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Effect of daily sedative interruption on sleep stages of mechanically ventilated patients receiving midazolam by infusion.

The importance of improving the quality and quantity of sleep for critically ill patients is increasingly recognised (1-7). Sleep is a physiological state that permits the maintenance and healing of the human body. The sleep cycle is divided into rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep (2-7). A normal sleep cycle lasts approximately 90 minutes, cycling continuously between REM and NREM sleep. NREM sleep is sub-divided into four stages, 1 through 4, scaled according to increasing depth of sleep. The more restful sleep of stages 3 and 4 is slow wave sleep (SWS) and generally comprises about 15 to 20% of sleep in healthy, middle-aged individuals (2,3). REM sleep, also considered to be restful sleep, comprises about 20 to 25% of sleep in healthy subjects (2,3).

In intensive care units (ICU) mechanically ventilated patients often exhibit sleep fragmentation and a suppression of REM sleep and SWS (1-7). Some investigators have demonstrated that the sleep of mechanically ventilated patients is frequently disrupted, with as many as 63 arousals and awakenings per hour5, decreased SWS (0 to 9% of sleep) and less REM sleep (0 to 14% of sleep) (8-11). These sleep disturbances have been associated with neurocognitive dysfunction (1-4,6,7), abnormalities in host defence mechanisms (1-4,6,7,12), alterations in protein catabolism (1-4,6,7,13) and respiratory dysfunction (2,6,14,15). The causes of sleep disruption in critically ill patients include the ICU environment itself, medical illness, psychological stress, mechanical ventilation, medications and treatments (1-11).

Sedatives and analgesics are indispensable for the treatment of critically ill patients, however many commonly used drugs have adverse effects on sleep architecture (1-7). For example, it is well known that patients receiving benzodiazepines have more stage 2 NREM sleep and less SWS and REM sleep (1-7). Opioids increase stage 1 NREM sleep and reduce SWS and REM sleep (1-7). While SWS is believed to help the speedy recovery of normal physiological functions (2,3), REM sleep deprivation is associated with impaired attention or psychomotor performance, memory alteration and delirium (3). When sedatives are suddenly discontinued, a REM sleep rebound phenomenon follows, often associated with respiratory and haemodynamic instability in critically ill patients (3).

Avoiding excessive sedation, daily sedative interruption (DSI) lessens the unnecessary use of sedatives and improves the prognosis of mechanically ventilated patients (16-17). Furthermore, while it is known that DSI reduces post traumatic stress disorder, or recall of events (18), we still do not clearly know how DSI affects sleep characteristics. For mechanically ventilated patients, we investigated the effects of DSI in comparison with patients receiving continuous infusion of sedatives. We conjectured that DSI may reduce the amount of sedatives administered to patients while avoiding some of their adverse effects on sleep characteristics.


The study was conducted in the ICU at Tokushima University Hospital. Adult patients admitted to the ICU were enrolled to the study when they had been mechanically ventilated and had received sedative infusions for longer than 48 hours. The ventilator was set at assist-control mode and pressure control ventilation. Exclusion criteria were the presence of psychiatric illness, anoxic brain injury, suspected encephalopathy (drug overdose, hepatic failure or renal failure), seizure disorder and severe haemodynamic instability marked by systolic blood pressure of <90 mmHg despite vasopressor support (19). The study protocol was approved by the ethics committee of Tokushima University Hospital (IRB Number: 937). Written informed consent was obtained from all participating patients or their families.

