The PROtective Ventilation Using Open Lung Approach Or Not Trial
Keywords
Abstract
Description
1. Sample size calculation, randomization and patients safety. The required sample size is calculated from previous studies on the incidence of postoperative pulmonary complications. A two group chi-square test with a 0.05 two-sided significance level will have 80% power to detect the difference (in primary outcome) between conventional mechanical ventilation strategy (25%) and open lung approach mechanical ventilation strategy (12.5%) when the sample size in each group is 126. In consideration of a 10% loss rate, 280 cases to be included in this trial.
Research will be carried out in two stages. Completely-randomized design was used in the first stage, and randomized block design in the second stage. The interim analysis will be performed when 100 patients (first stage) have successfully been included and followed-up. The Data Monitoring and Safety Group (DMSG) will provide recommendations about stopping or continuing the trial to the principal investigator. The DMSG will recommend stopping the trial, if significant group-difference in adverse events is found at the interim analysis (p<0.025), or if postoperative pulmonary complications occur more frequently in the intervention group (p<0.025). If the intervention has a strong trend for improving postoperative pulmonary complications (p<0.018) at the first stage, termination of the study is considered.
2. Protocol drop-out. Anesthesiologists are allowed to change the ventilation protocol if there is any concern about patient's safety. The level of PEEP can be modified according to the anesthesiologist in charge if the systolic arterial pressure (SBP)< 80 mmHg and SBP drop ≥30% baseline values for more than 3 minutes despite intravenous fluid infusion and/or start of vasopressors, if dosages of vasopressors are at the highest level tolerated, if new arrhythmias develop which are unresponsive to treatment suggested by the Advanced Cardiac Life Support Guidelines. If there is pneumothorax or hypoxemia (SpO2 < 90% for more than 3 minutes）, if there is need of massive transfusion (>8 units packed red blood cell) to maintain hemoglobin >7 mg/dl, if the duration of pneumoperitoneum is less then 1h or mechanical ventilation time is less then 2h, if there is a surgical complication (such as severe hypercapnia, unexpected conversion to open surgery, unplanned reoperation in 24h after surgery, unplanned ICU admission for surgical reasons) or if patient die during operation, then the patient will be dropped out of the study. All drop-out cases will be included in the safety analysis.
3. Trial settings for intraoperative ventilation. Patients in the conventional mechanical ventilation strategy group will have a tidal volume of 6 to 8 ml per kilogram Predicted Body Weight (PBW), zero PEEP and no recruitment maneuver. Patients in the open lung approach mechanical ventilation strategy group will have a tidal volume of 6 to 8 ml per kilogram PBW, a PEEP level of 6 to 8 cm of water and recruitment maneuvers. Recruitment maneuvers consist of a stepwise increase of tidal volume （as detailed below） and will be applied immediately after tracheal intubation and every 30 min thereafter until the end of surgery.
In each group, anesthesiologists will be advised to use an inspired oxygen fraction (FIO2) between 0.4 to 0.5 and to maintain oxygen saturation ≥ 92%. The inspiratory to expiratory time ratio will be set at 1:2, with a respiratory rate adjusted to maintain normocapnia (end-tidal carbon dioxide concentration of 30-50 mmHg).
PBW is calculated according to a predefined formula with: 50 + 0.91 x (centimeters of height - 152.4) for males and 45.5 + 0.91 x (centimeters of height - 152.4) for females. In each group, patients will be ventilated using the volume-controlled ventilation strategy using an anesthesia ventilator: 1. Avance® (Datex-Ohmeda, General Electric, Helsinki, Finland) 2. Tiro® (Dräger, Lübeck, Germany)
4. Recruitment maneuvers.
Stepwise increase of tidal volume will be used as a method of recruitment maneuvers in this trial. Recruitment maneuvers should not be performed when patients are hemodynamic unstable, as judged by the attending anesthesiologist. Recruitment maneuvers will be performed as follows:
4-1. Peak inspiratory pressure limit is set at 45 cmH2O. 4-2. Tidal volume is set at 8 ml/kg PBW and respiratory rate at 6 breaths/min, while PEEP is set at 12 cmH2O.
4-3. Inspiratory to expiratory ratio (I:E) is set at 1:2. 4-4. Tidal volumes are increased in steps of 4 ml/kg PBW until a plateau pressure of 30-35 cmH2O (if tidal volume reach the biggest volume of the ventilator and plateau pressure cannot reach 30-35 cmH2O, then PEEP is set at 16 cmH2O for a plateau pressure of 30-35 cmH2O).
