Delirium Prophylaxis

Key Question

Among older patients undergoing surgery and anesthesia, does dexmedetomidine administered during the perioperative period decrease the risk of postoperative delirium or other adverse cognitive outcomes?

(The original question included ketamine, ramelteon, and melatonin. These unGRADEd results are included here but not in the advisory.)

Balance Tables

Dexmedetomidine

Benefits, harms, and strength of evidence (GRADE) for dexmedetomidine versus placebo or no delirium prophylaxis.

Outcome	RCT	NRSI	Dexmedetomidine	Placebo^*	GRADE^†	Effect	Estimate (95% CI)	I²	(95% PI)
Outcome	RCT	NRSI	N (Total)	N (Total)	GRADE^†	Effect	Estimate (95% CI)	I²	(95% PI)
Delirium	31		457 (4,035)	666 (3,739)	⨁⨁⨁◯	RR	0.58 (0.49–0.67)	46%	(0.30–1.10)
Neurocognitive disorder <30 days	9		68 (666)	83 (392)	⨁⨁⨁◯	RR	0.54 (0.39–0.73)	0%	(0.39–0.74)
Neurocognitive disorder 30 days to 1 yr	2		5 (50)	22 (50)	⨁◯◯◯	RR	0.24 (0.11–0.55)	0%	^‡
Physical function	1		(30)	(31)	⨁◯◯◯	SMD	0.39 (-1.57 to 2.34)		^‡
Bradycardia	17		236 (2,031)	129 (1,755)	⨁⨁⨁⨁	RR	1.52 (1.22–1.88)	0%	(0.97–2.37)
	18		236 (2,121)	129 (1,842)		RD/100	2.0 (-0.4 to 4.4)	57%	(-2.2 to 6.2)
Hypotension	20		611 (2,797)	409 (2,539)	⨁⨁⨁⨁	RR	1.38 (1.10–1.72)	52%	(0.65–2.91)
	22		611 (2,916)	409 (2,662)		RD/100	4.3 (0.5 to 8.0)	77%	(-10.5 to 19.0)
Other complications	27	3					see below
Length of stay (days)	20		(3,051)	(3,075)	⨁⨁◯◯	MD	-0.8 (-1.3 to -0.2)^§	95%	(-3.3 to 1.7)
Mortality, in-hospital and 30-day	11		17 (2,123)	31 (2,141)	⨁⨁◯◯	RR	0.64 (0.35–1.16)	0%	(0.31–1.32)
	12		17 (2,479)	31 (2,495)		RD/1000	-0.8 (-4.7 to 3.1)	17%	(-4.7 to 3.2)
RCT: randomized clinical trial; NRSI: nonrandomized studies of interventions; GRADE: Grades of Recommendation, Assessment, Development, and Evaluation; PI: prediction interval; RR: risk ratio; SMD: standardized mean difference; RD: risk difference; MD: mean difference.
^* In some studies (randomized or not) the control incorporated neither placebo or prophylaxis.
^† Very low: ⨁◯◯◯; Low: ⨁⨁◯◯; Moderate: ⨁⨁⨁◯; High: ⨁⨁⨁⨁.
^‡ Insufficient data to estimate a valid prediction interval.
^§ With Hartung-Knapp adjustment MD -0.8 (-1.5 to -0.08).

Other complications and strength of evidence (GRADE) for dexmedetomidine versus placebo or no delirium prophylaxis.

Outcome	RCT	NRSI	Dexmedetomidine	Placebo^*	GRADE^†	Effect	Estimate (95% CI)	I²	(95% PI)
Outcome	RCT	NRSI	N (Total)	N (Total)	GRADE^†	Effect	Estimate (95% CI)	I²	(95% PI)
Myocardial infarction	2	1	7 (763)	8 (830)	⨁⨁◯◯	RR	0.98 (0.36–2.67)	0%	^‡
	3	1	7 (1,107)	8 (1,161)		RD/1000	0.3 (-4.6 to 5.2)	0%	(-10.5 to 11.0)
Cardiac arrest	1		2 (222)	1 (283)	⨁◯◯◯	RR	0.85 (0.14–5.04)		^‡
	1		2 (222)	1 (283)		RD/1000	-1.6 (-18.8 to 15.6)		^‡
Stroke	5	1	12 (1,139)	16 (1,231)	⨁⨁◯◯	RR	0.84 (0.40–1.77)	0%	(0.30–2.41)
	6	1	12 (1,483)	16 (1,562)		RD/1000	-1.4 (-6.0 to 3.2)	0%	(-7.4 to 4.7)
Acute kidney injury	5	1	101 (1,034)	107 (1,092)	⨁⨁◯◯	RR	1.05 (0.69–1.59)	31%	(0.35–2.56)
	5	1	101 (1,034)	107 (1,092)		RD/1000	3.1 (-12.3 to 18.6)	38%	(-18.8 to 25.0)
Pneumonia	3		14 (315)	13 (329)	⨁◯◯◯	RR	1.09 ( 0.52–2.30)	0%	^‡
	3		14 (315)	13 (329)		RD/1000	8.4 (-14.5 to 31.2)	0%	^‡
Pulmonary congestion	1		1 (147)	0 (157)	⨁◯◯◯	RR	3.20 (0.13–78.02)
	1		1 (147)	0 (157)		RD/1000	6.8 (-11.6 to 25.2)
Pulmonary embolism	1		1 (147)	1 (157)	⨁◯◯◯	RR	1.07 (0.07–16.92)
	1		1 (147)	1 (157)		RD/1000	0.4 (-17.8 to 18.6)
Respiratory Depression/Failure	3		5 (230)	9 (242)	⨁◯◯◯	RR	0.65 (0.22–1.94)	0%	^‡
	5		5 (621)	9 (416)		RD/1000	0.2 (-10.6 to 11.0)	0%	(-17.3 to 17.7)
RCT: randomized clinical trial; GRADE: Grades of Recommendation, Assessment, Development, and Evaluation; RR: risk ratio; RD: risk difference.
^* In some studies (randomized or not) the control incorporated neither placebo or prophylaxis.
^† Very low: ⨁◯◯◯; Low: ⨁⨁◯◯; Moderate: ⨁⨁⨁◯; High: ⨁⨁⨁⨁.
^‡ Insufficient data to estimate a valid prediction interval.

Outcomes Reported

Dexmedetomidine

Table 1. Publications reporting dichotomous or count outcomes in dexmedetomidine studies (not necessarily unique studies).

Outcome	RCT, N = 71	NR Trial, N = 6	Prosp Coh, N = 1	Retro Coh, N = 6
ADL	—	—	—	—
Complications	37 (52%)	2 (33%)	—	2 (33%)
DNCR/POCD	21 (30%)	3 (50%)	—	—
Delirium	40 (56%)	1 (17%)	1 (100%)	5 (83%)
Delirium duration	2 (2.8%)	—	—	—
Discharge location	—	—	—	—
Mortality	15 (21%)	—	—	2 (33%)
Opioid use	2 (2.8%)	—	—	—
Pain	—	—	—	—
QoR	—	—	—	—
Readmission	2 (2.8%)	—	—	1 (17%)
Satisfaction	—	—	—	—
ADL: activities of daily living; DNCR: delayed neurocognitive recovery (neurocognitive disorder < 30 days); POCD: postoperative neurocognitive disorder (neurocognitive disorder 30 days to 1 year); QoR: quality of recovery; RCT: randomized clinical trial; NR Trial: non-randomized trial; Prosp Coh: prospective cohort; Retro Coh: retrospective cohort.

Table 2. Publications reporting continuous outcomes in dexmedetomidine studies (not necessarily unique studies).

Outcome	RCT, N = 71	NR Trial, N = 6	Prosp Coh, N = 1	Retro Coh, N = 6
Delirium duration	9 (13%)	—	—	1 (17%)
Length of stay	24 (34%)	—	—	1 (17%)
Opioid use	7 (9.9%)	—	—	—
RCT: randomized clinical trial; NR Trial: non-randomized trial; Prosp Coh: prospective cohort; Retro Coh: retrospective cohort.

Table 3. Publications reporting likert or ordinal outcomes in dexmedetomidine studies (not necessarily unique studies).

Outcome	RCT, N = 71	NR Trial, N = 6	Prosp Coh, N = 1	Retro Coh, N = 6
ADL	1 (1.4%)	—	—	—
DNCR/POCD	35 (49%)	5 (83%)	—	1 (17%)
Delirium	1 (1.4%)	—	—	—
Complications	—	—	—	—
Pain	16 (23%)	—	—	—
Quality of life	—	—	—	—
QoR	2 (2.8%)	—	—	—
Satisfaction	—	—	—	—
ADL: activities of daily living; NCR: neurocognitive recovery; POCD: postoperative neurocognitive disorder; QoR: quality of recovery; RCT: randomized clinical trial; NR Trial: non-randomized trial; Prosp Coh: prospective cohort; Retro Coh: retrospective cohort.

Ketamine

Table 4. Publications reporting dichotomous or count outcomes in ketamine studies (not necessarily unique studies).

Outcome	RCT, N = 12	Prosp Coh, N = 3	Retro Coh, N = 4
ADL	—	—	—
Complications	2 (17%)	—	—
DNCR/POCD	7 (58%)	—	—
Delirium	4 (33%)	3 (100%)	4 (100%)
Delirium duration	—	—	—
Discharge location	—	—	—
Mortality	—	—	—
Opioid use	1 (8.3%)	—	—
Pain	2 (17%)	—	—
QoR	—	—	—
Readmission	1 (8.3%)	—	—
Satisfaction	—	—	—
ADL: activities of daily living; NCR: neurocognitive recovery; POCD: postoperative neurocognitive disorder; QoR: quality of recovery; RCT: randomized clinical trial; Prosp Coh: prospective cohort; Retro Coh: retrospective cohort.

Table 5. Publications reporting continuous outcomes in ketamine studies (not necessarily unique studies).

Outcome	RCT, N = 12	Prosp Coh, N = 3	Retro Coh, N = 4
Delirium duration	—	—	—
Length of stay	2 (17%)	1 (33%)	—
Opioid use	4 (33%)	—	—
RCT: randomized clinical trial; Prosp Coh: prospective cohort; Retro Coh: retrospective cohort.

Table 6. Publications reporting likert or ordinal outcomes in ketamine studies (not necessarily unique studies).

Outcome	RCT, N = 12	Prosp Coh, N = 3	Retro Coh, N = 4
ADL	—	—	—
DNCR/POCD	6 (50%)	—	—
Delirium	2 (17%)	—	—
Complications	—	—	—
Pain	1 (8.3%)	—	—
Quality of life	—	—	—
QoR	—	—	—
Satisfaction	—	—	—
ADL: activities of daily living; NCR: neurocognitive recovery; POCD: postoperative neurocognitive disorder; QoR: quality of recovery; RCT: randomized clinical trial; Prosp Coh: prospective cohort; Retro Coh: retrospective cohort.

Melatonin or ramelteon

Table 7. Publications reporting dichotomous or count outcomes in melatonin or ramelteon studies (not necessarily unique studies).

Outcome	RCT, N = 16	NR Trial, N = 2	Quasi-exp, N = 2	Retro Coh, N = 1
ADL	—	—	—	—
Complications	1 (6.3%)	—	2 (100%)	—
DNCR/POCD	1 (6.3%)	—	—	—
Delirium	15 (94%)	2 (100%)	2 (100%)	1 (100%)
Delirium duration	1 (6.3%)	—	—	—
Discharge location	—	—	—	—
Mortality	3 (19%)	—	1 (50%)	—
Opioid use	—	—	—	—
Pain	—	—	—	—
QoR	—	—	—	—
Readmission	—	—	—	—
Satisfaction	—	—	—	—
ADL: activities of daily living; NCR: neurocognitive recovery; POCD: postoperative neurocognitive disorder; QoR: quality of recovery; RCT: randomized clinical trial; NR Trial: non-randomized trial; Quasi-exp: before-after or time series; Retro Coh: retrospective cohort.

Table 8. Publications reporting continuous outcomes in melatonin or ramelteon studies (not necessarily unique studies).

Outcome	RCT, N = 16	NR Trial, N = 2	Quasi-exp, N = 2	Retro Coh, N = 1
Delirium duration	4 (25%)	—	1 (50%)	—
Length of stay	5 (31%)	—	2 (100%)	—
Opioid use	1 (6.3%)	—	—	—
RCT: randomized clinical trial; NR Trial: non-randomized trial; Quasi-exp: before-after or time series; Retro Coh: retrospective cohort.

Table 9. Publications reporting likert or ordinal outcomes in melatonin or ramelteon studies(not necessarily unique studies).

Outcome	RCT, N = 16	NR Trial, N = 2	Quasi-exp, N = 2	Retro Coh, N = 1
ADL	1 (6.3%)	—	—	—
DNCR/POCD	2 (13%)	—	—	—
Delirium	3 (19%)	—	—	—
Complications	—	—	—	—
Pain	—	—	—	—
Quality of life	—	—	—	—
QoR	—	—	—	—
Satisfaction	—	—	—	—
ADL: activities of daily living; NCR: neurocognitive recovery; POCD: postoperative neurocognitive disorder; QoR: quality of recovery; RCT: randomized clinical trial; NR Trial: non-randomized trial; Quasi-exp: before-after or time series; Retro Coh: retrospective cohort.

Included Studies

See Appendix for detailed summary study and patient characteristics including primary outcomes.

Table 10. Number of studies by design.

Design	Studies
Dexmedetomidine
Randomized Clinical Trial	71
Nonrandomized Trial	6
Prospective Cohort	1
Retrospective Cohort	6
Total	84
Studies with multiple publications counted only once (applied to 1 trial with 2 publications).

Design	Studies
Ketamine
Randomized Clinical Trial	12
Prospective Cohort	3
Retrospective Cohort	4
Total	19

Design	Studies
Melatonin or Ramelteon
Randomized Clinical Trial	16
Nonrandomized Trial	2
Before-After/Time Series	2
Retrospective Cohort	1
Total	21

Design, centers, country, and surgery

Table 11. Study design, enrollment, centers, country, and surgery (see References for citations).

