JAMA 2012;307:1151-1160

Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α2-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.

Objective
To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients’ interaction with nursing care.

Design, setting, and patients
Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251).

Interventions
Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials.

Main outcome measures
For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients’ ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223).

Results
Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients’ interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001).

Conclusions
Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients’ ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine.

Critical Care 2010, 14:R26

Mechanical ventilation of patients may be accomplished by either translaryngeal intubation or tracheostomy. While numerous ICU studies have compared various outcomes between the two techniques, there is no definitive consensus that tracheostomy is superior. Comparable studies have not been performed in a respiratory care center (RCC) setting.

Methods
This was a retrospective observational study of 985 tracheostomy and 227 translaryngeal intubated patients who received treatment in a 24-bed RCC between November 1999 and December 2005. Treatment and mortality outcomes were compared between tracheostomized and translaryngeal intubated patients, and the factors associated with positive outcomes in all patients were determined.

Results
Duration of RCC (22 vs. 14 days) and total hospital stay (82 vs. 64 days) and total mechanical ventilation days (53 vs. 41 days) were significantly longer in tracheostomized patients (all P<0.05). The rate of in-hospital mortality was significantly higher in the translaryngeal group (45% vs. 31%, P<0.05). There were no significant differences in weaning success between the groups (both were over 55%), nor RCC mortality. Due to significant baseline between group heterogeneity, case match analysis was performed. This analysis confirmed the whole cohort findings, except for the fact that there was only a trend for in-hospital mortality to be higher in the translaryngeal group (P=0.08). Stepwise logistic regression revealed that patients with a lower median severity of disease (APACHE II score <18) who were properly nourished (albumin >2.5 g/dL) or had normal metabolism (BUN <40 mg/dL) were more likely to be successfully weaned and survive (all P<0.05). Patients who were tracheostomized were also significantly more likely to survive (P<0.05)

Conclusions
These findings suggest that the type of mechanical ventilation does not appear to be an important determinant of weaning success in an RCC setting. Focused care administered by experienced providers may be more important for facilitating weaning success than the ventilation method used. However, our findings do suggest that tracheostomy may increase the likelihood of patient survival.

The Lancet 2010;375:475-480

Standard treatment of critically ill patients undergoing mechanical ventilation is continuous sedation. Daily interruption of sedation has a benefi cial eff ect, and in the general intesive care unit of Odense University Hospital, Denmark, standard practice is a protocol of no sedation. We aimed to establish whether duration of mechanical ventilation could be reduced with a protocol of no sedation versus daily interruption of sedation.

Methods
Of 428 patients assessed for eligibility, we enrolled 140 critically ill adult patients who were undergoing mechanical ventilation and were expected to need ventilation for more than 24 h. Patients were randomly assigned in a 1:1 ratio (unblinded) to receive: no sedation (n=70 patients); or sedation (20 mg/mL propofol for 48 h, 1 mg/mL midazolam thereafter) with daily interruption until awake (n=70, control group). Both groups were treated with bolus doses of morphine (2·5 or 5 mg). The primary outcome was the number of days without mechanical ventilation in a 28-day period, and we also recorded the length of stay in the intensive care unit (from admission to 28 days) and in hospital (from admission to 90 days). Analysis was by intention to treat.

Findings
27 patients died or were successfully extubated within 48 h, and, as per our study design, were excluded from the study and statistical analysis. Patients receiving no sedation had signifi cantly more days without ventilation (n=55; mean 13·8 days, SD 11·0) than did those receiving interrupted sedation (n=58; mean 9·6 days, SD 10·0; mean diff erence 4·2 days, 95% CI 0·3–8·1; p=0·0191). No sedation was also associated with a shorter stay in the intensive care unit (HR 1·86, 95% CI 1·05–3·23; p=0·0316), and, for the fi rst 30 days studied, in hospital (3·57, 1·52–9·09; p=0·0039), than was interrupted sedation. No diff erence was recorded in the occurrences of accidental extubations, the need for CT or MRI brain scans, or ventilator-associated pneumonia. Agi tat ed delirium was more frequent in the intervention group than in the control group (n=11, 20% vs n=4, 7%; p=0·0400).

Interpretation
No sedation of critically ill patients receiving mechanical ventilation is associated with an increase in days without ventilation. A multicentre study is needed to establish whether this eff ect can be reproduced in other facilities.

