Effect of Early vs Standard Approach to Tracheostomy
on Functional Outcome at 6 Months Among Patients
With Severe Stroke Receiving Mechanical Ventilation:
The SETPOINT2 Randomized Clinical Trial

Bösel J. JAMA 2022; doi:10.1001/jama.2022.4798

Clinical Question

• In patients with severe stroke does early (≤5 days of intubation) tracheostomy when compared to standard timing (from day 10) of tracheostomy improve functional outcome at 6 months?

Background

• TRACMAN was one of the largest multi-centre RCTs looking at timing of tracheostomy in ICU
  • The results did not provide any evidence supporting early tracheostomy
  • The number of patients with a primary neurological reason for ICU admission were low (~5%) within this trial
• Rates of tracheostomy have been shown to be higher in those with acute brain injury compared to the general ICU population
• Concerns around weak cough, impaired swallow or an inability to maintain a patent upper airway often delay extubation in this population
• The SETPOINT trial looked at the timing of tracheostomy in stroke patients
  • This small pilot RCT of 60 patients found no difference in ICU LOS (the primary outcome) but did show a lower ICU mortality (a secondary outcome)

Design

• Investigator initiated, multi-centre, randomised trial
• Blinding of outcome assessors (long term functional and cause of mortality)
• Outcomes assessed using pre-structured telephone interview
• Informed consent by patient or their legally authorised representative prior to day 4 of intubation
• Randomised in 1:1 ratio
  • Central web-based tool
  • Blocks stratified in groups of 4 to achieve equal group size per centre
• Only centres with routine use of percutaneous dilatational tracheostomy (PDT) were recruited
• Sample sized based on pilot trial
  • 15% increase from 30% to 45% in intervention group
  • With 80% power and alpha of 0.05 and 15% drop out rate a sample size of 380 (190 per group was required)
• Pre-specified subgroups
• Confidence intervals for secondary end-points and subgroups not adjusted for multiplicity
  • Thus, these can only be interpreted as exploratory
• Missing values for mRS at 6 months handled by a multiple imputation approach
• Appropriate ethical approval
• Registered with Clinical Trials

Setting

• 26 neurocritical care units in Germany and USA
• July 2015 – August 2020

Population

• Inclusion:
  • 18 years or older
  • Invasive mechanical ventilation (IMV)
  • Acute ischemic stroke (AIS), intracerebral haemorrhage (ICH) or sub arachnoid haemorrhage (SAH) (all non traumatic)
  • SETscore > 10
    • Predicts the need for IMV for at least 2 weeks
    • Calculated on day of enrolment
  • Clinical judgement of treating neuro-intensivist that tracheostomy likely to be needed
  • Principle indication for tracheostomy had to be at least one of:
    • Ongoing demand for suctioning secretions
    • CNS related respiratory insufficiency
    • aspiration or danger of aspiration due to dysphagia
• Exclusion:
  • mRS > 1 (pre-morbid)
  • IMV > 4 days
  • Clinical conditions prohibiting early tracheostomy or mandating surgical tracheostomy
  • Pregnancy
  • Life expectancy < 3 weeks
  • Anticipated withdrawal of life sustaining therapies
  • Inability to obtain informed consent
  • Participation in other interventional trial
• 4562 assessed for eligibility –> 4180 excluded for not meeting eligibility criteria
  • 188 randomised to early tracheostomy –> 177 had tracheostomy (95.2%)
    • 177 in primary analysis as 9 lost to follow up and 2 withdrew consent
  • 194 randomised to late tracheostomy –> 130 had tracheostomy (67%)
    • 189 in primary analysis as 4 lost to follow up and 1 withdrew consent
• Comparing baseline characteristics (early vs. standard tracheostomy groups):
  • Age: 59.2 vs 57.6
  • Male: 48.4% vs 52.1%
  • Pre-hospital mRS of 0: 86.0% vs 87.1 %
  • Admission:
    • Median NIHSS: 21 vs 21
    • Median GCS: 7 vs 6
    • Median SETscore: 14 vs 14
  • Diagnosis:
    • AIS: 26.3% vs 30.4%
      • Decompressive Craniectomy: 49.0% vs 50.8%
    • ICH: 41.9% vs 40.2%
      • Volume > 30cc: 60.5% vs 71.8%
      • Supratentorial: 71.8% vs 75.6%
    • SAH: 31.7% vs 29.4%
      • WFNS Score: 5 vs 5
      • Fisher Scale of 4: 67.2% vs 73.7%
  • Baseline Lung Injury Score: 1.0 vs 1.0
  • PDT (if tracheostomy performed): 89.3% vs 83.1%
  • Time from intubation: 4 days vs 11 days