ID	Study^a	Centers	Enrolled	Country^b	Surgery
Dexmedetomidine - Nonrandomized Trial
13361	Wang 2020c	1	110	China^b	GI/Abdominal
5183	Xu 2017	1	96	China^b	GI/Abdominal
5052	Zhang 2019b	1	140	China^b	GI/Abdominal
120	Xie 2018	1	140	China^b	Ortho
13368	Zhang 2020b	1	165	China^b	Spine
13301	Li 2020a	1	87	China^b	Thoracic
Dexmedetomidine - Prospective Cohort
18819	Sun 2023a	1	676	China^b	GI/Abdominal
Dexmedetomidine - Randomized Clinical Trial
13579	Azeem 2018	1	70	Egypt^b	Cardiac
7240	Chitnis 2022	1	70	Canada	Cardiac
2288	Djainai 2016	1	185	Canada	Cardiac
1819	Gao 2020	1	60	China^b	Cardiac
5269	Gao 2021 (Gao 2020)	1	40	China^b	Cardiac
13777	Ge 2016	1	50	China^b	Cardiac
17683	Kowalczyk 2022	1	49	Poland	Cardiac
24	Li 2017	2	285	China^b	Cardiac
2173	Momeni 2021	1	420	Belgium	Cardiac
17019	Qu 2023	1	469	USA	Cardiac
18870	Racman 2023	1	78	Slovenia	Cardiac
20454	Soh 2020	1	108	South Korea	Cardiac
2624	Subramaniam 2019	1	140	USA	Cardiac
16008	Turan 2020	6	798	USA	Cardiac
16023	Wu 2020	1	80	China^b	Cardiac
13406	Zhou 2019b	1	156	China^b	Cardiac
335	van Norden 2021	1	63	Germany	Cardiac\|GI/Abdominal
18597	Liu 2023c	1	304	China^b	ENT
5436	Chen 2013	1	126	China^b	GI/Abdominal
889	Chen 2020	1	88	China^b	GI/Abdominal
1288	Du 2019	1	87	China^b	GI/Abdominal
17531	Guo 2022	1	90	China^b	GI/Abdominal
5024	Li 2015	1	100	China^b	GI/Abdominal
4914	Li 2021b	1	120	China^b	GI/Abdominal
18582	Liao 2023	1	104	China^b	GI/Abdominal
13941	Mohamed 2014	1	58	Egypt^b	GI/Abdominal
12900	Tang 2021	1	100	China^b	GI/Abdominal
18909	Xie 2023	1	240	China^b	GI/Abdominal
1919	Xin 2021	1	60	China^b	GI/Abdominal
8558	Lu 2021	13	808	China^b	GI/Abdominal\|Hepatic
5480	Zhang 2021	1	174	China^b	GI/Abdominal\|Neuro\|Urol
13483	Wang 2019	1	198	China^b	GI/Abdominal\|Ortho\|Thoracic
261	Lee 2018a	1	354	South Korea	GI/Abdominal\|Urol
328	Zhang 2018b	1	120	China^b	Headneck
1117	Mansouri 2019	1	150	Iran^b	Ophtho
18690	Oriby 2023	1	90	Egypt^b	Ophtho
5452	Guo 2015	1	184	China^b	Oralmax
16845	Liu 2022b	1	120	China^b	Oralmax
1625	Wang 2020a	1	44	China^b	Oralmax
18346	Deng 2023	2	108	China^b	Ortho
17503	Gao 2022	1	95	China^b	Ortho
5240	Hong 2021	2	712	China^b	Ortho
17575	Hu 2022	1	60	China^b	Ortho
2748	Lee 2018b	1	132	South Korea	Ortho
742	Li 2019	1	164	China^b	Ortho
18575	Li 2023	1	98	China^b	Ortho
1419	Liu 2016	1	200	China^b	Ortho
3130	Lu 2017	1	152	China^b	Ortho
1735	Mei 2018	1	336	China^b	Ortho
1267	Mei 2020a	1	415	China^b	Ortho
17001	Shin 2023	1	748	South Korea	Ortho
13075	Xing 2021	1	110	China^b	Ortho
16303	Yan 2021	1	100	China^b	Ortho
18937	Yoo 2023	1	128	South Korea	Ortho
5147	Zhang 2020a	1	240	China^b	Ortho
18958	Zhao 2023	1	88	China^b	Ortho
11129	Zhu 2021	1	187	China^b	Ortho
13568	He 2018	1	90	China^b	Thoracic
3046	Hu 2021	1	177	China^b	Thoracic
69	Huyan 2019	1	360	China^b	Thoracic
18558	Lai 2023	1	90	China^b	Thoracic
16741	Liu 2022a	1	60	China^b	Thoracic
3391	Shi 2020	1	106	China^b	Thoracic
13731	Yu 2017	1	92	China^b	Thoracic
4798	Ding 2015	1	40	China^b	Urol
7151	Wang 2022a	1	125	China^b	Urol
5251	Chawdhary 2020	1	87	India^b	Various^c
2022	Deiner 2017	10	429	USA	Various^c
20465	Li 2020b	1	620	China^b	Various^c
16718	Lv 2022	1	327	China^b	Various^c
16734	Wang 2022b	1	100	China^b	Various^c
3716	Zhao 2020	1	432	China^b	Various^c
Dexmedetomidine - Retrospective Cohort
2517	Cheng 2016	1	505	USA	Cardiac
103	Chuich 2019	1	278	USA	Cardiac
5066	Park 2021	1	714	South Korea	Ortho
16830	Xu 2022	1	60	China^b	Ortho
13367	Yin 2020	1	120	China^b	Ortho
17150	Liu 2023b (Liu 2023a)	1	195	China^b	Urol
Ketamine - Prospective Cohort
1140	Juliebo 2009	1	187	Norway	Ortho
17147	Ke 2022b (Ke 2022a)	4	98	Singapore	Other
9616	Barreto Chang 2022	1	98	USA	Spine
Ketamine - Randomized Clinical Trial
181	Hudetz 2009a	1	78	USA	Cardiac
1847	Hudetz 2009b (Hudetz 2009a)	1	58	USA	Cardiac
5189	Siripoonyothai 2021	1	75	Thailand	Cardiac
18435	Han 2023	1	84	China^b	GI/Abdominal
18610	Ma 2023	1	68	China	GI/Abdominal
15285	Bornemann-Cimenti 2016	1	60	Austria	GI/Abdominal\|Hepatic
18690	Oriby 2023	1	90	Egypt^b	Ophtho
2217	Rascon-Martinez 2016	1	80	Mexico^b	Ophtho
2578	Lee 2015	1	56	South Korea	Ortho
3788	Remerand 2009	1	160	France	Ortho
13184	Tu 2021	1	80	China^b	Ortho
2866	Avidan 2017	5	672	USA	Various^c
1937	Hollinger 2021	2	143	Switzerland	Various^c
Ketamine - Retrospective Cohort
17130	Memtsoudis 2019b (Memtsoudis 2019a)	4,400	564,226	USA	Ortho^d
17136	Memtsoudis 2019g (Memtsoudis 2019a)	4,400	1,130,569	USA	Ortho^e
18978	Poeran 2020d (Poeran 2020a)		527,254	USA	Ortho
17144	Weinstein 2018c (Weinstein 2018a)	1	41,766	USA	Ortho^f
17145	Weinstein 2018d (Weinstein 2018a)	1	41,766	USA	Ortho
17149	Fuchita 2019c (Fuchita 2019a)	1	84	USA	Thoracic
Melatonin - Nonrandomized Trial
16537	Artemiou 2015	1	500	Slovakia	Cardiac
13824	Bily 2015	1	500	Slovakia	Cardiac
Melatonin - Randomized Clinical Trial
17055	Dianatkhah 2015	1	145	Iran^b	Cardiac
17057	El-Naggar 2018	1	50	Egypt^b	Cardiac
16558	Ford 2020	2	210	Australia	Cardiac
9256	Javaherforoosh 2021	1	60	Iran^b	Cardiac
9741	Shi 2021	1	297	China^b	Cardiac
17152	Esmaeii 2022	1	150	Iran^b	General\|Neuro\|Ortho
602	Fan 2017	1	148	China^b	Ortho
17153	Fazel 2022	1	80	Iran^b	Ortho
17154	Mohamed 2022	1	80	Egypt^b	Ortho
5164	Sultan 2010	1	152	Egypt^b	Ortho
16552	de Jonghe 2014	3	452	Netherlands	Ortho
Ramelteon - Before-After/Time Series
693	Hokuto 2020	1	309	Japan	Hepatic
2997	Miyata 2017	1	82	Japan	Thoracic
Ramelteon - Randomized Clinical Trial
17084	Tanifuji 2022	1	112	Japan	GI/Abdominal\|Hepatic
18530	Kinouchi 2023	1	108	Japan	General\|Thoracic\|Urol\|Vasc
3841	Oh 2021	1	80	USA	Ortho
4150	Jaiswal 2019	1	120	USA	Thoracic
13512	Gupta 2019	1	100	India^b	Various^c
Ramelteon - Retrospective Cohort
20438	Ishibashi-Kanno 2020a	1	69	Japan	Headneck
GI: gastrointestinal; Ortho: orthopedic; Neuro: neurological; Oralmax: oral maxillofacial; Vasc: vascular; ENT: ear nose and throat.
^a Studies examining drugs not directly relevant to recommendations but potentially to the evidence space (eg, a connected network including indirect evidence) are included here.
^b Non very-high Human Development Index country.
^c Described as various or more than 4 different types of surgery.
^d Hip arthroplasty.
^e Knee arthroplasty.
^f Intraoperative ketamine.

Country Summary

Table 12. Summary of randomized clinical trials according to country.

	N = 98^a
Country
China	56 (57%)
USA	8 (8.2%)
Egypt	6 (6.1%)
South Korea	6 (6.1%)
Iran	5 (5.1%)
Canada	2 (2.0%)
India	2 (2.0%)
Japan	2 (2.0%)
Australia	1 (1.0%)
Austria	1 (1.0%)
Belgium	1 (1.0%)
France	1 (1.0%)
Germany	1 (1.0%)
Mexico	1 (1.0%)
Netherlands	1 (1.0%)
Poland	1 (1.0%)
Slovenia	1 (1.0%)
Switzerland	1 (1.0%)
Thailand	1 (1.0%)
^a n (%)

Interventions & Comparators

Dexmedetomidine

Table 13. Selected characteristics, comparators, and dosing in dexmedetomidine trials.