Crit Care Med 2010;38:288-291

To develop and validate an equation to predict dead space to tidal volume ratio (Vd/Vt) from clinically available data in critically ill mechanically ventilated patients.

Design
Prospective, observational study using a convenience sample of patients whose arterial blood gas and respiratory gas exchange had been measured with indirect calorimetry.

Setting
Medical and surgical critical care units of a university medical center.

Patients
Adult, mechanically ventilated patients at rest with Fio2 ≤0.60 and no air leaks who had recent arterial blood gas recordings and end-tidal carbon dioxide concentration monitoring.

Intervention
Observational only.

Measurements and main results
Indirect calorimetry was used to determine carbon dioxide production and expired minute ventilation in 135 patients. Tidal volume and respiratory rate were recorded from the ventilator. End tidal carbon dioxide concentration, body temperature, arterial carbon dioxide partial pressure (Paco2), and other clinical data were recorded. Vd/Vt was calculated using the Enghoff modification of the Bohr equation (Paco2 − PECO2/Paco2). Regression analysis was then used to construct a predictive equation for Vd/Vt using the clinical data: Vd/Vt = 0.32 + 0.0106 (Paco2 − ETCO2) + 0.003 (RR) + 0.0015 (age) (R2 = 0.67). A second group of 50 patients was measured using the same protocol and their data were used to validate the equations developed from the original 135 patients. The equation was found to be unbiased and precise.

Conclusions
Vd/Vt is predictable from clinically available data. Whether this predicted quantity is valuable clinically must still be determined.

Critical Care 2009, 13:R205

Mortality of severe acute respiratory distress syndrome in adults is still unacceptably high. Extracorporeal membrane oxygenation (ECMO) could represent an important treatment option, if complications were reduced by new technical developments.

Methods
Efficiency, side effects and outcome of treatment with a new miniaturized device for veno-venous extracorporeal gas transfer were analysed in 60 consecutive patients with life-threatening respiratory failure.

Results
A rapid increase of PaO2/FiO2 from 64 (48-86) mmHg to 120 (84-171) mmHg and a decrease of PaCO2 from 63 (50-80) mmHg to 33 (29-39) mmHg were observed after start of the extracorporeal support (p<0.001). Gas exchange capacity of the device averaged 155 (116-182) mL/min for oxygen and 210 (164-251) mL/min for carbon dioxide. Ventilatory parameters were reduced to a highly protective mode, allowing a fast reduction of tidal volume from 495 (401-570) mL to 336 (292-404) mL (p < 0.001) and of peak inspiratory pressure from 36 (32-40) cmH2O to 31 (28-35) cmH2O (p < 0.001). Transfusion requirements averaged 0.8 (0.4-1.8) units of red blood cells per day. 62% of patients were weaned from the extracorporeal system, and 45% survived to discharge.

Conclusions
Veno-venous extracorporeal membrane oxygenation with a new miniaturized device supports gas transfer effectively, allows for highly protective ventilation and is very reliable. Modern ECMO technology extends treatment opportunities in severe lung failure.

Crit Care Med – published ahead of print

To evaluate the predictive value of central venous saturation to detect extubation failure in difficult-to-wean patients.

Design
Cohort, multicentric, clinical study.

Setting
Three medical-surgical intensive care units.

Patients
All difficult-to-wean patients (defined as failure to tolerate the first 2-hr T-tube trial), mechanically ventilated for >48 hrs, were extubated after undergoing a two-step weaning protocol (measurements of predictors followed by a T-tube trial). Extubation failure was defined as the need of reintubation within 48 hrs.

Interventions
The weaning protocol evaluated hemodynamic and ventilation parameters, and arterial and venous gases during mechanical ventilation (immediately before T-tube trial), and at the 30th min of spontaneous breathing trial.

Measurements and main results
Seventy-three patients were enrolled in the study over a 6-mo period. Reintubation rate was 42.5%. Analysis by logistic regression revealed that central venous saturation was the only variable able to discriminate outcome of extubation. Reduction of central venous saturation by >4.5% was an independent predictor of reintubation, with odds ratio of 49.4 (95% confidence interval = 12.1-201.5), a sensitivity of 88%, and a specificity of 95%. Reduction of central venous saturation during spontaneous breathing trial was associated with extubation failure and could reflect the increase of respiratory muscles oxygen consumption.

