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High Wean Trial

Dr Swapnil Pawar December 23, 2019 1101 4

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Liberating high-risk patients from mechanical ventilation poses a unique challenge to all intensive care physicians. The use of high flow has increased over the last decade, however, the combination of high flow nasal oxygen and NIV has not been tested so far. The present study published in JAMA tries to answer this dilemma.

Effect of Postextubation High-Flow Nasal Oxygen With Noninvasive Ventilation vs High-Flow Nasal Oxygen Alone on Reintubation Among Patients at High Risk of Extubation Failure: A Randomized Clinical Trial

The decision regarding when to liberate patients from mechanical ventilation faces intensive care unit (ICU) clinicians regularly. While this decision is typically based on a variety of data, there is often considerable uncertainty about the success of extubation.

The data from a study by Thille et al published in Am J Resp Crit care in 2013 suggested that approximately 10% to 15% of patients ready to be separated from a ventilator experience extubation failure leading to reintubation. This figure is controversial itself as in my ICU we have less than 3 % reintubation rates. Also, it partly because how do you define the reintubation. However, we all agree and the evidence supports that reintubation is associated with particularly high mortality.

What’s known so far –

Nava et al. enrolled 97 patients who were randomised 1 h after extubation, following a successful SBT, to receive either NIV (minimum 8 h·day–1 for 2 days) or standard treatment (oxygen therapy). NIV reduced the rate of re-intubation, which resulted in reduced ICU mortality. Ferrer et al. randomised 162 patients considered to be at risk for extubation failure to either NIV (near-continuously for 24 h) or oxygen therapy only. NIV decreased the number of patients developing post-extubation respiratory failure and ICU mortality; however, the rate of re-intubation, ICU and hospital length of stay, and hospital mortality were not significantly different between the two groups. A post hoc analysis showed that NIV improved hospital and 90-day survival in the subgroup of patients who developed hypercapnia during the SBT prior to extubation. Subsequent to these observations, the same authors enrolled a select group of 106 patients with chronic respiratory disorders developing hypercapnia during the SBT to investigate the benefits of NIV, as opposed to oxygen therapy alone, after extubation. The rate of respiratory failure after extubation was lower in the NIV group than in the controls. While ICU and hospital mortality were not different between the treatment and control groups, the 90-day survival rate was significantly improved in the NIV group, as opposed to controls.

Two small single-centre trials (40 patients each) also randomised patients to NIV or standard treatment after planned extubation. Kihlnani et al. enrolled COPD patients and found no differences in intubation rate or ICU and hospital lengths of stay. In a small group of patients for whom the only inclusion criterion was mechanical ventilation for >72 h because of ARF, predominantly secondary to COPD exacerbations, Ornico et al. found a reduction in re-intubation and death in the NIV group.

ATS/ERS guidelines 2017 –

We suggest that NIV be used to prevent post-extubation respiratory failure in high-risk patients post-extubation. (Conditional recommendation, low certainty of evidence.)


Among mechanically ventilated patients at high risk of extubation failure, does the use of high-flow nasal oxygen with noninvasive ventilation after extubation reduce the risk of reintubation compared with high-flow nasal oxygen alone?

Design: Multicentric study including thirty ICUs in France. Patients were randomly assigned to receive high- flow nasal oxygen alone or HFNO combined with noninvasive ventilation after extubation. Computerized randomization in permuted blocks of four. Stratification based on the center and the PaCO2 levels at the end of a SBT of ≤45 or >45 mm Hg).

Population: Inclusion: Adult patients ventilated for more than 24 hours, undergone a successful SBT and were ready for extubation. Patients were enrolled if they were at high risk of extubation failure defined as:

  • Age more than 65 years
  • Left ventricular dysfunction due to any cause with EF less than 45%
  • History of cardiogenic pulmonary edema
  • Documented ischemic heart disease
  • Atrial fibrillation  
  • COPD
  • Obesity-hypoventilation syndrome
  • Restrictive lung disease

Excluded: Home NIV, contraindication to non-invasive ventilation, chronic neuromuscular disease, traumatic brain injury, patients who suffered accidental extubation, do-not-reintubate status at extubation

Intervention: NIV commenced immediately after extubation with an initial period of at least 4 hours. The minimum duration of NIV of at least 12 hours a day during the first 48 hours after extubation. Uninterrupted NIV was encouraged during the night. Pressure support mode with a minimal pressure-support level of 5 cm H2O with a target tidal volume of 6–8 ml/kg of predicted body weight. PEEP between 5–10 cm H2O, FiO2 titrated to >92%. HFNO was applied during the periods of time when NIV was interrupted. This type of therapy was continued for 48 hours.

Control: HFNO at 50 L/min and a fraction of inspired oxygen (FIO2) titrated to pulse oximetry (SpO2) of at 92% or more. Humidifier temperature set at 37°C. This was continued for 48 hours after extubation as well.

Common management:

Standard oxygen therapy after 48 hours in both groups

Reintubation criteria

Severe respiratory failure

  • Respiratory >35 breaths per minute
  • Use of accessory respiratory muscles
  • Respiratory acidosis: pH level below 7.25 units and PaCO2 greater than 45 mmHg
  • Hypoxemia: FIO2 requirement of 80% or more to maintain an SpO2 level at 92% or more, or a P/F ratio 100 or less.
  • Hemodynamic failure with the requirement for vasopressors
  • Neurological failure (altered consciousness with a Glasgow Coma Scale score <12),
  • Cardiac or respiratory arrest

How did they calculate the sample size? The investigators assumed an 8% reduction in the rate of reintubation with combination therapy from 18% to 10%. 590 patients for a power of 80% at a 2-sided α level of 0.05.

