Acute Respiratory Distress Syndrome
Conditions
Brief summary
Some people develop the condition called acute respiratory distress syndrome (ARDS). This is a condition where the lungs have become injured from one of a number of various causes, and do not work as they normally do to provide oxygen and remove carbon dioxide from the body. This can lead to a reduced amount of oxygen in the patient's bloodstream. Patients with ARDS are admitted to the intensive care unit (ICU) and need help with their breathing by being connected to a ventilator (breathing machine). ARDS can lead to injury in other organs of the body causing other problems but also death. Over the past few years, reducing the size of each breath delivered by the ventilator in conjunction with the use of an occasional sustained deep breath called a recruitment manoeuvre have been used to try to prevent further damage to the lungs in people with ARDS. This ventilator strategy (termed the PHARLAP strategy) has been shown in a small research study to have some beneficial effects without causing any obvious harm, when compared to a current best practice ventilator strategy. The main beneficial effects of the PHARLAP strategy were to increase the amount of oxygen in the blood and to reduce markers of inflammation (the body reacting to a disease process) in the body. This study was too small to make a strong conclusion, so this study will be much larger and will assess whether patients who have developed ARDS are better off when we use the PHARLAP strategy. Three hundred and forty patients will be enrolled into this study in multiple ICUs across Australia and New Zealand. The study hypothesis is that the PHARLAP strategy group will have a higher number of ventilator free days at day 28 than the control group.
Detailed description
340 adult patients who have developed ARDS within the last 72 hours (and within 10 days of commencing mechanical ventilation) will be enrolled in 25- 30 intensive care units (ICUs) and randomly allocated to either the PHARLAP or a control ventilation strategy. PHARLAP strategy: Pressure control ventilation to maintain tidal volume 4-6 ml/kg and plateau pressure ≤ 30 cmH2O while tolerating respiratory acidosis if pH \> 7.15; daily staircase recruitment manoeuvre and individualised Positive-end expiratory pressure (PEEP) titration. Control strategy: Mechanical ventilation based on the ARDSnet protocol with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and fraction inspired oxygen (FiO2)/PEEP titration according to a FiO2/PEEP/oxygen saturation combination chart. This has been modified for Australian and New Zealand practice to allow pressure control and pressure support ventilation. A standardised weaning from mechanical ventilation guideline will be used in both groups
Interventions
OTHERPHARLAP mechanical ventilation strategy
Pressure control ventilation to maintain tidal volume 4-6 ml/kg and plateau pressure ≤ 30 cmH2O while tolerating respiratory acidosis if pH \> 7.15; daily staircase recruitment manoeuvre and individualised PEEP titration.
OTHERControl group mechanical ventilation strategy
Mechanical ventilation based on the ARDSnet protocol using volume control ventilation with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and FiO2/PEEP titration according to a FiO2/PEEP/oxygen saturation combination chart. This has been modified for Australian and New Zealand practice to allow pressure control and pressure support ventilation.
Sponsors
University College Dublin
Australian and New Zealand Intensive Care Research Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Adult ICU patients who met all of the following criteria: * Currently intubated and receiving mechanical ventilation * Within 72 Hours of a diagnosis of ARDS (moderate and severe) based on the following Berlin definition: * Within 1 week of a known clinical insult or new or worsening respiratory symptoms * Bilateral opacities on chest x-ray (CXR) which are not fully explained by effusions, lobar/lung collapse or nodules * Respiratory failure not fully explained by cardiac failure or fluid overload * Arterial oxygen pressure (PaO2)/FiO2 \< 200mmHg with PEEP ≥ 5cmH2O
Exclusion criteria
* \> 72 hours since diagnosis of ARDS * \> 10 days of continuous mechanical ventilation * Barotrauma (pneumothorax, pneumomediastinum, subcutaneous emphysema or any intercostal catheter for the treatment of air leak) * Significant chest trauma i.e. multiple rib fractures * Active bronchospasm or a history of significant chronic obstructive pulmonary disease or asthma * Clinical suspicion for significant restrictive lung disease (history of pulmonary fibrosis or suggestive pulmonary function tests) * Moderate or severe traumatic brain injury, the presence of an intracranial pressure monitor, or any medical condition associated with a clinical suspicion of raised intracranial pressure * Unstable cardiovascular status defined as sustained heart rate \< 40 or \> 140 bpm, ventricular tachycardia, or SBP \< 80mmHg * Pregnancy * Receiving ECMO * Receiving high frequency oscillatory ventilation * Death is deemed imminent and inevitable * The treating physician believes it is not in the best interest of the patient to be enrolled in the trial * Consent not obtained or refused by patient's legal surrogate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Ventilator Free Days at Day 28 Post Randomisation | 28 days post randomisation | This is the total number of days calculated from day 1 (randomisation) to day 28 on which the patient was alive and received no assistance from invasive mechanical ventilation. Scores range between 0 (no ventilator free days) to 28 (no days on ventilator). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline to Day 3 Change in IL-8 and IL-6 Concentrations in Broncho-alveolar Lavage and Plasma | Day 3 post randomisation | IL-8 is an important protein related to inflammation, Interleukin (IL)-6 is produced at the site of inflammation and plays a key role in the acute phase response |