Conclusions
Central venous saturation was an early and independent predictor of extubation failure and may be a valuable accurate parameter to be included in weaning protocols of difficult-to-wean patients.

QJM 2009 102(6):389-399  http://qjmed.oxfordjournals.org/cgi/content/full/102/6/389

Decisions about the intensity of treatment for patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are influenced by predictions about survival and quality of life. Evidence suggests that these predictions are poorly calibrated and tend to be pessimistic.

Aim
The aim of this study was to develop an outcome prediction model for COPD patients to support treatment decisions.

Methods
A prospective multi-centre cohort study in Intensive Care Units (ICU) and Respiratory High Dependency Units (RHDU) in the UK recruited patients aged 45 years and older admitted with an exacerbation of obstructive lung disease. Data were collected on patientsí characteristics prior to ICU admission, and on their survival and quality of life after 180 days. An outcome prediction model was developed using multivariate logistic regression and bootstrapping.

Results
Ninety-two ICUs (53% of those in the UK) and three RHDUs took part. A total of 832 patients were recruited. Cumulative 180-day mortality was 37.9%. Using data available at the time of admission to the units, a prognostic model was developed which had an estimated area under the receiver operating characteristic curve (ëcí) of 74.7% after bootstrapping that was more discriminating than the clinicians (P = 0.033) and was well calibrated.

Discussion
This study has produced an outcome prediction model with slightly better discrimination and much better calibration than the participating clinicians. It has the potential to support risk adjustment and clinical decision making about admission to intensive care.

Crit Care Med 2009;37:2740-2745

To determine whether high rates of ineffective triggering within the first 24 hrs of mechanical ventilation (MV) are associated with longer MV duration and shorter ventilator-free survival (VFS).

Design
Prospective cohort study.

Setting
Medical intensive care unit (ICU) at an academic medical centre.

Patients
Sixty patients requiring invasive MV.

Interventions
None.

Measurements
Patients had pressure-time and flow-time waveforms recorded for 10 mins within the first 24 hrs of MV initiation. Ineffective triggering index (ITI) was calculated by dividing the number of ineffectively triggered breaths by the total number of breaths (triggered and ineffectively triggered). A priori, patients were classified into ITI >=10% or ITI <10%. Patient demographics, MV reason, codiagnosis of chronic obstructive pulmonary disease (COPD), sedation levels, and ventilator parameters were recorded.

Measurements and main results
Sixteen of 60 patients had ITI >=10%. The two groups had similar characteristics, including COPD frequency and ventilation parameters, except that patients with ITI >=10% were more likely to have pressured triggered breaths (56% vs. 16%, p = .003) and had a higher intrinsic respiratory rate (22 breaths/min vs. 18, p = .03), but the set ventilator rate was the same in both groups (9 breaths/min vs. 9, p = .78). Multivariable analyses adjusting for pressure triggering also demonstrated that ITI >=10% was an independent predictor of longer MV duration (10 days vs. 4, p = .0004) and shorter VFS (14 days vs. 21, p = .03). Patients with ITI >=10% had a longer ICU length of stay (8 days vs. 4, p = .01) and hospital length of stay (21 days vs. 8, p = .03). Mortality was the same in the two groups, but patients with ITI >=10% were less likely to be discharged home (44% vs. 73%, p = .04).

Conclusions
Ineffective triggering is a common problem early in the course of MV and is associated with increased morbidity, including longer MV duration, shorter VFS, longer length of stay, and lower likelihood of home discharge.

Crit Care Med 2009; 37:2709-2718

To determine the attributable mortality of ventilator-associated pneumonia in a systematic review and meta-analysis of observational studies. Ventilator-associated pneumonia is generally believed to increase the mortality of patients. This notion is predominantly based on the results of observational studies.

Data source
We performed a systematic search strategy using PubMed, Web of Science, and Embase from their inception through February 2007. In addition, a reference and related article search was performed.