Sedation protocol and randomisation

Patients were assigned to one of two groups using shuffled sealed envelopes: the sedation regimen of the DSI group was interrupted, while the continuous sedation (CS) group received continuous infusion of sedatives. In general, midazolam, opioids or both were infused. Midazolam was selected as the sedative in this study protocol because it is the only benzodiazepine approved for continuous infusion and is commonly used for long-term sedation in Japan. DSI avoids excessive sedation and, for mechanically ventilated patients who receive benzodiazepine infusion, is associated with a better prognosis than CS (16). For each patient, the study day had daytime (0600 to 2100 hours) and night-time (2100 to 0600 hours) phases. In the DSI group, sedatives were interrupted at 0600 hours until the patient was awake enough to follow commands (7). If the patients complained of discomfort or became agitated, midazolam was intermittently administered as needed. Agitation was characterised as frequent unpurposeful movement, patient-ventilator dyssynchrony, pulling on the catheter or aggressive behaviour toward medical staff. At 2100 hours, midazolam was restarted to maintain Ramsay sedation scale (RSS) 4 to 5 (20). In the CS group, throughout the 24 hours, patients were sedated with midazolam continuously to maintain RSS at 4 to 5. Apparent pain was treated with morphine or fentanyl. The administration of sedatives or analgesics was done at the discretion of the attending physician. No neuromuscular agents were administered in either group. Scored according to the RSS, sedation was assessed by the duty nurse or attending physician at two hour intervals or when nursing care was given. During night-time, the duty nurse decreased environmental stimulation by minimising noise and lighting levels. For the two groups, records for RSS, dosage of midazolam and opioids during the day and night-time period were recorded and compared.


All patients were continuously monitored with 24-hour polysomnography (PSG) (Sandman Elite version 7.2, Covidien, MO, USA). According to the international 10/20 system of electrode placement, electrode leads were placed on the subject's head in the left and right parietal lobes, and left and right occipital lobe positions. These leads were referenced to two electrodes A1 (left) and A2 (right) over the subjects' mastoid regions. To differentiate REM sleep from NREM sleep and wakefulness, two extraocular leads and two chin electromyogram leads were applied to assess ocular movements and muscle tone. The PSG recorder was calibrated using a 50 [micro]V signal at 5 [micro]V/mm sensitivity; if skin impedance exceeded 10 k[ohm], the electrodes were reapplied. After recording, using the criteria of Rechtschaffen and Kales (21), the polysomnograms were scored in 30-second epochs by two PSG sleep technicians. The total sleep time (TST) was defined as the amount of time recorded as a type of sleep. Amounts of each of the sleep stages were expressed as total hours during study period. The arousal index was scored as the number of arousals per hour during study period. For each group, these data were compared to show relative sleep fragmentation.


Statistical analysis

Data are presented as the mean [+ or -] standard deviation or, if not normally distributed, as median values (interquartile range). The Mann-Whitney U test was applied to evaluate non-paired measurements. Categorical variables were analysed using the chi-square test. Relationships between dosage of midazolam and the amounts of each sleep stage were assessed using Spearman's rho (rs). All statistical tests were two-sided and a P value of <0.05 was considered to be statistically significant.


The study population of 22 patients comprised 16 males and six females aged 70 [+ or -] 10 years (range 53 to 87). The DSI group (n=11) and CS group (n=11) were comparable in terms of age, gender, body weight, body mass index, Acute Physiology and Chronic Health Evaluation II score, days of mechanical ventilation prior to the study, diagnosis, positive culture results, vasopressor use and serum creatinine. Table 1 presents the clinical features of patients.

Polysomnographic study

Figure 1 shows typical hypnograms for each group. In the DSI group, although the amounts were small, SWS and REM sleep were observed during the night-time. In the CS group, sleep was typically distributed evenly throughout the day and stage 1 and 2 NREM sleep were predominant; SWS and REM sleep were not apparent. Figure 2A shows typical polysomnographic 30-second epochs, from the DSI group, scored as SWS. Delta waves (1 to 2 Hz) occupied nearly half of the electroencephalogram (EEG) trace. Figure 2B shows typical polysomnographic 30-second epochs, from the DSI group, scored as REM sleep. A low-voltage, rapid-frequency EEG pattern with rapid eye movements appeared on the extraocular record, and electromyogram recordings were of low amplitude. Figure 2C shows typical polysomnographic 30-second epochs, from the DSI group, scored as stage 1 and arousal. An abrupt shift in EEG frequency to more than 16 Hz, but without spindles, is apparent. Figure 2D shows typical poly-somnographic 30-second epochs, from the CS group, scored as stage 2. The tracer shows K-complex followed by EEG spindle activity.

Table 2 shows the median amounts of TST and distribution of sleep stages. During the 24-hour monitoring period, the TST was greater in the CS group. In the CS group, 57% of sleep was observed during the daytime compared with 40% in the DSI group. In the CS group, stage 1 and 2 NREM sleep were predominant; SWS was detected in only two patients, and REM sleep in four patients during the night-time. In the DSI group, SWS and REM sleep were detected in nine patients and the amounts of SWS and REM sleep were longer than in the CS group during night-time. In the DSI group, the incidence of arousal during the night-time was higher than in the CS group (Table 2).

