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
Dating back to the 1980s, sedative agents were increasingly used to improve patient comfort during mechanical ventilation. The practice evolved over time with the nearly routine use of a cocktail of narcotics, benzodiazepines, propofol, and major tranquilizers. These drugs provide analgesia, a sense of comfort during stressful, often painful interventions, enable synchronization with mechanical ventilation, and offer a margin of safety with invasive lines and devices in patients who may become restless or agitated (1). Unfortunately, in many situations, sedation use may go overboard to the point of drug-induced “suspended animation”. According to John Kress, the lead author of this landmark paper, by the 1990s, it was fairly common to administer deep sedation, often in combination with neuromuscular blockers, to mechanically ventilated patients in the ICU – a practice that took roots from the operating room (2). The late Thomas Petty poignantly wrote in 1998, “What I see these days are paralyzed, sedated patients, lying without motion, appearing to be dead, except for the monitors that tell me otherwise”(3). At the University of Chicago, where the study was conducted, patients would take several days to wake up after ceasing sedative agents. Although there was a policy of daily cessation of sedation, this was rarely followed (2).
Sedative medications are usually administered as intravenous infusions. Compared to intermittent bolus administration, continuous infusions maintain a constant level of sedation and presumably, an increased level of comfort (4). Clearly, excessive sedation carries the risk of adverse outcomes. Too much sedation may prolong the duration of mechanical ventilation and ICU stay, and may lead to an increase in the incidence of ventilator-associated pneumonia (5). Besides, neurological assessment may be rendered difficult, often leading to needless, often misguided imaging or other modalities of investigation. Interruption of sedation on a daily basis may offer a window allowing patients to awaken without compromising comfort. Against this background, the authors hypothesized that a policy of daily interruption of sedation might reduce the duration of mechanical ventilation, ICU, and hospital stay.
Population and design
The study was conducted in the medical intensive care unit of the University of Chicago (6). Patients were intubated and mechanically ventilated and required continuous infusion of sedatives according to clinician judgment. Those who were transferred from elsewhere and already on sedation, and those who were resuscitated after cardiac arrest were excluded. Patients were randomly assigned to daily interruption or continued sedation.
Sedatives were interrupted daily, beginning 48 hours after study enrollment. The sedative (midazolam or propofol) and morphine (as analgesic) infusions were interrupted until patients were awake and able to follow commands or if they became uncomfortable, restless, or agitated. The sedative and morphine infusions were resumed as deemed appropriate. If patients were on neuromuscular blockade, it was ceased before stopping the sedative infusion.
Sedatives were continued; cessation was at the discretion of the ICU team.
Within each group, patients were randomized to receive either midazolam or propofol as the sedative infusion, thus creating four groups of patients. Midazolam was administered as an initial bolus of 0.5–5 mg every 1–5 minutes, followed by a continuous infusion of 1–2 mg/h. The infusion rate was increased by 1–2 mg/h for the desired level of sedation. Propofol was commenced at 5 mcg/kg/min; the infusion rate was increased by 5–10 mcg/kg/min every 2 min until the desired level of sedation was attained.
Bedside nurses titrated the dose of the sedative infusion to a score of 3–4 on the Ramsay sedation scale. All four groups of patients received morphine as analgesic. Morphine was administered as an initial bolus of 2–10 mg and followed up with a continuous infusion of 1–5 mg/h. The overall care was left to the discretion of the ICU team. Patients were considered awake if they were able to perform three of the following four actions: (1) open eyes to call, (2) follow the investigator with their eyes, (3) squeeze hand on command, and (4) protrude tongue on command.
A total of 150 patients were randomized, 75 to each group. After excluding patients who were extubated early or died, 68 patients in the intervention group and 60 in the control group were included in the final analyses. In the interruption group, 37 patients received midazolam while 31 received propofol as the sedative agent. In the control group, 29 received midazolam, while 31 received propofol infusion. Baseline characteristics, including demographic characteristics, the baseline APACHE II scores, and the underlying diagnosis, were similar between the two groups.
The median duration of mechanical ventilation was significantly shorter in the daily interruption group compared to the control group [4.9 (2.5–8.6) vs. 7.3 (3.4–16.1) days, p = 0.004]. Patients in the daily interruption group were extubated earlier compared to the control group. The median ICU length of stay was also significantly shorter with daily interruption of sedation [6.4 (3.9–12.0) vs. 9.9 (4.7–17.9) days, p = 0.02]. The duration of hospital stay was longer in the control group; however, the difference was not statistically significant. Failed extubation requiring reintubation was similar between the two groups. The hospital mortality was also similar in both groups; 36% of patients died in the daily interruption group compared with 47.6% in the control group. Significantly more patients in the daily interruption group were discharged home compared to the control group. The choice of the sedative agent, midazolam vs. propofol, did not affect the duration of mechanical ventilation, ICU stay, and hospital stay.
