Sigh Test, Randomization, and Interventions

After enrollment, all patients underwent a 30-min test of addition of sigh to clinical PSV to assess the prevalence of sigh responders vs nonresponders as defined by improved oxygenation. Briefly, the ventilator Fio ₂ was titrated to obtain a peripheral oxygen saturation (Spo ₂) of 90% to 96%, while keeping the same clinical PEEP and PSV levels. Sigh was then added as a pressure control phase set at total end-inspiratory pressure of 30 cm H₂O for a 3-s insufflation time, once per minute. At the beginning and after 30 min, the Spo ₂/Fio ₂ ratio was determined. On the basis of a previous physiologic study, the expected prevalence of sigh responders (ie, patients improving Spo ₂/Fio ₂ by > 1%) was estimated to be 50%.⁵

After completion of the sigh test, patients were randomized by a 1:1 ratio to a strategy of PSV titrated according to a predefined protocol with addition of sigh (sigh group) or to a strategy of PSV titrated according to the same protocol but without sigh (no-sigh group). The local investigators randomized patients using a central, dedicated, password-protected, web-based, automated randomization system. The randomization sequence was generated using a permuted blocks randomization scheme (block size of six).

After randomization, in the sigh group, PSV was targeted to a tidal volume of 6 to 8 mL/kg of predicted body weight (PBW), with a respiratory rate 20 to 35 breaths/min (bpm) and clinical PEEP. Fio ₂ was left as selected during the prerandomization sigh test. Sigh was promptly added as a pressure control breath at total end-inspiratory pressure of 30 cm H₂O for 3 s delivered once per minute. Ventilators were switched to biphasic synchronized positive airway pressure mode (also known as synchronized intermittent mandatory ventilation combining pressure control and PSV) with the lower pressure level set at clinical PEEP and the higher pressure level set at 30 cm H₂O with a 3-s inspiratory time. Sigh settings were left unchanged until switch to controlled ventilation, day 28, death, or performance of a successful spontaneous breathing trial (SBT; see below). In the no-sigh group, after randomization, PSV was set to obtain the same targets as above with clinical PEEP and the Fio ₂ selected during the prerandomization sigh test.

Then, in both groups at least every 8 h, the PSV level was adjusted to maintain a tidal volume of 6 to 8 mL/kg PBW and respiratory rate of 20 to 35 bpm, while PEEP and Fio ₂ were managed to keep the Spo ₂ at 90% to 96%.

In both groups, switch to protective controlled ventilation was indicated when patients fulfilled specific predefined criteria.⁸ Patients switched to controlled ventilation were reassessed at least every 8 h and switched back to the sigh or no-sigh group as soon as predefined criteria for improvement were met.⁸

Patients with Spo ₂ ≥ 90% on Fio ₂ ≤ 0.4 and PEEP ≤ 5 cm H₂O, no agitation, and who were hemodynamically stable underwent an SBT. For patients in the sigh group, the attending physician withdrew sigh, waited 60 min, confirmed the above-mentioned criteria, and performed the SBT; if criteria were no longer met, sigh was reintroduced and this procedure was repeated after at least 8 h. The SBT lasted at least 60 min with a combination of PEEP of 0 to 5 cm H₂O and PSV level of 0 to 5 cm H₂O. Criteria for success vs failure of the SBT were predefined by study protocol.⁸ Subjects successfully completing the SBT were promptly extubated or, in the presence of tracheostomy, mechanical ventilation was discontinued. Patients who failed the SBT were switched back to the sigh or no-sigh group, and criteria for SBT were checked again after at least 6 h. After extubation, reintubation was performed if at least one of the criteria predefined by the study protocol was present.⁸