4-5. Three breaths are administered with a plateau pressure of 30-35 cmH2O. 4-6. Peak inspiratory pressure limit, respiratory rate, I: E, and tidal volume are set back to settings preceding each recruitment maneuver, while maintaining PEEP at 8 cmH2O.
5. Definitions for postoperative complications. All definitions for postoperative complications refer to the IMPROVE trial and the PROVHILO trial.
6. Composition and responsibilities of the DMSG. Members of the DMSG are the management team of anesthesia department in the research hospital. The DMSG will be responsible for safeguarding the interests of trial participants, assessing the safety and efficacy of the intervention during the trial, and for monitoring the overall conduct of the trial. To enhance the integrity of the trial, the DMSG may also formulate recommendations relating to the selection or recruitment of participants, and the procedures of data management and quality control. The DMSG will be advisory to the principal investigator. The principal investigator will be responsible for reviewing the DMSG recommendations, decide whether to continue or terminate the trial, and determine whether changes in trial conduct are required. Any DMSG members who develop significant conflicts of interest during the course of the trial should resign from the DMSG.
7. Data management. Data will be collected and recorded into case report forms (CRFs) by researchers under the supervision of DMSG members. Data manager will scan handwritten data first and then enter data into electronic database. Source data verification will be performed using a cross-check method by researchers when 7-days follow-up have successfully been completed.
All adverse events, serious adverse events, unexpected or possibly related events will be recorded in the CRF and reported to the DMSG.
8. Statistics. Statisticians will be in blind state for data analysis. Analysis will be by intention-to-treat comparing the primary outcome measure at 7 days in the two groups by chi-squared test (or Fisher's exact test as appropriate). Continuous variables will be compared using the One-way analysis of variance or the Mann-Whitney U test. Categorical variables will be compared using the chi-square test or the Fisher's exact test. The time-to-event curves will be calculated with the use of the Kaplan-Meier method. All analyses will be conducted using the SPSS 16.0 statistical software.
Dates
| Last Verified: | 11/30/2019 |
| First Submitted: | 04/20/2017 |
| Estimated Enrollment Submitted: | 05/16/2017 |
| First Posted: | 05/18/2017 |
| Last Update Submitted: | 11/30/2019 |
| Last Update Posted: | 12/02/2019 |
| Actual Study Start Date: | 01/11/2017 |
| Estimated Primary Completion Date: | 09/19/2018 |
| Estimated Study Completion Date: | 10/11/2018 |
Condition or disease
Intervention/treatment
Procedure: open lung approach ventilation strategy
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: open lung approach ventilation strategy Procedure: open lung approach ventilation strategy (OLV). Patients receive volume-controlled mechanical ventilation with a tidal volume of 6 to 8 ml per kilogram of predicted body weight, a PEEP of 6 to 8 cm of water, and recruitment maneuvers repeated every 30 minutes after tracheal intubation. | Procedure: open lung approach ventilation strategy |
| No Intervention: conventional ventilation strategy Procedure: conventional ventilation strategy (NOLV). Patients receive volume-controlled mechanical ventilation with a tidal volume of 6 to 8 ml per kilogram of predicted body weight, no PEEP and no recruitment maneuver. |
Eligibility Criteria
| Ages Eligible for Study | 40 Years To 40 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: 1. Age ≥ 40 years. 2. Undergo elective laparoscopic resection of colorectal cancer. 3. With an expected duration of pneumoperitoneum ≥1.5h. 4. With a preoperative risk index for pulmonary complications ≥ 2. 5. With no contraindication of epidural anesthesia. 6. Pulse oxygen saturation in air ≥ 92%. 7. And informed consent obtained. Exclusion Criteria: 1. American Society of Anesthesiologists (ASA) physical status ≥ IV. 2. Body mass index ≥30kg/m2. 3. Duration of mechanical ventilation ≥ 1h within 2 weeks preceding surgery. 4. A history of acute respiratory failure within 1 month preceding surgery. 5. With a sepsis or septic shock or instable hemodynamics. 6. With a progressive neuromuscular illness such as myasthenia gravis. 7. With a epilepsy or schizophrenia or Parkinson's disease. 8. With a severe chronic obstructive pulmonary disease (COPD) or pulmonary bulla. 9. Severe organ dysfunction (acute coronary syndrome, uremia, hepatic encephalopathy, classification of function capacity of the NYHA ≥III, malignant arrhythmia and so on). 10. Coma, severe cognitive deficit, language or hearing impairment who cannot communicate. 11. Not proper controlled hypertension. 12. Involved in other clinical studies or refused to join in the research. |