| Number of Severe Hypotension Events | Up to 28 days post randomisation | Hypotension requiring increased vasopressor Days 1-28 |
| Number of Participants With Barotrauma | Up to 90 days post randomisation | Evidence of Pneumothorax requiring Drainage |
| Use of Rescue Therapies for Severe Hypoxaemia - Inhaled Nitric Oxide, Inhaled Prostacyclin, Prone Positioning, High Frequency Oscillatory Ventilation and Extracorporeal Membrane Oxygenation (ECMO) | Within hospital admission | The use of various rescue therapies (each of the therapies is compared between groups - per patient). the various therapies measured are inhaled nitric oxide, inhaled prostacyclin, prone positioning, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO) |
| Mortality | at day 28 | At timepoints: day 28 |
| PaO2/FiO2 Ratio and Static Lung Compliance | Up to day 28 post randomisation | PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage). ARDS severity Mild 200-300 / Moderate 100-200 / Severe \<100. |
| Incidence of Acute Kidney Injury (AKI) | Within hospital admission | The incidence of Acute Renal Injury - measured by the use of Continuous Renal Replacement Therapy (CRRT) in each person |
| Quality of Life Assessment | 6 months post randomisation | SF36v2 will be used Medical Outcomes Study. Scoring the RAND is a two-step process. First, pre-coded numeric values are recoded. Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores. |
| Cost Effectiveness Analysis | 6 months post randomisation | This will be based on EQ-5D. EQ-5D is the most widely used health-related quality of life questionnaire in health economic evaluations.\[62\] EQ-5D can be used to derive a set of values that reflect people's opinions of the relative importance of different health problems. These values can be used to derive QALYs for application in cost-effectiveness and cost-utility evaluations. |
| Hospital Length of Stay | From admission up to 6 months | The length of time in days a participant stayed in hospital. A fraction of a day is considered 1 day. |
| ICU Length of Stay | From admission to ICU up to 6 months | The number of days a person stayed in the ICU. A fraction of a day is considered a day |
Countries
Australia, Ireland, New Zealand, Saudi Arabia, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PHARLAP Intervention Arm PHARLAP strategy (21) included pressure control mode, Tidal Volume (VT) of 4-6 ml/kg, and plateau airway pressures \<28cm H2O (online supplement). Patients underwent daily maximal RMs with PEEP titration (a combined open lung procedure \[COLP\]) for up to the first 5 days The COLP was performed as follows. A staircase RM (SRM) was applied in pressure control ventilation at 15 6 3 cm H2O, with the PEEP increased to 20 cm H2O, then 30 cm H2O, and then 40 cm H2O for 2 minutes each. This step was followed by decremental PEEP titration from 25 cm H2O in 2.5-cm H2O steps for 3 minutes until the SpO2 decreased by 2% or more or to a minimum of 15 cm H2O PEEP if desaturation did not occur. Last, a brief RM returned the PEEP to a level 2.5 cm H2O above the level of desaturation. Airway pressures were minimized with permissive hypercapnia and targeting VT and plateau pressures ,6 ml/kg and ,28 cm H2O, respectively. Brief RMs could be performed throughout the day in case of hypoxemia (online supplement). The study's weaning protocol included daily assessments to identify patients who met weaning criteria and were suitable for a spontaneous breathing trial (online supplement) (24). After a successful spontaneous breathing trial, the ICU clinician reviewed the patient with a view to prompt extubation. | 58 |
| Control Group patients were ventilated according to the Acute Respiratory Distress Syndrome Network's low-VT/low PEEP ventilation protocol (4), including volume control mode, VT of 6 ml/kg, plateau airway pressures \<30 cm H2O, and the low PEEP strategy (Table E2). RMs were not permitted. | 56 |
| Total | 114 |
Baseline characteristics
| Characteristic | Control Group | Total | PHARLAP Intervention Arm |
|---|---|---|---|
| Age, Continuous | 53.2 years STANDARD_DEVIATION 14.4 | 53.7 years STANDARD_DEVIATION 14.2 | 54.2 years STANDARD_DEVIATION 14 |
| APACHE II score | 22.3 units on a scale STANDARD_DEVIATION 7.7 | 22.8 units on a scale STANDARD_DEVIATION 7.2 | 23.2 units on a scale STANDARD_DEVIATION 6.8 |
| BMI | 30.3 kg/m^2 STANDARD_DEVIATION 7.2 | 30.8 kg/m^2 STANDARD_DEVIATION 8.6 | 31.3 kg/m^2 STANDARD_DEVIATION 10.1 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Sex: Female, Male Female | 26 Participants | 48 Participants | 22 Participants |
| Sex: Female, Male Male | 30 Participants | 66 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 14 / 57 | 17 / 56 |
| other Total, other adverse events | 9 / 58 | 4 / 56 |
| serious Total, serious adverse events | 23 / 58 | 15 / 56 |
Outcome results
Primary
Number of Ventilator Free Days at Day 28 Post Randomisation
This is the total number of days calculated from day 1 (randomisation) to day 28 on which the patient was alive and received no assistance from invasive mechanical ventilation. Scores range between 0 (no ventilator free days) to 28 (no days on ventilator).
