Maximal Recruitment Open Lung Ventilation in Acute Respiratory Distress Syndrome (PHARLAP). A Phase II, Multicenter Randomized Controlled Clinical Trial.

Rationale: Open lung ventilation strategies have been recommended in patients with acute respiratory distress syndrome (ARDS).Objectives: To determine whether a maximal lung recruitment strategy reduces ventilator-free days in patients with ARDS.Methods: A phase II, multicenter randomized controlled trial in adults with moderate to severe ARDS. Patients received maximal lung recruitment, titrated positive end expiratory pressure and further Vt limitation, or control "protective" ventilation.Measurements and Main Results: The primary outcome was ventilator-free days at Day 28. Secondary outcomes included mortality, barotrauma, new use of hypoxemic adjuvant therapies, and ICU and hospital stay. Enrollment halted October 2, 2017, after publication of ART (Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial), when 115 of a planned 340 patients had been randomized (57% male; mean age, 53.6 yr). At 28 days after randomization, there was no difference between the maximal lung recruitment and control ventilation strategies in ventilator-free days (median, 16 d [interquartile range (IQR), 0-21 d], n = 57, vs. 14.5 d [IQR, 0-21.5 d], n = 56; P = 0.95), mortality (24.6% [n = 14/56] vs. 26.8% [n = 15/56]; P = 0.79), or the rate of barotrauma (5.2% [n = 3/57] vs. 10.7% [n = 6/56]; P = 0.32). However, the intervention group showed reduced use of new hypoxemic adjuvant therapies (i.e., inhaled nitric oxide, extracorporeal membrane oxygenation, prone; median change from baseline 0 [IQR, 0-1] vs. 1 [IQR, 0-1]; P = 0.004) and increased rates of new cardiac arrhythmia (n = 17 [29%] vs. n = 7 [13%]; P = 0.03).Conclusions: Compared with control ventilation, maximal lung recruitment did not reduce the duration of ventilation-free days or mortality and was associated with increased cardiovascular adverse events but lower use of hypoxemic adjuvant therapies.Clinical trial registered with www.clinicaltrials.gov (NCT01667146).

Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP): a protocol for a phase 2 trial in patients with acute respiratory distress syndrome.

BACKGROUND: Mechanical ventilation is a life-saving intervention that maintains gas exchange in patients with acute respiratory distress syndrome (ARDS); however, it is associated with high mortality and it may augment, or even initiate, lung injury. An open lung ventilation strategy that combines alveolar recruitment manoeuvres with individually titrated positive end-expiratory pressure (PEEP) and targeting lower tidal volumes, or driving pressures by a permissive approach to hypercapnia, may reduce the lung injury associated with mechanical ventilation. This protocol reports the rationale, study design and analysis plan of the Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP) trial. METHODS AND DESIGN: PHARLAP is a phase 2, international, multicentre, prospective, randomised, controlled, parallel-group clinical trial, which aims to determine if staircase alveolar recruitment and individually titrated PEEP, when combined with permissive hypercapnia and low airway pressures, increases ventilator-free days to Day 28 when compared with conventional mechanical ventilation (Acute Respiratory Distress Syndrome Clinical Network [ARDSNet] strategy) in patients with moderate to severe ARDS. This study will enrol 340 patients. The intervention group will receive daily staircase alveolar recruitment manoeuvres with incremental PEEP to a maximum of 40 cmH2O and peak pressures to a maximum of 55 cmH2O. PEEP will be titrated individually against peripheral oxygen saturation, targeting lower tidal volumes by a permissive approach to hypercapnia. In the control group, patients will receive mechanical ventilation following the ARDSNet-ARMA trial protocol, including PEEP titrated with a PEEP/fraction of inspired oxygen (FiO2) chart. Both groups will receive airway pressures ≤30 cmH2O and tidal volumes of ≤ 6 mL/kg predicted bodyweight or less. The primary outcome is ventilator-free days to Day 28. Secondary outcomes include oxygenation and lung compliance, intensive care unit (ICU) and hospital length of stay, use of rescue therapies for refractory hypoxaemia, rate of barotrauma, mortality (ICU, hospital and at 28, 90 and 180 days), quality of life and a health economic analysis at 6 months. DISCUSSION: The PHARLAP trial will determine whether the intervention strategy is effective in increasing ventilator-free days in patients with ARDS. If the PHARLAP strategy is proven to improve ventilator-free days, it will provide a strong impetus to conduct an international phase 3 trial to determine the effects of this strategy on mortality. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01667146.

Recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation.

BACKGROUND: Recruitment manoeuvres involve transient elevations in airway pressure applied during mechanical ventilation to open ('recruit') collapsed lung units and increase the number of alveoli participating in tidal ventilation. Recruitment manoeuvres are often used to treat patients in intensive care who have acute respiratory distress syndrome (ARDS), but the effect of this treatment on clinical outcomes has not been well established. This systematic review is an update of a Cochrane review originally published in 2009. OBJECTIVES: Our primary objective was to determine the effects of recruitment manoeuvres on mortality in adults with acute respiratory distress syndrome.Our secondary objective was to determine, in the same population, the effects of recruitment manoeuvres on oxygenation and adverse events (e.g. rate of barotrauma). SEARCH METHODS: For this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), the Cumulative Index to Nursing and Allied Health Literature (CINAHL, EBSCO), Latin American and Caribbean Health Sciences (LILACS) and the International Standard Randomized Controlled Trial Number (ISRCTN) registry from inception to August 2016. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of adults who were mechanically ventilated that compared recruitment manoeuvres versus standard care for patients given a diagnosis of ARDS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Ten trials met the inclusion criteria for this review (n = 1658 participants). We found five trials to be at low risk of bias and five to be at moderate risk of bias. Six of the trials included recruitment manoeuvres as part of an open lung ventilation strategy that was different from control ventilation in aspects other than the recruitment manoeuvre (such as mode of ventilation, higher positive end-expiratory pressure (PEEP) titration and lower tidal volume or plateau pressure). Six studies reported mortality outcomes. Pooled data from five trials (1370 participants) showed a reduction in intensive care unit (ICU) mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.72 to 0.97, P = 0.02, low-quality evidence), pooled data from five trials (1450 participants) showed no difference in 28-day mortality (RR 0.86, 95% CI 0.74 to 1.01, P = 0.06, low-quality evidence) and pooled data from four trials (1313 participants) showed no difference in in-hospital mortality (RR 0.88, 95% CI 0.77 to 1.01, P = 0.07, low-quality evidence). Data revealed no differences in risk of barotrauma (RR 1.09, 95% CI 0.78 to 1.53, P = 0.60, seven studies, 1508 participants, moderate-quality evidence). AUTHORS' CONCLUSIONS: We identified significant clinical heterogeneity in the 10 included trials. Results are based upon the findings of several (five) trials that included an "open lung ventilation strategy", whereby the intervention group differed from the control group in aspects other than the recruitment manoeuvre (including co-interventions such as higher PEEP, different modes of ventilation and higher plateau pressure), making interpretation of the results difficult. A ventilation strategy that included recruitment manoeuvres in participants with ARDS reduced intensive care unit mortality without increasing the risk of barotrauma but had no effect on 28-day and hospital mortality. We downgraded the quality of the evidence to low, as most of the included trials provided co-interventions as part of an open lung ventilation strategy, and this might have influenced results of the outcome.

Dynamics of end expiratory lung volume after changing positive end-expiratory pressure in acute respiratory distress syndrome patients.

INTRODUCTION: Lung recruitment maneuvers followed by an individually titrated positive end-expiratory pressure (PEEP) are the key components of the open lung ventilation strategy in acute respiratory distress syndrome (ARDS). The staircase recruitment maneuver is a step-by-step increase in PEEP followed by a decremental PEEP trial. The duration of each step is usually 2 minutes without physiologic rationale. METHODS: In this prospective study, we measured the dynamic end-expiratory lung volume changes (ΔEELV) during an increase and decrease in PEEP to determine the optimal duration for each step. PEEP was progressively increased from 5 to 40 cmH2O and then decreased from 40 to 5 cmH2O in steps of 5 cmH2O every 2.5 minutes. The dynamic of ΔEELV was measured by direct spirometry as the difference between inspiratory and expiratory tidal volumes over 2.5 minutes following each increase and decrease in PEEP. ΔEELV was separated between the expected increased volume, calculated as the product of the respiratory system compliance by the change in PEEP, and the additional volume. RESULTS: Twenty-six early onset moderate or severe ARDS patients were included. Data are expressed as median [25th-75th quartiles]. During the increase in PEEP, the expected increased volume was achieved within 2[2-2] breaths. During the decrease in PEEP, the expected decreased volume was achieved within 1 [1-1] breath, and 95 % of the additional decreased volume was achieved within 8 [2-15] breaths. Completion of volume changes in 99 % of both increase and decrease in PEEP events required 29 breaths. CONCLUSIONS: In early ARDS, most of the ΔEELV occurs within the first minute, and change is completed within 2 minutes, following an increase or decrease in PEEP.

Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why, when, what and which one?

Acute respiratory distress syndrome (ARDS) is an inflammatory condition of the lungs which can result in refractory and life-threatening hypoxaemic respiratory failure. The risk factors for the development of ARDS are many but include trauma, multiple blood transfusions, burns and major surgery, therefore this condition is not uncommon in the severely injured patient. When ARDS is severe, high-inspired oxygen concentrations are frequently required to minimise hypoxaemia. In these situations clinicians commonly utilise interventions termed 'hypoxaemic rescue therapies' in an attempt to improve oxygenation, as without these, conventional mechanical ventilation can be associated with high mortality. However, their lack of efficacy on mortality when used prophylactically in generalised ARDS cohorts has resulted in their use being confined to clinical trials and the subset of ARDS patients with refractory hypoxaemia. First line hypoxaemic rescue therapies include inhaled nitric oxide, prone positioning, alveolar recruitment manoeuvres and high frequency oscillatory ventilation, which have all been shown to be effective in improving oxygenation. In situations where these first line rescue therapies are inadequate extra-corporeal membrane oxygenation has emerged as a lifesaving second line rescue therapy. Rescue therapies in critically ill patients with traumatic injuries presents specific challenges and requires careful assessment of both the short and longer term benefits, therapeutic limitations, and specific adverse effects before their use.

Long-term quality of life in patients with acute respiratory distress syndrome requiring extracorporeal membrane oxygenation for refractory hypoxaemia.

INTRODUCTION: The purpose of the study was to assess the long term outcome and quality of life of patients with acute respiratory distress syndrome (ARDS) receiving extracorporeal membrane oxygenation (ECMO) for refractory hypoxemia. METHODS: A retrospective observational study with prospective health related quality of life (HRQoL) assessment was conducted in ARDS patients who had ECMO as a rescue therapy for reversible refractory hypoxemia from January 2009 until April 2011 in a tertiary Australian centre. Survival and long-term quality of life assessment, using the Short-Form 36 (SF-36) and the EuroQol health related quality of life questionnaire (EQ5D) were assessed and compared to international data from other research groups. RESULTS: Twenty-one patients (mean age 36.3 years) with ARDS receiving ECMO for refractory hypoxemia were studied. Eighteen (86%) patients were retrieved from external intensive care units (ICUs) by a dedicated ECMO retrieval team. Eleven (55%) had H1N1 influenza A-associated pneumonitis. Eighteen (86%) patients survived to hospital discharge. Of the 18 survivors, ten (56%) were discharged to other hospitals and 8 (44%) were discharged directly home. Sequelae and health related quality of life were evaluated for 15 of the 18 (71%) long-term survivors (assessment at median 8 months). Mean SF-36 scores were significantly lower across all domains compared to age and sex matched Australian norms. Mean SF-36 scores were lower (minimum important difference at least 5 points) than previously described ARDS survivors in the domains of general health, mental health, vitality and social function. One patient had long-term disability as a result of ICU acquired weakness. Only 26% of survivors had returned to previous work levels at the time of follow-up. CONCLUSIONS: This ARDS cohort had a high survival rate (86%) after use of ECMO support for reversible refractory hypoxemia. Long term survivors had similar physical health but decreased mental health, general health, vitality and social function compared to other ARDS survivors and an unexpectedly poor return to work.

A randomised controlled trial of an open lung strategy with staircase recruitment, titrated PEEP and targeted low airway pressures in patients with acute respiratory distress syndrome.

