Individualized Positive End-expiRatory Pressure Guided by End-Expiratory Lung Volume in Moderate-to-severe Acute resPiratory Distress Syndrome.The IPERPEEP Study
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 18
- 试验地点
- 10
- 主要终点
- Composite clinical outcome that incorporates ICU mortality, 60-day ventilation-free days (VFD60) and the Area Under the Curve of the InterLeukin-6 serum concentration (IL6AUC) during the first 72 hours of observation
研究概览
简要总结
During the acute respiratory distress syndrome (ARDS), patients' response to positive end-expiratory pressure (PEEP) is variable according to different degrees of lung recruitability. The search for a tool to individualize PEEP on the basis of patients' individual response is warranted.
Measurement of end-expiratory lung volume (EELV) by the nitrogen washin-washout technique, bedside available from recent ICU ventilators, has been shown to reliably estimate PEEP-induced alveolar recruitment and may therefore help titrate PEEP on patient's individual requirements.
The authors designed an open-label, multicenter, randomized trial to test whether an individualized PEEP setting protocol driven by EELV may improve a composite clinical outcome in patients with moderate-to-severe ARDS.
详细描述
ARDS patients with a PaO2/FiO2 ratio equal or below 150 mmHg (during mechanical ventilation with PEEP 5 cmH2O) will be enrolled within 24 hours from endo-tracheal intubation.
To standardize lung volumes at study initiation, all patients will undergo mechanical ventilation with tidal volume set at 6 ml/kg of predicted body weight and PEEP set to obtain a plateau pressure within 28 and 30 cmH2O for thirty minutes (Express PEEP).
Afterwards, a 5-step decremental PEEP trial will be conducted (Express PEEP to PEEP 5 cmH2O), and EELV will be measured at each step. PEEP-induced alveolar recruitment will be calculated for each PEEP range as the difference between PEEP-induced change EELV and the predicted increase in lung volume due to PEEP (PEEP-induced overdistension, equal to the product of respiratory system compliance and PEEP change).
Patients will be then randomized to receive mechanical ventilation with PEEP set according to the optimal recruitment observed in the PEEP trial (IPERPEEP arm) trial or according to the Express strategy (Control arm, PEEP set to achieve a plateau pressure of 28-30 cmH2O).
In both groups, tidal volume size, the use of prone positioning and neuromuscular blocking agents will be standardized.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Pneumothorax;
- •Acute brain injury;
- •Clinical signs of history of decompensated heart failure (New York Heart Association class 3-4 before the acute phase of the disease or documented ejection fraction<35% or pulmonary capillary wedge pressure>18 mmHg) or acute coronary syndrome;
- •Intubation as a result of an acute exacerbation of chronic pulmonary disease: chronic obstructive pulmonary disease, asthma, cystic fibrosis, etc;
- •Clinically evident intrinsic PEEP (≥2 cmH2O) during screening visit (End-expiratory pause to achieve Flow=0);
- •BMI<15 or body weight<35 Kg;
- •Any chronic disease requiring long-term oxygen therapy or mechanical ventilation at home;
- •Neuromuscular disease of any kind;
- •Severe chronic liver disease (Child-Pugh C or worse);
- •Bone marrow transplantation or chemotherapy-induced neutropenia;
- •History of liver or lung transplant;
- •Decision to withhold life-sustaining treatment;
- •Need for therapy with inhaled nitric oxide due to documented pulmonary arterial hypertension;
- •Life-threatening hypoxemia deemed to require extracorporeal membrane oxygenation (ECMO);
- •Presence of documented barotrauma;
- •High risk of mortality within 3 months from other than ARDS (severe neurological damage, age >85 years and cancer patients in terminal stages of the disease).
- •Persistent hemodynamic instability, intractable shock (norepinephrine>1 mcg/kg/h and/or blood lactate>5 mmol/L and/or considered too hemodynamically unstable for enrolment in the study by the patient's managing physician).
- •More than 24 hours from endotracheal intubation to the time of the screening visit.
