Propofol or benzodiazepines for short- and long-term sedation in intensive care units? An economic evaluation based on meta-analytic results

Figures & data

Figure 1 Graphic structure of the model used to assess costs of consumed resources.

Abbreviation: ICU, intensive care unit.

Table 1 Model effectiveness inputs

	Recovery times (hours; mean[SD])*
	LTS (RCTs)		LTS (RCTs + non-RCTs)		STS (RCTs)
	Propofol	Propofol vs BDZ	Propofol	Propofol vs BDZ	Propofol	Propofol vs BDZ
ICU length of stay	299.98 (50.28)	−12.28 (1.51)	285.71 (38.91)	−22.43 (11.35)	57.2 (9.16)	−4.95 (1.81)
Mechanical ventilation	122.99 (35.34)	−5.39 (6.62)	131 (26.4)	−7.19 (6.93)	12.66 (1.53)	−1.95 (0.9)
Weaning time	1.13 (0.21)	−12.73 (2.43)	1.13 (0.21)	−16.04 (2.51)	0.9 (0.07)	−1.61 (0.44)

Notes:

* Only the mean difference between propofol and BDZ was used to synthesize the BDZ cohort in the base case. SD was used to examine parameter uncertainty in the sensitivity analysis. Mean recovery times are presented as hours (SD).

Abbreviations: BDZ, benzodiazepines; ICU, intensive care unit; LTS, long-term sedation; RCTs, randomized controlled trials; STS, short-term sedation; SD, standard deviation.

Table 2 ICU costs per hour stratified by use of mechanical ventilation and successive ICU days

Country	ICU costs (€/day)	Reference	MV			No MV
			First 24 hours	Second 24 hours	>48 hours	First 24 hours	Second 24 hours	>48 hours
Italy	1,138	^Citation64	113	50	41	97	34	26
Germany	1,230	^Citation65	122	54	45	105	37	28
France	1,213	^Citation66	120	53	44	103	36	27
UK	2,025	^Citation65	200	89	74	172	61	45
USA	3,453	^Citation63	342	152	126	294	104	77

Abbreviations: ICU, intensive care unit; MV, mechanical ventilation.

Table 3 Meta-analytic results: duration of mechanical ventilation

Comparators	Sedation duration	N studies	N patients		MD	SE	95% CI		p-value
			Propofol	Comparator			Lower	Upper
Duration of mechanical ventilation (hours) – primary analysis
Propofol vs BDZ	STS	9	311	304	−1.95	0.90	−3.72	−0.18	0.03
Propofol vs Dx	STS	3	224	220	0.46	1.23	−1.95	2.87	0.71
Propofol vs BDZ	LTS	5	228	231	−5.39	6.62	−18.36	7.58	0.42
Duration of mechanical ventilation (hours) – broad analysis
Propofol vs BDZ	STS	9	311	304	−1.95	0.90	−3.72	−0.18	0.03
Propofol vs Dx	STS	5	302	298	1.25	0.86	−0.42	2.93	0.14
Propofol vs BDZ	LTS	7	298	260	−7.19	6.93	−20.77	6.39	0.30

Abbreviations: BDZ, benzodiazepines; CI, confidence interval; Dx, dexmedetomidine; LTS, long-term sedation; MD, mean difference; SE, standard error; STS, short-term sedation.

Table 4 Meta-analytic results: weaning time

Comparators	Sedation duration	N studies	N patients		MD	SE	95% CI		p-value
			Propofol	Comparator			Lower	Upper
Weaning time (hours) – primary analysis
Propofol vs BDZ	STS	10	276		−1.61	0.44	−2.47	−0.76	0.00
Propofol vs Dx	STS	2	158		0.00	0.11	−0.23	0.22	0.97
Propofol vs BDZ	LTS	9	229	222	−12.73	2.43	−17.50	−7.97	0.00
Weaning time (hours) – broad analysis
Propofol vs BDZ	STS	10	276	272	−1.61	0.44	−2.47	−0.76	0.00
Propofol vs Dx	STS	2	158	157	0.00	0.11	−0.23	0.22	0.97
Propofol vs BDZ	LTS	10	283	276	−16.04	2.51	−20.96	−11.11	0.00

Abbreviations: BDZ, benzodiazepine; CI, confidence interval; Dx, dexmedetomidine; LTS, long-term sedation; MD, mean difference; SE, standard error; STS, short-term sedation.