INTRODUCTION: Tidal volume and plateau pressure minimisation are the standard components of a protective lung ventilation strategy for patients with acute respiratory distress syndrome (ARDS). Open lung strategies, including higher positive end-expiratory pressure (PEEP) and recruitment manoeuvres to date have not proven efficacious. This study examines the effectiveness and safety of a novel open lung strategy, which includes permissive hypercapnia, staircase recruitment manoeuvres (SRM) and low airway pressure with PEEP titration. METHOD: Twenty ARDS patients were randomised to treatment or ARDSnet control ventilation strategies. The treatment group received SRM with decremental PEEP titration and targeted plateau pressure < 30 cm H2O. Gas exchange and lung compliance were measured daily for 7 days and plasma cytokines in the first 24 hours and on days 1, 3, 5 and 7 (mean ± SE). Duration of ventilation, ICU stay and hospital stay (median and interquartile range) and hospital survival were determined. RESULTS: There were significant overall differences between groups when considering plasma IL-8 and TNF-α. For plasma IL-8, the control group was 41% higher than the treatment group over the seven-day period (ratio 1.41 (1.11 to 1.79), P = 0.01), while for TNF-α the control group was 20% higher over the seven-day period (ratio 1.20 (1.01 to 1.42) P = 0.05). PaO2/FIO2 (204 ± 9 versus 165 ± 9 mmHg, P = 0.005) and static lung compliance (49.1 ± 2.9 versus 33.7 ± 2.7 mls/cm H2O, P < 0.001) were higher in the treatment group than the control group over seven days. There was no difference in duration of ventilation (180 (87 to 298) versus 341 (131 to 351) hrs, P = 0.13), duration of ICU stay (9.9 (5.6 to 14.8) versus 16.0 (8.1 to 19.3) days, P = 0.19) and duration of hospital stay (17.9 (13.7 to 34.5) versus 24.7 (20.5 to 39.8) days, P = 0.16) between the treatment and control groups. CONCLUSIONS: This open lung strategy was associated with greater amelioration in some systemic cytokines, improved oxygenation and lung compliance over seven days. A larger trial powered to examine clinically-meaningful outcomes is warranted. TRIAL REGISTRATION: ACTRN12607000465459.

A positive response to a recruitment maneuver with PEEP titration in patients with ARDS, regardless of transient oxygen desaturation during the maneuver.

UNLABELLED: Recruitment maneuvers (RMs) can expand collapsed alveoli in ventilated patients. The optimal method for delivering RMs is unknown. PURPOSE: To evaluate the safety and the respiratory and hemodynamic effects of a staircase recruitment maneuver (SRM) with decremental positive end expiratory pressure (PEEP) titration and the consequences of desaturation during the SRM in patients with early acute lung injury (ALI). METHODS: In total, 20 consecutive patients with early ALI were enrolled and received an SRM. Patients were given 15 ± 3 cm H(2)O pressure-controlled ventilation. Positive end expiratory pressure was increased from baseline (range 10-18) to 20, 30, and 40 cm H(2)O every 2 minutes to achieve maximum alveolar pressure of 55 ± 3 cm H(2)O, then decreased at 3-minute intervals to 25, 22.5, 20, 17.5, and 15 cm H(2)O until a decrease of 1% to 2% oxygen saturation from maximum was detected. Positive end expiratory pressure was left at the level where the fall in oxygen saturation occurred. Standard respiratory and circulatory variables, arterial and central venous gases were measured before, during, and after the SRM. RESULTS: There were significant improvements in shunt fraction (36.3% ± 10% to 26.4% ± 14%, P < .001), oxygen saturation (93.4% ± 2% to 96.8% ± 3%, P = .007), partial pressure of oxygen, arterial (PaO(2))/fraction of inspired oxygen ([FIO(2)]; 150 ± 42 to 227 ± 100, P = .004), lung compliance (33.9 ± 9.1 to 40.1 ± 11.4 mL/cm H(2)O, P < .01), and chest x-ray (CXR) after the SRM. Briefly, 80% of the patients responded and the response was maintained at 1 hour. In total, 8 patients desaturated 6.1% ± 2.8% in SaO(2) during the SRM but 5 of those improved SaO(2) relative to baseline by the end of the SRM. CONCLUSIONS: In all, 80% of the patients with early ALI responded to the SRM with decremental PEEP titration. Desaturation during the SRM did not indicate a failed response 1 hour later.

Recruitment manoeuvres for adults with acute lung injury receiving mechanical ventilation.