Outcome
Primary Outcome Measures
1. Occurrence rate of major pulmonary and extrapulmonary complications [Day 0 to 7 after surgery]
Secondary Outcome Measures
1. Peak airway Pressure [Intraoperative, period of mechanical ventilation]
2. Plateau airway pressure [Intraoperative, period of mechanical ventilation]
3. Static lung compliance [Intraoperative, period of mechanical ventilation]
4. Dynamic lung compliance [Intraoperative, period of mechanical ventilation]
5. Arterial partial pressure of oxygen [pre-anesthesia, 0.5 hour after pneumoperitoneum, 1.5 hours after pneumoperitoneum, 20 minutes after entering PACU]
6. Alveolar-arterial oxygen tension difference [pre-anesthesia, 0.5 hour after pneumoperitoneum, 1.5 hours after pneumoperitoneum, 20 minutes after entering PACU]
7. Arterial- alveolar oxygen tension ratio [pre-anesthesia, 0.5 hour after pneumoperitoneum, 1.5 hours after pneumoperitoneum, 20 minutes after entering PACU]
8. Respiratory index [pre-anesthesia, 0.5 hour after pneumoperitoneum, 1.5 hours after pneumoperitoneum, 20 minutes after entering PACU]
9. Oxygenation index [pre-anesthesia, 0.5 hour after pneumoperitoneum, 1.5 hours after pneumoperitoneum, 20 minutes after entering PACU]
10. Alveolar dead space fraction [pre-anesthesia, 0.5 hour after pneumoperitoneum, 1.5 hours after pneumoperitoneum, 20 minutes after entering PACU]
11. Lactic acid [pre-anesthesia, 0.5 hour after pneumoperitoneum, 1.5 hours after pneumoperitoneum, 20 minutes after entering PACU]
12. Oxygen extraction ratio [The first stage of the study: 0.5 hour after pneumoperitoneum, 1.5 hours after pneumoperitoneum, 20 minutes after entering PACU]
13. Central venous blood oxygen saturation [The first stage of the study: 0.5 hour after pneumoperitoneum, 1.5 hours after pneumoperitoneum, 20 minutes after entering PACU]
14. Advanced glycation end products receptor [Intraoperative (pre-anesthesia, post-operation) and postoperative (postoperative day 3)]
15. S100 beta protein [Intraoperative (pre-anesthesia, post-operation) and postoperative (postoperative day 3)]
16. Tumor Necrosis Factor alpha [Intraoperative (pre-anesthesia, post-operation) and postoperative (postoperative day 3)]
17. Interleukin 6 [Intraoperative (pre-anesthesia, post-operation) and postoperative (postoperative day 3)]
18. The occurrence rate of hypoxemia in PACU [20 minutes after entering PACU]
19. Length of PACU stay [Though study completion, an average of half an hour.]
20. The recovery time from anesthesia [Though study completion, an average of one hour.]
21. Postoperative pulmonary complications [Day 0 to 7 after surgery]
22. Postoperative acute respiratory failure [Day 0 to 7 after surgery]
23. Postoperative suspected pneumonia [Day 0 to 7 after surgery]
24. Pulse oximetry less than 92% [Day 0 to 7 after surgery]
25. Sustained hypoxia [Day 0 to 7 after surgery]
26. Saturation of pulse oximetry [Day 0 to 7 after surgery]
27. Occurrence rate of intervention-related adverse events [Intraoperative, period of mechanical ventilation]
28. Postoperative delirium [Day 1 to 3 after surgery]
29. Occurrence rate of related complications [Day 0 to 7 after surgery]
30. Unplanned reoperation after 24h [Up to 30 days after surgery]
31. Postoperative hospital stay [Up to 30 days after surgery]
32. Lung recruitment maneuver systolic blood pressure changes [The first stage of the study: intraoperative, when lung recruitment maneuver is operated.]
33. Lung recruitment maneuver related diastolic blood pressure changes [The first stage of the study: intraoperative, when lung recruitment maneuver is operated.]
34. Lung recruitment maneuver related mean arterial pressure changes [The first stage of the study: intraoperative, when lung recruitment maneuver is operated.]
35. Lung recruitment maneuver related heart rate changes [The first stage of the study: intraoperative, when lung recruitment maneuver is operated.]
36. Death from any cause. [Up to 30 days after surgery]
37. Unplanned admission to ICU [Up to 30 days after surgery]
38. Impaired oxygenation [before anesthesia induction, 0.5 h and 1.5 h after pneumoperitoneum induction, and 20 min after postanesthesia care unit (PACU) admission]