Table 5 Meta-analytic results: time to extubation

Comparators	Sedation duration	N studies	N patients		MD	SE	95% CI		p-value
			Propofol	Comparator			Lower	Upper
Time to extubation (hours) – primary analysis
Propofol vs BDZ	STS	4	176	168	−2.22	1.76	−5.66	1.22	0.21
Propofol vs Dx	STS	2	178	177	0.88	1.51	−2.08	3.84	0.56
Propofol vs BDZ	LTS	1	31	36	−42.00	30.89	−102.54	18.54	0.17
Time to extubation (hours) – broad analysis
Propofol vs BDZ	STS	4	176	168	−2.22	1.76	−5.66	1.22	0.21
Propofol vs Dx	STS	3	228	227	0.99	0.68	−0.33	2.32	0.14
Propofol vs BDZ	LTS	1	31	36	−42.00	30.89	−102.54	18.54	0.17

Abbreviations: BDZ, benzodiazepines; CI, confidence interval; Dx, dexmedetomidine; LTS, long-term sedation; MD, mean difference; SE, standard error; STS, short-term sedation.

Table 6 Meta-analytic results: ICU length of stay

Comparators	Sedation duration	N studies	N patients		MD	SE	95% CI		p-value
			Propofol	Comparator			Lower	Upper
ICU length of stay (hours) – primary analysis
Propofol vs BDZ	STS	6	200	202	−4.95	1.81	−8.48	−1.41	0.01
Propofol vs Dx	STS	2	76	73	11.75	12.75	−13.25	36.74	0.36
Propofol vs BDZ	LTS	12	363	361	−12.28	1.51	−15.25	−9.32	0.00
ICU length of stay (hours) – broad analysis
Propofol vs BDZ	STS	6	200	202	−4.95	1.81	−8.48	−1.41	0.01
Propofol vs Dx	STS	3	104	101	6.43	7.24	−7.76	20.63	0.37
Propofol vs BDZ	LTS	16	604	506	−22.43	11.35	−44.68	−0.18	0.05

Abbreviations: BDZ, benzodiazepines; CI, confidence interval; Dx, dexmedetomidine; LTS, long-term sedation; MD, mean difference; SE, standard error; STS, short-term sedation; ICU, intensive care unit.

Table 7 Costs and cost differences (€ per patient) between propofol and benzodiazepines for long-term sedation based on results extracted from RCTs in France, Germany, Italy, UK, and USA

Country	Costs	LTS based on results extracted from RCTs (primary analysis)
		Propofol		Benzodiazepines		Savings (Propofol vs Benzodiazepines)
		Mean	95% CI*	Mean	95% CI*	Mean	95% CI*
France	ICU	12,234	8,686–15,905	12,788	9,050–16,647	−554	−804 to −303
	With MV	7,448	5,016–10,973	8,009	5,385–11,807	−562	−873 to −256
	Drugs	113	70–155	28	18–37	85	42–128
	Sedation	109	66–151	24	14–33	85	42–128
	Total costs	12,347	8,798–16,018	12,816	9,078–16,674	−469	−722 to −214
Germany	ICU	12,406	8,808–16,129	12,967	9,177–16,881	−562	−815 to −307
	With MV	7,552	5,191–11,248	8,122	5,574–12,102	−570	−886 to −260
	Drugs	189	121–256	88	58–115	101	31–174
	Sedation	173	105–240	72	43–98	101	30–174
	Total costs	12,595	8,995–16,318	13,056	9,264–16,967	−461	−722 to −196
Italy	ICU	11,481	8,154–14,921	12,000	8,497–15,617	−520	−754 to −284
	With MV	6,989	4,249–9,829	7,516	4,561–10,576	−527	−820 to −240
	Drugs	141	88–195	28	18–37	114	60–168
	Sedation	138	84–191	24	14–33	114	60–168
	Total costs	11,622	8,295–15,062	12,028	8,524–15,644	−406	−646 to −164
UK	ICU	25,336	18,003–32,925	26,483	18,758–34,462	−1,147	−1,665 to −627
	With MV	15,423	28,098–40,455	16,587	30,199–43,516	−1,163	−1,809 to −530
	Drugs	339	208–469	59	36–79	279	150–412
	Sedation	335	204–466	56	33–76	279	149–412
	Total costs	25,675	18,339–33,266	26,542	18,816–34,519	−868	−1,399 to −331
USA	ICU	34,826	24,729–45,263	36,403	25,767–47,376	−1,577	−2,288 to −862
	With MV	21,200	56,300–73,246	22,800	60,514–78,784	−1,599	−2,486 to −729
	Drugs	393	241–545	449	267–610	−56	−270 to 179
	Sedation	390	237–541	445	263–607	−56	−270 to 179
	Total costs	35,219	25,121–45,657	36,852	26,207–47,812	−1,632	−2,362 to −880