研究组 & 干预措施
IPERPEEP
End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial.
PEEP will be ≥5 cmH2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O.
In particular, when interpreting the results of the PEEP trial, recruitment-to-inflation (RI) ratio calculated across two adjacent PEEP levels will drive PEEP setting.
- RI≥1.5 between two PEEP levels will lead to the setting of the higher PEEP.
- RI<0.5 will lead to the setting of the lower PEEP value.
- In case of RI≥0.5 and <1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static and dynamic strain and of optimizing oxygenation and haemodynamics.
干预措施: Invasive Mechanical ventilation (Device)
IPERPEEP
End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial.
PEEP will be ≥5 cmH2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O.
In particular, when interpreting the results of the PEEP trial, recruitment-to-inflation (RI) ratio calculated across two adjacent PEEP levels will drive PEEP setting.
- RI≥1.5 between two PEEP levels will lead to the setting of the higher PEEP.
- RI<0.5 will lead to the setting of the lower PEEP value.
- In case of RI≥0.5 and <1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static and dynamic strain and of optimizing oxygenation and haemodynamics.
干预措施: Neuromuscular Blocking Agents (Drug)
IPERPEEP
End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial.
PEEP will be ≥5 cmH2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O.
In particular, when interpreting the results of the PEEP trial, recruitment-to-inflation (RI) ratio calculated across two adjacent PEEP levels will drive PEEP setting.
- RI≥1.5 between two PEEP levels will lead to the setting of the higher PEEP.
- RI<0.5 will lead to the setting of the lower PEEP value.
- In case of RI≥0.5 and <1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static and dynamic strain and of optimizing oxygenation and haemodynamics.
干预措施: Prone positioning (Procedure)
IPERPEEP
End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial.
PEEP will be ≥5 cmH2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O.
In particular, when interpreting the results of the PEEP trial, recruitment-to-inflation (RI) ratio calculated across two adjacent PEEP levels will drive PEEP setting.
- RI≥1.5 between two PEEP levels will lead to the setting of the higher PEEP.
- RI<0.5 will lead to the setting of the lower PEEP value.
- In case of RI≥0.5 and <1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static and dynamic strain and of optimizing oxygenation and haemodynamics.
干预措施: Resume of spontaneous breathing (Procedure)
IPERPEEP
End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial.
PEEP will be ≥5 cmH2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O.
In particular, when interpreting the results of the PEEP trial, recruitment-to-inflation (RI) ratio calculated across two adjacent PEEP levels will drive PEEP setting.
- RI≥1.5 between two PEEP levels will lead to the setting of the higher PEEP.
- RI<0.5 will lead to the setting of the lower PEEP value.
- In case of RI≥0.5 and <1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static and dynamic strain and of optimizing oxygenation and haemodynamics.
干预措施: Rescue treatments (Procedure)
IPERPEEP
End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial.
PEEP will be ≥5 cmH2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O.
In particular, when interpreting the results of the PEEP trial, recruitment-to-inflation (RI) ratio calculated across two adjacent PEEP levels will drive PEEP setting.
- RI≥1.5 between two PEEP levels will lead to the setting of the higher PEEP.
- RI<0.5 will lead to the setting of the lower PEEP value.
- In case of RI≥0.5 and <1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static and dynamic strain and of optimizing oxygenation and haemodynamics.
干预措施: Weaning from PEEP (Procedure)
IPERPEEP
End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial.
PEEP will be ≥5 cmH2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O.
In particular, when interpreting the results of the PEEP trial, recruitment-to-inflation (RI) ratio calculated across two adjacent PEEP levels will drive PEEP setting.
- RI≥1.5 between two PEEP levels will lead to the setting of the higher PEEP.
- RI<0.5 will lead to the setting of the lower PEEP value.
- In case of RI≥0.5 and <1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static and dynamic strain and of optimizing oxygenation and haemodynamics.
干预措施: Weaning from mechanical ventilation (Procedure)
IPERPEEP
End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial.