Ramsay sedation scale and sedatives and opioids

Table 3 shows the RSS and dosages of midazolam and opioids. Patients in the DSI group received less midazolam during the 24-hour monitoring period (P <0.001), both during the daytime (P <0.001) and during the night-time (P=0.048). While nine patients in the DSI group required fentanyl, two in the CS group required fentanyl and two required morphine. There was no difference between the two groups in the median dosage of fentanyl. No patient received antidepressants or psychotropic medication. In the DSI group, RSS was 1 to 3 during 95% of the daytime, when median RSS was 2.4. RSS 4 to 6 occupied 87% of the night-time, when median RSS was 4.7. RSS values during the daytime and night-time were statistically significantly different in the DSI group (P <0.001). In the CS group, RSS was recorded as 1 to 3 for 12% of the daytime, and we found no statistically significant difference in the median RSS between the daytime (4.6) and night-time (5.0) (P=0.51). There was a significant inverse correlation between midazolam dosage during the 24-hour monitoring period and amounts of SWS (rs=-0.55, P <0.001) and REM sleep (rs=-0.51, P=0.016) during the night-time. In data from the night-time, no significant correlations were found between midazolam dosage during the night-time and amounts of SWS (rs=-0.3, P=0.18) or REM sleep (rs=-0.34, P=0.12).



Compared with normal people of the same age range, we recorded higher proportions of stage 1 or 2 NREM sleep and lower proportions of SWS and REM sleep in all patients in the present study. However, patients on the DSI regimen had more SWS and REM sleep than other mechanically ventilated patients continuously receiving midazolam.

In mechanically ventilated patients, sedatives and opioids are commonly administered to decrease agitation and promote amnesia and sleep. Sedatives and opioids, however, alter sleep architecture in mechanically ventilated patients (1-7). Benzodiazepines decrease awakening and increase sleep continuity, but they do so by prolonging stage 2 NREM sleep at the expense of SWS and REM sleep (1-7). Meanwhile, although we know that DSI decreases the duration of mechanical ventilation and shortens ICU stay (16), we do not know how it affects sleep quality.

In the present study, amounts of SWS and REM sleep were longer in the DSI group; over the course of the 24-hour monitoring period these patients received less midazolam than CS patients, but target sedation was maintained during night-time. In the present study, the lesser amount of midazolam could have contributed to there being more SWS and REM sleep in the DSI than in the CS group. Although the incidence of arousal was higher in the DSI group, it was less than the normal range (10 to 15 /hour) during nocturnal sleep (22).

The amount of midazolam during night-time was lower in the DSI group compared with CS group. One possible reason was that drug tolerance was less in the DSI group due to sedation interruption. Acute tolerance appears to be a common finding in ICU patients receiving continuous infusions of midazolam for more than 24 hours (23). Another reason was that lighter sedation levels were maintained in the DSI group compared with the CS group. RSS in the DSI group tended to be lower compared with the CS group (RSS 4.7 in DSI group vs 5.0 in CS group; P=0.06). However, RSS 4 to 5 was within the target sedation range in the present study. Additional opioids would also influence sleep characteristics because opioids increase stage 1 NREM sleep while decreasing SWS and REM sleep (1-7). In our study, nine DSI patients required fentanyl and four CS patients required fentanyl or morphine. The cumulative effects of midazolam possibly reduced the analgesic requirement in the CS group. Opioids also lessen the proportion of SWS and REM sleep. The total amount of fentanyl administered was about the same for both groups: we think that opioids probably did not have a significant effect on the overall results, but we cannot discount this possibility.

