Sleep during and following critical illness: A narrative review

Table 1 Simplified polysomnographic features of the American Academy of Sleep Medicine’s phases of sleep

Sleep stage	Electroencephalogram	Electrooculogram	Chin electromyogram
Wake	Alpha activity (sinusoidal 8-13 Hz)	Rapid eye movements; Reading eye movements; Slow eye movements; Blinks	Normal or high tone
N1	< 50% alpha activity; > 50% low amplitude mixed frequency activity (4-7 Hz)	Slow eye movements	Variable, usually lower than wake
N2	Sleep spindles; K-complexes	None	Variable tone
N3	Slow (delta) wave (0.5-2 Hz) ≥ 20%; Sleep spindles may occur	None	Variable tone
REM	Low amplitude mixed frequency activity; No sleep spindles or K-complexes	Rapid eye movements	Low tone

REM: Rapid eye movement.

Table 2 Comparison of studies assessing the effects of ventilator mode on sleep quantity and quality

Ref.	Study Design	n	Treatment arms		Sedation	Outcomes
Studies comparing pressure support ventilation against assist control ventilation
Parthasarathy et al[79], 2002	Single centre, randomised, cross over study	11	2 h each of: PSV; PS to achieve Vt 8 ml/kg	ACV; Vt: 8 mL/kg; f: Set as patient RR minus 4/min	Yes	Sleep efficiency: Arousal index, mean (SD)	Not reported; ACV 39 (6); PSV 35 (7); No statistically significant difference between ventilation modes
Toublanc et al[81], 2007	Single centre, randomised, cross over study	20	4 h each of: PSV; PS = 6 cmH2O; Trigger sens = 0.5 cmH2O	ACV; Vt: 10 ml/kg; f: 12/min; Increased until no spontaneous inspiratory effort	Free from sedation for 48 h	Sleep efficiency: Arousal index, mean (SD)	No difference, values not reported; ACV 7 (SD 5); PSV 7 (SD 5); No statistically significant difference between ventilation modes
Cabello et al[82], 2008	Single centre, randomised, cross over study	15	6 h each of: cPSV; PS to achieve Vt 6-8 ml/kg (PBW); RR < 35/min; aPSV	ACV; Vt: 8 mL/kg; f: 10/min (back up)	Free from sedation for 24 h	Sleep efficiency, median [IQR]: Arousal index, median [IQR]	ACV 58 [48-82], cPSV 44 [29-30], aPSV 63 [29-80]; ACV 30 [17-41], PSV 28 [17-53], aPSV 23 [21-45]; No statistically significant difference between ventilation modes
Studies comparing pressure support ventilation against pressure control ventilation
Andréjak et al[83], 2013	Single centre, randomised,cross over study	26	4 h each of: PSV; PS = 6 cmH2O; Trigger sens = 0.5 cmH2O	PCV; PS = 20 cmH2O; f: Greater than patient RR I/E ratio: 1/1.2 to 1/1.5	Not reported	Sleep efficiency, median [IQR]: Arousal index	PCV 63 [9-100]; PSV 37 [0-96] Not reported; Significantly improved sleep efficiency with PCV
Studies comparing pressure support ventilation against proportional assist ventilation
Bosma et al[84], 2007	Single centre, randomised, cross over study	13	1 night each of: PSV	PAV	Propofol, midazolam or lorazepam	Sleep efficiency, mean (SD): Arousal index, median [IQR]: Patient-ventilator asynchrony per hour, mean (SD)	PSV 58% (25); PAV 60 (23); PSV 16 (2-74); PAV 9 (1-41); PSV 53 (59); PAV 24 (15); PAV associated with statistically significantly fewer arousals and episodes of asynchrony
Alexopoulou et al[85], 2007	Single centre, randomised, cross over study	17	1 night each of: PSVbase; PS as before study; PShigh; Pressure assist increased by 40%-50% from PSVbase or until Paw = 30 cmH2O	PAV+base; Set to achieve mean inspiratory pressure similar to PSVbase; PAV+high; Percentage of unloading increased by 40%-50% from PSVbase or until it reached 85%	Group A; n = 11; Propofol; Group B; n = 9; Non-sedated	Group A; Sleep efficiency, mean (SD): Arousal index, mean (SD): Group B; Sleep efficiency, mean (SD): Arousal index, mean (SD)	PAV+base 99 (2); PAVhigh 98 (5); PSVbase 93 (11); PSVhigh 88 (16) (P < 0.05); PAV+base 4.6 (4.9); PAVhigh 7.4 (11); PSVbase 5.4 (3.6); PSVhigh 6.5 (6.7); PAV+base 76 (11); PAVhigh 71 (21); PSVbase 68 (19); PSVhigh 72 (15); PAV+base 12 (8.0); PAVhigh 11 (7.6); PSVbase 8.4 (4.8); PSVhigh 10.5 (9.9); In sedated patients (Group A), PAV+ is associated with a modest, albeit statistically significant at the 0.05 level, improvement in sleep efficiency; No statistically significant differences found between ventilation modes in non-sedated group
Alexopoulou et al[86], 2013	Single centre, randomised,cross over study	14	Alternating 4-h blocks over 24 h of:		Free from sedation and opioids for 24 h	Sleep efficiency, median [IQR]: Arousal index, median [IQR]	PAV+ 51 [13-66]; PSV 27 [6-22]; PAV+ 11 [4-25]; PSV 12 [3-16]; No statistically significant improvement found with PAV+
			PSV; PS maintained at pre-study level	PAV+; % of unloading set to achieve a mean inspiratory pressure similar to PSV
Studies comparing pressure support ventilation against neurally adjusted ventilatory assist
Delisle et al[236], 2011	Single centre, randomised, cross over study	14	2 non-consecutive 4-h blocks (d/night) of:		Free from sedation and opioids for 24 h	Sleep efficiency, median [IQR]: Fragmentation index, median [IQR]	NAVA 74 [52-77]; PSV 44 [29-74]; NAVA 18 [8-22]; PSV 34 [25-54]; NAVA statistically significant improvement in the efficiency and reduced fragmentation of sleep
			PSV; PS to achieve Vt 8 mL/kg; RR < 35/min	NAVA

