because it is based on quantitative, clearly defined data elements) and limits case
detection to serious events (only events severe enough to require sustained increases
in ventilator settings at or above the VAE minimums are detected). VAE criteria miss
pneumonias that do not require sustained increases in patients’ ventilator settings,
but in doing so they help sidestep arguments about ambiguous cases based on sub-
jective criteria and focus quality-improvement workers’ efforts on preventing the most
morbid cases. VAE surveillance is not intended to detect every single possible case of
pneumonia but rather to help hospitals to develop comprehensive VAE prevention
programs to prevent as many complications as possible. Interventions put into place
to prevent the severe pneumonias that flag VAE criteria are also likely to prevent milder
pneumonias that would not flag VAE criteria.
Ventilator-Associated Events and Their Prevention 901
VAE definitions have also been criticized for being subject to manipulation and
gaming that can prevent VAE detection. Lilly and colleagues,106 for example, modeled
the effect of alternately increasing and then decreasing the daily minimum PEEP by
1 cm H2O each day. They anticipated that this strategy would eliminate 93% of
VAEs. It is questionable, however, whether any hospital would tolerate, much less
endorse, a deliberate ventilator-management strategy designed solely to avoid VAE
detection. There is no clinical rationale for alternately raising and lowering PEEP by
1 cm H2O each day. Anyone embarking on manipulation of this nature is doing so
purely to avoid VAE detection. Presumably this activity would, therefore, risk investi-
gation and sanction if discovered. This is a different problem from the longstanding
concern with NHSN’s old VAP definitions that hospitals might report progressively
lower rates over time attributable to surveillance bias rather than true decreases in
VAP.107 The concern with the old definitions was that thoughtful and sincere surveyors
might interpret subjective VAP criteria (“change in character of sputum,” “new or pro-
gressive infiltrates,” “worsening oxygenation,” and so forth) more strictly over time,
leading to artefactual decreases in VAP rates. The difference is that interpreting sub-
jective criteria more strictly could reasonably be subconscious or part of a well-
intentioned effort to make surveillance more rigorous. Manipulating ventilator settings
solely to avoid VAE detection by contrast is deliberate and intended to deceive.
Finally, some investigators have argued that VAEs are simply surveillance markers
of severe illness rather than preventable complications of care.31,106,108–110 Boyer and
colleagues,24 for example, reviewed the charts of all VAEs accrued over the course of
a year in the medical and surgical ICUs of a large academic hospital. They estimated
that only 37% of the VAEs were potentially preventable. Although it is likely true that
some VAEs are due to unavoidable increases in ventilator settings in patients with se-
vere and progressive pulmonary disease, a growing body of observational and inter-
ventional studies suggests that a large fraction of VAEs are preventable. First of all,
VAEs by definition can only occur in a patient after at least 2 days of stable or
improving ventilator settings. This limits VAE detection to patients with nosocomial
onset of deterioration after at least 2 days of being on a ventilator. Observational
studies suggest that VAEs are complications insofar as patients who develop VAEs
suffer worse outcomes compared with matched patients without VAEs. The observa-
tional studies also suggest that most VAEs are triggered by clear clinical complica-
tions, such as pneumonia, fluid overload, ARDS, and atelectasis. Interventional
studies extend these observations by demonstrating that improvements in care,
such as enhanced performance of SATs and SBTs or conservative fluid management,
can individually lower VAE rates by 37% to 52%.40,48,65 It remains to be seen how
many VAEs might be preventable by bundling these interventions together with mini-
mizing sedation, early mobility programs, low tidal volume ventilation, and conserva-
tive transfusion thresholds.
SUMMARY
with patients without VAEs. Excess fluid balance, deeper levels of sedation, prolonged
sedation, and high tidal volumes are risk factors for VAEs. The most common and
consistent complications that trigger VAE criteria are pneumonia, pulmonary edema,
ARDS, and atelectasis. Interventional studies suggest that conservative fluid manage-
ment and enhancing the performance of SATs and SBTs can prevent VAEs.
A strategic framework for preventing VAEs is to bundle together interventions that
minimize duration of mechanical ventilation and prevent 1 or more of the clinical con-
ditions that most frequently trigger VAEs. Promising candidates for a VAE prevention
bundle, therefore, include minimizing sedation, paired daily SATs and SBTs, early
exercise and mobility, low tidal volume ventilation, conservative fluid management,
and conservative blood transfusion thresholds. To date, no study has evaluated the
potential impact of bundling all of all these interventions into a single comprehensive
VAE prevention set. We therefore still do not have a clear sense of the preventable
fraction of VAEs and to what extent a comprehensive VAE prevention program can
improve global outcomes for ventilated patients. Further studies of VAE epidemiology,
risk factors, and prevention are needed to solidify and extend our capacity to predict
and prevent VAEs.
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