BACKGROUND: Recruitment manoeuvres are often used to treat patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) but the effect of this treatment on clinical outcomes has not been well established. OBJECTIVES: The objective of this review was to examine recruitment manoeuvres compared to standard care as therapy for adults with acute lung injury in order to quantify the effects on patient outcomes (mortality, length of ventilation, and other relevant outcomes). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 2); MEDLINE (January 1966 to May 2008); EMBASE (January 1980 to May 2008); LILACS (1982 to May 2008); CINAHL (1982 to May 2008); and Current Controlled Trials (www.controlled-trials.com). SELECTION CRITERIA: We included randomized controlled trials of adults who were mechanically ventilated comparing recruitment manoeuvres to standard care for those patients diagnosed with ALI or ARDS. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Seven trials met the inclusion criteria for this review (the total number of included participants was 1170). All trials included a recruitment manoeuvre as part of the treatment strategy for patients on mechanical ventilation for ARDS or ALI. However, two of the trials included a package of ventilation that was different from the control ventilation in aspects other than the recruitment manoeuvre. The intervention group showed no significant difference on 28-day mortality (RR 0.73, 95% CI 0.46 to 1.17, P = 0.2). Similarly there was no statistical difference for risk of barotrauma (RR 0.50, 95% CI 0.07 to 3.52, P = 0.5) or blood pressure (MD 0.9 mm Hg, 95% CI -4.28 to 6.08, P = 0.73). Recruitment manoeuvres significantly increased oxygenation above baseline levels for a short period of time in four of the five studies that measured oxygenation. There were insufficient data on length of ventilation or hospital stay to pool results. AUTHORS' CONCLUSIONS: There is not evidence to make conclusions on whether recruitment manoeuvres reduce mortality or length of ventilation in patients with ALI or ARDS.

Predictors of independent lung ventilation: an analysis of 170 single-lung transplantations.

OBJECTIVE: Single-lung transplantation for chronic obstructive pulmonary disease can cause unique postoperative problems that might require independent lung ventilation. We evaluated preoperative and immediate postoperative factors to predict the need for independent lung ventilation. METHODS: We retrospectively studied 170 patients who received a single-lung transplant over a 15-year period, 20 (12%) of whom required independent lung ventilation. RESULTS: Patients requiring independent lung ventilation were similar in age, sex, ischemic time, and donor characteristics to those who required conventional ventilation. Patients receiving independent lung ventilation had a greater degree of preoperative airflow limitation, more hyperinflation, lower postoperative PaO2/fraction of inspired oxygen ratios, more radiologic mediastinal shift, and more transplant lung infiltrate on the postoperative chest radiograph. Multivariate logistic regression analysis showed that independent lung ventilation was associated with increasing levels of recipient hyperinflation (percentage total lung capacity compared with predicted value; odds ratio, 1.04; 95% confidence interval, 1.01-1.07; P = .032) and reduced early postoperative PaO2/fraction of inspired oxygen ratio (odds ratio, 0.97; 95% confidence interval, 0.95-0.99; P = .005). Length of ventilation and intensive care unit stay and mortality were higher in the independent lung ventilation group. Among patients who survived to hospital discharge, there were no differences in long-term mortality between the 2 groups. CONCLUSIONS: The need for independent lung ventilation in patients undergoing single-lung transplantation for obstructive lung disease is predicted by the combination of increased hyperinflation measured on recipients' preoperative lung function tests and a low PaO2/fraction of inspired oxygen ratio, indicating graft dysfunction in the immediate postoperative period.

Where to now with carbon monoxide poisoning?

The controversy regarding the role of hyperbaric oxygen (HBO) in the treatment of carbon monoxide (CO) poisoning has been re-ignited following the publication of a further randomized controlled trial by Weaver et al., the results of which appear to conflict with our findings. Comparative analysis suggests that the apparent outcome differences may be secondary to the design, analysis and interpretation of the results of the two studies. Following careful analysis of these two papers and further results from a study by Raphael et al on 385 CO-poisoned patients, we can still find no convincing evidence favouring HBO therapy. Pending further research to determine optimal oxygen therapy for CO-poisoning, current therapy should involve stratifying patients for risk of a poor outcome. This stratification may be aided by the evolving availability of biochemical markers of brain injury and the finding that patients with transient loss of consciousness and poor performance on neuropsychological tests of the supervisory attention system are at higher risk of neuropsychological sequelae. We propose that those patients most at risk be admitted and receive more prolonged normobaric oxygen therapy whilst those with more minor CO-poisoning should be provided with normobaric oxygen of no less than 6 h duration and certainly until sign and symptom free.