Study selection
Studies were included if they reported mortality rates of patients with and without ventilator-associated pneumonia.
Data extraction and synthesis
Fifty-two studies with a total of 17,347 patients met the inclusion criteria. Pooling of all studies resulted in relative risk of 1.27 (95% Confidence Interval = 1.15-1.39), but heterogeneity was considerable (I2 statistic = 69%). The origin of heterogeneity could not be explained by differences in study design, study quality, and diagnostic approach. However, heterogeneity was limited for studies investigating only trauma patients (I2 = 1.3%) or patients with acute respiratory distress syndrome (I2 = 0%), with estimated relative risk of 1.09 (95% Confidence Interval = 0.87-1.37) among trauma patients and 0.86 (95% Confidence Interval = 0.72-1.04) among patients with acute respiratory distress syndrome.

Conclusions
There is no evidence of attributable mortality due to ventilator-associated pneumonia in patients with trauma or acute respiratory distress syndrome. However, in other nonspecified patient groups, there is evidence for attributable mortality due to ventilator-associated pneumonia, but this could not be quantified due to heterogeneity in study results. More detailed studies, allowing subgroup analyses, are needed to determine the attributable mortality of ventilator-associated pneumonia in these patient populations.

Crit Care Med 2009; 37:1696-1701

Weaning-induced pulmonary edema is a cause of weaning failure in high-risk patients. The diagnosis may require pulmonary artery catheterization to demonstrate increased pulmonary artery occlusion pressure (PAOP) during weaning. Transthoracic echocardiography can estimate left ventricular filling pressures using early (E) and late (A) peak diastolic velocities measured with Doppler transmitral flow, and tissue Doppler imaging of mitral annulus velocities including early (Ea) peak diastolic velocity. We tested the hypothesis that E/A and E/Ea could be used to detect weaning-induced PAOP elevation defined by a PAOP >=18 mm Hg during a spontaneous breathing trial (SBT).

Measurements and main results
We included 39 patients who previously failed two consecutive SBTs. A third SBT was performed over a maximum 1-hour period using a T-piece. The PAOP, E/A, and E/Ea were measured before and during this SBT. Receiver operating characteristic curves were constructed to determine the optimal sensitivity and specificity values of E/A and E/Ea obtained at the end of the SBT for predicting a weaning-induced PAOP elevation. Weaning-induced PAOP elevation occurred in 17 patients. A value of E/A >0.95 at the end of the SBT predicted weaning-induced PAOP elevation with a sensitivity of 88% and a specificity of 68%. A value of E/Ea >8.5 at the end of the SBT predicted weaning-induced PAOP elevation with a sensitivity of 94% and a specificity of 73%. The combination of E/A >0.95 and E/Ea >8.5 predicted a weaning-induced PAOP elevation with a sensitivity of 82% and a specificity of 91%.

Conclusion
At the end of an SBT, the combination of E/A >0.95 and E/Ea >8.5 measured with transthoracic echocardiography allowed an accurate noninvasive detection of weaning-induced PAOP elevation.

JAMA. 2009;301:489-499

Aminobutyric acid receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the {alpha}2 agonist dexmedetomidine may have distinct advantages.

Objective
To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients.

Design, setting and patients
Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among 375 medical/surgical ICU patients with expected mechanical ventilation for more than 24 hours. Sedation level and delirium were assessed using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the ICU.

Interventions
Dexmedetomidine (0.2-1.4 µg/kg per hour [n = 244]) or midazolam (0.02-0.1 mg/kg per hour [n = 122]) titrated to achieve light sedation (RASS scores between –2 and +1) from enrollment until extubation or 30 days.

Main outcome measures
Percentage of time within target RASS range. Secondary end points included prevalence and duration of delirium, use of fentanyl and open-label midazolam, and nursing assessments. Additional outcomes included duration of mechanical ventilation, ICU length of stay, and adverse events.

Results
There was no difference in percentage of time within the target RASS range (77.3% for dexmedetomidine group vs 75.1% for midazolam group; difference, 2.2% [95% confidence interval {CI}, –3.2% to 7.5%]; P = .18). The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidine-treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, 22.6% [95% CI, 14% to 33%]; P < .001). Median time to extubation was 1.9 days shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6 days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days [95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P = .24). Dexmedetomidine-treated patients were more likely to develop bradycardia (42.2% [103/244] vs 18.9% [23/122]; P < .001), with a nonsignificant increase in the proportion requiring treatment (4.9% [12/244] vs 0.8% [1/122]; P = .07), but had a lower likelihood of tachycardia (25.4% [62/244] vs 44.3% [54/122]; P < .001) or hypertension requiring treatment (18.9% [46/244] vs 29.5% [36/122]; P = .02).