PEEP will be ≥5 cmH2O and set to ensure the maximum recruitment observed in the PEEP trial, with a maximum permitted PPLAT of 30 cmH2O.
In particular, when interpreting the results of the PEEP trial, recruitment-to-inflation (RI) ratio calculated across two adjacent PEEP levels will drive PEEP setting.
- RI≥1.5 between two PEEP levels will lead to the setting of the higher PEEP.
- RI<0.5 will lead to the setting of the lower PEEP value.
- In case of RI≥0.5 and <1.5, the choice among two adjacent PEEP levels will be left to the attending physician, who will indicate the set PEEP in order to best balance between the commitment of limiting total, static and dynamic strain and of optimizing oxygenation and haemodynamics.
干预措施: Extubation (Procedure)
EXPRESS
PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
干预措施: Extubation (Procedure)
EXPRESS
PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
干预措施: Invasive Mechanical ventilation (Device)
EXPRESS
PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
干预措施: Neuromuscular Blocking Agents (Drug)
EXPRESS
PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
干预措施: Prone positioning (Procedure)
EXPRESS
PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
干预措施: Resume of spontaneous breathing (Procedure)
EXPRESS
PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
干预措施: Rescue treatments (Procedure)
EXPRESS
PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
干预措施: Weaning from PEEP (Procedure)
EXPRESS
PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
干预措施: Weaning from mechanical ventilation (Procedure)
结局指标
主要结局
Composite clinical outcome that incorporates ICU mortality, 60-day ventilation-free days (VFD60) and the Area Under the Curve of the InterLeukin-6 serum concentration (IL6AUC) during the first 72 hours of observation
时间窗: 60 days
Composite clinical outcome that incorporates ICU mortality, 60-day ventilation-free days (VFD60) and the Area Under the Curve of the InterLeukin-6 serum blood cytokine concentration (IL6AUC) during the first 72 hours of observation. Every participant in the treatment group will be compared with every participant in the control group and assigned a score resulting from each comparison. Mortality takes precedence over VFD60, which takes precedence over IL6AUC. Two VFD60's will be considered different for the purpose of scoring only if their difference is larger than 5 days. Similarly, two IL6AUC's measurements will be considered different only if their difference exceeds 10% of the smaller of the two. These individual-comparison scores are added up to obtain the cumulative score primary endpoint for each participant. The sum of scores for patients in the treatment group is compared to the sum of scores of subjects in the control group and compared according by use of Mann-Whitney test
次要结局
- AUC IL-6(72 hours)
- Total Lung stress-End-inspiratory transpulmonary pressure derived from elastance ratio(72 hours)
- In-ICU mortality(90 days)
- 90-day mortality(90 days)
- 28-day Ventilator free days(28 days)
- Arterial pressure(72 hours)
- In-Hospital mortality(90 days)
- 60-day Ventilator free days(28 days)
- Time to successful weaning(90 days)
- Set PEEP variability(72 hours)
- Time spent on assisted ventilation after the enrolment(28 days)
- AUC IL-8(72 hours)
- End-expiratory transpulmonary pressure(72 hours)
- Respiratory system compliance(72 hours)
- Oxygenation(72 hours)
- Oxygenation stretch index(72 hours)
- Carbon dioxide(72 hours)
- Heart rate(72 hours)
- Organ failure(28 days)
- Need for rescue recruitment maneuvers(72 hours)
- Plateau pressure(72 hours)
- Respiratory system driving pressure(72 hours)
- AUC TNF(72 hours)
- Set PEEP(72 hours)
- Simplified organ failure assessment(28 days)
- Nedd for rescue extra-corporeal membrane oxygenation(90 days)
- Nedd for tracheostomy(90 days)
- Static stress(72 hours)
- Dynamic stress-Transpulmonary driving pressure(72 hours)
- Respiratory system compliance normalized to predicted body weight(72 hours)
- Lung compliance(72 hours)
- Dynamic strain(30 minutes)
- Static strain(30 minutes)
- Catecholamine requirements per day(72 hours)