Study	N	Arm	ASA	Anesthetic				Age^b	MMSE^c,b	Dexmedetomidine mcg/kg			Timing^e
Study	N	Arm	PS^a	Vol	TIVA	Reg	Sed	Age^b	MMSE^c,b	Load	Maint/hr^d	Postop	Timing^e
Cardiac - Randomized Clinical Trial
Djainai 2016	92	Prop	NR	✓				72.4 (6.2)
	91	Dex		✓	✓	✓	✓	72.7 (6.4)		0.4	(0.2–0.7)		▁▁▁▆
Ge 2016	24	Plac	123		✓			72.0 (4.0)	26.9 (0.8)
	24	Dex		✓	✓	✓	✓	70.0 (3.0)	27.2 (0.9)	0.3	0.3		▁▆▆▁
Li 2017	143	Plac	234	✓	✓			67.5 (5.3)	29 [28-30]
	142	Dex		✓	✓	✓	✓	66.4 (5.4)	29 [28-30]	0.6	0.4	0.1	▁▁▆▆
Azeem 2018	30	Mid	NR		✓			66.7 (5.6)
	30	Dex		✓	✓	✓	✓	65.3 (4.8)			(0.4–0.7)		▁▁▁▆
Subramaniam 2019	61	Prop	NR					70.0 {64-79}
	59	Dex		✓	✓	✓	✓	66.5 {63-74}		0.5	(0.1–0.4)		▁▁▁▆
Zhou 2019b	38	Plac	123	✓	✓			70.0 (4.9)
	39	Ulin		✓	✓	✓	✓	70.6 (4.4)
	39	Dex/Ulin		✓	✓	✓	✓	69.6 (5.0)			0.4		▁▁▆▁
	38	Dex		✓	✓	✓	✓	69.8 (5.1)			0.4		▁▁▆▁
Gao 2020	30	Plac	23		✓			70.4 (4.2)
	30	Dex		✓	✓	✓	✓	69.5 (5.1)		1.0	(0.3–0.5)		▁▆▆▁
Soh 2020	54	Plac	NR	✓	✓			65.0 [37-83]
	54	Dex		✓	✓	✓	✓	65.0 [23-82]					▁▁▆▁
Turan 2020	396	Plac	1234	✓	✓			62.0 (12.0)
	398	Dex		✓	✓	✓	✓	63.0 (11.0)			0.1	0.4	▁▆▆▆
Wu 2020	40	Plac	23				✓	67.7 (8.8)	28.2
	40	Dex		✓	✓	✓	✓	68.2 (8.6)	28.1	0.5	0.6		▁▆▆▁
Gao 2021	20	Plac	23		✓			71.4 (4.5)	28.4 (1.3)
	20	Dex		✓	✓	✓	✓	71.4 (4.5)	28.5 (1.4)	0.6	0.2		▁▆▆▁
Momeni 2021	203	Plac	NR	✓				70.0 {59-81}	28 {26-29}
	205	Dex		✓	✓	✓	✓	71.0 {61-81}	28 {26-29}		0.4		▁▁▁▆
Chitnis 2022	33	Prop	NR	✓				78.8	30.2
	34	Dex		✓	✓	✓	✓	78.7	30.1		0.5 (0–1.5)		▁▁▁▆
Kowalczyk 2022	23	None	23		✓			66.0 (5.0)
	23	Dex		✓	✓	✓	✓	67.0 (10.0)		0.5	0.25		▁▆▆▁
Qu 2023	206	Plac	NR					70.0 {65-75}
	188	Dex		✓	✓	✓	✓	67.5 {63-73}				1	▁▁▁▆
Racman 2023	34	Prop	NR				✓	83.5 {79-87}	26 {25-28}
	37	Dex		✓	✓	✓	✓	83.0 {77-85}	27 {25-28}	0.5	(0.2–1)		▁▆▆▁
Ortho - Randomized Clinical Trial
Liu 2016 (MCI)	40	Plac	23		✓			75.2 (7.8)	22.4 (2.6)
	39	Dex		✓	✓	✓	✓	72.8 (8.2)	23.3 (2.7)		(0.2–0.4)		▁▁▆▁
Liu 2016 (no MCI)	58	Plac	23		✓			72.8 (9.2)	25.4 (2.4)
	60	Dex		✓	✓	✓	✓	71.2 (8.1)	26.2 (3.5)		(0.2–0.4)		▁▁▆▁
Lu 2017	76	Dex	23		✓	✓		65.0 (5.8)	28.3 (1.3)	0.5	0.5		▁▆▆▁
	75	Dex		✓	✓	✓	✓	65.5 (5.3)	28.5 (1.2)	0.5	0.5	0.06	▁▆▆▆
Lee 2018b	31	Plac	12			✓		67.2 (5.0)
	33	Preg		✓	✓	✓	✓	68.4 (5.1)
	29	Dex/Preg		✓	✓	✓	✓	65.4 (9.7)		0.5	0.5
	31	Dex		✓	✓	✓	✓	68.8 (5.9)		0.5	0.5		▁▆▆▁
Mei 2018	148	Prop	23			✓		74.0 (6.0)	25.7 (1.7)
	148	Dex		✓	✓	✓	✓	76.0 (7.0)	26.2 (2.1)	0.9	(0.1–0.5)		▁▆▁▁
Li 2019	55	Prop	123			✓		68.2 (6.4)
	54	Mid		✓	✓	✓	✓	66.9 (6.6)
	55	Dex		✓	✓	✓	✓	69.3 (7.1)					▁▁▆▁
Mei 2020a	183	Prop	NR			✓		73.0 (11.0)	27.1 (1.4)
	183	Dex		✓	✓	✓	✓	72.0 (9.0)	26.6 (2.9)	0.9	(0.1–0.5)		▁▁▆▁
Zhang 2020a	120	Plac	123			✓		79.0 (6.8)
	120	Dex		✓	✓	✓	✓	78.1 (6.4)		0.5	0.3		▆▁▆▁
Hong 2021	354	Plac	1234	✓		✓		71.0 (5.0)	26.1 (3.0)
	356	Dex		✓	✓	✓	✓	71.0 (5.0)	26.1 (2.9)			0.03	▁▁▁▆
Xing 2021	55	Plac	23	✓				69.2 (3.8)
	55	Dex		✓	✓	✓	✓	68.3 (3.9)		0.5			▁▆▁▁
Yan 2021	50	Plac	12		✓			72.7 (4.3)	29.2 (0.3)
	50	Dex		✓	✓	✓	✓	73.2 (5.8)	29.5 (0.2)		0.3		▁▆▁▁
Zhu 2021	92	Plac	123			✓		75.2 (6.1)	28.6 (0.9)
	95	Dex		✓	✓	✓	✓	74.1 (4.4)	28.9 (0.8)	1.0	0.5		▆▁▆▁
Gao 2022	48	Plac	123	✓				67.2 (5.2)
	47	Dex		✓	✓	✓	✓	68.2 (6.0)		1.0	0.4	2	▁▆▆▆
Hu 2022	20	None	NR		✓			68.9 (4.3)
	20	Dex		✓	✓	✓	✓	69.2 (5.0)			0.4		▁▆▆▁
Deng 2023	52	Dex	23			✓		70.8 (4.4)
	53	Dex		✓	✓	✓	✓	71.8 (5.5)			(0.2–0.7)		▁▁▆▁
Li 2023	49	None	NR	✓				68.5 (2.2)
	49	Dex		✓	✓	✓	✓	67.7 (2.8)		4	0.2		▁▆▆▁
Shin 2023	366	Prop	12			✓		71.0 {67-75}
	366	Dex		✓	✓	✓	✓	72.0 {68-76}		1.0	(0.1–0.5)		▁▁▆▁
Yoo 2023	64	Plac	123	✓				74.2 (6.2)
	64	Dex		✓	✓	✓	✓	74.4 (6.0)		1.0	0.2		▁▁▆▁
Zhao 2023	42	Plac	NR			✓		69.7 (7.2)	25.8 (0.6)
	40	Dex		✓	✓	✓	✓	70.9 (7.2)	25.9 (0.4)			200	▁▁▁▆
GI/Abd - Randomized Clinical Trial
Chen 2013	63	Plac	NR		✓			67.9 (6.6)	28.5 (1.1)
	59	Dex		✓	✓	✓	✓	66.2 (7.5)	28.2 (0.8)	1.0	0.4		▁▆▆▁
Mohamed 2014	25	Plac	123	✓	✓			67.8 (5.4)
	25	Dex		✓	✓	✓	✓	63.9 (5.0)		0.17	0.4		▆▆▆▁
Li 2015	50	Plac	123	✓				70.0 (6.0)	28.3 (1.4)
	50	Dex		✓	✓	✓	✓	69.0 (5.0)	28.4 (1.3)	1.0	0.4		▁▆▆▁
Du 2019	20	Plac	12	✓				68.7 (13.5)	26.8 (1.5)
	20	Dex		✓	✓	✓	✓	69.3 (12.5)	26.5 (1.7)		0.6		▁▁▆▁
Chen 2020	45	Plac	12		✓			65.4 (11.7)	29.3 (0.4)
	43	Dex		✓	✓	✓	✓	64.9 (11.4)	29.4 (0.5)	0.3	1		▁▁▆▁
Li 2021b	30	Plac	123		✓			73.4 (5.1)	28.7 (2.1)
	30	Dex		✓	✓	✓	✓	74.7 (2.6)	27.6 (3.2)	0.3	0.2		▆▁▆▁
	30	Dex		✓	✓	✓	✓	71.2 (3.5)	28.0 (1.7)	0.3	0.5		▆▁▆▁
	30	Dex		✓	✓	✓	✓	69.8 (4.3)	28.4 (2.6)	0.3	0.8		▆▁▆▁
Lu 2021	331	Plac	123		✓			70.4 (6.5)
	344	Dex		✓	✓	✓	✓	70.1 (5.8)		0.5	0.2		▁▆▆▁
Tang 2021	50	Plac	12	✓	✓			70.7 (6.5)
	50	Dex		✓	✓	✓	✓	69.7 (6.6)		0.5	0.4		▁▆▆▁
Xin 2021	30	Plac	23		✓			68.0 [66-71]
	30	Dex		✓	✓	✓	✓	69.0 [67-70]		0.5	0.4		▆▁▆▁
Guo 2022	45	None	23			✓		68.5 (3.8)
	45	Dex		✓	✓	✓	✓	68.5 (3.8)		1.0	0.5		▁▆▆▁
Liao 2023	35	Plac	NR		✓			69.7 (2.5)	27.7 (1.9)
	34	Rem		✓	✓	✓	✓	70.1 (3.6)	27.7 (1.7)
	35	Dex		✓	✓	✓	✓	71.3 (3.6)	27.8 (2.1)	0.5	(0.3–0.5)		▁▆▆▁
Xie 2023	119	Plac	NR		✓			68.6 (5.5)
	117	Dex		✓	✓	✓	✓	67.9 (5.6)				3	▁▁▁▆
Various - Randomized Clinical Trial
Deiner 2017	201	Plac	1234	✓	✓			74.0 {71-78}
	189	Dex		✓	✓	✓	✓	74.0 {71-78}			0.5		▁▁▆▆
Lee 2018a	109	Plac	123	✓				73.1 (6.1)
	95	Dex		✓	✓	✓	✓	72.2 (5.4)		1.0	(0.2–0.7)		▁▆▆▁
	114	Dex		✓	✓	✓	✓	73.1 (6.4)		1.0			▁▁▆▁
Wang 2019	100	Mid	123		✓			69.4 (4.5)	25.0 (3.3)
	98	Dex		✓	✓	✓	✓	70.5 (5.0)	24.9 (3.9)	0.5			▆▁▁▁
Chawdhary 2020	40	Prop	123	✓				64.7 (5.9)	26.4 (1.3)
	40	Dex		✓	✓	✓	✓	66.2 (6.6)	26.1 (1.2)		(0.5–0.7)		▁▁▆▁
Li 2020b	310	Plac	123	✓	✓			69.0 (6.4)	27.4 (2.7)
	309	Dex		✓	✓	✓	✓	69.0 (6.6)	27.4 (2.6)	0.6	0.5		▁▁▆▁
Zhao 2020	101	None	23		✓			69.2 (4.1)	27 {24-30}
	108	Dex		✓	✓	✓	✓	70.0 (4.5)	27 {24-30}	1.0	100^f		▁▆▆▁
	105	Dex		✓	✓	✓	✓	69.4 (3.9)	27 {24-30}	1.0	200^f		▁▆▆▁
	102	Dex		✓	✓	✓	✓	69.3 (4.1)	27 {24-30}	1.0	400^f		▁▆▆▁
Zhang 2021	87	Plac	23	✓				71.4 (4.9)	25.8 (0.8)
	87	Dex		✓	✓	✓	✓	70.6 (4.2)	26.1 (0.7)	1.0	0.4		▁▆▆▁
van Norden 2021	32	Plac	1234	✓	✓			70.5 (6.2)
	28	Dex		✓	✓	✓	✓	70.4 (7.1)		0.7			▁▁▆▁
Lv 2022	157	Plac	NR		✓			68.4 (6.6)
	152	Dex		✓	✓	✓	✓	67.9 (5.9)					▁▁▁▆
Wang 2022b	40	None	123		✓			71.0 (7.1)	27 {23-30}
	42	Dex		✓	✓	✓	✓	69.4 (6.8)	27 {23-30}	0.6			▁▆▆▁
Thoracic - Randomized Clinical Trial
Yu 2017	46	Mid	12		✓			69.1 (4.9)	29.8 (0.7)
	46	Dex		✓	✓	✓	✓	68.7 (4.3)	29.8 (0.7)	0.2	0.5 (0.2–0.7)		▁▆▆▁
He 2018	30	Plac	123	✓	✓			83.2 (5.1)
	30	Mid		✓	✓	✓	✓	81.9 (6.2)
	30	Dex		✓	✓	✓	✓	82.5 (5.4)		0.5	0.4		▆▆▆▁
Huyan 2019	173	Plac	23		✓			71.0 (6.0)
	173	Dex		✓	✓	✓	✓	70.0 (5.0)		0.5	0.1		▆▁▆▁
Shi 2020	53	Plac	23		✓	✓		68.7 (3.4)	28.0 (0.9)
	53	Dex		✓	✓	✓	✓	68.7 (4.6)	27.9 (0.9)		0.5		▁▆▆▁
Hu 2021	87	Plac	123		✓			69.1 (5.1)
	90	Dex		✓	✓	✓	✓	69.6 (4.5)		0.4	0.1		▁▆▆▁
Liu 2022a	31	Plac	12		✓			68.5 (2.3)
	29	Dex		✓	✓	✓	✓	68.1 (2.6)		1.0			▁▆▁▁
Lai 2023	30	None	23	✓				71.2 (5.1)
	29	Dex		✓	✓	✓	✓	70.6 (5.3)		1.0	0.5		▁▆▆▁
Oralmax - Randomized Clinical Trial
Guo 2015	73	Plac	123	✓				71.3 (5.1)	28.0 (1.6)
	76	Dex		✓	✓	✓	✓	70.7 (5.2)	28.2 (1.6)			0.2	▁▁▁▆
Wang 2020a	20	Mid	NR		✓			60.5 (8.2)
	20	Dex		✓	✓	✓	✓	60.0 (10.1)		1.0	(0.2–0.7)		▁▁▁▆
Liu 2022b	60	Plac	12		✓			72.1 (5.9)
	60	Dex		✓	✓	✓	✓	71.3 (6.7)		0.5	0.4		▁▆▆▁
Urol - Randomized Clinical Trial
Ding 2015	20	Plac	NR	✓
	20	Dex		✓	✓	✓	✓			2			▁▆▁▁
Wang 2022a	60	Plac	12		✓			66.7 (4.1)	25.4 (2.2)
	60	Dex		✓	✓	✓	✓	65.6 (3.4)	25.5 (2.5)		0.4		▁▆▁▁
Headneck - Randomized Clinical Trial
Zhang 2018b	30	Mid/Prop	NR		✓			69.9 (2.8)	28.5 (1.2)
	30	Mid/Sevo		✓	✓	✓	✓	70.1 (3.2)	28.6 (1.2)
	30	Dex		✓	✓	✓	✓	68.8 (3.0)	29.0 (0.9)	1.0	0.5		▁▆▆▁
	30	Dex		✓	✓	✓	✓	69.3 (3.1)	28.8 (1.1)	1.0	0.5		▁▆▆▁
ENT - Randomized Clinical Trial
Liu 2023c	149	Plac	NR	✓	✓			70.1 (4.2)	23.9 (4.9)
	150	Dex		✓	✓	✓	✓	70.4 (5.0)	24.3 (4.8)	0.5	0.2		▁▁▆▁
Ortho - Nonrandomized Trial
Xie 2018	70	Plac	NR		✓			69.7 (5.3)	27.3 (0.7)
	70	Dex		✓	✓	✓	✓	68.2 (5.6)	27.6 (0.5)	0.5	0.4		▁▆▆▁
Spine - Nonrandomized Trial
Zhang 2020b	46	Plac	123	✓				70.6 (6.1)	25.6 (4.8)
	57	Dex		✓	✓	✓	✓	71.4 (6.7)	24.1 (4.6)		0.5		▁▆▆▁
	62	Dex		✓	✓	✓	✓	72.5 (7.2)	25.8 (4.5)		1		▁▆▆▁
Ophtho - Randomized Clinical Trial
Mansouri 2019	50	Plac	12		✓			64.0 (7.2)
	50	Mid		✓	✓	✓	✓	63.6 (8.3)
	50	Dex		✓	✓	✓	✓	66.5 (1.6)			1		▁▁▆▁
Oriby 2023	30	Plac	23			✓		70.6 (5.6)
	30	Ket		✓	✓	✓	✓	72.8 (5.3)					▁▆▆▁
	30	Dex		✓	✓	✓	✓	73.3 (5.1)			0.5		▁▆▆▁
GI/Abd - Nonrandomized Trial
Xu 2017	48	Plac	12		✓			72.1 (32.2)
	48	Dex		✓	✓	✓	✓	71.9 (31.4)			0.5		▁▁▆▁
Zhang 2019b	60	Plac	NR		✓			74.1 (13.9)	28.9 (1.2)
	80	Dex		✓	✓	✓	✓	73.8 (14.5)	28.9 (1.2)	1.0	(0.2–0.7)		▁▁▆▁
Wang 2020c	50	Plac	NR	✓	✓			68.3 (2.1)	28.5 (4.2)
	60	Dex		✓	✓	✓	✓	68.4 (3.3)	28.5 (4.3)	0.5	0.4		▆▁▁▁
Thoracic - Nonrandomized Trial
Li 2020a	46	None	NR		✓			67.3 (2.1)	28.5 (4.2)
	41	Dex		✓	✓	✓	✓	67.4 (3.3)	28.5 (4.3)	0.5	0.1		▁▁▆▁
GI/Abd - Prospective Cohort
Sun 2023a	289	None	123					69.3 (5.1)
	354	Dex		✓	✓	✓	✓	69.3 (5.1)					Unspecified
Cardiac - Retrospective Cohort
Cheng 2016	283	None	NR	✓				73.5 (6.2)
	222	Dex		✓	✓	✓	✓	73.6 (6.1)			(0.24–0.6)		▁▁▆▆
Chuich 2019	209	Prop	NR	✓				62.0 (13.0)
	69	Dex		✓	✓	✓	✓	63.0 (13.0)			0.19 (0.08–0.31)		▁▁▆▁
Ortho - Retrospective Cohort
Yin 2020	58	Plac	12				✓	72.1 (0.2)	28.7 (1.1)
	62	Dex		✓	✓	✓	✓	72.2 (0.3)	28.6 (1.3)	0.5	0.4		▆▁▆▁
Park 2021	357	Prop	123			✓		74.0 {70-78}
	357	Dex		✓	✓	✓	✓	74.0 {70-79}		1.0	(0.1–0.5)		▁▆▆▁
Xu 2022	30	None	NR			✓		67.9 (5.0)	18.0 (1.5)
	30	Dex		✓	✓	✓	✓	67.3 (5.5)	18.3 (2.0)	0.5	0.4		▁▆▆▁
Urol - Retrospective Cohort
Liu 2023b	35	None	1234					68.0 [66-72]
	160	Dex		✓	✓	✓	✓	68.0 [66-72]					▁▁▆▁
GI: gastrointestinal; Abd: abdominal (includes hepatic); Ortho: orthopedic; Various: more that one procedure category; Oralmax: oral and maxillofacial; Ophtho; ophthalmologic; Urol: urologic; Dex: dexmedetomidine; Ulin: ulinastatin; Mid: midazolam; Mid/Prop: midazolam/propofol; Mid/Seve: midazolam/sevoflurane; Preg: pregabalin; Prop: propofol; Plac; placebo; PS: physical status; Vol: volatile; TIVA: total intravenous anesthesia; Reg: regional; Sed: sedation; MMSE: Mini-Mental State Exam.
^a ASA Physical Status of patients included (proportions can be found here[link to table add]).
^b Mean Med (SD)[Range]{IQR}.
^c No studies reported including cognitively impaired patients except Liu 2016 as indicated.
^d Maintenance range if reported in parentheses.
^e Bars indicate adminstration times from left to right: preoperative, induction, intraoperative, and postoperative (includes PACU).
^f Given as a single dose.

Ketamine

Table 14. Selected characteristics, comparators, and dosing in ketamine studies.

Study	N	Arm	ASA	Anesthetic			Age^b	MMSE^b,c	Dose	Maintenance	Timing^d
Study	N	Arm	PS^a	Vol	TIVA	Reg	Age^b	MMSE^b,c	(mg/kg)	(mg/kg)	Timing^d
Cardiac - Randomized Clinical Trial
Hudetz 2009a	26	None	NR	✓			64.0 (7.0)
	26	Plac					67.0 (8.0)
	26	Ket					68.0 (7.0)		0.5		▁▆▁▁
Hudetz 2009b	29	Plac	34	✓			60.8 (8.0)
	29	Ket					68.0 (8.0)		0.5		▁▆▁▁
Siripoonyothai 2021	32	Prop	NR	✓
	32	Ket								1	▁▆▆▁
Ortho - Randomized Clinical Trial
Remerand 2009	75	Plac	NR	✓			65.0 (14.0)
	79	Ket					64.0 (13.0)		0.5		▁▁▆▆
Lee 2015	26	Plac	123	✓			68.4 (6.5)	26 {24-28}
	25	Ket					68.3 (5.3)	25 {24-28}	0.5		▁▆▁▁
Tu 2021	40	Suf	123		✓		65.3 (5.2)
	40	Ket^e					66.0 (5.3)		0.5		▁▆▁▁
GI/Abd - Randomized Clinical Trial
Bornemann-Cimenti 2016	19	Plac	123	✓	✓		61.0 (12.4)
	19	Ket^e					58.4 (8.1)			0.01	▁▁▆▆
	18	Ket^e					62.2 (9.8)		0.25	0.12	▁▁▆▆
Han 2023	34	Plac	NR		✓		70.0 (6.2)	27.9 (1.6)
	33	Ket					70.6 (7.6)	28.6 (1.1)	0.15		▁▆▁▁
Ma 2023	31	Plac	23		✓		70.5 (4.2)
	31	Ket					69.5 (4.3)		0.25	0.12	▁▆▆▁
Various - Randomized Clinical Trial
Avidan 2017	222	Plac	NR				70.0 (6.9)
	227	Ket					70.0 (7.2)		0.5		▁▁▆▁
	223	Ket					70.0 (7.3)		1
Hollinger 2021	44	Plac	NR				74.8 (6.6)	28.3 (2.3)
	45	Hal					73.4 (6.3)	28.0 (1.3)
	47	Ket					73.4 (6.1)	27.7 (1.7)	1		▆▁▁▁
Ophtho - Randomized Clinical Trial
Rascon-Martinez 2016	32	Plac	123			✓	70.5 (4.7)
	33	Ket					68.7 (7.1)		0.3
Oriby 2023	30	Plac	23			✓	70.6 (5.6)
	30	Dex					73.3 (5.1)			0.3	▁▆▆▁
	30	Ket					72.8 (5.3)			0.3	▁▆▆▁
Ortho - Prospective Cohort
Juliebo 2009	119	None	NR			✓
	68	Ket									▁▁▆▁
Spine - Prospective Cohort
Barreto Chang 2022	38	None	123				71.0 {68-78}
	60	Ket					70.0 {67-75}				Unspecified
Other - Prospective Cohort
Ke 2022b	92	None	NR
	6	Ket									▁▁▆▁
Ortho - Retrospective Cohort
Weinstein 2018c	31,796	None	NR			✓
	4,070	Ket
Weinstein 2018d	36,852	None	NR			✓
	99	Ket									▁▁▁▆
Memtsoudis 2019b	538,559	None	NR
	25,667	Ket									▁▁▆▆
Memtsoudis 2019g	1,081,139	None	NR
	49,430	Ket									▁▁▆▆
Poeran 2020d	468,004	None	NR	✓	✓	✓
	37,148	Ket									▆▁▁▆
Thoracic - Retrospective Cohort
Fuchita 2019c	74	None	NR				61.7 (10.5)
	10	Ket					61.7 (10.5)				▁▁▆▁
GI: gastrointestinal; Abd: abdominal (includes hepatic); Ortho: orthopedic; Various: more that one procedure category; Dex: dexmedetomidine; Hal: haloperidol; Suf: sufentanil; Prop: propofol; Plac; placebo; PS: physical status; Vol: volatile; TIVA: total intravenous anesthesia; Reg: regional; MMSE: Mini-Mental State Exam.
^a ASA Physical Status of patients included (proportions can be found here[link to table add]).
^b Mean Med (SD)[Range]{IQR}.
^c No studies reported including cognitively impaired patients.
^d Bars indicate adminstration times from left to right: preoperative, induction, intraoperative, and postoperative (includes PACU).
^e S-Ketamine.

