Study Intervention

Mechanical ventilation will be administered through the anesthesia ventilators in use in each individual center participating in the study. Patients will undergo volume–controlled mechanical ventilation with the lowest possible oxygen fraction (but at least 0.4) to maintain an oxygen saturation of 93% or higher, an inspiratory to expiratory ratio (I:E) of 1:2 and a respiratory rate adjusted to normocapnia (end–tidal carbon dioxide partial pressure between 35 and 45 mmHg). It is left to the discretion of the attending anesthesiologist to use a higher fraction of inspired oxygen.

Tidal volume will be set to 7 ml/kg Ideal Body Weight (IBW). The IBW is calculated according to a predefined formula: 50 + 0.91 x (centimeters of height – 152.4) for males and 45.5 + 0.91 x (centimeters of height – 152.4) for females. Tidal volume throughout this protocol refers to the actual inspired tidal volume in the ventilator circuit. The PEEP level is selected according to the randomization group, i.e. 4 cmH2O with the lower PEEP level, and 12 cmH2O with the higher PEEP level.

The recruitment maneuver, as part of the high-PEEP strategy, will be performed directly after induction of anesthesia, after any disconnection from the mechanical ventilator, every one hour during surgery, and before end of surgery, in a hemodynamically stable situation as judged by the anesthesiologist. The recruitment maneuver is not easily applied with available anesthesia ventilators since not all machines have an inspiratory hold function and adequate facilities. To obtain standardization among centers, recruitment maneuvers will be performed in volume–controlled ventilation, as follows:

1. Set peak inspiratory pressure limit to 55 cmH2O
2. Set tidal volume to 7 ml/kg IBW and respiratory rate to 6 or higher breaths/min, while PEEP is 12 cmH2O (or higher if during rescue)
3. Set inspiratory to expiratory ratio (I:E) to 1:1
4. Increase tidal volume in steps of 4 ml/kg IBW until plateau pressure reaches 40 – 50 cmH2O
5. If the maximum tidal volume allowed by the anesthesia ventilator is achieved and the plateau pressure is lower than 40 cmH2O, increase the PEEP as needed, but maximum 20 cmH2O
6. Allow three breaths while maintaining plateau pressure of 40 – 50 cmH2O
7. Set respiratory rate, I:E, inspiratory pause and tidal volume back to pre-recruitment values, while maintaining PEEP at 12 cmH2O (or higher if during rescue)

Anesthesiologists may deviate from the ventilation protocol at any time if concerns about the patient’s safety arise, or upon the surgeon’s request. If one of the following complications occurs and is unresponsive to specific conventional therapy, PEEP may be modified according to the anesthesiologist's judgment:

• Systolic arterial pressure lower than 90 mmHg unresponsive to fluids and/or vasoactive drugs
• New arrhythmias unresponsive to the treatment suggested by the Advanced Cardiac Life Support Guidelines
• Need for a dosage of vasoactive drugs at the tolerance limit, as judged by the anesthesiologist
• Need of massive transfusion, defined as replacement of >100% blood volume in 24 hours or >50% of blood volume in 4 hours (adult blood volume is approximately 70 mL/kg), to maintain Hct > 21% (Hb > 7 mg/dl)
• Life-threatening surgical complication (injury to the hemodynamic and respiratory system and brain, including major bleeding, tension pneumothorax, intracranial injury)

In case of oxyhemoglobin desaturation (SpO2 ≤ 92%) of a patient in the lower PEEP level group, after exclusion airway problems, auto-PEEP hemodynamic impairment, and ventilator malfunction, a rescue strategy is provided according to a predefined table (first stepwise increase of FiO2, second stepwise increase of PEEP, ultima ratio: recruitment maneuver)

In case of desaturation (SpO2 ≤ 92%) of a patient in the higher PEEP level group, it is crucial to exclude hemodynamic impairment as a possible cause. Also, airway problems, auto-PEEP, and ventilator malfunction must be ruled out as possible causes. Provided those factors are excluded, a rescue strategy is allowed according to a predefined table (first stepwise increase of PEEP with optional recruitment maneuver, second stepwise increase of FiO2). If SpO2 deteriorates further during this rescue in an otherwise hemodynamic stable patient, consider reducing the PEEP to 10 and then 8 cmH2O.

Routine general anesthesia, post–operative pain management, physiotherapeutic procedures and fluid management will be performed in the intra–operative and/or post–operative period according to each center's specific expertise and clinical routine. However, the investigators suggest:

• To use inhalational isoflurane, desflurane or sevoflurane, intravenous propofol, remifentanil or sufentanil, and cis-atracurium, atracurium, vecuronium, or rocuronium (as required)
• To use balanced solution of prostigmine, or neostigmine and atropine or glycopyrrolate for reversal of muscle relaxation, guided by neuromuscular function monitoring (for example train-of-our)
• To perform postoperative pain management in order to achieve a VAS pain score below 3. Regional or neuraxial analgesia should be used whenever indicated
• To use physiotherapy by early mobilization, deep breathing exercises with and without incentive spirometry and stimulation of cough in the postoperative period
• To avoid fluid under and overload (according to the discretion of the anesthesiologist) To use invasive measurement of arterial blood pressure whenever indicated
• To use appropriate prophylactic antibiotics whenever indicated

Routine intra–operative monitoring should include noninvasive blood pressure measurements, pulse oximetry, end–tidal carbon dioxide fraction and electrocardiography. Every patient should receive at least one peripheral venous line to allow adequate fluid resuscitation during the study period. Nasogastric tubes, urinary bladder catheters and/or other intravenous catheters, as well as other, more invasive monitoring may be used according to local practice and/or guidelines. Other procedures should follow the Safe Surgery Checklist