Conclusions
There was no difference between dexmedetomidine and midazolam in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension. The most notable adverse effect of dexmedetomidine was bradycardia.

Critical Care Medicine 2009;37:32-38

To compare the incidence of ventilator-associated pneumonia (VAP) with or without isotonic saline instillation before tracheal suctioning. As a secondary objective, we compared the incidence of endotracheal tube occlusion and atelectasis.

Design
Randomized clinical trial.

Setting and patients
The study was conducted in a medical surgical intensive care unit of an oncologic hospital. We selected consecutive patients needing mechanical ventilation for >72 hrs. Patients were allocated into two groups: a saline group that received instillation of 8 mL of saline before tracheal suctioning and a control group which did not. VAP was diagnosed based on clinical suspicion and confirmed by bronchoalveolar lavage quantitative culture. The incidence of atelectasis on daily chest radiography and endotracheal tube occlusions were recorded. The sample size was calculated to a power of 80% and a type I error probability of 5%.

Measurements and main results
One hundred thirty patients were assigned to the saline group and 132 to the control group. The baseline demographic variables were similar between groups. The rate of clinically suspected VAP was similar in both groups. The incidence of microbiological proven VAP was significantly lower in the saline group (23.5% × 10.8%; p = 0.008) (incidence density/1.000 days of ventilation 21.22 × 9.62; p < 0.01). Using the Kaplan-Meier curve analysis, the proportion of patients remaining without VAP was higher in the saline group (p = 0.02, log-rank test). The relative risk reduction of VAP in the saline instillation group was 54% (95% confidence interval, 18%-74%) and the number needed to treat was eight (95% confidence interval, 5-27). The incidence of atelectases and endotracheal tube occlusion were similar between groups.

Conclusions
Instillation of isotonic saline before tracheal suctioning decreases the incidence of microbiological proven VAP.

Respir Care 2007;52:1710-7

To derive a clinical prediction rule that uses bedside clinical variables to predict extubation failure (reintubation within 48 h) after a successful spontaneous breathing trial.

Methodes
This prospective observational cohort study was performed at the Northwestern Memorial Hospital in Chicago, Illinois, which is a large tertiary-care university hospital. Among 673 consecutive patients who received mechanical ventilation during a 15-month period, 122 were ventilated for at least 2 days and did not undergo withdrawal of support or tracheostomy. These patients were followed after extubation to identify those who were reintubated within 48 h (extubation failure). We used logistic regression analysis to identify variables that predict reintubation, and we used bootstrap resampling to internally validate the predictors and adjust for overoptimism.

Results
Sixteen (13%) of the 122 patients required reintubation within 48 h. Three clinical variables predicted reintubation: moderate to copious endotracheal secretions (p = 0.001), Glasgow Coma Scale score < or =10 (p = 0.004), and hypercapnia PaCO₂ > or = 44 mm Hg) during the spontaneous breathing trial (p = 0.001). Using logistic regression and bootstrap resampling to adjust for overfitting, we derived a clinical prediction rule that combined those 3 clinical variables (area under the receiver operating characteristic curve 0.87, 95% confidence interval 0.74-0.94).

Conclusions
With our clinical prediction rule that incorporates an assessment of mental status, endotracheal secretions, and pre-extubation PaCO₂, clinicians can predict who will fail extubation despite a successful spontaneous breathing trial.

Intensive Care Med 2008:34;1487-1491

We examined the effect on survival of prone positioning as an early and continuous treatment in ARDS patients already treated with protective ventilation.

Design and setting
Open randomized controlled trial in 17 medical-surgical ICUs.

Patients
Forty mechanically ventilated patients with early and refractory ARDS despite protective ventilation in the supine position.
Interventions  Patients were randomized to remain supine or be moved to early (within 48h) and continuous (=20h/day) prone position until recovery or death. The trial was prematurely stopped due to a low patient recruitment rate.