Compared with previous studies, we recorded less night-time SWS and REM sleep (8-11). Several factors might contribute to this discrepancy. First, the amounts of SWS and REM sleep and frequency of arousal in critically ill patients who require mechanical ventilation have varied across studies: investigators have reported that for mechanically ventilated patients, SWS accounted for 0 to 9% of TST and REM sleep for 0 to 14% of TST and the incidence of arousal was from 9 to 35 /hour (8-11). All the patients in our study received continuous night-time sedation, but the majority of patients in previous reports did not receive sedation11 or received it only intermittently (8-10) during PSG recording. Our patients were also older (70 years old) than in previous studies (54 to 62 years old) (8-11). It is well documented that older people sleep less at night, moreover, SWS and REM sleep accounts for a smaller proportion of their night-time sleep and they have a greater incidence of arousal during sleep (24,25). Healthy subjects aged 70 or over experience markedly less SWS (1.4% of TST) and moderately less REM sleep (15.1% of TST) than people aged in their 20s (SWS 18.7%, REM 23.2% of TST) (25). In the present study, duration of mechanical ventilation prior to PSG recording was about four days (range two to seven days), while the reported durations of mechanical ventilation prior to PSG recordings in previous studies were 17 to 48 days (8-11). Acute medical illness is associated with greater sleep fragmentation, less TST and less SWS or REM sleep (26). Finally, two-thirds of our patients received vasopressor agents, while most patients in previous studies did not (9-11). Vasopressor agents increase sleep disruption and suppress SWS and REM sleep (6).

DSI, with patients being allowed to wake in the daytime, lessens the use of sedatives. Patients in the DSI group, with RSS 1 to 3 being defined as awake, were awake for 95% of the daytime compared with 12% in the CS group. In normal subjects, as a factor in the homeostatic need for sleep, SWS during night-time is strongly related to wakefulness on the day before (27). DSI may benefit mechanically ventilated patients both by promoting restorative sleep related to awakening and by reducing the total amount of sedatives received.

Our study has several limitations. Unfortunately, the sample size is too small to allow for logistic regression and several factors may confound the results. Because we did not measure midazolam blood levels, we are unable to report the actual midazolam levels for the two groups. Neither for the two groups did we evaluate or compare the effects of noise, lighting, nursing care intervention and other environmental factors in the ICU, factors which could possibly lead to selection bias related to the medication regimen. Even so, we think it fair to assume that differences in these factors were negligible for both groups. High doses or continuous infusions of midazolam throughout 24 hours are not in line with many contemporary sedation practices. Most intensivists would argue, in principle, that it is preferable to maintain light sedation. Normally, the severity of illness influences sleep characteristics. Statistically, we found no significant difference in the severity of illness between the two groups. The need for deep sedation may simply be related to the small patient population; it may have been the case that sicker patients were found in the CS group.

In conclusion, the sleep architecture of mechanically ventilated patients is severely disturbed. Compared with CS, DSI avoided excessive sedation and increased the amounts of SWS and REM sleep. Many factors may interfere with normal sleep and an integrated strategy to promote restorative sleep is needed to minimise the sleep disturbance of mechanically ventilated patients. With and without DSI, further research is required to evaluate the effects of different sedative agents on sleep characteristics.


Financial support: Departmental funding. Trial registration: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR). Identifier: UMIN000002362.


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J. OTO *, K. YAMAMOTO ([dagger]), S. KOIKE ([double dagger]), H. IMANAKA ([section]), M. NISHIMURA **

Emergency and Critical Care Medicine, The University of Tokushima Graduated School, Tokushima, Japan

* M.D., Instructor.

([dagger]) R.P.S.G.T., Clinical Engineer in Sleep Disorder Center, Toyohashi Mates Clinic, Toyohashi, Aichi.

([double dagger]) M.D., Director of Sleep Disorder Center, Toyohashi Mates Clinic, Toyohashi, Aichi.

([section]) M.D., Designated Professor.

** M.D., Professor.

Address for correspondence: Dr J. Oto, Department of Emergency and Critical Care Medicine, The University of Tokushima Graduated School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Email:

Accepted for publication on January 7, 2011.
Table 1

Demographic data

 DSI group CS group

Age, y 68 [+ or -] 11 72 [+ or -] 9
Gender, M/F 7/4 9/2
Body weight, kg 62 [+ or -] 10 55 [+ or -] 14
Body mass index 23 [+ or -] 3 21 [+ or -] 4
APACHE II score 14 [+ or -] 3.6 17 [+ or -] 4.5
Days of MV prior to
 the study 4.0 [+ or -] 1.9 3.8 [+ or -] 1.4
Sedatives prior to the study