Diagnostic imaging to assess the neurological status was performed less often in the daily interruption group. In the control group, 13 CT scans, two MRI scans, and one lumbar puncture and cerebrospinal fluid examination were carried out compared to six CT scans in the daily interruption group. In the control group, 15 patients (13 died in a coma) never awakened during the ICU stay compared with seven patients (six died in a coma) in the daily interruption group.
Adverse events were similar in both groups; two accidental extubations and one accidental removal of a central venous catheter occurred in the daily interruption group; none of these events occurred during the period of interruption of sedation. Four accidental extubations occurred in the control group.
Relevance of the study
This landmark study by Kress et al. revealed that daily interruption of sedative agents is safe, practicable, and helps reduce the duration of mechanical ventilation and ICU stay. Besides, this strategy enables a more precise clinical evaluation of the neurological status and results in fewer investigations being performed. This landmark trial turned out to be a wake-up call for ICU physicians and reaffirmed the “less is more” principle regarding the depth of sedation in the critically ill. The study triggered a departure from the widespread use of sedatives as a continuous infusion in mechanically ventilated patients during the 1980s and 90s. When sedative agents are used indiscriminately, without titration to objective endpoints, patients may remain obtunded for a prolonged duration, leading to adverse clinical outcomes. The long-term impact of sedative agents may be more profound in the critically ill, with alterations in the volume of distribution and elimination due to impaired hepatic and renal function. Heavy-handed use of sedative agents may also be more prevalent in units that may have less than optimal skilled nursing available by the bedside.
Although the study did not reveal any evidence of compromised safety with a policy of daily interruption of sedation, the number of events was too few to come to a definite conclusion. The psychological impact emanating from the daily cessation of sedation was not assessed, particularly regarding the perception of pain and discomfort. Cardiovascular compromise arising from the sympathetic surge that may accompany the interruption of sedation could conceivably lead to harm, particularly in patients with coronary artery disease. The study was unblinded, which may have led to bias. In the control group, some patients had cessation of sedation in between, which could have impacted outcomes. The findings of the study, conducted in a medical ICU, may not be directly extrapolatable to surgical ICUs.
Many RCTs followed in light of the findings of this landmark trial on “sedation vacation”, as it came to be popularly known in intensive care circles.
Girard et al. compared daily awakening combined with a spontaneous breathing trial with a usual sedation practice combined with daily awakening. The strategy of a spontaneous breathing trial combined with daily awakening led to more ventilator-free days, ICU and hospital stay compared with daily awakening alone (7). Another study by Mehta et al. demonstrated that a protocolized sedation strategy is as effective as daily interruption combined with protocolized sedation (8). The NONSEDA trial compared a strategy of no sedation with light sedation to an arousable level. The authors did not find a significant difference in the mortality, ventilation-free days, and duration of ICU stay between the two groups. However, the intended difference in the level of sedation between the two groups was not attained (9).
More than three decades ago, it was customary to maintain mechanically ventilated patients under deep sedation, often combined with neuromuscular blockade. This practice percolated through contemporary anesthetic practice and was based on the presumption that a deep level of sedation improved patient comfort. Besides, a deeper level of sedation facilitated nursing care, especially in understaffed units. The question of patient safety was also a consideration with the likely potential for accidental removal of care-related devices and the possibility of adverse outcomes from such incidents. The authors of this landmark trial embarked upon a policy of daily interruption, with the resumption of sedative medication as appropriate. This strategy was compared to a conventional approach with continued sedation and cessation based on the judgment of the ICU team. They found that daily interruption of sedation among mechanically ventilated patients led to earlier extubation and resulted in a shorter duration of ventilator support overall. The length of stay in the ICU was also shorter with the daily interruption strategy.
Although there have been conflicting results from subsequent RCTs, the Kress et al. study marked a paradigm shift from the traditional practice of deep sedation in mechanically ventilated patients. This study is particularly relevant considering the relatively unpredictable effect of sedative agents among critically ill patients with altered pharmacokinetic profile, especially in the presence of multiorgan dysfunction.
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6. 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.
7. Girard TD, Kress JP, Fuchs BD, Thomason JWW, Schweickert WD, Pun BT, et al. Eﬃcacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. 2008;371:9.
8. Mehta S. 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.
9. Olsen HT, Nedergaard HK, Strøm T, Oxlund J, Wian KA, Ytrebø LM, et al. Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients. N Engl J Med. 2020 Mar 19;382(12):1103–11.
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