Measurements and results
Clinical characteristics, oxygenation, lung pressures, and hemodynamics were monitored. Need for sedation, complications, length of MV, ICU, and hospital stays, and outcome were recorded. PaO₂/FIO₂ tended to be higher in prone than in supine patients after 6h (202±78 vs. 165±70mmHg); this difference reached statistical significance on day 3 (234±85 vs. 159±78). Prone-related side effects were minimal and reversible. Sixty-day survival reached the targeted 15% absolute increase in prone patients (62% vs. 47%) but failed to reach significance due to the small sample.

Conclusions
Our study adds data that reinforce the suggestion of a beneficial effect of early continuous prone positioning on survival in ARDS patients.

Crit Care Med 2008;36:2753-2762

Objective
Evidence-based practice recommendations abound, but implementation is often unstructured and poorly audited. We assessed the ability of a peer network to implement an evidence-based best practice protocol and to measure patient outcomes.

Design
Consensus definition of spontaneous breathing trial followed by implementation in eight academic medical centers.

Setting
Six medical, two surgical, and two combined medical/surgical adult intensive care units among eight academic medical centers.

Study Population
Patients initiating mechanical ventilation through an endotracheal tube during a 12-wk interval formed the study population.

Interventions
Adoption and implementation of a common spontaneous breathing trial protocol across multiple intensive care units.

Measurements and Main Results
Seven hundred five patients had 3,486 safety screens for conducting a spontaneous breathing trial; 2072 (59%) patients failed the safety screen. Another 379 (11%) patients failed a 2-min tolerance screen and 1,122 (34%) patients had a full 30-120 min spontaneous breathing trial performed. Seventy percent of eligible patients were enrolled. Only 55% of passing spontaneous breathing trials resulted in liberation from mechanical ventilatory support before another spontaneous breathing trial was performed.

Conclusions
Peer networks can be effective in promoting and implementing evidence-based best practices. Implementation of a best practice (spontaneous breathing trial) may be necessary for, but by itself insufficient to achieve, consistent and timely liberation from ventilator support.

Crit Care Med 2008; 36:2547-2557

Tracheostomy is common in intensive care unit patients, but the appropriate timing is controversial.

Objective
To determine whether earlier tracheostomy is associated with greater long-term survival.

Design
Retrospective cohort analysis.

Setting
Acute care hospitals in Ontario, Canada (n = 114).

Patients
All mechanically ventilated intensive care unit patients who received tracheostomy between April 1, 1992 and March 31, 2004, excluding extreme cases (<2 or >=28 days) and children (<18 yrs).

Measurements
For crude analyses, tracheostomy timing was classified as early (<=10 days) vs. late (>10 days) with mortality measured at multiple follow-up intervals. Proportional hazards analyses considered tracheostomy as a time-dependent variable to adjust for measurable confounders and possible survivor treatment bias. We used stratification, propensity score, and instrumental variable analyses to adjust for patient differences.

Results
A total of 10,927 patients received tracheostomy during the study, of which one-third (n = 3758) received early and two-thirds late (n = 7169). Patients receiving early tracheostomy had lower unadjusted 90-day (34.8% vs. 36.9%; p = 0.032), 1 yr (46.5% vs. 49.8%; p = 0.001), and study mortality (63.9% vs. 67.2%; p < 0.001) than patients receiving late tracheostomy. Multivariable analyses treating tracheostomy as a time-dependent variable showed that each additional delay of 1 day was associated with increased mortality (hazard ratio 1.008, 95% confidence interval 1.004-1.012), equivalent to an increase in 90-day mortality from 36.2% to 37.6% per week of delay (relative risk increase 3.9%; number needed to treat, 71 patients to save one life per week delay).

Limitations
This analysis provides guidance regarding timing but not patient selection for tracheostomy.

Conclusions
Physicians performing early tracheostomy should not anticipate a large potential survival benefit. Future research should concentrate on identifying which patients will receive the most benefit

Crit Care Med 2008;36:2225-2231

To analyze the effect on clinical outcomes of prophylactic positive end expiratory pressure in nonhypoxemic ventilated patients.

Design
Multicenter randomized controlled clinical trial.

Setting
One trauma and two general intensive care units in two university hospitals.

Patients
One hundred thirty-one mechanically ventilated patients with normal chest radiograph and Pao2/Fio2 above 250.

Interventions
Patients were randomly allocated to receive mechanical ventilation with 5-8 cm H2O of positive end-expiratory pressure (PEEP) (PEEP group, n = 66) or no-PEEP (control group, n = 65).