 Propofol, n 4 3
 Cumulative dose of
 propofol, mg/kg 65 (60, 73) 64 (59, 101)
 Midazolam, n 7 8
 Cumulative dose of
 midazolam, mg/kg 8.2 (5.4, 9.9) 8.4 (7.1, 11.4)

ICU diagnosis, n (%)


 Heart failure 1 (9) 1 (9)
 Pneumonia 1 (9) 2 (18)
 Myasthenia gravis 2 (18) 1 (9)
 Sepsis 1 (9) 2 (18)


 Cardiovascular surgery 5 (40) 3 (27)
 Abdominal surgery 1 (9) 2 (18)

Positive culture
 results, n (%) 4 (36) 5 (45)
Vasopressors, n (%) 7 (63) 8 (72)
Serum creatinine, mmol/l 0.07 [+ or -] 0.02 0.1 [+ or -] 0.06

Data were presented as median (interquartile range), mean [+ or -] SD
or percentage unless otherwise noted.

DSI=daily sedative interruption, CS=continuous sedation, M=male,
F=female, APACHE=Acute

Physiology and Chronic Health Evaluation, MV=mechanical ventilation,
ICU=intensive care unit.

Table 2

Sleep architecture during study period between two groups

Variables DSI group CS group P value

Whole day, 24 h

 Total sleep time, h 12.3 (9.0,14.6) 23.3 (22.1, 23.5) 0.002
 Stage 1, min 222 (186, 246) 474 (168, 846) 0.16
 Stage 2, min 408 (312, 462) 654 (306, 1242) 0.27
 Stage 3, 4, min 6 (6, 7.2) 0 (0, 0) 0.04
 REM, min 54 (24, 84) 0 (0, 12) 0.02
 Arousal index, n/h 3.4 (2.6, 6.7) 2.2 (0, 2.8) 0.04

Night-time period, 9 h

 Total sleep time, h 7.3 (6.6, 8.2) 8.7 (8.2, 8.8) 0.047
 Stage 1, min 96 (60, 144) 180 (54, 342) 0.46
 Stage 2, min 264 (222, 360) 282 (66, 468) 0.55
 Stage 3, 4, min 1.8 (0.6, 4.2) 0 (0, 0) 0.03
 REM, min 30 (12, 48) 0 (0, 9) 0.01
 Arousal index, n/h 4.4 (2.5, 8.3) 2.2 (0, 2.6) 0.03

Data were presented as median (quartile) unless otherwise noted. REM=
rapid eye movement. DSI=daily sedative interruption, CS=continuous
sedation, REM=rapid eye movement.

Table 3

Comparison of Ramsay sedation scale and drug dosages in the daily
sedative interruption and continuous infusion groups

 DSI group CS group P value

Whole day

 Midazolam (mg/kg) 0.6 (0.5, 0.9) 2.7 (2.0, 3.4) <0.001
 Morphine (mg/kg) -- 0.5 (0.47, 0.54) --
 Fentanyl ([micro]g/kg) 5.1 (3.9, 6.3) 6.0 (5.6, 6.3) 0.5

Daytime (0600-2100 hours)

 RSS 2.4 (2.1, 2.6) 4.6 (4.4, 4.9) <0.001
 Midazolam (mg/kg) 0 (0-0.03) 1.7 (1.3, 2.1) <0.001
 Morphine (mg/kg) -- 0.3 (0.28, 0.32) --
 Fentanyl ([micro]g/kg) 1.7 (1.6, 2.6) 2.9 (2.3, 3.6) 0.37

Night-time (2100-0600 hours)

 RSS 4.7 (4.0-4.8) 5.0 (4.4-5.1) 0.06
 Midazolam (mg/kg) 0.6 (0.4-0.8) 1.0 (0.7-1.2) 0.048
 Morphine (mg/kg) -- 0.18 (0.17, 0.19) --
 Fentanyl ([micro]g/kg) 4.3 (3.3, 5.7) 3.0 (2.7, 3.2) 0.27

Data were presented as median (quartile) unless otherwise noted.
DSI=daily sedative interruption, CS=continuous sedation, RSS=Ramsay
sedation scale.
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Author:Oto, J.; Yamamoto, K.; Koikes, S.; Imanaka, H.; Nishimura, M.
Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:9JAPA
Date:May 1, 2011
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