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Dr Swapnil Pawar February 28, 2020 119

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Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients

Invasive mechanical ventilation after tracheal intubation is among the most frequently performed procedures in adult patients admitted to the intensive care unit (ICU). Sedation and analgesia are provided at the time of intubation and may be maintained for hours or days. The aim of sedation is to minimize oxygen consumption and facilitate a patient’s ability to remain comfortably connected to a ventilator. Over the past two decades, it has been recognized that prolonged and deep sedation can increase the duration of mechanical ventilation, delay weaning, impair neuromuscular function, produce delirium, and have side effects specific to certain sedative drugs,1 such as prolongation of their effect after discontinuation because of pharmacokinetic changes. However, omitting sedation for mechanical ventilation is complicated by the reluctance of caregivers to nurse patients who are agitated or in pain.

Daily sedation interruption (DSI) is thought to limit drug bioaccumulation, promote a more awake state, and thereby reduce the duration of mechanical ventilation

 Although advances in technology have made modern ventilators more comfortable for patients, it has generally been believed that light sedation should accompany mechanical ventilation.

 What’s known on this topic so far?

In a trial published in the Journal in 2000, daily interruption of sedation resulted in fewer days on mechanical ventilation and in the ICU than usual care.2 This approach was extended in a trial in which early implementation of daily interruption of sedation was combined with a weaning protocol; the trial showed that the time to extubation and the length of ICU stay were shorter and survival was longer with this combined approach than with usual care.

However, that a meta-analysis did not entirely support the hypothesis that the approach of daily interruption of sedation was better than foregoing daily interruption.

In a single-center trial published in 2010 in Lancet, we reported that a plan of no sedation was associated with more days without mechanical ventilation and a shorter stay in the ICU or hospital than a plan of sedation with daily interruption.5 The trial was not statistically powered to show a difference in mortality between the trial groups (the nonsedation group and the sedation group).

Of 428 patients assessed for eligibility, we enrolled 140 critically ill adult patients who were undergoing mechanical ventilation and were expected to need ventilation for more than 24 h. Patients were randomly assigned in a 1:1 ratio (unblinded) to receive: no sedation (n=70 patients); or sedation (20 mg/mL propofol for 48 h, 1 mg/mL midazolam thereafter) with daily interruption until awake (n=70, control group). Both groups were treated with bolus doses of morphine (2.5 or 5 mg).

A post hoc analysis showed a lower incidence of acute renal failure in the nonsedation group.

According to recent international guidelines on sedation for mechanical ventilation, a RASS score of −2 to + 1 is defined as light sedation.

(SPICE) III trial, which was recently published in the Journal, the sedation goal was light sedation, but the investigators reported a median RASS score of −3 to −5 for more than 40% of the patients both groups. So there is discrepancy in what we want and what we achieve on day to day basis.

Question –

Whether a plan of no sedation in patients receiving mechanical ventilation would result in a better survival outcome than a plan of light sedation with daily interruption.

Design: This study was a randomized controlled trial involving eight Scandinavian ICUs (Denmark 5, Norway 2, Sweden 1). The assignment sequence was computer generated with a variable block size. Patients were stratified according to participating center, age (≤65 years or >65 years), and the presence or absence of shock on arrival (systolic blood pressure, <70 mm Hg or ≥70 mm Hg)

Study population

Inclusion criteria:

Adult patients, 18 years and older, within 24 hours of intubation, and expected to receive mechanical ventilation for more than 24 hours.


Severe TBI

Patients who underwent therapeutic hypothermia

Status epilepticus

Patients who were in a coma


P/F ratio of 9 (67.5 mm Hg) or lower

Sedation necessary for oxygenation or patients were prone ventilated.

No sedation group: Bolus morphine for pain relief as judged by the physician; no sedatives were administered.  Patients were awake and able to communicate and allowed to have a natural sleep rhythm. If, sedation was considered necessary, in spite of nonpharmacologic management or analgesic treatment, similar sedative medications as in the sedation group were administered. Crossover to the sedation group was not allowed.

Sedation group: Sedatives administered as continuous infusion; propofol for the first 48 h, and midazolam after 48 h. Titrated to −2 to−3 on the Richmond Agitation and Sedation Scale. Sedation was interrupted every morning aiming for a fully awake state. This meant,  at least three of the following requirements were met. 1. Open eyes to call 2. Follow instructions with the eyes 3. Squeeze the examiners hand on command 4. Protrude tongue on command. Weaning was attempted during this period; if the PEEP could be reduced to 5 cm H2O and FiO2 to 0.4, sedation was not recommenced. Otherwise, sedation was continued at half the dose. Sedation was recommenced if the patient was uncomfortable. Boluses of clonidine were administered for anxiety.