Melatonin/Ramelteon

Table 15. Selected characteristics, comparators, and dosing in melatonin and ramelteon studies.

Study	N	Arm	ASA	Anesthetic			Age^b	MMSE^b,c	Dosing	Timing^d
Study	N	Arm	PS^a	Vol	TIVA	Reg	Age^b	MMSE^b,c	Dosing	Timing^d
Cardiac - Randomized Clinical Trial
Dianatkhah 2015	71	Oxaz	NR				61.7 (9.9)
	66	Mel					60.0 (10.2)		3mg × 10	▆▆
El-Naggar 2018	25	Plac	34	✓			67.9 (4.1)	29 [28-30]
	25	Mel					66.6 (4.8)	29 [27-30]	3mg × 5	▆▆
Ford 2020	104	Plac	NR				67.6 (8.0)
	98	Mel					69.0 (8.3)		3mg × 7	▆▆
Javaherforoosh 2021	30	Plac	NR	✓			62.9 (8.1)
	30	Mel					60.3 (9.5)		3mg × 3	▆▆
Shi 2021	149	Plac	NR				71.6 (6.6)
	148	Mel					71.5 (6.7)		3mg × 7	▁▆
Ortho - Randomized Clinical Trial
Sultan 2010	49	None	123			✓	72.3 (6.4)
	50	Mid					69.9 (8.2)
	53	Mel					70.4 (7.1)		5mg × 2	▆▁
de Jonghe 2014	192	Plac	NR				83.4 (7.5)	23 {10-28}
	186	Mel					84.1 (8.0)	23 {12-29}	3mg × 5	▆▆
Fan 2017	70	Plac	123			✓	74.6 (5.4)	27.1 (0.3)
	69	Mel					74.5 (5.7)	27.3 (0.2)	1mg × 6	▆▆
Oh 2021	39	Plac	NR				75.4 (5.0)	28.2 (1.9)
	41	Ram					74.3 (5.5)	28.6 (1.5)	8mg × 3	▆▆
Fazel 2022	36	Plac	NR			✓
	36	Mel							5mg × 4	▆▆
Mohamed 2022	40	Plac	123
	40	Mel							5mg × 2	▆▁
GI/Abd - Randomized Clinical Trial
Tanifuji 2022	19	Plac	NR				73.7 (5.8)
	23	Ram					72.7 (5.2)		4mg × 14	▆▁
Thoracic - Randomized Clinical Trial
Jaiswal 2019	58	Plac	NR				56.1 (15.8)
	59	Ram					58.1 (14.1)		8mg × 6	▆▆
Various - Randomized Clinical Trial
Gupta 2019	50	Plac	12			✓	70.6 (3.8)
	50	Ram					69.3 (4.0)		8mg × 2	▆▁
Esmaeii 2022	49	None	NR	✓	✓		73.7 (6.0)	26.2 (2.2)
	51	Mel					75.9 (6.1)	26.4 (2.1)	5mg × 2	▆▁
Kinouchi 2023	49	Plac	123	✓	✓		75.4 (5.6)
	54	Ram					78.1 (6.9)		8mg × 6	▆▆
Cardiac - Nonrandomized Trial
Artemiou 2015	250	None	NR	✓			65.2 (10.3)
	250	Mel					64.3 (10.1)		5mg × 4	▆▆
Bily 2015	250	None	NR	✓			65.2 (10.3)
	250	Mel					64.3 (10.1)		5mg × 4	▆▆
GI/Abd - Before-After/Time Series
Hokuto 2020	186	None	123				69.0 [30-88]
	120	Ram					71.0 [34-85]		8mg × 4	▆▆
Thoracic - Before-After/Time Series
Miyata 2017	58	None	NR	✓		✓	76.5 [70-87]
	24	Ram					79.0 [70-89]		8mg × 7	▁▆
Headneck - Retrospective Cohort
Ishibashi-Kanno 2020a	34	None	NR				62.9 (11.9)
	35	Ram					62.9 (11.9)		NR	▁▆
GI: gastrointestinal; Abd: abdominal (includes hepatic); Ortho: orthopedic; Various: more that one procedure category; PS: physical status; Vol: volatile; TIVA: total intravenous anesthesia; Reg: regional; MMSE: Mini-Mental State Exam; Mel: melatonin; Ram: ramelteon; Oxaz: oxazepam; Dex: dexmedetomidine; Mid: midazolam; Plac; placebo; NR: not reported.
^a ASA Physical Status of patients included (proportions can be found here[link to table add]).
^b Mean Med (SD)[Range]{IQR}.
^c No studies reported including cognitively impaired patients.
^d Bars indicate adminstration times: preoperative left and postoperative right.

Delirium Incidence

Figure 1. Box plots displaying delirium incidence by surgical category across all treatment arms in randomized clinical trials.

Dex: dexmedetomidine; Ket: ketamine; Mel: melatonin; Ram: ramelteon; Oxaz: oxazepam; MS: morphine sulfate; Prop: propofol; Plac: placebo or no delirium prophylaxis.
The “Any” and “Plac” box plots are not mutually exclusive.
Outliers not designated.

Dexmedetomidine

Table 16. Delirium incidence and ascertainment during hospitalization in randomized clinical trials of dexmedetomidine.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR (95% CI)	Timing^b
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR (95% CI)	Timing^b
Cardiac
Djainai 2016	92	Prop	CAM	5	29 (31.5)		—
	91	Dex^c			16 (17.6)		0.56 (0.33-0.95)	▁▁▁▆
Li 2017	143	Plac	CAM	5	11 (7.7)		—
	142	Dex			7 (4.9)		0.64 (0.26-1.61)	▁▁▆▆
Azeem 2018	30	Mid	CAM	7	2 (6.7)		—
	30	Dex^c			1 (3.3)		0.50 (0.05-5.22)	▁▁▁▆
Subramaniam 2019	61	Prop	CAM	Stay	13 (21.3)		—
	59	Dex^c			10 (16.9)		0.80 (0.38-1.67)	▁▁▁▆
Soh 2020	54	Plac	DSM	7	7 (13.0)		—
	54	Dex			2 (3.7)		0.29 (0.06-1.31)	▁▁▆▁
Turan 2020	396	Plac	CAM	5	46 (11.6)		—
	398	Dex			67 (16.8)		1.45 (1.02-2.05)	▁▆▆▆
Gao 2021	20	Plac	DSM	Note^d	10 (50.0)^e		—
	20	Dex			3 (15.0)^e		0.30 (0.10-0.93)	▁▆▆▁
Momeni 2021	203	Plac	CAM	Stay	33 (16.3)		—
	205	Dex^c			31 (15.1)		0.93 (0.59-1.46)	▁▁▁▆
Chitnis 2022	33	Prop	ICDSC	5	14 (42.4)		—
	34	Dex^c			8 (23.5)		0.55 (0.27-1.14)	▁▁▁▆
Kowalczyk 2022	23	None	NS	Stay	5 (21.7)		—
	23	Dex			2 (8.7)		0.40 (0.09-1.86)	▁▆▆▁
Qu 2023	206	Plac	CAM	3	25 (12.1)		—
	188	Dex^c			14 (7.4)		0.61 (0.33-1.14)^f	▁▁▁▆
Racman 2023	34	Prop	CAM	2	4 (11.8)		—
	37	Dex			1 (2.7)		0.23 (0.03-1.96)	▁▆▆▁
Ortho
Liu 2016 (MCI)	40	Plac	CAM	7	25 (62.5)		—
	39	Dex			10 (25.6)		0.41 (0.23-0.74)	▁▁▆▁
Liu 2016 (no MCI)	58	Plac	CAM	7	18 (31.0)		—
	60	Dex			5 (8.3)		0.27 (0.11-0.68)	▁▁▆▁
Lee 2018b	31	Plac	Psych	Stay	11 (35.5)		—
	33	Preg			14 (42.4)		1.20 (0.64-2.22)
	29	Dex/Preg			7 (24.1)		0.68 (0.31-1.52)
	31	Dex			3 (9.7)		0.27 (0.08-0.88)	▁▆▆▁
Mei 2018	148	Prop	CAM	3	24 (16.2)		—
	148	Dex			11 (7.4)		0.46 (0.23-0.90)	▁▆▁▁
Mei 2020a	183	Prop	CAM	7	43 (23.5)		—
	183	Dex			26 (14.2)		0.60 (0.39-0.94)	▁▁▆▁
Zhang 2020a	120	Plac	CAM/DSM	3	36 (30.0)		—
	120	Dex			20 (16.7)		0.56 (0.34-0.90)	▆▁▆▁
Hong 2021	354	Plac	CAM	5	26 (7.3)		—
	356	Dex^c			17 (4.8)		0.65 (0.36-1.18)	▁▁▁▆
Xing 2021	55	Plac	Note^g	1	8 (14.5)		—
	55	Dex			2 (3.6)		0.25 (0.06-1.12)	▁▆▁▁
Yan 2021	50	Plac	CAM	7	13 (26.0)		—
	50	Dex			5 (10.0)		0.38 (0.15-1.00)	▁▆▁▁
Hu 2022	20	None	DOC	5	3 (15.0)		—
	20	Dex			1 (5.0)		0.33 (0.04-2.94)	▁▆▆▁
Shin 2023	366	Prop	CAM	3	24 (6.6)		—
	366	Dex			11 (3.0)		0.46 (0.23-0.92)	▁▁▆▁
Yoo 2023	64	Plac	CAM	Stay	10 (15.6)		—
	64	Dex			4 (6.2)		0.40 (0.13-1.21)	▁▁▆▁
Various
Deiner 2017	201	Plac	CAM	5	23 (11.4)		—
	189	Dex			23 (12.2)		1.06 (0.62-1.83)	▁▁▆▆
Lee 2018a	109	Plac	CAM	5	27 (24.8)		—
	95	Dex			9 (9.5)		0.38 (0.19-0.77)	▁▆▆▁
	114	Dex			21 (18.4)		0.74 (0.45-1.23)	▁▁▆▁
Li 2020b	310	Plac	CAM	5	32 (10.3)		—
	309	Dex			17 (5.5)		0.53 (0.30-0.94)	▁▁▆▁
Zhao 2020	101	None	CAM	7	19 (18.8)		—
	108	Dex			15 (13.9)		0.74 (0.40-1.37)	▁▆▆▁
	105	Dex			5 (4.8)		0.25 (0.10-0.65)	▁▆▆▁
	102	Dex			5 (4.9)		0.26 (0.10-0.67)	▁▆▆▁
van Norden 2021	32	Plac	CAM/ICDSC	14	14 (43.8)		—
	28	Dex			5 (17.9)		0.41 (0.17-0.99)	▁▁▆▁
Lv 2022	157	Plac	CAM	7	46 (29.3)		—
	152	Dex^c			21 (13.8)		0.47 (0.30-0.75)	▁▁▁▆
Thoracic
Yu 2017	46	Mid	CAM	3	10 (21.7)		—
	46	Dex			3 (6.5)		0.30 (0.09-1.02)	▁▆▆▁
He 2018	30	Plac	CAM	Note^d	15 (50.0)^e		—
	30	Mid			17 (56.7)^e		1.13 (0.70-1.82)
	30	Dex			7 (23.3)^e		0.47 (0.22-0.98)	▆▆▆▁
Huyan 2019	173	Plac	ICDSC	Note^d	47 (27.2)^e		—
	173	Dex			27 (15.6)^e		0.57 (0.38-0.88)	▆▁▆▁
Shi 2020	53	Plac	CAM	7	6 (11.3)		—
	53	Dex			4 (7.5)		0.67 (0.20-2.23)	▁▆▆▁
Hu 2021	87	Plac	CAM	4	32 (36.8)		—
	90	Dex			15 (16.7)		0.45 (0.26-0.78)	▁▆▆▁
Lai 2023	30	None	CAM	Note^d	9 (30.0)^e		—
	29	Dex			5 (17.2)^e		0.57 (0.22-1.51)	▁▆▆▁
Oralmax
Wang 2020a	20	Mid	NS	Stay	9 (45.0)		—
	20	Dex^c			1 (5.0)		0.11 (0.02-0.80)	▁▁▁▆
Liu 2022b	60	Plac	CAM	5	8 (13.3)		—
	60	Dex			5 (8.3)		0.62 (0.22-1.80)	▁▆▆▁
GI/Abd
Lu 2021	331	Plac	CAM	Note^d	43 (13.0)^e		—
	344	Dex			41 (11.9)^e		0.92 (0.61-1.37)	▁▆▆▁
Xin 2021	30	Plac	CAM	7	10 (33.3)		—
	30	Dex			3 (10.0)		0.30 (0.09-0.98)	▆▁▆▁
Xie 2023	119	Plac	CAM	7	12 (10.1)		—
	117	Dex^c			4 (3.4)		0.34 (0.11-1.02)	▁▁▁▆
ENT
Liu 2023c	149	Plac	CAM	5	36 (24.2)		—
	150	Dex			32 (21.3)		0.88 (0.58-1.34)	▁▁▆▁
GI: gastrointestinal; Abd: abdominal (includes hepatic); Ortho: orthopedic; Various: more that one procedure category; Oralmax: oral and maxillofacial; Ophtho; ophthalmologic; Urol: urologic; RR: risk ratio; Dex: dexmedetomidine; Mid: midazolam; Prop: propofol; Preg: pregabalin; Plac: placebo; DSM: Diagnostic and Statistical Manual of Mental Disorders; ICDSC: Intensive Care Delirium Screening Checklist; Psych: psychiatrist interview; Nu-DESC: Nursing Delirium Screening Scale; NS: not specified.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.
^b Bars indicate adminstration times from left to right: preoperative, induction, intraoperative, and postoperative (includes PACU).
^c Postoperative dexmedetomidine only.
^d Reported only daily incidence.
^e Maximum of reported daily incidence.
^f Primary outcome was delirium on postoperative day 1 — OR 0.32 (95% CI, 0.10–0.83)
^g Tool reported in the `Chinese Expert Consensus on the Prevention and Treatment of Postoperative Delirium in Elderly Patients.'

