Effects of intraoperative PEEP optimization on postoperative pulmonary complications and the inflammatory response: study protocol for a randomized controlled trial

The main objectives of this trial are to compare the effects of a standard LPV applying 6 cmH₂O of PEEP to a LPV using an individually titrated optimal PEEP on: (1) oxygenation and PPC, (2) the degree of inflammatory response evaluated by early PCT kinetics (0, 2, 6, 12, 24, 48 and 72 h after surgical incision) and (3) to evaluate the relationship between the degree of inflammation and postoperative pulmonary and extrapulmonary complications.

The primary outcome variables are PPC and PCT kinetics. PPC are defined as new infiltrates or atelectasis on a chest X-ray, abnormal breathing sounds on auscultation, respiratory failure defined as PaO₂/FiO₂ < 300 or the need for noninvasive or invasive ventilatory support within the first three postoperative days. PCT kinetics will be evaluated during and after surgery. Blood samples will be taken at 0, 2, 6, 12, 24, 48 and 72 h after surgical incision. According to recent data it is expected that PCT values will peak at approximately 24 h after surgery and that they should decline by approximately 50% daily in the case of an uneventful postoperative course. Therefore, in addition to the absolute values the change between T₀–T₂₄–T₄₈ will also be evaluated [16, 22].

Secondary outcome variables are extrapulmonary complications: incidence of circulatory failure, gastrointestinal and renal dysfunction, hematologic and coagulation disorders and infection (Table 1).

Tertiary endpoints are intensive care unit (ICU) days, in-hospital stay, in-hospital and 28-day mortality.

This is an investigator-initiated, double-center, parallel-group, single-blinded, interventional, prospective, randomized controlled trial conducted at the Department of Anesthesiology and Intensive Care of Péterfy Sándor Hospital Budapest and at the Department of Anesthesiology and Intensive Therapy of University of Szeged. The first patient will be randomized in October 2016. This protocol conforms to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Figure 1 shows the Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) schedule of enrollment, interventions and assessments. The SPIRIT 2013 Checklist is given in Additional file 1.

This is a single-blinded (participant) study. Patient data, intraoperative and postoperative measurements, fluid balance, respiratory parameters, laboratory results and clinical status (Sequential Organ Failure Assessment (SOFA) score) will be collected onto Case Report Forms (CRF). CRF and the patient evaluation chart will not be assessed in front of the patient.

Participants will be randomized to the SG or CG in a ratio of 1:1. Randomization will be carried out by a computer-generated blocked randomization list with 10 blocks of four patients per block. Allocation will be stored in sealed, opaque and numbered envelopes. Participants will be included and allocated in numerical order.

All original records (CRF and relevant correspondence) will be archived and secured for 15 years, and then destroyed according to the hospital standards concerning destruction of confidential information.

Patients with bladder cancer scheduled for open radical cystectomy and urinary diversion will be screened and recruited during routine perioperative assessment. Participants fulfilling the inclusion criteria will be asked for their signed informed consent. Withdrawal of consent may be initiated by the participant at any time during the trial.

Inclusion criteria are age over 18 years, patients with bladder cancer undergoing radical cystectomy and urinary diversion (ileal conduit or orthotopic bladder substitute) and provision of signed informed consent.

Exclusion criteria are age below 18 years, American Society of Anesthesiologists (ASA) physical status IV, history of severe chronic obstructive pulmonary disease (COPD, GOLD grades III or IV), history of severe or uncontrolled bronchial asthma, history of severe restrictive pulmonary disease, pulmonary metastases, history of any thoracic surgery, need for thoracic drainage before surgery, renal replacement therapy prior to surgery, congestive heart failure (NYHA grades III or IV), extreme obesity (Body Mass Index, BMI > 35 Kg/m²) and lack of patient’s consent.

A total number of 40 patients with bladder cancer submitted to general anesthesia and open radical cystectomy and urinary diversion will be enrolled in this study. An equal number of patients will be randomized into the two groups.