Notes:

* Calculated from PSA results. Within each country, the bold lines “ICU” and “Drugs” add up to “Total Costs”. The non-bold lines “with MV” and “Sedation” denote the share of MV and sedation drugs in these costs.

Abbreviations: CI, confidence interval; ICU, intensive care unit; LTS, long-term sedation; MV, mechanical ventilation; RCT, randomized controlled trial; PSA, probabilistic sensitivity analyses.

Table 8 Costs and cost differences (€ per patient) between propofol and benzodiazepines for long-term sedation based on results extracted from RCTs and observational studies in France, Germany, Italy, UK, and USA

Country	Costs	LTS based on results extracted from RCTs and non-RCTs (broad analysis)
		Propofol		Benzodiazepines		Savings (Propofol vs Benzodiazepines)
		Mean	95% CI*	Mean	95% CI*	Mean	95% CI*
France	ICU	11,996	8,446–15,653	12,728	8,930–16,611	−732	−1,428 to −14
	With MV	7,808	5,251–11,497	8,125	5,418–12,021	−317	−952 to 303
	Drugs	120	74–165	103	61–141	17	−41 to 78
	Sedation	116	71–161	99	57–137	17	−41 to 78
	Total costs	12,116	8,565–15,773	12,831	9,031–16,712	−715	−1,415 to 10
Germany	ICU	12,164	8,567–15,870	12,906	9,058–16,841	−742	−1,448 to −15
	With MV	7,917	5,446–11,773	8,239	5,619–12,311	−322	−965 to 307
	Drugs	200	127–272	88	56–116	113	37–190
	Sedation	185	112–255	72	41–99	113	37–190
	Total costs	12,364	8,765–16,070	12,994	9,144–16,927	−629	−1,343 to 107
Italy	ICU	11,257	7,929–14,687	11,944	8,383–15,586	−687	−1,340 to −14
	With MV	7,327	4,445–10,301	7,624	4,581–10,774	−298	−893 to 284
	Drugs	151	94–207	28	17–37	123	66–180
	Sedation	147	90–203	24	14–33	123	66–180
	Total costs	11,407	8,079–14,838	11,971	8,410–15,613	−564	−1,222 to 115
UK	ICU	24,842	17,495–32,406	26,358	18,499–34,389	−1,516	−2,957 to −30
	With MV	16,169	29,439–42,370	16,826	30,551–44,224	−657	−1,971 to 627
	Drugs	361	222–499	59	35–80	303	163–442
	Sedation	357	218–495	55	32–76	302	163–442
	Total costs	25,204	17,855–32,767	26,417	18,557–34,447	−1,213	−2,668 to 287
USA	ICU	34,147	24,039–44,564	36,230	25,416–47,292	−2,083	−4,065 to −41
	With MV	22,225	58,969–76,726	23,129	61,260–80,039	−903	−2,709 to 862
	Drugs	420	257–580	446	258–614	−26	−254 to 218
	Sedation	416	253–576	442	255–610	−26	−254 to 218
	Total costs	34,567	24,456–44,983	36,676	25,853–47,727	−2,109	−4,111 to −30

Notes:

* Calculated from PSA results. Within each country, the bold lines “ICU” and “Drugs” add up to “Total Costs”. The non-bold lines “with MV” and “Sedation” denote the share of MV and sedation drugs in these costs.

Abbreviations: CI, confidence interval; ICU, intensive care unit; LTS, long-term sedation; MV, mechanical ventilation; RCT, randomized controlled trial; PSA, probabilistic sensitivity analyses.

