Sedative agents are commonly administered to patients who undergo mechanical ventilation in the ICU.1 Alleviation of anxiety and stress, and ensuring ventilator synchrony are considered to be important reasons for the administration of sedatives. However, the newer generation ventilators synchronize better with spontaneous respiratory efforts and may be more comfortable to patients. The duration of action of conventional sedative drugs, including opioids and benzodiazepines may be prolonged in the critically ill with organ dysfunction and may lead to a longer duration of ventilation, besides increasing the risk of delirium and cognitive impairment.2 Furthermore, observational studies have revealed that early, deep sedation may be an independent predictor of mortality.3,4 On the other hand, lack of adequate sedation incurs the risk of accidental device removal5 and may complicate the nursing care of patients who undergo mechanical ventilation.6
There are several subgroups of critically ill patients in whom an adequate level of sedation is a crucial component of care. These include patients who require mechanical ventilation for severe hypoxia, those with raised intracranial pressure, refractory seizures, and in combination with neuromuscular blocking drugs. However, in most other clinical situations, a deep level of sedation may be unnecessary among critically ill patients on mechanical ventilation.
Importance of monitoring the level of sedation
In an ideal world, the level of sedation must ensure a calm, co-operative patient who can comply with therapeutic interventions, and enable mobilization as required. However, in the real world, titration of sedative agents to an ideal level is often elusive. Several scales have been proposed to guide the titration of sedation by the bedside. The commonly used tools include the Richmond Agitation and Sedation Scale (RASS)7 and Riker Sedation-Agitation Scale (SAS).8 The RASS score ranges from –5 (unresponsive) to +4 (combative); a score of –2 (light sedation; briefly awakens and makes eye contact to voice) to –3 (any movement, but no eye contact to voice) is generally considered appropriate. The Riker scale ranges from 1 (unarousable) to 7 (dangerously agitated); a score of 4 (calm and easy to arouse, obeys commands) is the ideal target to aim for. Although these are useful tools to employ by the bedside, the subjective nature of assessment is a disadvantage. There is no general consensus on the frequency of monitoring; fluctuating levels of sedation may be difficult to monitor if the assessment is infrequent. Besides, assessment is not possible in the presence of neuromuscular blockade.
Evidence supporting the level of sedation
Several controlled trials have evaluated the impact of the level of sedation among critically ill patients on mechanical ventilation. These studies have compared different levels of sedation or a strategy of sedation compared with no sedation. The basic approach has revolved around seeking the most optimal methodology to titrate sedative agents to ensure patient comfort and safety without compromising clinical outcomes.
Daily interruption of sedation
Kress et al., in a seminal study, evaluated the impact of daily interruption of sedative infusions on the duration of mechanical ventilation and the length of stay in the ICU and in hospital.9 The sedative agents used included infusions propofol and midazolam, combined with morphine for analgesia. In the intervention group (68 patients), all sedative infusions were stopped until patients were awake or became uncomfortable or agitated necessitating the resumption of sedation. In the control group (60 patients), the requirement for sedation and dosage adjustment were left to physician judgment. Apart from sedation interruption and titration, all other decision-making was carried out as deemed appropriate by the treating clinician.
The median duration of mechanical ventilation was significantly lower with a daily interruption strategy compared to the control arm (4.9 vs. 7.3 days, p = 0.004). Patients who underwent daily interruption of sedation had a significantly shorter ICU stay (6.4 vs. 9.9 days, p = 0.02). Besides, diagnostic testing for the evaluation of neurological impairment was less frequent among patients who underwent daily interruption of sedation compared to the control group. Accidental removal of devices was uncommon and similar in both groups of patients.
The multicentric SLEAP trial conducted by the Canadian Critical Care Trials Group across 16 centers in Canada and the US came up with contrasting findings.10 In this study, among patients receiving continuous infusion of sedative agents, protocolized sedation combined with daily interruption did not improve clinical outcomes compared with protocolized sedation alone. However, among patients who underwent daily interruption, a higher dose of benzodiazepines and opioids were administered; besides, the requirement for bolus sedation was also greater to achieve sedation targets in this group. Furthermore, this study also used a high dose of benzodiazepines, compared to other studies that evaluated daily interruption, which could explain the conflicting findings.
Daily interruption combined with a spontaneous breathing trial
Girard et al. compared a strategy of a daily awakening trial combined with a spontaneous breathing trial with usual sedation practice and spontaneous breathing trial in mechanically ventilated patients.11 In this multicentric RCT, 335 patients were included in the final analysis, with 167 in the intervention and 168 in the control group. Patients in the daily awakening combined with spontaneous breathing trial group experienced more ventilation-free days during the 28-day study period (14·7 days vs. 11·6 days p = 0.02); the duration of ICU and hospital stay were also significantly shorter. Self extubations were more common in the intervention arm, but this did not lead to a higher rate of reintubation compared to the control arm.