During the approximately one-year study period, 3121 patients were extubated.

Out of this, 1460 were excluded; 927 (majority) were at low risk of extubation failure (who were obviously not included in the study) 414 were ventilated for <24 h.

 Among 1661 who were extubated after 24 h of ventilation 692 were excluded for various reasons, including 274 do-not-reintubate status, 182 were on long-term NIV at home, 119 accidental extubations, 41 had a contraindication to NIV, 30 had a chronic neuromuscular disease, 37 had TBI.

969 patients were assessed for eligibility; 321 not included (270 No staff available or logistic issues 51 declined participation). Finally out of 648 patients, 306 randomized to receive HFNO (302 received the allocated intervention); 342 to NIV plus HFNO (339 received the allocated intervention).

Primary outcome: Reintubation within 7 days of extubation: was significantly lower 11.8% (95% CI, 8.4%- 15.2%) vs. 18.2% (95% CI, 13.9%- 22.6%) (difference, −6.4% [95% CI, −12.0 to −0.9]; P = .02)

Secondary outcomes:

Reintubation at 48 hours: Significantly higher with HFNC alone

Reintubation at 72 hours: Significantly higher with HFNC alone

Reintubation until ICU discharge: Significantly higher with HFNC alone

Post-extubation respiratory failure within 7 days following extubation

  • Respiratory rate >25 breaths per minute
  • Clinical signs of respiratory distress
  • Respiratory acidosis: pH level <7.35 and PaCO2 >45 mm Hg
  • Hypoxemia: FIO2 of 50% or higher for SpO2 level minimum 92%,
  • P/F ratio 150 mm Hg or less.

Higher with HFNC alone

Not different were the ICU and hospital length of stay

ICU mortality: Not different

Hospital mortality: Not different

28-d mortality: Not different

90-d mortality: Not different

Exploratory outcomes

Arterial blood gases 1 hour after treatment initiation: higher with NIV

Time to reintubation: Not different

The proportion of patients who met criteria for reintubation: Higher with HFNC alone

Indication for reintubation

Severe respiratory failure: 88 patients

Neurological failure: 37 patients

Hemodynamic failure: 16 patients

Respiratory or cardiac arrest: 10 patients

Use of NIV as rescue therapy: 20 patients in the HFNC group received rescue NIV; 10 were reintubated

Mortality or reintubation in ICU: More with HFNC

Mortality of reintubated patients: Not different

Additional analysis

Among patients with a PaCO2 of 45 mm Hg or less, re-intubation rates at day 7 were not significantly different between groups (13% with noninvasive ventilation vs 18% with high-flow nasal oxygen alone; difference, −5.0% [95% CI, −11.2% to 1.1%]; P = .10). After adjustment for PaCO2 level at enrollment (≤45 or >45 mm Hg) and underlying chronic lung disease, the odds ratio for reintubation at day 7 remained significantly lower with noninvasive ventilation than with high-flow nasal oxygen alone.

The post hoc analysis showed a lower reintubation rate with noninvasive ventilation after adjustment for the hospital random effect

Strengths –

the combination of high-flow nasal oxygen with noninvasive ventilation had not been previously assessed after extubation in the ICU

Largest RCT on this topic

Reintubation rates almost exactly the expected rates in the 2 groups (18.2% and 11.8%), reinforcing the external validity of the study.

Multicentre with a standardised protocol, baseline similarity, a sick cohort of patients and objective criteria for reintubation.

Limitations –

  • high-flow nasal oxygen rather than standard oxygen was used in the control group. ( 3 – group design would have been preferable.
  • attending physicians could not be blinded to the study group and this could have modified the decision of reintubation by promoting early reintubation in patients treated with high-flow nasal oxygen alone.
  • inclusion criteria identifying patients at high risk were different from previous studies.
  • the weaning protocol and the type of spontaneous breathing trial performed before extubation may have influenced the results.
  • Approximately one-third of patients treated with high-flow nasal oxygen alone received noninvasive ventilation as rescue therapy in case of post-extubation respiratory failure.
  • 14 % of patients in each group went from assist control to t-piece trial.
  • t-piece trial as SBT is itself questionable. Also, PEEP used prior to and post-extubation is 5 cm H2O.
  • At the end of the t-piece trial, approximately 25% of patients in each group had an ineffective cough and nearly 40% of patients in each group had abundant secretions.
  • More patients with underlying chronic lung disease, especially COPD, in the NIV group
  • The study applies only to patients with a relatively short duration of ventilation (median duration of ventilation of 5 days)
  • It is possible that the beneficial effect seen with the combination therapy may have been entirely due to NIV; HFNO may not have offered any extra benefit in the combination arm
  • Could the beneficial effect of NIV have been solely among patients with a high PCO2?
  • NIV was used as rescue therapy in 20/70 patients in the HFNC group who developed post-extubation respiratory failure

Summary –

Combination of NIV and High flow nasal oxygen is beneficial in high-risk patients to prevent re-intubation

Appropriate selection of patients for the combined strategy is warranted.

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