Key Question :
Does the use of a protocolised interruption to sedation infusions of critically ill adults influence their outcomes?
Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation
Kress JP, et al
New England Journal of Medicine (2000); 342:1471-77
At a glance
- Randomised - Yes
- Controlled - Yes
- Placebo used - Yes
- Blinded - Debatable. Interruption was performed by independent study investigator, but its hard to imagine the treating team were not unblinded
- Population / Sample size calculation - 128 patients
- Groups same at randomisation - Yes
- Groups treated the same after randomisation - It appears so
- Intention to treat analysis - Yes (but those who died or were extubated within 48 hours were excluded?)
- Follow-up - Complete at hospital discharge
- Significant primary endpoint - Yes, ventilation times were significantly shorter in the intervention group (4.9 versus 7.3 days)
- Harms analysed - Mostly. Limited followup on psychological impact of reduced sedation levels
Sedative infusions have been used to enable patients to tolerate mechanical ventilation since the birth of intensive care 50 years ago.
For most of that time, it had been accepted as fact that it was much kinder to patients, and probably safer, for them to be sedated to a point of being unaware of their surroundings while they endured their ICU stay. Heavy sedation allowed for uncomfortable procedures to be performed and mechanical ventilation to be administered. It was felt that this also reduced the risk of patient accidentally removing tubes and lines on which they depended. Infusions have often been preferred as this provides more consistent sedation, fewer complications such as hypotension, and is more practical for workforce resources.
In the latter years of the 20th century however, evidence began to accumulate that perhaps heavy-handed sedation practices, particularly by continuous infusion, might in fact be contributing to iatrogenic harm. The use of continuous infusions likely leads to inadvertent overdosing and accumulation of drugs with attendant consequences. Heavy sedation was associated with longer ventilation times, and this, it was inferred, exposed the patient to higher risks of misadventure such as ventilator associated pneumonia, central venous line infections, pulmonary embolus and so on.
The concept of "daily interruption of sedation" was born from these concerns, and the authors of this study sought to compare this approach with the conventional treatment of the time.
150 patients who were intubated and ventilated in a single medical tertiary intensive care unit and deemed to require ongoing sedation were enrolled in a randomised fashion.
Patients were randomised to either a protocolised daily interruption of the sedative infusions, or to "standard practice". In the intervention arm, the sedatives were ceased once daily until the patient either awoke and could follow simple commands, or became agitated to the point of requiring reinstitution of sedation. Patients on muscle relaxant infusions were not woken. Sedation was then restarted at half the infusion rates prior to the interruption, and then titrated to achieve the goal required by the unit protocol. This process was performed by a study investigator who was independent of the treating medical team.
Sedation in the control arm of the study was interrupted (other than on the final day of the infusion) at the discretion of the treating physician. This occurred in 30% of the control group, to a varying degree.
Within each group, the patients were randomised to either midazolam or propofol as their sedative agent in an open-label fashion. All patients received analgesia via a titrated infusion of morphine. All sedatives infusions were controlled by an existing sedative protocol within the unit, targeting a Ramsay Sedation Scale score of 3-4. The published protocol provides details on how sedation infusions should be increased, but no information is provided on how sedation infusions are decreased if the sedation target is exceeded, suggesting down titration was not controlled.
The primary outcomes studied were the duration of mechanical ventilation, ICU length of stay and hospital length of stay. In addition to a range of secondary outcomes, adverse events were screened, including mortality, reintubation, tracheostomy and accidental intubation. However, psychological testing does not appear to have been followed.
The groups appear similar prior to the intervention being commenced, and there is nothing to suggest that the patients in the groups were treated differently other than the study intervention. Of note however, the paper states that the study investigator who reviewed the patient "decided whether to resume the infusions". It is not clear if this means they simply decided when to turn the infusions on again, or whether they actually changed the course of the patient's clinical care. The latter scenario would of course significantly weaken the study.
Similar quantities of morphine were used in both arms of the study. Interestingly, there was a clear reduction in the quantity of midazolam used between the two arms (by almost half), but not propofol. In an attempt to demonstrate the study protocol's ability to separate the groups, the percentage of the infusion days that the patients were "awake" were recorded. In the intervention arm, patients were considered "awake" 85% of the infusion days, compared with 9% in the control group.
The intervention arm was associated with a significant reduction in the primary endpoint of duration of mechanical ventilation. A whopping 2.4 days was shaved off the intubation time of 7.3 days in the control arm. This translated to a reduction in ICU length of stay, but not hospital length of stay. In hospital mortality was the same in each group.
Curiously, the ventilation times were not different between the arms when analysing the propofol and midazolam groups separately. Given there was no difference in propofol dose between the arms, the possibility exists that the overall results are only relevant to patients receiving a benzodiazepine-based sedative strategy.
There was no demonstrable increase in complication rates between the two groups, with 2 accidental extubations in the intervention group, and 4 in the control arm.
This study provided important information upon which our current sedation practices are founded.
Overall, the study suggested that daily interruption of sedation is practical and has the potential to reduce ventilation times significantly, leading to better patient centred outcomes and reduced costs.
However, there are a number of limitations which warrant some caution in interpreting the results.
