Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients

Olsen et al. NEJM. Published February 16, 2020. DOI: 10.1056/NEJMoa1906759

Clinical Question

• In critically ill, mechanically ventilated patients, does a strategy of no sedation, as compared with light sedation with daily sedation breaks, impact day 90 mortality?

Background

• Sedation during mechanical ventilation improves patient comfort and may help with ventilator synchronisation
• However prolonged and deep sedation has significant side effects, including increased duration of mechanical ventilation, impaired neuromuscular function and delirium (Guerin editorial NEJM 2020)
• Several major trials (Kress et al NEJM 2000, Girard et al Lancet 2008) demonstrated that reducing the amount sedation during mechanical ventilation improved outcomes, although the optimal “dose” is not clear
• A single center RCT by the same authors of this study (Strom et al Lancet 2010) suggested that no sedation, as compared to light sedation with daily interruption of sedation, was associated with more days free of mechanical ventilation (13 vs 9 p=0.019) and shorter stay in the ICU (13 vs 22 p=0.031)
• The following multicentre trial investigated whether a strategy of no sedation compared to one of light sedation (with daily interruption of sedation), would impact day 90 mortality

Design

• Investigator-initiated, randomised, clinical, parallel-group, multinational, superiority trial
• Patients randomly assigned in a 1:1 ratio using a computer generated assignment sequence with a variable block size
• Stratification by participating center, age ≤65 yo or >65 and the presence of absence of shock (<70mmHg or ≥70mmHg)
• No blinding of investigators, patients or relatives
• Pre published statistical plan with an intention to treat analysis
• No provision for correcting for multiple comparisons of secondary outcomes
• No industry funding
• Sample Size
  • Calculated from the groups previous study where mortality in the no sedation group was 36%, and in the light sedation 47% (Risk reduction 25%)
  • Assuming a relative risk reduction of 25%, an alpha score of 5%, and beta score of 20%, the sample size to provide 80% power is 700 patients

Setting

• 8 Scandinavian ICUs (5 Denmark, 2 Norway, 1 Sweden)
• 1:1 nursing-patient ratios in most of the participating ICUs
• January 2014 to November 2017

Population

• Inclusion: ≥18 years old, intubated <24hours prior and expected to be ventilated ≥24hours
• Exclusion: Severe head trauma, therapeutic hypothermia, status epilepticus or had participated in the previous trial, transferred from another ICU with a length of stay ≥48 hours, were comatose on admission, were brain dead, or had a partial pressure of oxygen to fraction of inspired oxygen of ≤9 kPa, or if sedation was anticipated to be necessary for oxygenation or proning.
• 2300 patients were screened
• 710 enrolled in trial (336 declined)
• 354 in the no sedation group and 356 in light sedation
• 10 patients excluded leaving 700 in modified ITT analysis.
• No loss to follow-up
• Mean age was 71 years old
• Median APACHE score 25.5
• 68% medical admissions
• Pneumonia/ARDS most common cause (42%)
• The two groups were similar at baseline except APACHE II was 1 point higher in the non sedation group

Intervention

• No sedation
  • Patients received no routine sedation
  • Bolus doses of morphine for analgesia
  • Sedation (ie cross over) could be given after both non pharmocological (reassurance or mobilisation) and pharmacological (analgesia) were given, but was discouraged

Control

• Light sedation
  • Patients received continuous sedation aiming for RASS (Richmond Agitation Sedation Scale) of -2 to -3
  • Propofol for first 48hours, then swapped to midazolam
  • Daily sedation breaks each morning aiming to get to full wakefulness
  • Sedation was
    • Weaned to half dose if able to complete simple commands
    • Not resumed if PEEP ≤5cmH20 and FiO2 ≤40
    • Resumed if patient not comfortable during wake up period
  • Anxiety or withdrawal was treated with clonidine

Management common to both groups

• Analgesia (ie paracetamol and morphine bolus) given as required
• CAM ICU delirium screen done at least twice daily
  • Treatment started with non pharmacological means, then haloperidol or olanzapine
• Prophylactic low molecular weight heparin

Outcome

• Primary outcome 90 day mortality – no significant difference
  • No sedation vs light sedation 148 (42.4%) vs 130 (37.0%) (5.4 percentage points; 95% CI −2.2 to 12.2; P = 0.65)
• Secondary outcomes:
• Comparing no sedation vs light sedation patients:
  • No significant difference in:
    • Days until death: 13 vs 12
    • Mechanical ventilation free days in 1st 28 days: 20 vs 19
    • ICU days: 13 vs 14
    • Days free from coma or delirium: 27 vs 26
    • Highest RIFLE score: 2 vs 2
    • Accidental extubation requiring reintubation within 1 hour 4 (1.1%) vs 1 (0.3%)
  • Significant reduction in no sedation group
    • Major thrombotic events (PE or DVT)
      • 1 (0.3%) vs 10 (2.8%)
  • Significant increase in no sedation group of
    • Accidental extubation requiring reintubation <24 hours
      • 31 (8.9%) vs 14 (4%) p=0.01
    • Accidental removal of other equipment (NGT, art line)
      • 53 (15%) vs 32 (9%) p=0.01
• Impact of the protocol:
  • No sedation group received higher doses of morphine over the first 3 days (0.0073 vs 0.006 Mg/kg/hr), while sedation group received more propofol and midazolam over the whole study (Supplement)
    • However 27% of no sedation group crossed over to receive sedation during the first 24hours after randomization
    • Agitation was the commonest reason for sedation, followed by oxygenation difficulties
  • Separation of the RASS score was only 1 on day 1 (-1.3 vs -2.3) and 1 on day 7 (-1.8 vs 2.8)

Authors’ Conclusions

• Among critically ill adults receiving mechanical ventilation in the ICU, mortality at 90 days did not differ significantly between those assigned to a plan of no sedation and those assigned to a plan of light sedation (i.e. to a level at which the patient was rousable) with daily interruption

Strengths

• Clinically important question applying to significant number of mechanically ventilated ICU patients
• A priori publication of trial protocol and statistical plan
• Conducted in three countries across 8 sites
• No loss to follow up

Weaknesses

• Separation of the two groups (RASS of 1 point) was arguably too little to test the study hypothesis.
  • Significant cross over from no sedation to light sedation  likely contributed to this
• No blinded assessments
• 14% of screened patients declined to participate in the study potentially leading to selection bias
• Other interventions that occurred while not sedated were not described (e.g mobilisation, communication)
• Mortality as a primary outcome in sedation trials is controversial
• No PTSD/psychological or patient wellbeing assessments presented
• Not generalisable to ICUs without 1:1 nursing:patient ratios
• No assessment of nursing workload
• Powered to detect a 25% relative risk reduction in mortality. Differences less than this would still be clinically significant

The Bottom Line

• This study reported no significant difference in 90 day mortality with the use of no sedation vs. light sedation strategies
• Although there were reduced DVT/PE episodes in the no sedation group, there were more accidental extubations and removal of other equipment
• I will continue to my practice to target light sedation (ie RASS -2 to 1) combined with daily sedation breaks, while being careful to avoid over sedation
• The mortality point estimate favours light sedation and raises questions about the safety of a no sedation strategy
• Further studies in this area should include assessment of the psychological effects on patients of no sedation, nursing workload, as well as whether this is feasible in other ICU environments

 

External Links

• [article] Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients
• [further reading] SCCM Guideline: Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU

Metadata

Summary author: @aidanburrell
Summary date:  19th Feb 2020
Peer-review editor: @davidslessor