The effect of benzodiazepines on insomnia in patients with chronic obstructive pulmonary disease: a meta-analysis of treatment efficacy and safety

Figures & data

Figure 1 Flow diagram of the search process and study selection.

Abbreviation: CNKI, China National Knowledge Infrastructure.

Table 1 Characteristics of the studies included in the meta-analysis

Study	Region	Study design	n	FEV1% predicted (mean ± SD)	Trial drug (dose)	Trial time	Outcome
Block et al^Citation14	USA	DB, COS, R, PC	20	29–99 (53±21)	Flurazepam (30 mg)	2 consecutive nights	TST, apnea
Timms et al^Citation15	UK	DB, COS, R, PC	10	17–76 (38±19)	Triazolam (0.125 mg, 0.25 mg)	3 nights within a2-week period	TST, sleep duration, arousals/hour of sleep, percentage of time below 90% SaO2, time spent in stage 2 non-REM sleep, subjective sleep quality, mean SaO2, minimum SaO2, number of apneic and hypopneic events
Midgren et al^Citation16	Sweden	DB, COS, R, PC	14	31±11	Nitrazepam (5 mg) flunitrazepam (1 mg)	3 nights within a1-week period	Sleep latency, TST, SE, periods of wakefulness, apneas, maximum tcPCO2 increase
Steens et al^Citation17	Canada	DB, COS, R, PC	23	40–80 (61±12)	Triazolam (0.25 mg)	4 consecutive nights	TST, sleep latency, arousals/total sleep time, SE, sleep quality (VAS)
Stege et al^Citation13	the Netherlands	DB, COS, R, PC	14	33.5±9.2	Temazepam (10 mg)	1 week	TST, SE, NWAK, sleep quality (VAS) (AHI, %TST) with SaO290%

Abbreviations: DB, double-blind; COS, crossover study; R, randomized; PC, placebo-controlled; TST, total sleep time; SaO₂, arterial oxygen saturation; REM, rapid eye movement; SE, sleep efficiency; tcPCO₂, transcutaneous carbon dioxide pressure; VAS, visual analog scale; NWAK, number of awakenings; AHI, Apnea–Hypopnea Index.

Table 2 Quality assessments of the studies included

Study	Random-sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Other bias
Block et al^Citation14	Unclear	Unclear	Low	Unclear	Low	Low	Low
Midgren et al^Citation16	Unclear	Unclear	Low	Unclear	Low	Low	Low
Stege et al^Citation13	Low	Unclear	Low	Unclear	Low	Low	Low
Timms et al^Citation15	Unclear	Unclear	Low	Unclear	Low	Low	Low
sSteens et al^Citation17	Unclear	Unclear	Low	Unclear	Low	Low	Low

Figure 2 Effect of BZD on TST in COPD patients with insomnia.

Notes: ^#Flunitrazepam; *nitrazepam. Data was analyzed by Review Manager 5.3. Heterogeneity was predefined as I²>50%. The random-effect model was used if heterogeneity was observed. Otherwise, the fixed-effect model was used.

Abbreviations: BZD, benzodiazepine; TST, total sleep time; SD, standard deviation; SMD, standardized mean difference; IV, independent variable; CI, confidence interval.

Figure 3 Funnel plot of published studies in relation to TST meta-analysis.

Abbreviations: TST, total sleep time; SE, sleep efficiency; SMD, standardized mean difference.

Figure 4 Subgroup meta-analysis of different half-life of BZD on TST in COPD patients with insomnia.

Notes: ^#Flunitrazepam; *nitrazepam. As there is limited data, there is no value from statistical software in this section.
Abbreviations: SMD, standardized mean difference; CI, confidence interval.

Figure 5 Effect of BZD on SE in COPD patients with insomnia.

Notes: ^#Flunitrazepam; *nitrazepam. Data was analyzed by Review Manager 5.3. Heterogeneity was predefined as I²>50%. The random-effect model was used if heterogeneity was observed. Otherwise, the fixed-effect model was used.
Abbreviations: BZD, benzodiazepine; SE, sleep efficiency; SD, standard deviation; SMD, standardized mean difference; IV, independent variable; CI, confidence interval.

Figure 6 Effect of BZD on sleep latency in COPD patients with insomnia.

Notes: ^#Flunitrazepam; *nitrazepam.
Abbreviations: BZD, benzodiazepine; SD, standard deviation; WMD, weighted mean difference; IV, independent variable; CI, confidence interval.

Figure 7 Effect of BZD on arousal number during sleep in COPD patients with insomnia.

Notes: ^#Flunitrazepam; *nitrazepam.
Abbreviations: BZD, benzodiazepine; SD, standard deviation; SMD, standardized mean difference; IV, independent variable; CI, confidence interval.

Figure 8 Effect of BZD on subjective sleep quality in COPD patients with insomnia.

Abbreviations: BZD, benzodiazepine; SD, standard deviation; SMD, standardized mean difference; IV, independent variable; CI, confidence interval.

Figure 9 Effect of BZD on AHI in COPD patients with insomnia.

Abbreviations: BZD, benzodiazepine; AHI, Apnea–Hypopnea Index; SD, standard deviation; SMD, standardized mean difference; IV, independent variable; CI, confidence interval.

Figure 10 Effect of BZD on sleep apnea in COPD patients with insomnia.

Notes: ^#Flunitrazepam; *nitrazepam.
Abbreviations: BZD, benzodiazepine; SD, standard deviation; SMD, standardized mean difference; IV, independent variable; CI, confidence interval.

Figure 11 Effect of BZD on percentage of time below 90% SaO₂ in COPD patients with insomnia.

Abbreviations: BZD, benzodiazepine; SaO₂, arterial oxygen saturation; SD, standard deviation; WMD, weighted mean difference; IV, independent variable; CI, confidence interval.

Figure 12 The effect of BZD on mean SaO₂ in night sleep in COPD patients with insomnia.

Abbreviations: BZD, benzodiazepine; SaO₂, arterial oxygen saturation; SD, standard deviation; SMD, standardized mean difference; IV, independent variable; CI, confidence interval.

Figure 13 The effect of BZD on max tcPCO₂ increase during sleep in COPD patients with insomnia.

Notes: ^#Flunitrazepam; *nitrazepam.
Abbreviations: BZD, benzodiazepine; tcPCO₂, transcutaneous carbon dioxide pressure; SD, standard deviation; WMD, weighted mean difference; IV, independent variable; CI, confidence interval.

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