Patients randomized into the SG group undergo an alveolar recruitment maneuver using the sustained airway pressure by the CPAP method, applying 30 cmH₂O PEEP for 30 s followed by a decremental PEEP titration procedure directed by Cstat. During the PEEP titration procedure, PEEP will be decreased from 14 cmH₂O by 2 cmH₂O every 4 min, until a final PEEP of 6 cmH₂O is reached. On each level of PEEP, ABGs will be collected and evaluated. Optimal PEEP is considered as the PEEP value resulting the highest possible Cstat measured by the ventilator. After the PEEP titration procedure, lung-protective mechanical ventilation will be performed using optimal PEEP and low tidal volumes and ARM will be performed every 60 min.

Patients randomized into the CG group will undergo an alveolar recruitment maneuver using the sustained airway pressure by the CPAP method, applying 30 cmH₂O PEEP for 30 s followed by low-tidal-volume LPV using a PEEP value of 6 cmH₂O and ARM will be repeated every 60 min.

Data monitoring will be performed centrally for quality control purposes by an external, independent physician, who will not be involved in the study. Monitoring will evaluate the progress of the study and verify the accuracy and completeness of the data recording (CRF, source data, Informed Consent Forms and outcome variables).

Data will be analyzed by the research team in collaboration with a medically versed biostatistician after completion of the trial. There will be no interim analysis. Statistical analysis will be conducted on an intention-to-treat basis. IBM SPSS 20.0 statistical software will be used for analysis.

It is expected that the majority of source data will be recorded onto CRF; nonetheless, before starting the data analysis, the mechanism and pattern of missing data will be evaluated and these findings will be used to determine whether they have had an impact on the statistical analysis and results and how they can be managed.

Data distribution will be tested by the Kolmogorov-Smirnov analysis. Normally distributed data will be presented as mean and standard deviation (SD) and skewed data as median (interquartile range). Comparing related samples, the paired and unpaired t test will be used for normally distributed data and the Wilcoxon signed rank test and Mann-Whitney U test for skewed data. Differences in proportions will be evaluated using the Fisher’s exact test, and risk ratio with associated 95% confidence interval (CI). Analysis of the primary endpoint (PPC) will be carried out by the unpaired Student’s t test (95% CI). A two-way, repeated-measures analysis of variance (two-way RM ANOVA) will be used to compare the groups’ serum PCT levels. The relationship between PCT levels and organ dysfunctions will be evaluated using the Pearson correlation. Statistical analysis of SOFA scores, ICU days, in-hospital stay, in-hospital and 28-day mortality data of groups will be implemented by the chi-square test. A P value < 0.05 will be considered significant.

Every patient included in the trial will receive daily visits from an intensive care therapist and urologist in charge from POD 1 until leaving the hospital. During ICU stay, and if necessary on the intermediate care unit, all patients will be continuously monitored. The study nurse will be responsible for collecting blood samples and will record relevant required data onto CRF. During the out-of-hospital follow-up period (until POD 28) patients’ progress, particularly deterioration will be checked by daily phone-call visits.

The investigators will monitor the patients for any adverse events (AEs), which are defined as severe or prolonged hypotension (systolic blood pressure < 90 mmHg) and significant cardiac arrhythmias associated with the PEEP titration procedure. AEs will be documented on the CRF and the principal investigator will be informed.

Serious adverse events (SAEs) are defined as severe barotrauma leading to pneumothorax, significant prolongation of hospitalization, persistent or significant disability or incapacity, and severe deterioration (life-threatening state or even death) associated with the PEEP titration procedure. All treatment-related SAEs will be recorded and reported to the Hungarian Scientific and Medical Research Council Ethics Committee and the Local Ethics Committees. If any SAEs occur, the trial will be interrupted and an investigation will be performed.

The annual number of open radical cystectomy and urinary diversion is around 100 in the two study centers. Recruitment of the participants is expected within 18 months. The final data collection and estimated completion date of the trial is March 2018.

The trial is ongoing.