Time frame: 28 days post randomisation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PHARLAP Ventilation Group | Number of Ventilator Free Days at Day 28 Post Randomisation | 16 days |
| Control Group Ventilation | Number of Ventilator Free Days at Day 28 Post Randomisation | 14.5 days |
Secondary
Baseline to Day 3 Change in IL-8 and IL-6 Concentrations in Broncho-alveolar Lavage and Plasma
IL-8 is an important protein related to inflammation, Interleukin (IL)-6 is produced at the site of inflammation and plays a key role in the acute phase response
Time frame: Day 3 post randomisation
Secondary
Cost Effectiveness Analysis
This will be based on EQ-5D. EQ-5D is the most widely used health-related quality of life questionnaire in health economic evaluations.\[62\] EQ-5D can be used to derive a set of values that reflect people's opinions of the relative importance of different health problems. These values can be used to derive QALYs for application in cost-effectiveness and cost-utility evaluations.
Time frame: 6 months post randomisation
Secondary
Hospital Length of Stay
The length of time in days a participant stayed in hospital. A fraction of a day is considered 1 day.
Time frame: From admission up to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PHARLAP Ventilation Group | Hospital Length of Stay | 20.1 Days |
| Control Group Ventilation | Hospital Length of Stay | 17.9 Days |
Secondary
ICU Length of Stay
The number of days a person stayed in the ICU. A fraction of a day is considered a day
Time frame: From admission to ICU up to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PHARLAP Ventilation Group | ICU Length of Stay | 11.1 days |
| Control Group Ventilation | ICU Length of Stay | 13.8 days |
Secondary
Incidence of Acute Kidney Injury (AKI)
The incidence of Acute Renal Injury - measured by the use of Continuous Renal Replacement Therapy (CRRT) in each person
Time frame: Within hospital admission
Secondary
Mortality
At timepoints: day 28
Time frame: at day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PHARLAP Ventilation Group | Mortality | 14 Participants |
| Control Group Ventilation | Mortality | 15 Participants |
Secondary
Number of Participants With Barotrauma
Evidence of Pneumothorax requiring Drainage
Time frame: Up to 90 days post randomisation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PHARLAP Ventilation Group | Number of Participants With Barotrauma | 3 Participants |
| Control Group Ventilation | Number of Participants With Barotrauma | 2 Participants |
Secondary
Number of Severe Hypotension Events
Hypotension requiring increased vasopressor Days 1-28
Time frame: Up to 28 days post randomisation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PHARLAP Ventilation Group | Number of Severe Hypotension Events | 20 events |
| Control Group Ventilation | Number of Severe Hypotension Events | 12 events |
Secondary
PaO2/FiO2 Ratio and Static Lung Compliance
PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage). ARDS severity Mild 200-300 / Moderate 100-200 / Severe \<100.
Time frame: Up to day 28 post randomisation
Secondary
Quality of Life Assessment
SF36v2 will be used Medical Outcomes Study. Scoring the RAND is a two-step process. First, pre-coded numeric values are recoded. Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores.
Time frame: 6 months post randomisation
Secondary
Use of Rescue Therapies for Severe Hypoxaemia - Inhaled Nitric Oxide, Inhaled Prostacyclin, Prone Positioning, High Frequency Oscillatory Ventilation and Extracorporeal Membrane Oxygenation (ECMO)
The use of various rescue therapies (each of the therapies is compared between groups - per patient). the various therapies measured are inhaled nitric oxide, inhaled prostacyclin, prone positioning, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO)
Time frame: Within hospital admission