Sedation vs. no sedation
A single-center study from Denmark compared a strategy of no sedation with daily interruption of sedation until the patient was awake.12 In the sedation arm, propofol or midazolam was infused aiming for a target Ramsay score of 3–4. Patients in both groups were administered bolus morphine, 2.5 – 5.0 mg for pain relief. Seventy patients were included in each group. A strategy of no sedation resulted in a shorter duration of mechanical ventilation from intubation until day 28, with a mean difference of 4.2 days between the two groups. The duration of stay in the ICU and in hospital was also significantly shorter in the no sedation group. The incidence of accidental extubations, ventilator-associated pneumonia, and investigation with neurological imaging were not different between the two groups.
The NONSEDA trial was conducted across 8 centers in Denmark, Norway, and Sweden as a more detailed evaluation of the aforementioned trial. The study included patients who were intubated within 24 hours prior to screening and were expected to receive mechanical ventilation for longer than 24 hours.13 Randomization was carried out in a 1:1 ratio to a plan of no sedation or light sedation with daily cessation. In the no-sedation group, bolus morphine could be administered as deemed appropriate. In the light sedation group, a target score of –2 (wakes up briefly with eye contact to voice) to –3 (any movement, but no eye contact to voice) was targeted. A total of 710 patients were enrolled; 354 were assigned to the no sedation group and 356 to the light sedation group. The RASS scores in the no-sedation compared to the light sedation group were –2.3 vs. –1.3 on day 1 and –1.8 vs. – 0.8 on day 7.
The all-cause mortality at 90 days, the primary outcome, was not significantly different between the two groups (no sedation vs. light sedation: 42.4% vs. 37%, p = 0.65). Among the secondary outcomes, there was no significant difference in the number of mechanical ventilation-free days and the duration of ICU stay until 28 days after randomization. The number of delirium or coma-free days within 28 days was one day less in the no sedation group. A major thromboembolic event within 90 days occurred in 10 patients in the sedation group compared to one patient in the no sedation group. The peak RIFLE score was not significantly different between the two groups. Although this RCT did not reveal a significant difference in important clinical outcomes, this may have been because the intended difference in the level of sedation between groups was not attained.
Does sedation use lead to hemodynamic instability and organ dysfunction?
The use of sedative agents might lead to hemodynamic instability, an increase in the dose of vasopressor agents and a higher incidence of renal dysfunction. In a post-hoc analysis of their original study, Strom et al. evaluated the impact of sedative agents on the hemodynamic status, the requirement for vasopressors and additional intravenous fluid, and the incidence of acute kidney injury (AKI).14 No significant difference was observed in the dose of vasopressors between patients randomized to a strategy of no sedation compared with those who received targeted sedation. The cumulative fluid balance was higher in the sedation group, but the difference was not significant. Sedation use was associated with a higher frequency of AKI by the RIFLE criteria. However, the number of patients who required continuous renal replacement therapy was similar between groups.
The impact of sedation during the early phase of mechanical ventilation
The required depth of sedation varies depending on the stage of illness. Sedation requirements are usually higher during the first few days, followed by a reduced level depending on the trajectory of illness. Most studies have compared the level of sedation in critically ill patients after the initial 24–48 hours of mechanical ventilation. It is plausible that the depth of sedation in the early phase of critical illness may be an important predictor of clinical outcomes. In a prospective observational study, early, deep sedation was found to delay extubation and was an independent predictor of mortality.15 These findings were corroborated in a secondary analysis of a prospective cohort study.4 Deeper levels of sedation in the first 48 hours of mechanical ventilation were associated with a longer duration of ventilatory support and a higher rate of tracheostomies. The correlation between deep sedation and adverse outcomes persisted on multivariate analysis.
- Mechanically ventilated patients in the ICU occasionally require a deep level of sedation; however, the majority may be managed with light or no sedation. It is important to ensure that even when a no sedation strategy is followed, adequate pain relief is provided
- Excessive sedation in mechanically ventilated patients has been shown to prolong the duration of ventilation, ICU and hospital stay. On the other hand, inadequate sedation may lead to ventilator dyssynchrony, patient discomfort, accidental device removal, and an increase in the nursing workload. Hence, a balance has to be struck to avoid excessive sedation, while ensuring patient comfort and safety
- The currently available sedation scales rely mostly on subjective assessment, and may not be ideal with rapid, wide fluctuations in patient behavior
- The practice of a protocolized strategy with pre-defined target levels of sedation is likely to improve clinical outcomes including reduced duration of ventilation and a shorter ICU and hospital stay
- Daily interruption of sedation may be a reasonable strategy in patients who are improving from the underlying illness with a likelihood of liberation from mechanical ventilation. The basic concept revolves around cessation of sedation, re-evaluation, and re-titration to a minimum level if appropriate
- A spontaneous breathing trial is often combined with a sedation interruption strategy in patients who have recovered sufficiently from the underlying illness and are ready for liberation from mechanical ventilation
- A strategy of no sedation may be appropriate among patients who are co-operative and compliant with therapeutic interventions, provided caregivers are experienced with this approach
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