Ketamine

Table 17. Delirium incidence and days of ascertainment during hospitalization in ketamine studies.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR (95% CI)
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR (95% CI)
Cardiac - Randomized Clinical Trial
Hudetz 2009b	29	Plac	ICDSC	5	9 (31.0)		—
	29	Ket			1 (3.4)		0.11 (0.02-0.82)
Siripoonyothai 2021	32	Prop	CAM	1	18 (56.2)		—
	32	Ket			10 (31.2)		0.56 (0.31-1.01)
Ortho - Prospective Cohort
Juliebo 2009	119	None	CAM	5	38 (31.9)		—
	68	Ket			30 (44.1)		1.38 (0.95-2.01)
Various - Randomized Clinical Trial
Avidan 2017	222	Plac	CAM	3	43 (19.4)		—
	227	Ket			39 (17.2)		0.89 (0.60-1.31)
	223	Ket			46 (20.6)		1.06 (0.73-1.54)
Hollinger 2021	44	Plac	ICDSC	3	4 (9.1)		—
	45	Hal			5 (11.1)		1.22 (0.35-4.25)
	47	Ket			3 (6.4)		0.70 (0.17-2.96)
Ortho - Retrospective Cohort
Weinstein 2018c	31,796	None	ICD	Stay	713 (2.2)		—
	4,070	Ket			84 (2.1)		0.92 (0.74-1.15)
Weinstein 2018d	36,852	None	ICD	Stay	771 (2.1)		—
	99	Ket			13 (13.1)		6.28 (3.76-10.47)
Memtsoudis 2019b	538,559	None	Other^b	Stay	14,082 (2.6)		—
	25,667	Ket			703 (2.7)		1.05 (0.97-1.13)
Memtsoudis 2019g	1,081,139	None	Other^b	Stay	30,978 (2.9)		—
	49,430	Ket			1,406 (2.8)		0.99 (0.94-1.05)
Poeran 2020d	468,004	None	ICD	Stay	72,998 (15.6)		—
	37,148	Ket			6,549 (17.6)		1.13 (1.10-1.16)
Thoracic - Retrospective Cohort
Fuchita 2019c	74	None	CAM	Stay	24 (32.4)		—
	10	Ket			3 (30.0)		0.92 (0.34-2.52)
Spine - Prospective Cohort
Barreto Chang 2022	38	None	CAM/ICDSC	Stay	7 (18.4)		—
	60	Ket			19 (31.7)		1.72 (0.80-3.70)
Other - Prospective Cohort
Ke 2022b	92	None	Nu-DESC	Stay	10 (10.9)		—
	6	Ket			1 (16.7)		1.53 (0.23-10.07)
GI/Abd - Randomized Clinical Trial
Ma 2023	31	Plac	CAM	NA	4 (12.9)		—
	31	Ket			3 (9.7)		0.75 (0.18-3.08)
RR: risk ratio; Ket: ketamine; Plac: placebo; Prop: propofol; Hal: haloperidol; ICDSC: Intensive Care Delirium Screening Checklist; CAM: Confusion Assessment Method; Nu-DESC: Nursing Delirium Screening Scale; ICD: ICD codes.
^a Days over which incidence assessed. Stay indicates duration of hospital stay.
^b Claims-based algorithm.

Melatonin/Ramelteon

Table 18. Delirium incidence and days of ascertainment during hospitalization in melatonin and ramelteon studies.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR (95% CI)
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR (95% CI)
Cardiac - Randomized Clinical Trial
Dianatkhah 2015	71	Oxaz	Clinical	Stay	9 (12.7)		—
	66	Mel			4 (6.1)		0.48 (0.15-1.48)
El-Naggar 2018	25	Plac	ICDSC	3	7 (28.0)		—
	25	Mel			2 (8.0)		0.29 (0.07-1.24)
Ford 2020	104	Plac	CAM/DSM	7	21 (20.2)		—
	98	Mel			21 (21.4)		1.06 (0.62-1.82)
Javaherforoosh 2021	30	Plac	CAM	Note^b	14 (46.7)		—
	30	Mel			4 (13.3)		0.29 (0.11-0.77)
Shi 2021	149	Plac	CAM	7	59 (39.6)		—
	148	Mel			40 (27.0)		0.68 (0.49-0.95)
Ortho - Randomized Clinical Trial
Sultan 2010	49	None	AMT	3	16 (32.7)		—
	50	Mid			22 (44.0)		1.35 (0.81-2.24)
	53	Mel			5 (9.4)		0.29 (0.11-0.73)
de Jonghe 2014	192	Plac	DSM	8	49 (25.5)		—
	186	Mel			55 (29.6)		1.16 (0.83-1.61)
Oh 2021	39	Plac	CAM/DRS/DSM	2	2 (5.1)		—
	41	Ram			3 (7.3)		1.43 (0.25-8.09)
Fazel 2022	36	Plac	AMT	Note^b	16 (44.4)		—
	36	Mel			8 (22.2)		0.50 (0.25-1.02)
Mohamed 2022	40	Plac	AMT	3	21 (52.5)		—
	40	Mel			10 (25.0)		0.48 (0.26-0.88)
Various - Randomized Clinical Trial
Gupta 2019	50	Plac	CAM	3	6 (12.0)		—
	50	Ram			2 (4.0)		0.33 (0.07-1.57)
Esmaeii 2022	49	None	AMT	Note^b	10 (20.4)		—
	51	Mel			4 (7.8)		0.38 (0.13-1.14)
Thoracic - Randomized Clinical Trial
Jaiswal 2019	58	Plac	CAM	Stay	22 (37.9)		—
	59	Ram			19 (32.2)		0.85 (0.52-1.39)
GI/Abd - Before-After/Time Series
Hokuto 2020	186	None	DSM	7	28 (15.1)		—
	120	Ram			7 (5.8)		0.39 (0.17-0.86)
Thoracic - Before-After/Time Series
Miyata 2017	58	None	ICDSC	9	5 (8.6)		—
	24	Ram			0 (0)		Not estimated
Cardiac - Nonrandomized Trial
Artemiou 2015	250	None	CAM	Stay	52 (20.8)		—
	250	Mel			21 (8.4)		0.40 (0.25-0.65)
Bily 2015	250	None	CAM	Stay	52 (20.8)		—
	250	Mel			21 (8.4)		0.40 (0.25-0.65)
Headneck - Retrospective Cohort
Ishibashi-Kanno 2020a	34	None	DSM	Stay	12 (35.3)		—
	35	Ram			11 (31.4)		0.89 (0.46-1.74)
GI/Abd - Randomized Clinical Trial
Tanifuji 2022	19	Plac	CAM	7	4 (21.1)		—
	23	Ram			1 (4.3)		0.21 (0.03-1.70)
RR: risk ratio; MMSE: Mini-Mental State Examination; Mel: melatonin; Ram: ramelteon; Dex: dexmedetomidine; Oxaz: oxazepam; Mid: midazolam; AMT: Abbreviated Mental Test; DRS: Delirium Rating Scale; DSM: Diagnostic and Statistical Manual of Mental Disorders; CAM: Confusion Assessment Method; ICDSC: Intensive Care Delirium Screening Checklist.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.
^b Reported only daily incidence.

Pooled

Dexmedetomidine

Figure 2. Dexmedetomidine compared with placebo or no intervention.

Dex: dexmedetomidine; Plac: placebo; RR: risk ratio; D1: bias arising from the randomization process; D2: bias due to deviations from intended interventions; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result: All: overall risk of bias.
Risk of bias ratings: low +, some concerns ?, high – .
Harbord test for small study effects P = 0.00006.
Delirium a designated primary outcome in 71.0%; a secondary outcome in 12.9%.
Excluding Turan 2020: RR 0.56 (95% CI, 0.49-0.64; I² = 13%, \(\tau\)² = 0.04.
*Trials conducted in China.

Meta-analysis methods detail.

- Mantel-Haenszel method (common effect model)
- Inverse variance method (random effects model)
- Restricted maximum-likelihood estimator for τ²
- Q-Profile method for confidence interval of τ² and τ
- Hartung-Knapp adjustment for random effects model (df = 31)
- Hartung-Knapp prediction interval (df = 30)

Figure 3. Dexmedetomidine compared with placebo or no intervention — China vs. other countries.

Figure 4. Dexmedetomidine compared with placebo or no intervention — small study effects.

Estimates from random effects models — unadjusted OR 0.50 (95% CI, 0.41–0.61); adjusted for small study effects in a limit meta-analysis OR 0.78 (95% CI, 0.55–1.11).
*Trials conducted in China.

Figure 5. Dexmedetomidine compared with placebo or no intervention — significance funnel plots.

Black diamond represents pooled estimate for all studies and the grey for only non-affirmative ones (p>0.05). For the entire set of included trials, achieving a non-significant result would require affirmative studies >50 times more like to be published and unlikely plausible (see Mathur 2024 and Mathur 2020). For trials conducted outside of China, the pooled result for non-affirmative trials is null.

Figure 6. Dexmedetomidine compared with placebo or no intervention — small study effects for trials conducted in China.

Estimates from random effects models — unadjusted OR 0.46 (95% CI, 0.38–0.56); adjusted for small study effects in a limit meta-analysis OR 0.67 (95% CI, 0.46–0.99).
Harbord test for small study effects P = 0.0001.

Figure 7. Dexmedetomidine compared with placebo or no intervention — small study effects in trials conducted outside of China.

Estimates from random effects models — unadjusted OR 0.61 (95% CI, 0.38–0.99); adjusted for small study effects in a limit meta-analysis OR 1.11 (95% CI, 0.58–2.14).
Harbord test for small study effects P = 0.0021.

Figure 8. Dexmedetomidine compared with placebo or no intervention — postoperative administration only or at other times.

Figure 9. Dexmedetomidine compared with placebo or no intervention — any postoperative administration or at other times.

Figure 10. Dexmedetomidine compared with placebo or no intervention — by surgical category.

Orthopedic

Various

Cardiac

Thoracic

GI/Abdominal

Dex: dexmedetomidine; Plac: placebo; RR: risk ratio; D1: bias arising from the randomization process; D2: bias due to deviations from intended interventions; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result: All: overall risk of bias.
Risk of bias ratings: low +, some concerns ?, high – .
Hartung-Knapp adjustment not applied owing to < 5 trials in some subgroups.
*Trials conducted in China.

Figure 11. Dexmedetomidine compared with placebo or no intervention — according to risk of bias appraisal.

Figure 12. Dexmedetomidine compared with placebo or no intervention — according to reporting incidence proportion.

Dex: dexmedetomidine; Plac: placebo; RR: risk ratio; D1: bias arising from the randomization process; D2: bias due to deviations from intended interventions; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result: All: overall risk of bias.
Risk of bias ratings: low +, some concerns ?, high – .
Hartung-Knapp adjustment not applied.
*Trials conducted in China.

Figure 13. Placebo delirium incidence proportion and relative effects (standard and Bayesian meta-regression models).

Bubble plot of control arm/baseline delirium risk and odds ratios. Bubble size proportional to the number of patients. The red dashed line represents the pooled risk ratio. Obtained from a standard meta-regression.

Similar plot for odds ratios obtained from a Bayesian meta-regression (fitted using Stan and multinma).

Figure 14. Risk ratios according to baseline risk subgroups (placebo delirium incidence proportion) — <15%, 15% to 30%, and >30%.

Figure 15. Summary risk of bias from randomized clinical trials of dexmedetomidine compared with placebo or no intervention (delirium, weighted).

Subgroups

Figure 16. Summary of subgroup results.

Dex: dexmedetomidine; Plac: placebo; RR: risk ratio.

Ketamine

Figure 17. Ketamine compared with placebo (randomized clinical trials).

D1: bias arising from the randomization process; D2: bias due to deviations from intended interventions; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result: All: overall risk of bias.
Risk of bias ratings: low +, some concerns ?, high – .

Figure 18. Ketamine compared with placebo (non-randomized studies).

D1: Bias due to confounding; D2: Bias in selection of participants into the study; D3: Bias in classification of interventions; D4: Bias due to deviations from intended interventions; D5: Bias due to missing data; D6: Bias in measurement of outcomes; D7: Bias in selection of reported results; All: overall risk of bias.
Risk of bias ratings: low ++, moderate +, serious -, critical - - ; NI: no information; NA: not applicable.
Confidence intervals may not exactly match published; variances were calculated from rounded figures as reported.
Multilevel model accounting for within-study dependent effects.
Weinstein 2018c intraoperative ketamine; Weinstein 2018d postoperative ketamine; Memtsoudis 2019b hip arthroplasty; Memtsoudis 2019g total knee arthroplasty.

Figure 19. Ketamine versus none non-randomized designs small study effects (funnel plot).

Melatonin/Ramelteon

Figure 20. Melatonin and ramelteon compared with placebo or no intervention.

Mel: melatonin; Ram: ramelteon; D1: bias arising from the randomization process; D2: bias due to deviations from intended interventions; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result: All: overall risk of bias.

Risk of bias ratings: low +, some concerns ?, high – .

Harbord test for small study effects P = 0.03.

Delirium a designated primary outcome in 100.0%.

Figure 21. Melatonin or ramelteon compared with placebo or no intervention — small study effects.

quartz_off_screen 
                2

Estimates (odds ratio and 95% CI) from random effects models — unadjusted OR 0.50 (0.32–0.78); adjusted for small study effects OR 0.78 (0.40–1.51).

Figure 22. Melatonin or ramelteon compared with placebo or no intervention — significance funnel plot.

Black diamond represents pooled estimate for all studies and the grey for only non-affirmative ones (p>0.05). To achieve a non-significant result, would require affirmative studies 2.9 times more like to be published (see Mathur 2020) and the pooled result from non-affirmative studies does not appear to yield a clinically substantive decrease in risk.

Figure 23. Ramelteon compared with placebo (before-after studies).

Network

Characteristic	Value
Table 19. Summary of studies included in the network for delirium incidence.
Number of Interventions	7
Number of Studies	61
Total Number of Patients in Network	12,550
Total Possible Pairwise Comparisons	21
Total Number of Pairwise Comparisons With Direct Data	8
Is the network connected?	TRUE
Number of Two-arm Studies	61
Number of Multi-Arms Studies	0
Total Number of Events in Network	1,997
Number of Studies With No Zero Events	61
Number of Studies With At Least One Zero Event	0
Number of Studies with All Zero Events	0

Comparison	Studies	Patients	Events (%)
Table 20. Summary of events by comparisons in the network for delirium incidence.
Benzo vs. Dex	3	192	26 (13.5)
Benzo vs. Mel	1	137	13 (9.5)
Dex vs. Plac/None	32	7,774	1,123 (14.4)
Dex vs. Prop	7	1,834	234 (12.8)
Ket vs. Plac/None	4	878	152 (17.3)
Ket vs. Prop	1	64	28 (43.8)
Mel vs. Plac/None	9	1,341	362 (27.0)
Plac/None vs. Ram	4	330	59 (17.9)

Figure 24. Network structure of randomized clinical trials and comparators reporting delirium incidence.

Dex: dexmedetomidine; Ket: ketamine; Mel/Ram: melatonin or ramelteon; Benz: benzodiazepine (midazolam or oxazepam); Plac/None: placebo or no intervention; Prop: propofol.

Figure 25. Network meta-analysis of delirium incidence including all comparators.

Dex: Dexmedetomidine; Ket: Ketamine; Mel/Ram: Melatonin or Ramelteon; Benzo: Benzodiazepine; Prop: Propofol; Plac/None: Placebo or no comparator.

Table 21. League table of risk ratios and 95% confidence intervals from network meta-analysis of delirium incidence (random effects model). Comparisons from direct evidence displayed in the upper diagonal; network comparisons shown on the lower diagonal.

Dex			0.26 (0.09, 0.71)	0.55 (0.40, 0.77)	0.58 (0.50, 0.68)
0.81 (0.51, 1.29)	Ket			0.56 (0.25, 1.25)	0.78 (0.46, 1.32)
0.89 (0.66, 1.20)	1.10 (0.65, 1.86)	Mel/Ram	0.48 (0.14, 1.67)		0.64 (0.50, 0.83)
0.31 (0.14, 0.70)	0.39 (0.16, 0.97)	0.35 (0.16, 0.79)	Benzo
0.54 (0.39, 0.74)	0.66 (0.40, 1.10)	0.60 (0.39, 0.92)	1.71 (0.72, 4.02)	Prop
0.58 (0.50, 0.68)	0.72 (0.46, 1.13)	0.65 (0.51, 0.84)	1.85 (0.83, 4.13)	1.09 (0.77, 1.53)	Plac/None
Dex: Dexmedetomidine; Ket: Ketamine; Mel/Ram: Melatonin or Ramelteon; Mid: Midazolam; MS: Morphine; Prop: Propofol; Plac/None: Placebo or no comparator.

Figure 26. Comparison-adjusted funnel plot for delirium.

Figure 27. Comparison of direct and indirect evidence in network meta-analysis of delirium (node splitting forest plot).

Dex: Dexmedetomidine; Ket: Ketamine; Mel/Ram: Melatonin/Ramelteon; Mid: Midazolam; MS: Morphine; Prop: Propofol; Plac/None: Placebo or no comparator.

Neurocognitive Disorder
<30 days

Dexmedetomidine

Table 22. Neurocognitive disorder <30 days incidence and ascertainment in trials of dexmedetomidine (includes only trials conducting cognitive testing at day 3 or later).