Although the authors state they used an intention-to-treat analysis, they chose to exclude patients who either died or were extubated within the first 48 hours of the study. This effectively limited the study to 128 patients. Its unclear whether or not the exclusion of these patients would have affected the results significantly.
Despite the best of intentions, it seems unlikely that the treating team would be properly blinded to the study intervention, a fact acknowledged by the investigators. Inadvertent contamination of the control arm is also conceivable in a single centre, practice-based study such as this, as the change in practice in one group inevitably influences the control arm.
The major limitation is the size of the study. One major premise of the study is that the approach is safe, but there are not enough patients included to be confident that the strategies have similar risk profiles. In particular, there does not appear to be any analysis of the psychological impacts of the study on the patients, their families or indeed on the nursing staff caring for them. Additionally, cardiovascular complications such as hypertension or tachyarrhythmias are not specifically reported.
The other major point is that this may only apply to sedation strategies that implement midazolam, a drug well known to accumulate and potentially prolong mechanical ventilation.
Some commentators have suggested that the results are due to over-sedation of the control arm, arguing the target of a Ramsay Sedation Score of 3-4 was unnecessary. This view is reinforced by the fact that the protocols used do not appear to actively reduce sedative use when over-sedation is apparent. These observations lead many to suggest that the study simply demonstrates that over-sedation is bad, and that the specific mechanism for reducing this, be it daily interruption, goal directed protocols or bolus dosing rather than infusions, is less important.
Of note, patients who did wake were immediately re-sedated to the target Ramsay Sedation Score by reinstating infusions at half the dose previously set, and then titrating. This does raise the possibility that patient might not need even this much sedation, and that even better results could be achieved.
Can these results be extrapolated generally? Its hard to know for sure, given that this is a process change studied in a single medical intensive care unit, with the potential for unblinding of the management team. But the study seems plausible enough to cautiously believe so until better evidence comes along. Additionally, as mentioned previously, these results appear to have been achieved in a control setting that tends to sedate patients reasonably heavily. Would the results be as favourable in an environment where lighter sedation is the norm?
So what does this mean?
Many studies have been published subsequently that support the findings in this paper, whether it be using daily sedation interruption, or by use of tight sedation protocols. Girard et al  combined sedation interruption with attempts at spontaneous breathing trials, finding similar improvements in outcomes. In 2010, Strom et al  published a paper that demonstrated that a practice implementing sedation on an as-required basis once analgesia was adequately provided, significantly improved patient centred outcomes. While many more have followed, not all are consistent with this paper, culminating in an inconclusive met analysis in 2011 . In 2012, the SLEAP study , conducted in 14 institutions involving 423 medical and surgical ICU patients, was published. SLEAP compared a nurse driven daily waking protocol with a nurse driven goal directed sedation protocol, but did not include a "usual care" arm. It found no difference between the two on outcomes similar to those used in this study. A large, multi centre trial comparing traditional sedation practices with either protocolised sedation or daily interruption of sedation is lacking.
The concept has now been progressively expanded to the "ABCDE" approach - awake, breathing control, delirium assessment and early exercise model. Such models are now central to international recommendations such as the 2013 Society of Critical Care Medicine Sedation and Analgesia Guidelines .
Long term outcomes from such strategies have also now been studied, and the concerns related to psychological impact have largely dissipated. In fact, the inability to recall events in the ICU resulting from heavy sedation has been linked to the development of post traumatic stress disorder. Similarly, the practice has been studied in patients at risk of coronary artery disease and found little evidence that they suffered any harm - another concern dispelled.
The impact of this study is far more than the introduction of "interruption to sedation" into practice. Its true impact is to focus attention more on avoidance of the problem than the solution. Today, it is likely that patients have their sedation more actively titrated to avoid oversedation in the first place, such that the original concept of "daily interruption" has become obsolete.
Much like the Rivers' trial, the importance of this trial is too easily diminished by the passage of time. Newer, multicentered, better funded, better designed trials may overwhelm these initial studies, but would they have ever been done if it hadn't been for the originals? We owe Kress, Rivers and countless others much for bringing these issues to the fore, for others to follow up their pioneering work.
In medical ICU patients requiring ongoing sedation for mechanical ventilation, a period of interruption to sedation infusions appears safe and may reduce ventilation times, particularly if midazolam is used.
Additional References Girard T et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patient in intensive care (the ABC trial). Lancet (2008);371:126-34
 Strom T et al. A protocol of no sedation for critically ill patients receiving mechanical ventilation. Lancet (2010); 375:475-80.
 Barr J et al. Clinical pratice guidelines for the management of pain, agitation and delirium in adult patients in the intensive care unit. Crit Care Med (2013); 41:263-306
 Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000 May 18;342(20):1471-7
 Mehta S, et al; SLEAP Investigators. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA. 2012 Nov 21;308(19):1985-92
- The Bottom Line
- Wiki-Journal Club
- PulmCC : Sedation vacations don't improve outcomes in large trial
- Heffner. A Wake-Up Call in the Intensive Care Unit. N Engl J Med 2000; 342:1520-1522
- Jackson et al. A systematic review of the impact of sedation practice in the ICU on resource use, costs and patient safety. Critical Care 2010, 14:R59.
- An excellent editorial by Shehabi and Reade
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