Temporal disorganization of circadian rhythmicity and sleep-wake regulation in mechanically ventilated patients receiving continuous intravenous sedation

Abstract

Objectives: Sleep is regulated by circadian and homeostatic processes and is highly organized temporally. Our study was designed to determine whether this organization is preserved in patients receiving mechanical ventilation (MV) and intravenous sedation.

Design: Observational study.

Setting: Academic medical intensive care unit.

Patients: Critically ill patients receiving MV and intravenous sedation.

Methods: Continuous polysomnography (PSG) was initiated an average of 2.0 (1.0, 3.0) days after ICU admission and continued ≥ 36 h or until the patient was extubated. Sleep staging and power spectral analysis were performed using standard approaches. We also calculated the electroencephalography spectral edge frequency 95% SEF₉₅, a parameter that is normally higher during wakefulness than during sleep. Circadian rhythmicity was assessed in 16 subjects through the measurement of aMT6s in urine samples collected hourly for 24-48 hours. Light intensity at the head of the bed was measured continuously.

Measurements and results: We analyzed 819.7 h of PSG recordings from 21 subjects. REM sleep was identified in only 2/21 subjects. Slow wave activity lacked the normal diurnal and ultradian periodicity and homeostatic decline found in healthy adults. In nearly all patients, SEF₉₅ was consistently low without evidence of diurnal rhythmicity (median 6.3 [5.3, 7.8] Hz, n = 18). A circadian rhythm of aMT6s excretion was present in most (13/16, 81.3%) patients, but only 4 subjects had normal timing. Comparison of the SEF₉₅ during the melatonin-based biological night and day revealed no difference between the 2 periods (P = 0.64).

Conclusions: The circadian rhythms and PSG of patients receiving mechanical ventilation and intravenous sedation exhibit pronounced temporal disorganization. The finding that most subjects exhibited preserved, but phase delayed, excretion of aMT6s suggests that the circadian pacemaker of such patients may be free-running.

Keywords: Critical illness; circadian rhythm; intensive care; melatonin; polysomnography; sedation; sleep; slow wave activity; ventilator.

Figure 1

Twenty-four hour profiles of absolute delta activity (top panel) and spectral edge frequency 95% (SEF95, bottom panel) in a representative normal subject. SEF95 is higher during the daytime than at night and exhibits cyclic alterations that are inversely related to slow wave activity. Compared to absolute delta power, SEF95 is more robust to artifact (reflected in sharp spikes in delta power) in this unattended study performed in the field. The subject’s relatively early bedtime is typical of his society in this warm climate.

Figure 2

Temporal profiles of 6-sulfatoxymelatonin (aMT6s) excretion. Error bars denote standard error of the mean for each value. The arrows indicate median melatonin onset. The black bars denote usual sleep time (23:00-07:00). (A) aMT6s excretion on Day 1 (n = 16). The data are double plotted for easier visualization. (B) aMT6s excretion on Days 1 and 2 in the subset of subjects who had 48 hours of urinary collection (n = 10). The reproducibility of the profile is evident. (C, inset) Graphical depiction of individual rest periods as determined by melatonin assays. Each hashed band represents a putative 8-h rest period (e.g., recommended sleep time) for each subject as determined by analysis of individual aMT6s assays. The rest period is considered to begin 2 h after melatonin onset. The vertical dotted line represents change of shift for the nurses, and the beginning of the day shift.

Figure 3

Twenty-four hour profiles of absolute delta activity (top panel) and spectral edge frequency 95% (SEF95, bottom panel) on day 1 (n = 17). The dark symbols represent average values for each parameter. The shaded areas represent the standard error of the mean. The black bars denote usual sleep time (23:00-7:00).

Figure 4

Individual temporal profiles of slow wave activity and spectral edge frequency 95% on day 1. A 5-minute moving average was used to plot the slow wave activity profiles. The black bars denote usual sleep time (23:00-7:00). SEF95, spectral edge frequency 95%; EEG, electroencephalogram. (A) Lightening of sedation. 70-year-old woman with interstitial lung disease receiving propofol and fentanyl. Discontinuation of propofol alone (arrow) results in an increase in delta power and a simultaneous shift to higher frequencies as indicated by the small increase in SEF95. Given that propofol itself induces slow wave activity, the response in this case reflects significant cortical suppression prior to propofol discontinuation caused by the joint administration of a sedative and narcotic (fentanyl). The patient was interacting with visitors at noon. (B) Arousal. 64-year-old man receiving propofol and fentanyl continuously and unarousable except for cough and gag. The EEG was highly suppressed when delta power was low (< 100 μV²) and showed a monotonous (encephalopathic) delta pattern when delta power was high. Increases in delta power generally followed stimulation and were associated with an increase in heart rate and a transient decrease in SEF95, consistent with the “paradoxical arousal” or “synchronization” response to noxious stimuli occasionally seen in patients receiving anesthetics.^, Subsequent increases in SEF95 coincided with increased fast-frequency activity and persistently elevated heart rate, compatible with a classical arousal response. The two major episodes during the day (arrows) followed linen changes. (C) Periodic patterns. 70-year-old man with refractory septic shock and multiple organ failure. Propofol and fentanyl were discontinued at 11:00, after which he remained unresponsive. The raw EEG demonstrated a low-frequency pattern with intermittent 1- to 3-second periods of suppression, consistent with a marked encephalopathy. The increase in delta power at 21:00 is attributable to the appearance of rhythmic delta activity, as shown in the 15-sec EEG tracing. The early morning increase in SEF95 was not associated with an increase in responsiveness and is attributable to progressive attenuation of the EEG and a relatively greater contribution of higher frequencies to the overall EEG. He arrested at 07:34.

Figure 5

Relatively normal profile. 22-year-old woman with pneumonia and a history of prior lung transplantation. Propofol was administered continuously except between 11:30 and 14:00. The patient interacted with staff and family when awake and received the sleep and circadian rhythm intervention on this day. Cyclic decreases in SEF95 coincide with cyclic increases in delta activity and with periods of behaviorally scored sleep (bold arrows) as recorded by the bedside attendant. The raw EEG exhibited few pathologic features other than frequent stage transitions.