Intervention

• PDT within 5 days of IMV

Control

• PDT after 10 days of IMV

Management common to both groups

• Conversion to surgical tracheostomy allowed if clinically warranted
• All other management (including ventilator settings, weaning, analgesia and sedation) centre specific but followed guidelines from American Heart and Stoke Associations and Neurocritical Care Society

Outcome

• Primary outcome:
  • mRS of 0 – 4 or less at 6 months
  • 43.5% in early group vs 47.1% in standard group
    • Absolute difference -3.6% (95% CI -14.3 to 7.2%)
    • aOR 0.93 (95% CI 0.60 to 1.42)

• Secondary outcomes:
• Comparing early vs. standard group
  • No secondary outcome showed a significant difference
    • mRS 0 – 3 at 6 months
      • 24.3% vs 19.6%
        • aOR 1.48 (95% CI 0.89 – 2.48)
    • Death at 6 months
      • 35.0% vs 29.6%
        • aOR 1.06 (95% CI 0.74 – 1.53)
    • Median time to ICU discharge
      • 17 days vs 19 days
        • HR 1.12 (95% CI 0.90 – 1.39)
    • Median time to end mechanical ventilation
      • 14 days vs 11 days
        • HR 0.97 (0.73 to 1.31)
    • No difference in ICU stay without sedatives, opioids or vasopressors
• Subgroups:
  • No subgroup had 95% CI that fully favoured one approach or other
  • These included Age (< 55, 55 – 65, > 65), Sex, Location (USA or Germany), Recruitment Numbers (<30 or > 30), Primary diagnosis (AIS, SAH or ICH), and GCS (<6, ≥6)
• Safety Outcomes
  • (potentially) PDT related adverse event rate 17.3% (eTable 5)
    • 16.9% vs 17.7%
  • Periprocedural adverse events (up to 2 hours post tracheostomy): 15.8%
  • Any serious adverse event:
    • 47.3% vs 43.8%

Authors’ Conclusions

• In patients with severe stroke receiving IMV, early tracheostomy did not improve rate of survival without significant disability at 6 months compared to standard timing
• Clinically relevant benefit or harm can not be excluded due to wide confidence intervals

Strengths

• Multi centre RCT across 2 countries increase external validity
• Although 4130 were excluded, an accurate screening log minimises selection bias and shows that a majority were excluded for valid reasons (not meeting inclusion criteria or meeting exclusion criteria)
  • Only 1.3% (n=55) were excluded for “other” reasons
• Analysed on intention to treat basis
• Balanced baseline characteristics
• Achieved a meaningful separation in timing of tracheostomy
• Good adherence to protocol – no violations reported
• Minimal loss to follow up (3.4%)

Weaknesses

• The primary outcome of an mRS of 0-4 ranges from no disability to moderate severe disability that requires the assistance of others for mobility and daily needs
  • This is a very wide range of functional outcomes. One wonders if a patient who has an mRS of 4 would view this as a “better” functional outcome?
• Secondary end-points regarding ICU medications were defined post-hoc
• Understandably unable to blind clinicians and patients
• No standardised weaning protocol used
• 48.7% of all randomisations came from 4 centres (2 in USA, 2 in Germany)
• 33% of standard tracheostomy group did not receive a tracheostomy
  • 22% were extubated and 11% died prior
  • This confirms prior studies about the utility of the SETscore and its ability to predict those that will be extubated successfully in the short term
  • However, over 1 in 5 patients did not have a procedure that had a near 20% complication rate
• AIS, ICH and SAH may have different clinical courses
  • ICH may have worse functional prognosis than AIS in retrospective studies
• This appeared to be a cohort that had a poor prognosis (evidenced by high decompressive craniectomy rates, and high WFNS scores)
  • This is also evident in the fact that only ~10% in each group had a mRS of 0-2
  • Would a difference be shown if the cohort was less likely to have an unfavourable outcome?

The Bottom Line

• This trial provides no evidence that in patients with severe stroke an early tracheostomy is better than standard time for tracheostomy, and that an early tracheostomy may mean a patient has to undergo a procedure that they did not need

External Links

• [article] SETPOINT2
• [further reading] Early vs Late Tracheostomy in ICU patients: a meta analysis of randomised controlled trials

Metadata

Summary author: George Walker @hgmwalker89
Summary date: 13th May 2022
Peer-review editor: @davidslessor

Picture by: iStock