Common management: A basic analgesic regimen with paracetamol and bolus opioids. Epidural analgesia as appropriate. Delirium assessment using the CAM-ICU method twice a day (delirium present, no delirium, or unable to evaluate). Non-pharmacological methods by reassurance and mobilization if delirium was present. Haloperidol or olanzapine if non-pharmacological methods were ineffective. ICU discharge according to local practice and physician judgement. Thrombo-prophylaxis according to usual practice.

Sample size calculation: 700 patients (350 in each group) would provide the trial with 80% power to show that an intervention would result in a 25% lower relative risk of in-hospital death, assuming a of type I error of 5% and of type II error of 20%.

2300 patients assessed for eligibility  1590 excluded (mostly for not fulfilling inclusion criteria)  710 randomized

Acute Physiology and Chronic Health Evaluation (APACHE) II was 1 point higher in the non-sedation group than in the sedation group. Otherwise, both groups were matched at baseline.

Primary outcome (no sedation vs. sedation)

All-cause mortality at 90 d: Not different

148/349 (42.4) vs 130/351 (37.0). Absolute difference: 5.4 (−2.2 to 12.2)

Secondary outcomes (no sedation vs. sedation)

Patients with DVT/PE up to 90 d 1 (0.3) vs. 10 (2.8); −2.5% (−4.8 to −0.7) (significantly less with nonsedation)

No: of days until death up to 90 d: 13 (6–27) vs. 12 d (5–28);  1(−2to5)

Coma-free (RASS score of at least −3) and delirium-free (a negative CAM-ICU assessment)  days until 28 d: 27 vs. 26; 1(0to2). (One coma-free, delirium-free day in 28 d with nonsedation)

Highest score on RIFLE up to 28 d: 2 vs. 2 0; (−1to1)

ICU LOS until 28 d or until death (whichever occurred first): 13 (0-23) vs. 14 (0-23); −1(−7to4)

Ventilation-free days up to 28 d: 20 (0–26) vs.  19 (0–25); 1 (−3 to 3)

Exploratory outcomes

Accidental extubations (with reintubation within 1 h): An accidental extubation that led to reintubation within 1 hour occurred in four patients (1.1%) in the non-sedation group and in one patient (0.3%) in the sedation group (unadjusted risk difference, 0.8 percentage points; 95% CI, −0.7 to 2.6; P = 0.20).

Accidental CVC removals (with reinsertion within 4 h): None

Strengths –

  1. Multicentre RCT
  2. Challenges the dogma that every patient must receive sedation.
  3. More of feasibility
  4. Looked at Sick cohort of patients – mortality around 40% in each group and APAChe of 22-24
  5. Majority patients were ventilated for medical problems rather for post op elective ventilation.

Limitations –

  1. Non-blinded
  2. Large number of exclusions – 14.6% of the patients who were assessed for eligibility declined to participate in the trial, which is greater than the percentage of patients (8%) who declined to participate in a previous trial
  3. The patients were approximately 70 years of age on average, and the p/F ratio used for mandating sedation was 68 mmHg which is much lower than standard practice.
  4.  The patients in the nonsedation group had 1 more day free from coma or delirium than those in the sedation group. Because the trial outcomes were recorded on a daily basis, a difference of 1 day could encompass any duration between 1 and 24 hours.
  5. Even though crossover was discouraged, 27% of the patients in the nonsedation group received sedation during the first 24 hours after randomization.
  6. the Kaplan–Meier survival curves in Figure 3 of the article are shown to separate by day 15, which perhaps suggests that after ICU discharge, mortality tended to be higher in the nonsedation group than in the sedation group.
  7. The trial may have been underpowered because it depended on the outcomes from the preliminary trial to calculate the power. Actual power is 27% as per the editorial.
  8. Mortality at 90 days was 42% in the nonsedation group and 37% in the sedation group (relative risk, 1.10; 95% confidence interval, 0.90 to 1.35), a difference that was not significant; this finding is in contrast to that in the previous preliminary trial,5 in which mortality was 36% and 47%, respectively — a result in the opposite direction from the current trial.
  9. High incidence of adverse events in non-sedation group – Accidental self extubations requiring re-intubations, accidental removal of central lines of other equipment such as NG tubes, arterial lines were significantly higher.

Conclusion –

The results from this trial are important because they arouse concern about omitting sedation in mechanically ventilated patients and reinforce the need to monitor sedation clinically with the aim of discontinuing it as early as possible or at least interrupting it daily. Such monitoring should be performed continuously (24 hours per day, every day) on the basis of standardized criteria that can be applied uniformly in an ICU.

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