Study	N	Drug	Preop	Instrument				Day^b	Neurocognitive Disorder <30 days
Study	N	Drug	MMSE^a	MMSE	DST	MoCA	Other	Day^b	N (%)	0 — 100%	RR (95% CI)
GI/Abd - Randomized Clinical Trial
Mohamed 2014	25	Plac				✓		7	5 (20.0)		—
	25	Dex							6 (24.0)		1.20 (0.42-3.43)
Chen 2020	45	Plac	29.3 (0.4)	✓^c				3	29 (64.4)		—
	43	Dex	29.4 (0.5)						7 (16.3)		0.25 (0.12-0.51)
Li 2021b	30	Plac	28.7 (2.1)	✓^d				7	12 (40.0)		—
	30	Dex	27.6 (3.2)						11 (36.7)		0.92 (0.48-1.74)
	30	Dex	28.0 (1.7)						4 (13.3)		0.33 (0.12-0.92)
	30	Dex	28.4 (2.6)						2 (6.7)		0.17 (0.04-0.68)
Guo 2022	45	None					✓^e	7	6 (13.3)		—
	45	Dex							4 (8.9)		0.67 (0.20-2.20)
Liao 2023	35	Plac	27.7 (1.9)	✓		✓		3	10 (28.6)		—
	34	Rem	27.7 (1.7)						3 (8.8)		0.31 (0.09-1.03)
	35	Dex	27.8 (2.1)						3 (8.6)		0.30 (0.09-1.00)
Cardiac - Randomized Clinical Trial
Zhou 2019b	38	Plac				✓^f		7	12 (31.6)		—
	39	Ulin							7 (17.9)		0.57 (0.25-1.29)
	39	Dex/Ulin							4 (10.3)		0.32 (0.11-0.92)
	38	Dex							6 (15.8)		0.50 (0.21-1.19)
Gao 2020	30	Plac					✓^g	7	5 (16.7)		—
	30	Dex							0 (0)		Not estimated
Racman 2023	34	Prop	26 {25-28}	✓				3	20 (58.8)		—
	37	Dex	27 {25-28}						9 (24.3)		0.41 (0.22-0.78)
Various - Randomized Clinical Trial
Wang 2019	100	Mid	25.0 (3.3)	✓^h				7	28 (28.0)		—
	98	Dex	24.9 (3.9)						24 (24.5)		0.87 (0.55-1.40)
Chawdhary 2020	40	Prop	26.4 (1.3)	✓ⁱ				7	11 (27.5)		—
	40	Dex	26.1 (1.2)						8 (20.0)		0.73 (0.33-1.62)
Zhao 2020	101	None	27 {24-30}	✓^j				7	10 (9.9)		—
	108	Dex	27 {24-30}						14 (13.0)		1.31 (0.61-2.81)
	105	Dex	27 {24-30}						5 (4.8)		0.48 (0.17-1.36)
	102	Dex	27 {24-30}						2 (2.0)		0.20 (0.04-0.88)
Ortho - Randomized Clinical Trial
Lu 2017	76	Dex	28.3 (1.3)	✓^j				7	13 (17.1)		—
	75	Dex	28.5 (1.2)						5 (6.7)		0.39 (0.15-1.04)
Li 2019	55	Prop			✓^f	✓		7	10 (18.2)		—
	54	Mid							28 (51.9)		2.85 (1.54-5.28)
	55	Dex							22 (40.0)		2.20 (1.15-4.20)
Zhao 2023	42	Plac	25.8 (0.6)	✓				3	16 (38.1)		—
	40	Dex	25.9 (0.4)						7 (17.5)		0.46 (0.21-1.00)
Ophtho - Randomized Clinical Trial
Mansouri 2019	50	Plac		✓^k				7	10 (20.0)		—
	50	Mid							6 (12.0)		0.60 (0.24-1.53)
	50	Dex							6 (12.0)		0.60 (0.24-1.53)
Thoracic - Randomized Clinical Trial
Shi 2020	53	Plac	28.0 (0.9)			✓^l		7	19 (35.8)		—
	53	Dex	27.9 (0.9)						7 (13.2)		0.37 (0.17-0.80)
Urol - Randomized Clinical Trial
Ding 2015	20	Plac		✓^d	✓^d			5	4 (20.0)		—
	20	Dex							1 (5.0)		0.25 (0.03-2.05)
GI/Abd - Nonrandomized Trial
Xu 2017	48	Plac				✓		7	0 (0)		—
	48	Dex							0 (0)		Not estimated
Zhang 2019b	60	Plac	28.9 (1.2)	✓				3	8 (13.3)		—
	80	Dex	28.9 (1.2)						0 (0)		Not estimated
Mini-Mental State Exam; DST: Digit Span Test; MoCA: Montreal Cognitive Assessment; RR: risk ratio; Dex: Dexmedetomidine; Mid: Midazolam; Prop: Propofol; Ulin: ulinastatin; Plac/None: placebo or no intervention.
^a Mean Med (SD)[Range]{IQR}.
^b Day of assessment.
^c MMSE <24.
^d Difference from baseline ≥1 SD.
^e Not specified.
^f Z ≥1.96.
^g American Psychiatric Association postoperative cognitive dysfunction diagnostic criteria.
^h Threshold not specified.
ⁱ Difference from baseline ≥2 SD.
^j Difference from baseline >2 pts.
^k MMSE <26.
^l Z >2.

Ketamine

Table 23. Neurocognitive disorder <30 days incidence and ascertainment in randomized clinical trials of ketamine (includes only trials conducting cognitive testing at day 3 or later).

Study	N	Drug	Preop	Instrument				Day^b,b	Neurocognitive Disorder <30 days
Study	N	Drug	MMSE^a,a	MMSE	DST	MoCA	Other	Day^b,b	N (%)	0 — 100%	RR (95% CI)
GI/Abd - Randomized Clinical Trial
Han 2023	34	Plac	27.9 (1.6)		✓			7	13 (38.2)		—
	33	Ket	28.6 (1.1)						5 (15.2)		0.40 (0.16-0.99)
Ma 2023	31	Plac		✓				3	12 (38.7)		—
	31	Ket							5 (16.1)		0.42 (0.17-1.04)
Various - Randomized Clinical Trial
Hollinger 2021	44	Plac	28.3 (2.3)	✓^c				3	6 (13.6)		—
	45	Hal	28.0 (1.3)						7 (15.6)		1.14 (0.42-3.13)
	47	Ket	27.7 (1.7)						10 (21.3)		1.56 (0.62-3.93)
Cardiac - Randomized Clinical Trial
Hudetz 2009a	26	Plac			✓			7	21 (80.8)		—
	26	Ket							7 (26.9)		0.33 (0.17-0.65)
Ortho - Randomized Clinical Trial
Lee 2015	26	Plac	26 {24-28}	✓^d				6	0 (0)		—
	25	Ket	25 {24-28}						1 (4.0)		Not estimated
Mini-Mental State Exam; DST: Digit Span Test; MoCA: Montreal Cognitive Assessment; RR: risk ratio; Ket: ketamine; Hal: haloperidol; Plac: placebo.
Mini-Mental State Exam; DST: Digit Span Test; MoCA: Montreal Cognitive Assessment; RR: risk ratio; Dex: Dexmedetomidine; Mid: Midazolam; Prop: Propofol; Ulin: ulinastatin; Plac/None: placebo or no intervention.
^a Mean Med (SD)[Range]{IQR}.
^b Day of assessment.
^c MMSE <24.
^d Z ≥1.96.

Melatonin/Ramelteon

No studies

Pooled

Dexmedetomidine

Figure 28. Dexmedetomidine compared with placebo or no intervention (randomized clinical trials, neurocognitive disorder <30 days assessed on postoperative day 5 or later).

Dex: dexmedetomidine; Plac: placebo; RR: risk ratio; D1: bias arising from the randomization process; D2: bias due to deviations from intended interventions; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result: All: overall risk of bias.
Risk of bias ratings: low +, some concerns ?, high – .
Neurocognitive recovery a designated primary outcome in 19.4%; a secondary outcome in 6.5%.
*Trials conducted in China.

Figure 29. Dexmedetomidine compared with placebo or no intervention according to risk of bias appraisals (randomized clinical trials; neurocognitive disorder <30 days).

Dex: dexmedetomidine; Plac: placebo; RR: risk ratio; D1: bias arising from the randomization process; D2: bias due to deviations from intended interventions; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result: All: overall risk of bias.
Risk of bias ratings: low +, some concerns ?, high – .
0.5 added to cells of studies without events in one arm.

Figure 30. Dexmedetomidine compared with placebo or no intervention small study effects — funnel plot (neurocognitive disorder <30 days).

Figure 31. Summary risk of bias from randomized clinical trials of dexmedetomidine compared with placebo or no intervention (neurocognitive disorder <30 days, weighted).

Ketamine

Figure 32. Ketamine compared with placebo or no intervention (randomized clinical trials, delayed neurocognitive recovery).

Plac: placebo; RR: risk ratio; D1: bias arising from the randomization process; D2: bias due to deviations from intended interventions; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result: All: overall risk of bias.
Risk of bias ratings: low +, some concerns ?, high – .
Too few studies to examine small study effects.

Network

Characteristic	Value
Table 24. Summary of studies included in the network for neurocognitive disorder <30 days.
Number of Interventions	5
Number of Studies	15
Total Number of Patients in Network	1,720
Total Possible Pairwise Comparisons	10
Total Number of Pairwise Comparisons With Direct Data	6
Is the network connected?	TRUE
Number of Two-arm Studies	13
Number of Multi-Arms Studies	2
Total Number of Events in Network	335
Number of Studies With No Zero Events	13
Number of Studies With At Least One Zero Event	2
Number of Studies with All Zero Events	0

Comparison	Studies	Patients	Events (%)
Table 25. Summary of events by comparisons in the network for neurocognitive disorder <30 days.
Dex vs. Mid	3	407	114 (28.0)
Dex vs. Plac	9	1,058	151 (14.3)
Dex vs. Prop	2	190	51 (26.8)
Ket vs. Plac	3	170	47 (27.6)
Mid vs. Plac	1	100	16 (16.0)
Mid vs. Prop	1	109	38 (34.9)

Figure 33. Network structure of randomized clinical trials and comparators reporting neurocognitive disorder <30 days.

Dex: Dexmedetomidine; Ket: ketamine; Mid: midazolam; Prop: propofol; Plac: Placebo or no intervention; Prop: Propofol.
Zhao 2020 no intervention (usual care) arm included as placebo.

Figure 34. Network meta-analysis of neurocognitive disorder <30 days including all comparators.

Dex: Dexmedetomidine; Ket: ketamine; Mid: midazolam; Prop: propofol; Plac: Placebo or no intervention; Prop: Propofol.

Table 26. League table of risk ratios and 95% confidence intervals from network meta-analysis of neurocognitive disorder <30 days (random effects model). Comparisons from direct evidence displayed in the upper diagonal; network comparisons shown on the lower diagonal.

Dex		0.83 (0.62, 1.12)	1.42 (0.86, 2.34)	0.54 (0.40, 0.73)
1.41 (0.77, 2.58)	Ket			0.38 (0.22, 0.64)
0.78 (0.58, 1.04)	0.55 (0.29, 1.07)	Mid	2.85 (1.54, 5.28)	0.60 (0.24, 1.53)
1.49 (0.91, 2.43)	1.06 (0.49, 2.30)	1.91 (1.15, 3.17)	Prop
0.53 (0.39, 0.71)	0.38 (0.22, 0.64)	0.68 (0.46, 1.01)	0.36 (0.20, 0.63)	Plac
Dex: Dexmedetomidine; Ket: ketamine; Mid: midazolam; Prop: propofol; Ulin: ulinastatin; Prop: Propofol; Plac/None: Placebo or no intervention.

Figure 35. Comparison-adjusted funnel plot for neurocognitive disorder <30 days.

Figure 36. Comparison of direct and indirect evidence in network meta-analysis of neurocognitive disorder <30 days (node splitting forest plot).

Dex: Dexmedetomidine; Ket: Ketamine; Mel/Ram: Melatonin/Ramelteon; Mid: Midazolam; MS: Morphine; Prop: Propofol; Plac/None: Placebo or no comparator.

Neurocognitive Disorder
30 days to 1 year

Dexmedetomidine, Ketamine, and Melatonin

Table 27. Neurocognitive disorder 30 days to 1 year and ascertainment.

Study	N	Drug	Preop	Instrument				Day^b	Neurocognitive Disorder 30 days to 1 yr
Study	N	Drug	MMSE^a	MMSE	DST	MoCA	Other	Day^b	N (%)	0 — 100%	RR (95% CI)
Randomized Clinical Trial
de Jonghe 2014	151	Plac	23 {10-28}	✓				90	105 (69.5)		—
	147	Mel	23 {12-29}						87 (59.2)		0.85 (0.72-1.01)
Li 2019	55	Prop			✓^c			365	5 (9.1)		—
	54	Mid							7 (13.0)		1.43 (0.48-4.22)
	55	Dex							6 (10.9)		1.20 (0.39-3.70)
Wang 2019	100	Mid	25.0 (3.3)	✓^d				90	7 (7.0)		—
	98	Dex	24.9 (3.9)						9 (9.2)		1.31 (0.51-3.38)
Gao 2021	20	Plac	28.4 (1.3)	✓				90	2 (10.0)		—
	20	Dex	28.5 (1.4)						0 (0)		Not estimated
Han 2023	34	Plac	27.9 (1.6)		✓			90	5 (14.7)		—
	33	Ket	28.6 (1.1)						2 (6.1)		0.41 (0.09-1.98)
Oriby 2023	30	Plac					✓^e	90^f	20 (66.7)		—
	30	Ket							7 (23.3)		0.35 (0.17-0.70)
	30	Dex							5 (16.7)		0.25 (0.11-0.58)
Mini-Mental State Exam; DST: Digit Span Test; MoCA: Montreal Cognitive Assessment; RR: risk ratio; Dex: dexmedetomidine: Mel: melatonin; Plac: placebo.
^a Mean Med (SD)[Range]{IQR}.
^b Day of assessment.
^c Z ≥1.96.
^d Threshold not specified.
^e Failed at least 2 of Visual Verbal Learning Tests, Stroop color word test, Letter Digit Coding Test, or Concept Shifting Test
^f Assumed to be 90 days based on time of final reported neuropsychological assessment.

Pooled

Dexmedetomidine

Figure 37. Neurocognitive disorder 30 days to 1 year comparing dexmedetomidine with placebo.

Ketamine

Figure 38. Neurocognitive disorder 30 days to 1 year comparing ketamine with placebo.

Network (exploratory)

Exploratory network meta-analysis

Excludes midazolam and propofol arms as neither contributed (ie, not in a closed loops).

Physical Function

Table 28. Physical functional status following dexmedetomidine and melatonin for delirium prophylaxis.

Study	N	Arm	Age^a	Scale	Range	Days	Rating^a	SMD (95% CI)
30-90 days
de Jonghe 2014	192	Plac	83.4 (7.5)	Katz ADL score	15→0	90	9 [5-13]
	186	Mel	84.1 (8.0)				9 [5-13]	0.00 (-0.20 to 0.20)
>90 days
Chitnis 2022	31	Prop	78.8	SF-36 physical	0→100	182.5	73.7
	30	Dex	78.7				76.1	0.39 (-1.57 to 2.34)
SMD: standardized mean difference
^a Mean Med (SD)[Range]{IQR}.

Complications

Dexmedetomidine

Bradycardia

Table 29. Bradycardia in randomized and nonrandomized dexmedetomidine clinical trials.

