Early extubation followed by immediate noninvasive ventilation vs. standard extubation in hypoxemic patients: a randomized clinical trial (1)

Background: Non-invasive ventilation (NIV) has been established to be an effective modality to facilitate extubation in the presence of hypercapnia, especially in patients with chronic obstructive pulmonary disease, cardiogenic pulmonary edema, and following abdominal surgery.(2) However, NIV use to expedite liberation from invasive mechanical ventilation (iMV) in non-hypercapnic patients with hypoxemic respiratory failure has not been adequately investigated.  The present study was conducted to evaluate the efficacy of NIV in facilitating liberation from mechanical ventilation among non-hypercapnic patients with hypoxemic respiratory failure.

Setting: The study was conducted over a 3-y period in six Chinese and three Italian intensive care units of academic centers in both countries.

Population: Adult patients who were on mechanical ventilation for more than 48 h were eligible if they had (1) a P/F ratio of 200–300 on an FiO2of 0.6 or less on pressure support ventilation with a total applied pressure of  25 cm of H2O or less, with a PEEP of 8–13 cm of H2O; (2) a respiratory rate of 30/min or less; (3) PaCO2of 50 mm Hg or less and a pH of 7.35 or more; (4) a tidal volume of less than 8 ml/kg of ideal body weight, (5) a normal GCS, and (6) a temperature of less than 38.5 C. Patients had an adequate cough with requirement for endotracheal suctioning of less than two times per hour. After exclusion of 1129/1259 eligible patients for various reasons, including hemodynamic instability, vasoactive agent use, life-threatening arrhythmias, sepsis, two or more organ failures, and BMI of > 30 kg/cm2, 130 patients were randomized.

Intervention: Patients were extubated and commenced on NIV using the same settings on pressure support mode at the time of extubation. NIV pressures were weaned down according to a protocol. Briefly, this involved increasing the PEEP and waiting if the P/F was less than 225; once the P/F was more than 225, the PEEP and inspiratory pressure levels were weaned down. NIV was ceased when the P/F ratio was more than 250 mm Hg at a PEEP of 8 cm H2O and PS of 10 cm H2O. Following this, patients were put on a ventimask at FiO2of 0.35 to maintain pH ≥7.35, PaCO2 ≤50 mmHg, P/F ratio≥200 mmHg and respiratory rate of ≥ 30/min.

Control: Invasive ventilation was continued using the same protocol-based, stepwise reduction in inspiratory pressure and PEEP levels used to wean down NIV support in the intervention arm. Prophylactic NIV could be used soon after extubation for a maximum duration of 12 hours at the discretion of the treating physician.

In both groups, respiratory failure requiring reintubation, NIV, or non-invasive CPAP within 48 hours of unassisted breathing was considered as “treatment failure”.

Primary outcomes: The co-primary outcomes evaluated in the study were (1) the duration of iMV and (2) the duration of ICU stay. The duration of iMV was significantly less with early extubation to NIV [5.5 (4.0–9.0) vs. 4.0 (3.0–7.0) days; p = 0.004). The duration of ICU stay was not significantly different between groups [9.0 (6.5–12.5) vs. 8.0 (6.0–12.0) days, p = 0.259]. Surgical patients seemed to benefit most from NIV-facilitated early extubation.

Secondary outcomes: The incidence of treatment failure, serious adverse events, and requirement for tracheostomy were not significantly different between groups; the ICU and hospital mortality were also not significantly different. The incidence of ventilator-associated pneumonia and tracheobronchitis, use of sedatives, and hospital length of stay were significantly lower with early extubation to NIV. On Kaplan Meir analysis, the total duration of iMV and NIV combined was not significantly different between groups.

Comments: The study was conducted on patients with P/F ratios of 200–300, on pressure support ventilation. Conventional practice in most settings among such patients would be to expedite weaning, using a short spontaneous breathing trial and consider extubation if successful.(3,4) It is likely that extubation may have been unnecessarily delayed in most patients in the control group who underwent continued iMV and weaning using a stepwise protocolized approach. The similar duration of ICU length of stay, in spite of a minimal difference of approximately 1.5 days of iMV, would also support the possibility that most patients in the control arm were also ready for earlier extubation. The shorter duration of hospital stay in the treatment arm is hard to explain, considering that the duration of ICU stay was similar. Almost 90% of eligible patients were excluded for various reasons, which questions the validity of the findings in the real world. Besides, in an unblinded study, wherein observers are aware of group allocation, performance and detections biases are likely, that could have affected the final results. The study was conducted across multiple centers in only two countries which may limit generalizability.

My take: In our practice, a P/F ratio of 200–300 on any level of pressure support ventilation would be an indication for a short spontaneous breathing trial and extubation if the patient is able to sustain. We would use NIV post extubation in selected patients, based on clinical judgment. I strongly feel that this study just shows that a complex weaning protocol may delay extubation in patients who are otherwise ready for liberation from invasive mechanical ventilation

What is your weaning and extubation policy?  Please offer your valuable comments.


  1. Vaschetto R, Longhini F, Persona P, Ori C, Stefani G, Liu S, et al. Early extubation followed by immediate noninvasive ventilation vs. standard extubation in hypoxemic patients: a randomized clinical trial. Intensive Care Med [Internet]. 2018 Dec 10 [cited 2018 Dec 27]; Available from: http://link.springer.com/10.1007/s00134-018-5478-0
  2. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure | European Respiratory Society [Internet]. [cited 2018 Dec 27]. Available from: https://erj.ersjournals.com/content/50/2/1602426
  3. Perkins GD, Mistry D, Gates S, Gao F, Snelson C, Hart N, et al. Effect of Protocolized Weaning With Early Extubation to Noninvasive Ventilation vs Invasive Weaning on Time to Liberation From Mechanical Ventilation Among Patients With Respiratory Failure: The Breathe Randomized Clinical Trial. JAMA. 2018 Nov 13;320(18):1881.
  4. Nava S, Gregoretti C, Fanfulla F, Squadrone E, Grassi M, Carlucci A, et al. Noninvasive ventilation to prevent respiratory failure after extubation in high-risk patients: Crit Care Med. 2005 Nov;33(11):2465–70.


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