Measurements and main results
Primary end-point variable was hospital mortality. Secondary outcomes included microbiologically confirmed ventilator-associated pneumonia, acute respiratory distress syndrome, barotrauma, atelectasis, and hypoxemia (Pao2/Fio2 <175). Both groups were similar at randomization in demographic characteristics, intensive care unit admission diagnoses, severity of illness, and risk factors for ventilator-associated pneumonia. Hospital mortality rate was similar (p = 0.58) between PEEP (29.7%) and control (25.4%) groups. Ventilator-associated pneumonia was detected in 16 (25.4%) patients in the control group and 6 (9.4%) in the PEEP group (relative risk, 0.37; 95% confidence interval = 0.15-0.84; p = 0.017). The number of patients who developed hypoxemia was significantly higher in the control group (34 of 63 patients, 54%) than in the PEEP group (12 of 64, 19%) (p < 0.001), and the hypoxemia developed after a shorter period (median [interquartile range]) in the control group than in the PEEP group (38 [20-70] hrs vs. 77 [32-164] hrs, p < 0.001). Groups did not significantly differ in incidence of acute respiratory distress syndrome (14% in controls vs. 5% in the PEEP group, p = 0.08), barotrauma (8% vs. 2%, respectively, p = 0.12), or atelectasis (27% vs. 19%, respectively, p = 0.26).

Conclusions
These findings indicate that application of prophylactic PEEP in nonhypoxemic ventilated patients reduces the number of hypoxemia episodes and the incidence of ventilator-associated pneumonia.

NEJM 2008;359:142-151

Noninvasive ventilation (continuous positive airway pressure [CPAP] or noninvasive intermittent positive-pressure ventilation [NIPPV]) appears to be of benefit in the immediate treatment of patients with acute cardiogenic pulmonary edema and may reduce mortality. We conducted a study to determine whether noninvasive ventilation reduces mortality and whether there are important differences in outcome associated with the method of treatment (CPAP or NIPPV).

Methods
In a multicenter, open, prospective, randomized, controlled trial, patients were assigned to standard oxygen therapy, CPAP (5 to 15 cm of water), or NIPPV (inspiratory pressure, 8 to 20 cm of water; expiratory pressure, 4 to 10 cm of water). The primary end point for the comparison between noninvasive ventilation and standard oxygen therapy was death within 7 days after the initiation of treatment, and the primary end point for the comparison between NIPPV and CPAP was death or intubation within 7 days.

Results
A total of 1069 patients (mean [±SD] age, 77.7±9.7 years; female sex, 56.9%) were assigned to standard oxygen therapy (367 patients), CPAP (346 patients), or NIPPV (356 patients). There was no significant difference in 7-day mortality between patients receiving standard oxygen therapy (9.8%) and those undergoing noninvasive ventilation (9.5%, P=0.87). There was no significant difference in the combined end point of death or intubation within 7 days between the two groups of patients undergoing noninvasive ventilation (11.7% for CPAP and 11.1% for NIPPV, P=0.81). As compared with standard oxygen therapy, noninvasive ventilation was associated with greater mean improvements at 1 hour after the beginning of treatment in patient-reported dyspnea (treatment difference, 0.7 on a visual-analogue scale ranging from 1 to 10; 95% confidence interval [CI], 0.2 to 1.3; P=0.008), heart rate (treatment difference, 4 beats per minute; 95% CI, 1 to 6; P=0.004), acidosis (treatment difference, pH 0.03; 95% CI, 0.02 to 0.04; P<0.001), and hypercapnia (treatment difference, 0.7 kPa [5.2 mm Hg]; 95% CI, 0.4 to 0.9; P<0.001). There were no treatment-related adverse events.

Conclusions
In patients with acute cardiogenic pulmonary edema, noninvasive ventilation induces a more rapid improvement in respiratory distress and metabolic disturbance than does standard oxygen therapy but has no effect on short-term mortality.

JAMA 2008;299:637-645

Low-tidal-volume ventilation reduces mortality in critically ill patients with acute lung injury and acute respiratory distress syndrome. Instituting additional strategies to open collapsed lung tissue may further reduce mortality.