Study	N	Arm	Age	Surgery	N (%)	RD (95% CI)	Criteria
Randomized Clinical Trial
Chen 2020	45	Plac	65.4 (11.7)	GI/Abd	4 (8.9)	—	<40 bpm
	43	Dex	64.9 (11.4)		1 (2.3)	-6.6% (-16.0, 2.9)
Hu 2021	87	Plac	69.1 (5.1)	Thoracic	0 (0)	—	<40 bpm
	90	Dex	69.6 (4.5)		0 (0)	0.0% (-2.2, 2.2)
Guo 2015	73	Plac	71.3 (5.1)	Oralmax	2 (2.7)	—	<50 bpm
	76	Dex	70.7 (5.2)		5 (6.6)	3.8% (-2.9, 10.6)
Wang 2020a	20	Mid	60.5 (8.2)	Oralmax	2 (10.0)	—	<50 bpm
	20	Dex	60.0 (10.1)		8 (40.0)	30.0% (4.8, 55.2)
Hong 2021	354	Plac	71.0 (5.0)	Ortho	1 (0.3)	—	<50 bpm
	356	Dex	71.0 (5.0)		1 (0.3)	-0.0% (-0.8, 0.8)
Lu 2021	331	Plac	70.4 (6.5)	GI/Abd	12 (3.6)	—	<50 bpm
	344	Dex	70.1 (5.8)		22 (6.4)	2.8% (-0.5, 6.0)
Xie 2023	119	Plac	68.6 (5.5)	GI/Abd	12 (10.1)	—	<50 bpm
	117	Dex	67.9 (5.6)		11 (9.4)	-0.7% (-8.2, 6.9)
Shi 2020	53	Plac	68.7 (3.4)	Thoracic	13 (24.5)	—	<55 bpm
	53	Dex	68.7 (4.6)		26 (49.1)	24.5% (6.8, 42.3)
Zhang 2020a	120	Plac	79.0 (6.8)	Ortho	18 (15.0)	—	<60 bpm
	120	Dex	78.1 (6.4)		20 (16.7)	1.7% (-7.6, 10.9)
Li 2017	143	Plac	67.5 (5.3)	Cardiac	14 (9.8)	—	<45 bpm or ↓30%
	142	Dex	66.4 (5.4)		21 (14.8)	5.0% (-2.6, 12.6)
Lee 2018b	31	Plac	67.2 (5.0)	Ortho	7 (22.6)	—	<45 bpm or ↓30%
	33	Preg	68.4 (5.1)		8 (24.2)	1.7% (-19.1, 22.4)
	29	Dex/Preg	65.4 (9.7)		19 (65.5)	42.9% (20.2, 65.6)
	31	Dex	68.8 (5.9)		19 (61.3)	38.7% (16.1, 61.3)
Zhao 2023	42	Plac	69.7 (7.2)	Ortho	3 (7.1)	—	↓25%
	40	Dex	70.9 (7.2)		7 (17.5)	10.4% (-3.8, 24.5)
Wu 2020	40	Plac	67.7 (8.8)	Cardiac	2 (5.0)	—	NR
	40	Dex	68.2 (8.6)		1 (2.5)	-2.5% (-10.8, 5.8)
Zhao 2020	101	None	69.2 (4.1)	Various	3 (3.0)	—	NR
	108	Dex	70.0 (4.5)		8 (7.4)	4.4% (-1.5, 10.4)
	105	Dex	69.4 (3.9)		8 (7.6)	4.6% (-1.4, 10.7)
	102	Dex	69.3 (4.1)		8 (7.8)	4.9% (-1.3, 11.1)
Li 2021b	30	Plac	73.4 (5.1)	GI/Abd	7 (23.3)	—	NR
	30	Dex	74.7 (2.6)		8 (26.7)	3.3% (-18.6, 25.2)
	30	Dex	71.2 (3.5)		12 (40.0)	16.7% (-6.5, 39.8)
	30	Dex	69.8 (4.3)		20 (66.7)	43.3% (20.7, 66.0)
van Norden 2021	32	Plac	70.5 (6.2)	Various	19 (59.4)	—	NR
	28	Dex	70.4 (7.1)		17 (60.7)	1.3% (-23.5, 26.2)
Lv 2022	157	Plac	68.4 (6.6)	Various	9 (5.7)	—	NR
	152	Dex	67.9 (5.9)		16 (10.5)	4.8% (-1.3, 10.9)
Li 2023	49	None	68.5 (2.2)	Ortho	1 (2.0)	—	NR
	49	Dex	67.7 (2.8)		1 (2.0)	0.0% (-5.6, 5.6)
Liao 2023	35	Plac	69.7 (2.5)	GI/Abd	2 (5.7)	—	NR
	34	Rem	70.1 (3.6)		0 (0)	-5.7% (-14.9, 3.5)
	35	Dex	71.3 (3.6)		4 (11.4)	5.7% (-7.3, 18.8)
Nonrandomized Trial
Wang 2020c^a	50	Plac	68.3 (2.1)	GI/Abd	3 (6.0)	—	<55 bpm
	60	Dex	68.4 (3.3)		4 (6.7)	0.7% (-8.5, 9.8)
Li 2020a^a	46	None	67.3 (2.1)	Thoracic	2 (4.3)	—	NR
	41	Dex	67.4 (3.3)		1 (2.4)	-1.9% (-9.5, 5.6)
RD: risk difference; Dex: Dexmedetomidine; Dex/Preg: Dexmedetomidine/Pregabalin; Mid: Midazolam; Prop: Propofol; Ram: ramelteon; Plac: placebo; None: no active or placebo comparator; GI/Abd: gastrointestinal/abdominal; Ortho: orthopedic; Oralmax: oral or maxilofacial.
^a Nonrandomized Trial

Pooled

Figure 39. Risk ratio for bradycardia (dexmedetomidine versus placebo or no interventions; randomized clinical trials).

Harbord test for small study effects P = 0.39.
Similar arms combined in Li 2021b and Zhao 2020.

Figure 40. Dexmedetomidine compared with placebo or no intervention small study effects and bradycardia — funnel plot and limit meta-analysis.

Estimates (odds ratio and 95% CI) from random effects model — unadjusted 1.74 (1.32–2.31); adjusted for small study effects: 2.03 (1.21–3.40).

Figure 41. Risk difference for bradycardia (dexmedetomidine versus placebo or no interventions; randomized clinical trials).

Hypotension

Table 30. Hypotension in randomized and nonrandomized dexmedetomidine clinical trials.

Study	N	Arm	Age	Surgery	N (%)	RD (95% CI)	Criteria
Randomized Clinical Trial
Chen 2013	63	Plac	67.9 (6.6)	GI/Abd	0 (0)	—	MAP <60
	59	Dex	66.2 (7.5)		0 (0)	0.0% (-3.2, 3.2)
Chawdhary 2020	40	Prop	64.7 (5.9)	Various	4 (10.0)	—	MAP ≤70
	40	Dex	66.2 (6.6)		7 (17.5)	7.5% (-7.5, 22.5)
Wang 2020a	20	Mid	60.5 (8.2)	Oralmax	3 (15.0)	—	↓MAP >20%
	20	Dex	60.0 (10.1)		4 (20.0)	5.0% (-18.5, 28.5)
Lee 2018b	31	Plac	67.2 (5.0)	Ortho	11 (35.5)	—	SBP <90
	33	Preg	68.4 (5.1)		14 (42.4)	6.9% (-16.9, 30.8)
	29	Dex/Preg	65.4 (9.7)		21 (72.4)	36.9% (13.5, 60.3)
	31	Dex	68.8 (5.9)		19 (61.3)	25.8% (1.8, 49.8)
Liu 2022b	60	Plac	72.1 (5.9)	Oralmax	1 (1.7)	—	SBP <90
	60	Dex	71.3 (6.7)		3 (5.0)	3.3% (-3.1, 9.7)
Wang 2022a	60	Plac	66.7 (4.1)	Urol	0 (0)	—	SBP <90
	60	Dex	65.6 (3.4)		0 (0)	0.0% (-3.2, 3.2)
Qu 2023	206	Plac	70.0 {65-75}	Cardiac	13 (6.3)	—	SBP <90
	188	Dex	67.5 {63-73}		20 (10.6)	4.3% (-1.2, 9.8)
Subramaniam 2019	61	Prop	70.0 {64-79}	Cardiac	21 (34.4)	—	SBP <90 ≥5 min
	59	Dex	66.5 {63-74}		21 (35.6)	1.2% (-15.9, 18.2)
Xin 2021	30	Plac	68.0 [66-71]	GI/Abd	6 (20.0)	—	SBP <95
	30	Dex	69.0 [67-70]		4 (13.3)	-6.7% (-25.5, 12.1)
Azeem 2018	30	Mid	66.7 (5.6)	Cardiac	0 (0)	—	↓SBP >20%
	30	Dex	65.3 (4.8)		0 (0)	0.0% (-6.3, 6.3)
Lu 2021	331	Plac	70.4 (6.5)	GI/Abd	45 (13.6)	—	↓SBP >20% or <80
	344	Dex	70.1 (5.8)		30 (8.7)	-4.9% (-9.6, -0.1)
Zhang 2020a	120	Plac	79.0 (6.8)	Ortho	8 (6.7)	—	↓SBP >20% or <90
	120	Dex	78.1 (6.4)		10 (8.3)	1.7% (-5.0, 8.3)
Shi 2020	53	Plac	68.7 (3.4)	Thoracic	4 (7.5)	—	↓SBP >20% or <95
	53	Dex	68.7 (4.6)		6 (11.3)	3.8% (-7.3, 14.9)
Guo 2015	73	Plac	71.3 (5.1)	Oralmax	2 (2.7)	—	↓SBP >30%
	76	Dex	70.7 (5.2)		4 (5.3)	2.5% (-3.7, 8.8)
Hong 2021	354	Plac	71.0 (5.0)	Ortho	3 (0.8)	—	↓SBP >30% or <90
	356	Dex	71.0 (5.0)		2 (0.6)	-0.3% (-1.5, 0.9)
Li 2017	143	Plac	67.5 (5.3)	Cardiac	10 (7.0)	—	↓SPB >30% ≥15 min
	142	Dex	66.4 (5.4)		10 (7.0)	0.0% (-5.9, 6.0)
Zhao 2023	42	Plac	69.7 (7.2)	Ortho	6 (14.3)	—	<20% from baseline
	40	Dex	70.9 (7.2)		8 (20.0)	5.7% (-10.6, 22.0)
Deiner 2017	201	Plac	74.0 {71-78}	Various	95 (47.3)	—	NS
	189	Dex	74.0 {71-78}		102 (54.0)	6.7% (-3.2, 16.6)
Turan 2020	393	Plac	62.0 (12.0)	Cardiac	140 (35.6)	—	NS
	395	Dex	63.0 (11.0)		224 (56.7)	21.4% (14.6, 28.1)
Zhao 2020	101	None	69.2 (4.1)	Various	6 (5.9)	—	NS
	108	Dex	70.0 (4.5)		15 (13.9)	7.9% (-0.0, 15.9)
	105	Dex	69.4 (3.9)		6 (5.7)	-0.2% (-6.6, 6.2)
	102	Dex	69.3 (4.1)		7 (6.9)	0.9% (-5.8, 7.7)
Hu 2021	75	Plac	69.1 (5.1)	Thoracic	32 (42.7)	—	NS
	77	Dex	69.6 (4.5)		42 (54.5)	17.8% (2.7, 32.8)
Li 2021b	30	Plac	73.4 (5.1)	GI/Abd	8 (26.7)	—	NS
	30	Dex	74.7 (2.6)		11 (36.7)	10.0% (-13.4, 33.4)
	30	Dex	71.2 (3.5)		10 (33.3)	6.7% (-16.5, 29.8)
	30	Dex	69.8 (4.3)		21 (70.0)	43.3% (20.5, 66.1)
Xing 2021	55	Plac	69.2 (3.8)	Ortho	1 (1.8)	—	NS
	55	Dex	68.3 (3.9)		1 (1.8)	0.0% (-5.0, 5.0)
Lv 2022	157	Plac	68.4 (6.6)	Various	13 (8.3)	—	NS
	152	Dex	67.9 (5.9)		52 (34.2)	25.9% (17.2, 34.6)
Li 2023	49	None	68.5 (2.2)	Ortho	3 (6.1)	—	NS
	49	Dex	67.7 (2.8)		1 (2.0)	-4.1% (-11.9, 3.7)
Liao 2023	35	Plac	69.7 (2.5)	GI/Abd	2 (5.7)	—	NS
	35	Dex	71.3 (3.6)		3 (8.6)	2.9% (-9.2, 14.9)
Nonrandomized Trial
Wang 2020c^a	50	Plac	68.3 (2.1)	GI/Abd	6 (12.0)	—	SBP <90
	60	Dex	68.4 (3.3)		5 (8.3)	-3.7% (-15.1, 7.7)
Li 2020a^a	46	None	67.3 (2.1)	Thoracic	1 (2.2)	—	NS
	41	Dex	67.4 (3.3)		1 (2.4)	0.3% (-6.1, 6.6)
Retrospective Cohort
Xu 2022	30	None	67.9 (5.0)	Ortho	1 (3.3)	—	NS
	30	Dex	67.3 (5.5)		1 (3.3)	0.0% (-9.1, 9.1)
RD: risk difference; MAP: mean arterial blood pressure; Dex: Dexmedetomidine; Dex/Preg: Dexmedetomidine/Pregabalin; Mid: Midazolam; Prop: Propofol; Rem: remimazolam; Plac: placebo; None: no active or placebo comparator; GI/Abd: gastrointestinal/abdominal; Ortho: orthopedic; Urol: urologic; Oralmax: oral or maxilofacial; NS: not specified.
^a Nonrandomized Trial

Pooled

Figure 42. Risk ratio for hypotension (dexmedetomidine versus placebo or no interventions; randomized clinical trials).

Harbord test for small study effects P = 0.31.
Similar arms combined in Li 2021b and Zhao 2020.

Figure 43. Dexmedetomidine compared with placebo or no intervention small study effects and hypotension — funnel plot.

Estimates (odds ratio and 95% CI) from random effects models — unadjusted 1.57 (1.17–2.09); adjusted for small study effects: 1.79 (1.21–2.65).

Figure 44. Risk difference for hypotension (dexmedetomidine versus placebo or no interventions; randomized clinical trials).

Other

Table 31. Other complications reported in dexmedetomidine studies — cardiac, myocardial infarction, stroke, renal, and respiratory (randomized clinical trials unless noted).