PSV: Pressure support ventilation; cPSV: Clinician adjusted PSV; aPSV: Automatically adjusted PSV; PCV: Pressure control ventilation; PAV: Proportional assist ventilation; PAV+: Proportional assist ventilation with load adjustable factors; NAVA: Neurally adjusted ventilatory assist; IQR: Interquartile range; SD: Standard deviation; n: Number of patients. P=NS: Not statistically significant result; Vt: Tidal volume; RR: Spontaneous respiratory rate; f: Mechanical ventilatory cycle frequency; PS: Pressure support; I/E ratio: Inspiratory-expiratory ratio.

Table 3 Comparison of American Academy of Sleep Medicine’s and Rechtschaffen and Kales criteria sleep stage nomenclature

	AASM	R&K
Wake	Stage W	Stage W
NREM sleep	Stage N1	Stage 1
	Stage N2	Stage 2
	Stage N3	Stage 3
		Stage 4
REM sleep	Stage R	Stage REM

AASM: American Academy of Sleep Medicine; R&K: Rechtschaffen and Kales criteria; REM: Rapid eye movement.

Table 4 Summary of objective methods of sleep measurement in the critically ill

Method	Benefits	Limitations
Full polysomnography (PSG)	Gold standard technique; Provides polygraphic data on EEG, eye movements and chin tone; Established guidelines for interpreting data for normal sleep	Complex set up; Relatively expensive; Poorly tolerated in 25% of patients; Interferes with nursing care; May interfere with patient sleep; Interpretation requires sleep specialist; No validated criteria for atypical EEG found commonly in critically ill
Bispectral index (BIS) monitor	Small anatomic footprint; Simplified set up compared to PSG; Does not require sleep specialist for interpretation; Less affected by atypical EEG common in critically ill	Inaccurate differentiation of REM from N1/N2 sleep; Correlates weakly with RCSQ; No validated criteria for interpretation of results; Primarily designed to monitor depth of sedation
Limited lead EEG	Small anatomic footprint; Simplified set up compared to PSG; May not require sleep specialist for interpretation	Accuracy dependent on device and auto-staging software; Interpretation dependent on sleep specialist if not using auto-staging
Actigraphy	Minimally invasive; Simple set up; Easy to perform serial measures; Established use in outpatient setting	Poor accuracy compared to PSG and nurse observation, including over-estimation of total sleep time and sleep efficiency; Confounded by immobility, weakness, sedation, and neurological injury
Under mattress sensor	Non-invasive modality; Simple set up	Moderate agreement, but poor specificity compared to PSG; No correlation with RCSQ

EEG: Electroencephalogram; N1: Non-REM sleep stage 1; N2: Non-REM sleep stage 2; PSG: Polysomnography; REM: Rapid eye movement sleep; RCSQ: Richards-Campbell Sleep Questionnaire.

Table 5 Summary of randomised clinical trials assessing nocturnal melatonin as a pharmacological sleep aid

Ref.	Design	Patients	Intervention & control	Sedation	Outcome
Ibrahim et al[158], 2006	Single centre, double-blind, randomised trial	32 pts	I: Melatonin 4 mg; C: placebo; For ≥ 48 h	Infusions ceased for ≥ 12 h	No significant difference in total sleep time by modified SOT
Bourne et al[136], 2008	Single centre, double-blind, randomised trial	24 pts	I: Melatonin 10 mg; C: Placebo; For 4 nights	Ceased for ≥ 30 h	No significant difference in total RCSQ or sleep efficiency by BIS
Foreman et al[222], 2015	Single centre, pilot, randomised trial	12 pts	I: Melatonin 3 mg plus eye masks and headphonesC: Standard care; For 1-7 d	Propofol allowed. Opiates ceased > 24 h	Primary outcome not determined in 65% due to uninterpretable PSG
Mistraletti et al[221], 2015	Single centre, double-blind, randomised trial	82 pts	I: Melatonin 3+3 mg; C: Placebo; From day 3 of ICU until ICU discharge	Enteral hydroxyzine and lorazepam allowed	No significant difference in total sleep time by nurse observation
Gandolfi et al[224], 2020	Double centre, double-blind, randomised trial	203 pts	I: Melatonin 10 mg; C: Placebo For 7 d or until hospital discharge	As per treating clinician	Statistically improved total RCSQ, mean (SD): I: 61 (26) C: 70 (21) (P = 0.03); No significant difference in total sleep time by nurse observation
Wibrow et al[225], 2021	Multicentre (12), double blind, randomised, trial	841 pts	I: Melatonin 4 mg; C: Placebo; For 14 d or until ICU discharge	As per treating clinician	No significant difference in total RCSQ

BIS: Bispectral index; ICU: Intensive care unit; PSG: Polysomnography; RCSQ: Richards-Campbell Sleep Questionnaire; SOT: Sleep observation tool.