Table 9 Costs and cost differences (€ per patient) between propofol and benzodiazepines for short-term sedation based on results extracted from RCTs in France, Germany, Italy, UK, and USA

Country	Costs	STS based on results extracted from RCTs (primary analysis)
		Propofol		Benzodiazepines		Savings (Propofol vs Benzodiazepines)
		Mean	95% CI*	Mean	95% CI*	Mean	95% CI*
France	ICU	3,798	2,698–4,912	3,971	2,826–5,127	−173	−325 to −17
	With MV	1,517	1,020–2,234	1,751	1,149–2,611	−234	−473 to −1
	Drugs	14	43,709	3	42,096	11	5–16
	Sedation	14	43,678	3	42,096	11	5–16
	Total costs	3,812	2,712–4,926	3,974	2,829–5,130	−162	−315 to −6
Germany	ICU	3,852	2,736–4,981	4,027	2,866–5,198	−175	−330 to −18
	With MV	1,538	1,058–2,287	1,776	1,192–2,673	−237	−480 to −1
	Drugs	23	15–30	11	42,217	12	3–19
	Sedation	19	46,357	8	42,343	11	3–18
	Total costs	3,875	2,759–5,004	4,038	2,877–5,209	−164	−319 to −6
Italy	ICU	3,564	2,532–4,609	3,727	2,652–4,810	−162	−305 to −16
	With MV	1,423	863–2,001	1,643	969–2,341	−220	−444 to −1
	Drugs	18	11–24	3	2–5	14	8–21
	Sedation	17	10–24	3	2–4	14	8–21
	Total costs	3,582	2,549–4,626	3,730	2,655–4,813	−148	−291 to −2
UK	ICU	7,866	5,588–10,171	8,224	5,854–10,615	−358	−673 to −36
	With MV	3,141	5,721–8,230	3,626	6,546–9,573	−485	−980 to −3
	Drugs	37	23–51	7	4–9	30	16–44
	Sedation	37	22–50	6	4–9	30	16–44
	Total costs	7,903	5,625–10,208	8,231	5,861–10,621	−328	−644 to −5
USA	ICU	10,812	7,682–13,979	11,304	8,046–14,590	−492	−925 to −50
	With MV	4,318	11,457–14,905	4,984	13,150–17,308	−666	−1,347 to −4
	Drugs	40	25–55	49	28–69	−9	−34 to 16
	Sedation	40	24–55	49	28–69	−9	−34 to 16
	Total costs	10,852	7,722–14,019	11,354	8,095–14,638	−502	−936 to −57

Notes:

* Calculated from PSA results. Within each country, the bold lines “ICU” and “Drugs” add up to “Total Costs”. The non-bold lines “with MV” and “Sedation” denote the share of MV and sedation drugs in these costs.

Abbreviations: CI, confidence interval; ICU, intensive care unit; MV, mechanical ventilation; RCT, randomized controlled trial; STS, short-term sedation; PSA, probabilistic sensitivity analyses.

Figure 2 Deterministic sensitivity analyses results of the three effectiveness scenarios are shown as tornado diagrams.

Notes: The relative difference from the base case value (%) is shown for different input parameters. Each box contains estimates from the five payers’ perspectives resulting from the variation of one variable. Countries are presented in the following order, from the top: UK (red), USA (blue), Italy (green), Germany (yellow), and France (black). (A) LTS based on RCT results, (B) LTS based on RCT and non-RCT results, and (C) STS based on RCT results.
Abbreviations: ICU, intensive care unit; MV, mechanical ventilation; Pr, propofol; BDZ, benzodiazepines; LTS, long-term sedation; STS, short-term sedation; RCT, randomized controlled trial.

Figure 3 Probabilistic sensitivity analysis results in the three effectiveness scenarios for all countries.

Notes: The savings histograms show relative frequencies of savings achieved with propofol versus benzodiazepine sedation resulting from the simulations. (A) LTS based on RCT results, (B) LTS based on RCT and non-RCT results, and (C) STS based on RCT results.
Abbreviations: LTS, long-term sedation; RCT, randomized controlled trial; STS, short-term sedation.

Figure 4 Probabilistic sensitivity analysis results of the three scenarios for Italy.

Notes: The scatter plots show the results of individual simulations presented as effectiveness (ICU time saved) versus total monetary savings. (A) LTS based on RCT results, (B) LTS based on RCT and non-RCT results, and (C) STS based on RCT results.
Abbreviations: ICU, intensive care unit; LTS, long-term sedation; RCT, randomized controlled trial; STS, short-term sedation.

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