Objective
To compare an established low-tidal-volume ventilation strategy with an experimental strategy based on the original “open-lung approach,” combining low tidal volume, lung recruitment maneuvers, and high positive-end–expiratory pressure.

Design and setting
Randomized controlled trial with concealed allocation and blinded data analysis conducted between August 2000 and March 2006 in 30 intensive care units in Canada, Australia, and Saudi Arabia.

Patients
Nine hundred eighty-three consecutive patients with acute lung injury and a ratio of arterial oxygen tension to inspired oxygen fraction not exceeding 250.

Interventions
The control strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau airway pressures not exceeding 30 cm H2O, and conventional levels of positive end-expiratory pressure (n = 508). The experimental strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau pressures not exceeding 40 cm H2O, recruitment maneuvers, and higher positive end-expiratory pressures (n = 475).

Main outcome measure
All-cause hospital mortality.

Results
Eighty-five percent of the 983 study patients met criteria for acute respiratory distress syndrome at enrollment. Tidal volumes remained similar in the 2 groups, and mean positive end-expiratory pressures were 14.6 (SD, 3.4) cm H2O in the experimental group vs 9.8 (SD, 2.7) cm H2O among controls during the first 72 hours (P < .001). All-cause hospital mortality rates were 36.4% and 40.4%, respectively (relative risk [RR], 0.90; 95% confidence interval [CI], 0.77-1.05; P = .19). Barotrauma rates were 11.2% and 9.1% (RR, 1.21; 95% CI, 0.83-1.75; P = .33). The experimental group had lower rates of refractory hypoxemia (4.6% vs 10.2%; RR, 0.54; 95% CI, 0.34-0.86; P = .01), death with refractory hypoxemia (4.2% vs 8.9%; RR, 0.56; 95% CI, 0.34-0.93; P = .03), and previously defined eligible use of rescue therapies (5.1% vs 9.3%; RR, 0.61; 95% CI, 0.38-0.99; P = .045).

Conclusions
For patients with acute lung injury and acute respiratory distress syndrome, a multifaceted protocolized ventilation strategy designed to recruit and open the lung resulted in no significant difference in all-cause hospital mortality or barotrauma compared with an established low-tidal-volume protocolized ventilation strategy. This “open-lung” strategy did appear to improve secondary end points related to hypoxemia and use of rescue therapies.

JAMA. 2008;299:646-655

The need for lung protection is universally accepted, but the optimal level of positive end-expiratory pressure (PEEP) in patients with acute lung injury (ALI) or acute respiratory distress syndrome remains debated.

Objective
To compare the effect on outcome of a strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation to one aimed at minimizing alveolar distension in patients with ALI.

Design, setting and patients
A multicenter randomized controlled trial of 767 adults (mean [SD] age, 59.9 [15.4] years) with ALI conducted in 37 intensive care units in France from September 2002 to December 2005.

Intervention
Tidal volume was set at 6 mL/kg of predicted body weight in both strategies. Patients were randomly assigned to a moderate PEEP strategy (5-9 cm H(2)O) (minimal distension strategy; n = 382) or to a level of PEEP set to reach a plateau pressure of 28 to 30 cm H(2)O (increased recruitment strategy; n = 385).

Main outcome measures
The primary end point was mortality at 28 days. Secondary end points were hospital mortality at 60 days, ventilator-free days, and organ failure-free days at 28 days. RESULTS: The 28-day mortality rate in the minimal distension group was 31.2% (n = 119) vs 27.8% (n = 107) in the increased recruitment group (relative risk, 1.12 [95% confidence interval, 0.90-1.40]; P = .31). The hospital mortality rate in the minimal distension group was 39.0% (n = 149) vs 35.4% (n = 136) in the increased recruitment group (relative risk, 1.10 [95% confidence interval, 0.92-1.32]; P = .30). The increased recruitment group compared with the minimal distension group had a higher median number of ventilator-free days (7 [interquartile range {IQR}, 0-19] vs 3 [IQR, 0-17]; P = .04) and organ failure-free days (6 [IQR, 0-18] vs 2 [IQR, 0-16]; P = .04). This strategy also was associated with higher compliance values, better oxygenation, less use of adjunctive therapies, and larger fluid requirements.

Conclusions
A strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation did not significantly reduce mortality. However, it did improve lung function and reduced the duration of mechanical ventilation and the duration of organ failure.