Waking Morpheus up

Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation, by John Kress et al [1].


For how long have we been using sedatives in our critical patients to keep them flying with Morpheus? Well, probably since we have Intensive Care Units, mechanical ventilation and sedatives. Something around 63 years, right? So, we had ICUs all over the world with thousands of amazing doctors and nurses and it took us almost 50 years to decide wake our patients up. Which is not that bad if we take into consideration it took 100 years to wake Sleeping Beauty up.

We can discuss a lot of articles that improved our patients’ care, but few made such tremendous changes in our ICU environment and in the way all health care professionals see and interact with patients like the one our handsome Prince John Kress published in 2000. Can you imagine an ICU round in the middle 80’s, the only thing you could hear was the “bleeping of the hearts” and all those magnificent human beings moveless, like the scene of human fields in Matrix. Now, oh boy, is far more exciting. We can ask our patients how they are felling and chat with them. -Good morning Mr George, I’m Bruno and I’m going to be your doctor today. How cool is that?! -Good morning Linda, good to see you walking despite the breathing tube! John Kress’ article was the spark that really ignited the changes we saw in the las 16 yeas in ICU sedation.



In one hand we have the possible advantages of continuous sedation infusion in critically ill patients under mechanical ventilation. We can control their anxiety and agitation, facilitate their care, improve their mechanical ventilation, make them forget the nightmare of needles, catheters, tubes, noises and smells that only a good ICU can provide. Of course some of these are bullshit and in the other hand we have all the bad things that come along with sedation: longer duration of mechanical ventilation, longer length of stay, critical illness myopathy, delirium and also excessive sedation can undermine our physical examination. Despite some evidence from the 90’s showing benefits of less ferocious sedation strategies a good randomized controlled trial was still needed. That was the idea behind the daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation [1] trial.


Chicago, where the great tv show ER was hosted; single center trial; medical ICU. Patients receiving mechanical ventilation and requiring continuous infusion of sedative drugs determined by the ICU team were studied. The randomization strategy resembles a 2×2 factorial trial, but it was, in fact, a parallel trial. First the patient was randomized to intervention or control group and since they knew it was important to have balanced groups regarding the choice sedative control and intervention patients were randomized to receive either propofol or midazolam. Both groups received continuous infusion of opioids(morphine).

Intervention: The sedation was interrupted daily by an investigator not involved in the patients’ care, a research nurse also not involved in the patients’ care stood aside patients. One of two things could happen after the sedation interruption: 1-the patient could become agitated and/or uncomfortable or 2-the patient could awake and follow instructions. Here, the nurse would call the study physician who would decide wether resume the infusions. The sedation protocol for the intervention group was infusions of morphine (“as needed”) and the sedative drug titrated to a score of 3 or 4 on the Ramsay sedation scale ( 3-responsive to command only and 4- asleep). The patients were considered awake if they were able to perform at least three of the following investigator’s requests: open eyes to a voice, follow with eyes, squeeze a hand and stick out the tongue. In both situations (awake or agitated/uncomfortable), the sedation was resumed at 50% of the previous rate and then titrated as needed. For the control group the sedative strategy was left to the discretion of the ICU team.

The primary endpoints were: duration of mechanical ventilation, the length of stay in the intensive care unit, and the length of stay in the hospital. There is no information about sample size calculation, power or type I error. Kaplan–Meier and Cox proportional-hazards (adjusting for age, sex, weight, APACHE II score, and type of respiratory failure) were used for the primary outcome. Patients who died or were extubated within the first 48h were excluded from the analysis.
Few thoughts here: It’s a shame they used Ramsay scale ( 6 levels scale) instead of Richmond agitation sedation scale (RASS), which is a 10 levels sedation scale validated for ICU, but I can understand the preference for Ramsay since the RASS was only “invented” in 2002. Also, they claim that only the investigators knew which group the patients were assigned. Unless all the ICU team went for a 2 hour coffee every day when the investigators were performing the interventions we cannot call this a blind study. The authors attempted to minimize this problem by not disclosing the end points of the study to the clinicians

The real deal

They randomized 75 patients each arm and the analysis was made with 68 patients in the intervention and 60 in the control group. The main characteristics of the patients are summarized below:

There are some differences between groups, a recurrent problem with small sample sizes; maybe it was what the sample size calculation showed them, or maybe with such broad inclusion criteria they could have enrolled more patients.

Patients in the intervention group, as expected, received less sedation than the control as showed below:

The protocol worked as planned, patients in the intervention group were awake 85.5% of days, and the control 9% ( 30% of patients in the control had their infusion stopped temporarily on days other than the final day of administration). Patients under midazolam infusions from both groups received less morphine, probably due to synergism.

Regarding the primary outcomes, the intervention group had lower duration of mechanical ventilation ( 4.9 vs 7.3 days; p=0.004), shorter ICU length of stay ( 6.4 vs 9.9 days; p=0.02) and shorter hospital length of stay ( 13.3 vs 16.9 days; p=0.19). The relative risk for extubation was 1.9; 95% CI, 1.3 to 2.7; p<0.001, and the relative risk of ICU discharge, 1.6; 95% CI, 1.1 to 2.3; p=0.02, both favoring the intervention group. The Kaplan-Meier graphs for duration of mechanical ventilation and ICU length of stay showed good separation from the beginning.

One “secondary endpoint” worth mentioning is that the intervention group was subjected to fewer diagnostic tests to assess changes in mental status than the control group ( 6 vs 16; p=0.02), since the physicians were able to perform a reliable physical examination. There were no difference in adverse effects, re-intubation or in-hospital mortality.


I think we should always be grateful to the pioneers and despite some flaws, John Kress did give the Sleeping Beauty’s waking up kiss. Looking the data leaves no doubt about the benefits of the daily interruption of sedative infusions and its safety. The daily interruption of sedative infusions made physicians evaluate the possibility of extubation on daily basis instead of using intangibles factors. Not only the physical examination capabilities increase with an awake patient but also we are allowed to verbally communicate with them (at least we verbalize and try to understand their gestures) providing more individualized analgesia and patient centered care. They could see their families and communicate with them, they could actively exercise, walk, read, listen to music, write and inumerous other tasks only possible in an awake patient.

Both lower duration of mechanical ventilation and shorter ICU length of stay have a huge financial impact and for hospitals lacking ICU beds ( yeah guys, these things do happen here in Brazil) can change the ICU and hospital admission dynamics. This was the embryo of a broader research field that we saw develop in the last 16 years. Tons of articles related to sedation, delirium and analgesia would be in our daily discussions. The choice of sedative would be as important as the choice of antibiotics. And ICUs throughout the world would embrace sedation protocols. And for every single a physician saying that all patients on mechanical ventilation need sedation, I’ll quote my fellows anesthetists: “You can’t fix stupid. but you can sedate it!”.


1.    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;342(20):1471-1477.


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Waking Morpheus up

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