Sedation Administration Timing: Intermittent Dosing Reduces Time to Extubation (SATIRE Trial): A Prospective, Randomized Cohort Study

Background:

Sedation is a significant component in the comprehensive treatment of a critically ill patient. The presence of anxiety and pain can often be left unexpressed, particularly in patients on mechanical ventilation. Opioids are primarily used for the treatment of acute pain and sedative agents (i.e. benzodiazepines, propofol) are used to achieve sedation. Sedation is required in mechanically ventilated patients, yet the optimal strategy for its management is unclear. Daily interruptions of continuous intravenous (IV) sedation (i.e. sedation holiday) have shown to result in a shorter duration of time on mechanical ventilation and intensive care unit (ICU) stay. However, sedative agents have the potential to accumulate despite daily interruptions, leading to drug redistribution from the tissues into the circulation. This may delay mental status recovery and cause abrupt agitation despite decreased or discontinued sedatives. Therefore, daily sedation holidays do not always result in awakened and communicative patients. Optimal management for sedation is necessary to avoid accumulation of drug and prevent sedation-induced delirium.

According to the guidelines on the sustained use of sedatives and analgesics in the critically ill adult, published by the Society of Critical Care Medicine, maintenance of sedation with intermittent or "as needed" doses of diazepam, lorazepam, or midazolam may be adequate to accomplish the goal of sedation. Continuous infusions must be used cautiously due to accumulation of the parent drug and inadvertent over-sedation.

There are two main clinical trials that studied the use of continuous sedation compared to intermittent sedation in the critical care setting. In one study, a prospective, randomized, multicenter, open-labeled trial compared intermittent IV lorazepam with continuous infusion midazolam. The investigators concluded that intermittent lorazepam and continuous midazolam had similar levels of sedation and anxiolysis as measured by objective hemodynamic and laboratory data, along with patient and nurse scoring systems. However, it was determined that higher doses of continuous infusion midazolam were required to obtain adequate sedation and anxiolysis. In another prospective, cohort study, mechanically ventilated patients received either continuous or intermittent doses of sedation using a targeted Ramsay Scale of 3. Patients in the intermittent group required less hours on mechanical ventilation compared to the continuous IV sedation group, p<0.001. The authors of this trial concluded that continuous sedation may be associated with prolongation of mechanical ventilation. These two clinical trials conclude that the use of intermittent sedation may provide additional benefit to sedated patients in decreasing the days on mechanical ventilation and cumulative doses of sedative agents.

Using these studies as a starting point, the investigators conducted a prospective pilot study demonstrating that the use of intermittent sedation in medical intensive care unit patients significantly decreased amount of sedatives used, the hospital length of stay, and most importantly reduced duration of mechanical ventilation. In this study it was shown that intermittent sedation administered within twenty-four hours of mechanical ventilation reduced ventilation time by twenty-four hours (p<0.001). However, much like the studies that formed the basis of this pilot, this study suffered from some lack of control as well as small sample size. More importantly, this study analyzed only medically critically ill patients in whom large doses of narcotics are often not routinely employed. In surgical patients narcotics are often used concomitantly with a sedative in order to achieve anxiolysis and pain control while ventilated.