Study	N	Arm	Age	Surgery	N (%)	RD (95% CI)
Myocardial Infarction
Cheng 2016^a	283	None	73.5 (6.2)	Cardiac	5 (1.8)	—
	222	Dex	73.6 (6.1)		3 (1.4)	-0.4% (-2.6, 1.7)
Turan 2020	390	Plac	62.0 (12.0)	Cardiac	3 (0.8)	—
	394	Dex	63.0 (11.0)		3 (0.8)	-0.0% (-1.2, 1.2)
Lu 2021	331	Plac	70.4 (6.5)	GI/Abd	0 (0)	—
	344	Dex	70.1 (5.8)		0 (0)	0.0% (-0.6, 0.6)
Deiner 2017	157	Plac	74.0 {71-78}	Various	0 (0)	—
	147	Dex	74.0 {71-78}		1 (0.7)	0.7% (-1.2, 2.5)
Cardiac Arrest
Cheng 2016^a	283	None	73.5 (6.2)	Cardiac	3 (1.1)	—
	222	Dex	73.6 (6.1)		2 (0.9)	-0.2% (-1.9, 1.6)
Other Arrhythmia
Turan 2020	390	Plac	62.0 (12.0)	Cardiac	134 (34.4)	—
	394	Dex	63.0 (11.0)		121 (30.7)	-3.6% (-10.2, 2.9)
Gao 2021^b	20	Plac	71.4 (4.5)	Cardiac	0 (0)	—
	20	Dex	71.4 (4.5)		0 (0)	0.0% (-9.2, 9.2)
Xing 2021	55	Plac	69.2 (3.8)	Ortho	1 (1.8)	—
	55	Dex	68.3 (3.9)		1 (1.8)	0.0% (-5.0, 5.0)
Stroke
Cheng 2016^a	283	None	73.5 (6.2)	Cardiac	5 (1.8)	—
	222	Dex	73.6 (6.1)		2 (0.9)	-0.9% (-2.8, 1.1)
Djainai 2016	92	Prop	72.4 (6.2)	Cardiac	3 (3.3)	—
	91	Dex	72.7 (6.4)		4 (4.4)	1.1% (-4.4, 6.7)
Li 2017^c	143	Plac	67.5 (5.3)	Cardiac	3 (2.1)	—
	142	Dex	66.4 (5.4)		3 (2.1)	0.0% (-3.3, 3.3)
Soh 2020	53	Plac	65.0 [37-83]	Cardiac	2 (3.8)	—
	51	Dex	65.0 [23-82]		3 (5.9)	2.1% (-6.1, 10.4)
Turan 2020	390	Plac	62.0 (12.0)	Cardiac	4 (1.0)	—
	394	Dex	63.0 (11.0)		4 (1.0)	-0.0% (-1.4, 1.4)
Qu 2023	205	Plac	70.0 {65-75}	Cardiac	1 (0.5)	—
	183	Dex	67.5 {63-73}		0 (0)	-0.5% (-1.9, 0.9)
Lu 2021	331	Plac	70.4 (6.5)	GI/Abd	0 (0)	—
	344	Dex	70.1 (5.8)		0 (0)	0.0% (-0.6, 0.6)
Deiner 2017	157	Plac	74.0 {71-78}	Various	1 (0.6)	—
	147	Dex	74.0 {71-78}		0 (0)	-0.6% (-2.4, 1.1)
Acute Kidney Injury
Cheng 2016^a	283	None	73.5 (6.2)	Cardiac	13 (4.6)	—
	222	Dex	73.6 (6.1)		13 (5.9)	1.3% (-2.7, 5.2)
Li 2017^c	143	Plac	67.5 (5.3)	Cardiac	44 (30.8)	—
	142	Dex	66.4 (5.4)		37 (26.1)	-4.7% (-15.2, 5.7)
Soh 2020	53	Plac	65.0 [37-83]	Cardiac	17 (32.1)	—
	51	Dex	65.0 [23-82]		7 (13.7)	-18.3% (-34.1, -2.6)
Turan 2020	390	Plac	62.0 (12.0)	Cardiac	30 (7.7)	—
	394	Dex	63.0 (11.0)		41 (10.4)	2.7% (-1.3, 6.7)
Gao 2021^b	20	Plac	71.4 (4.5)	Cardiac	1 (5.0)	—
	20	Dex	71.4 (4.5)		1 (5.0)	0.0% (-13.5, 13.5)
Momeni 2021	203	Plac	70.0 {59-81}	Cardiac	2 (1.0)	—
	205	Dex	71.0 {61-81}		2 (1.0)	-0.0% (-1.9, 1.9)
Pulmonary
Li 2017^c	143	Plac	67.5 (5.3)	Cardiac	27 (18.9)	—
	142	Dex	66.4 (5.4)		15 (10.6)	-8.3% (-16.5, -0.2)
Gao 2021^b	20	Plac	71.4 (4.5)	Cardiac	5 (25.0)	—
	20	Dex	71.4 (4.5)		4 (20.0)	-5.0% (-30.8, 20.8)
Pneumonia
Soh 2020	53	Plac	65.0 [37-83]	Cardiac	6 (11.3)	—
	51	Dex	65.0 [23-82]		7 (13.7)	2.4% (-10.3, 15.1)
Xie 2023	119	Plac	68.6 (5.5)	GI/Abd	6 (5.0)	—
	117	Dex	67.9 (5.6)		4 (3.4)	-1.6% (-6.8, 3.5)
Deiner 2017	157	Plac	74.0 {71-78}	Various	1 (0.6)	—
	147	Dex	74.0 {71-78}		3 (2.0)	1.4% (-1.2, 4.0)
Pulmonary Congestion^d,e
Deiner 2017	157	Plac	74.0 {71-78}	Various	0 (0)	—
	147	Dex	74.0 {71-78}		1 (0.7)	0.7% (-1.2, 2.5)
Pulmonary Embolism
Deiner 2017	157	Plac	74.0 {71-78}	Various	1 (0.6)	—
	147	Dex	74.0 {71-78}		1 (0.7)	0.0% (-1.8, 1.9)
Respiratory Depression/Failure
Wu 2020	40	Plac	67.7 (8.8)	Cardiac	5 (12.5)	—
	40	Dex	68.2 (8.6)		3 (7.5)	-5.0% (-18.1, 8.1)
Chen 2020	45	Plac	65.4 (11.7)	GI/Abd	3 (6.7)	—
	43	Dex	64.9 (11.4)		0 (0)	-6.7% (-14.9, 1.6)
Guo 2015	73	Plac	71.3 (5.1)	Oralmax	0 (0)	—
	76	Dex	70.7 (5.2)		0 (0)	0.0% (-2.6, 2.6)
Wang 2020a	20	Mid	60.5 (8.2)	Oralmax	7 (35.0)	—
	20	Dex	60.0 (10.1)		1 (5.0)	-30.0% (-53.0, -7.0)
Deiner 2017	157	Plac	74.0 {71-78}	Various	1 (0.6)	—
	147	Dex	74.0 {71-78}		2 (1.4)	0.7% (-1.5, 3.0)
Zhao 2020	101	None	69.2 (4.1)	Various	0 (0)	—
	108	Dex	70.0 (4.5)		0 (0)	0.0% (-1.9, 1.9)
	105	Dex	69.4 (3.9)		0 (0)	0.0% (-1.9, 1.9)
	102	Dex	69.3 (4.1)		0 (0)	0.0% (-1.9, 1.9)
RD: risk difference.
^a Retrospective Cohort
^b Unspecified
^c Pulmonary infection, pneumothorax, or pleural effusion needing intervention.
^d Pulmonary congestion includes heart failure diagnosis.
^e Includes unspecified, composite, respiratory depression, pleural effusion.

Pooled

Figure 45. Risk ratios for other complications — cardiac arrest, myocardial infarction, other arrhythmia (excludes bradycardia), stroke, pulmonary, and renal (dexmedetomidine versus placebo or no interventions).

Similar arms combined for Zhao 2020.

Figure 46. Risk differences for other complications — cardiac arrest, myocardial infarction, other arrhythmia (excludes bradycardia), stroke, pulmonary, and acute kidney injury (dexmedetomidine versus placebo or no interventions).

Similar arms combined for Zhao 2020.

Ketamine

Table 32. Complications reported in ketamine randomized clinical trials — bradycardia, hypotension and renal.

Study	N	Arm	Age	Surgery	N (%)	RD (95% CI)	Note
Bradycardia
Ma 2023	31	Plac	70.5 (4.2)	GI/Abd	6 (19.4)	—	<50 bpm
	31	Ket	69.5 (4.3)		12 (38.7)	19.4% (-2.7, 41.4)
Hypotension
Ma 2023	31	Plac	70.5 (4.2)	GI/Abd	19 (61.3)	—	↓SBP >30% or <80
	31	Ket	69.5 (4.3)		9 (29.0)	-32.3% (-55.7, -8.8)
Acute Kidney Injury
Remerand 2009	75	Plac	65.0 (14.0)	Ortho	10 (13.3)	—
	79	Ket	64.0 (13.0)		9 (11.4)	-1.9% (-12.3, 8.5)

Ramelteon

Table 33. Complications reported in ramelteon studies — cardiac, myocardial infarction, stroke, pulmonary, pneumonia, and renal (all before-after designs).

Study	N	Arm	Age	Surgery	N (%)	RD (95% CI)
Arrhythmia^a
Miyata 2017^b	58	None	76.5 [70-87]	Thoracic	5 (8.6)	—
	24	Ram	79.0 [70-89]		0 (0)	-8.6% (-17.8, 0.6)
Pulmonary
Hokuto 2020^b	186	None	69.0 [30-88]	GI/Abd	4 (2.2)	—
	120	Ram	71.0 [34-85]		4 (3.3)	1.2% (-2.6, 5.0)
Pneumonia
Hokuto 2020^b	186	None	69.0 [30-88]	GI/Abd	3 (1.6)	—
	120	Ram	71.0 [34-85]		2 (1.7)	0.1% (-2.9, 3.0)
Miyata 2017^b	58	None	76.5 [70-87]	Thoracic	4 (6.9)	—
	24	Ram	79.0 [70-89]		1 (4.2)	-2.7% (-13.0, 7.6)
^a Not otherwise specified.
^b Before-After/Time Series

Figure 47. Risk difference in pneumonia (ramelteon versus no interventions; before-after studies).

Length of Stay

Dexmedetomidine

Table 34. Length of stay according to procedure classification and comparator in dexmedetomidine studies.

Study	N	Comparator	PS^a	Age^b	LOS^b	Country
Cardiac - Randomized Clinical Trial
Djainai 2016	92	Prop	NR	72.4 (6.2)	7.0 [4-74]	Canada
	91	Dex	NR	72.7 (6.4)	7.0 [4-35]
Ge 2016	24	Plac	123	72.0 (4.0)	4.6 (1.1)	China
	24	Dex	123	70.0 (3.0)	4.6 (1.3)
Li 2017	143	Plac	234	67.5 (5.3)	9.0 {8-10}	China
	142	Dex	234	66.4 (5.4)	9.0 {8-10}
Subramaniam 2019	61	Prop	NR	70.0 {64-79}	8.0 {6-11}	USA
	59	Dex	NR	66.5 {63-74}	8.0 {6-10}
Soh 2020	54	Plac	NR	65.0 [37-83]	15.0 {11-21}	South Korea
	54	Dex	NR	65.0 [23-82]	12.0 {10-17}
Turan 2020	396	Plac	1234	62.0 (12.0)	6.0 {5-7}	USA
	398	Dex	1234	63.0 (11.0)	6.0 {5-8}
Gao 2021	20	Plac	23	71.4 (4.5)	13.0 (2.0)	China
	20	Dex	23	71.4 (4.5)	10.0 (1.0)
Momeni 2021	203	Plac	NR	70.0 {59-81}	7.0 {7-10}	Belgium
	205	Dex	NR	71.0 {61-81}	8.0 {7-10}
Chitnis 2022	33	Prop	NR	78.8	12.2	Canada
	34	Dex	NR	78.7	10.2
Qu 2023	206	Plac	NR	70.0 {65-75}	6.0 {5-7}	USA
	188	Dex	NR	67.5 {63-73}	6.0 {5-8}
Ortho - Randomized Clinical Trial
Mei 2018	148	Prop	23	74.0 (6.0)	6.8 (2.0)	China
	148	Dex	23	76.0 (7.0)	6.3 (1.6)
Hong 2021	354	Plac	1234	71.0 (5.0)	5.0 {5-6}	China
	356	Dex	1234	71.0 (5.0)	5.0 {5-6}
Yan 2021	50	Plac	12	72.7 (4.3)	16.1 (0.7)	China
	50	Dex	12	73.2 (5.8)	13.2 (0.9)
Gao 2022	48	Plac	123	67.2 (5.2)	5.0 (0.8)	China
	47	Dex	123	68.2 (6.0)	4.2 (0.7)
Deng 2023	52	Dex	23	70.8 (4.4)	7.0 {6-10}	China
	53	Dex	23	71.8 (5.5)	7.0 {7-11}
GI/Abd - Randomized Clinical Trial
Lu 2021	331	Plac	123	70.4 (6.5)	15.0 {11-18}	China
	344	Dex	123	70.1 (5.8)	13.0 {10-17}
Guo 2022	45	None	23	68.5 (3.8)	25.5 (8.6)	China
	45	Dex	23	68.5 (3.8)	17.9 (8.1)
Xie 2023	119	Plac	NR	68.6 (5.5)	11.6 (8.5)	China
	117	Dex	NR	67.9 (5.6)	11.7 (9.1)
Thoracic - Randomized Clinical Trial
Huyan 2019	173	Plac	23	71.0 (6.0)	9.0 {7-11}	China
	173	Dex	23	70.0 (5.0)	8.0 {6-10}
ENT - Randomized Clinical Trial
Liu 2023c	149	Plac	NR	70.1 (4.2)	13.0 {10-15}	China
	150	Dex	NR	70.4 (5.0)	13.0 {9-15}
Oralmax - Randomized Clinical Trial
Liu 2022b	60	Plac	12	72.1 (5.9)	9.0 (2.8)	China
	60	Dex	12	71.3 (6.7)	9.0 (2.5)
Various - Randomized Clinical Trial
Deiner 2017	201	Plac	1234	74.0 {71-78}	4.0 {3-6}	USA
	189	Dex	1234	74.0 {71-78}	4.0 {3-6}
Li 2020b	310	Plac	123	69.0 (6.4)	10.3 (9.4)	China
	309	Dex	123	69.0 (6.6)	10.0 (7.6)
van Norden 2021	32	Plac	1234	70.5 (6.2)	21.0 (15.6)	Germany
	28	Dex	1234	70.4 (7.1)	23.5 (20.3)
Lv 2022	157	Plac	NR	68.4 (6.6)	17.2 (6.3)	China
	152	Dex	NR	67.9 (5.9)	15.6 (4.2)
Cardiac - Retrospective Cohort
Chuich 2019	209	Prop	NR	62.0 (13.0)	8.3 (4.4)	USA
	69	Dex	NR	63.0 (13.0)	7.8 (3.1)
NR: not reported
^a ASA Physical Status.
^b Mean Med (SD)[Range]{IQR}.

Ketamine

Table 35. Length of stay according to procedure classification and comparator in ketamine studies.

Study	N	Comparator	PS^a	Age^b	LOS^b	Country
Cardiac - Randomized Clinical Trial
Hudetz 2009a	26	Plac	34	67.0 (8.0)	7.0 (3.0)	USA
	26	Ket	34	68.0 (7.0)	8.0 (4.0)
Ortho - Randomized Clinical Trial
Remerand 2009	75	Plac	NR	65.0 (14.0)	8.3 (1.6)	France
	79	Ket	NR	64.0 (13.0)	8.8 (3.2)
Spine - Prospective Cohort
Barreto Chang 2022	38	None	123	71.0 {68-78}	4.0 {3-6}	USA
	60	Ket	123	70.0 {67-75}	4.0 {2-6}
NR: not reported
^a ASA Physical Status.
^b Mean Med (SD)[Range]{IQR}.

Melatonin or ramelteon

Table 36. Length of stay according to procedure classification and comparator in melatonin or ramelteon studies.

Study	N	Comparator	PS^a	Age^b	LOS^b	Country
Cardiac - Randomized Clinical Trial
Ford 2020	104	Plac	NR	67.6 (8.0)	7.0 {6-8}	Australia
	98	Mel	NR	69.0 (8.3)	8.0 {6-10}
Shi 2021	149	Plac	NR	71.6 (6.6)	13.4 (6.6)	China
	148	Mel	NR	71.5 (6.7)	15.9 (9.7)
Ortho - Randomized Clinical Trial
de Jonghe 2014	192	Plac	NR	83.4 (7.5)	11.0 {8-17}	Netherlands
	186	Mel	NR	84.1 (8.0)	11.0 {6-14}
Fan 2017	70	Plac	123	74.6 (5.4)	7.0 [5-21]	China
	69	Mel	123	74.5 (5.7)	7.0 [5-19]
Thoracic - Randomized Clinical Trial
Jaiswal 2019	58	Plac	NR	56.1 (15.8)	12.0 {10-14}	USA
	59	Ram	NR	58.1 (14.1)	12.0 {10-16}
Thoracic - Before-After/Time Series
Miyata 2017	58	None	NR	76.5 [70-87]	13.6 (7.8)	Japan
	24	Ram	NR	79.0 [70-89]	13.5 (9.6)
GI/Abd - Before-After/Time Series
Hokuto 2020	186	None	123	69.0 [30-88]	9.0 [5-162]	Japan
	120	Ram	123	71.0 [34-85]	9.0 [4-80]
NR: not reported
^a ASA Physical Status.
^b Mean Med (SD)[Range]{IQR}.

Pooled

Dexmedetomidine

Figure 48. Mean difference in lengths of stay (dexmedetomidine versus placebo; randomized clinical trials).

MD: mean difference; Dex: Dexmedetomidine.
When the mean or standard deviation were not reported, they were imputed from from the median, interquartile range, and/or range. Hartung-Knapp adjustment not applied owing to interest in subgroups.

Figure 49. Dexmedetomidine compared with placebo or no intervention small study effects — funnel plot (length of stay).

Melatonin/Ramelteon

Figure 50. Mean difference in lengths of stay (melatonin or ramelteon versus placebo; randomized clinical trials).

MD: mean difference; Mel: melatonin; Ram: ramelteon.
When the mean or standard deviation were not reported, they were imputed from from the median, interquartile range, and/or range.

Mortality

Dexmedetomidine

Table 37. Reported in-hospital, 30-day, 90-day, and 1-year mortality in dexmedetomidine randomized clinical trials by comparator and surgical category.

Study	N	Drug	Surgery	ASA	Age^a	Mortality		RD (95% CI)
Study	N	Drug	Surgery	PS	Age^a	N (%)	0 - 100%	RD (95% CI)
Hospital
Djainai 2016	92	Prop	Cardiac	NR	72.4 (6.2)	0 (0)		—
	91	Dex			72.7 (6.4)	1 (1.1)		1.1% (-1.9, 4.1)
Deiner 2017	201	Plac	Various	1234	74.0 {71-78}	3 (1.5)		—
	189	Dex			74.0 {71-78}	1 (0.5)		-1.0% (-2.9, 1.0)
Zhou 2019b	39	Plac	Cardiac	123	70.0 (4.9)	1 (2.6)		—
	39	Ulin			70.6 (4.4)	0 (0)		-2.6% (-9.4, 4.3)
	39	Dex/Ulin			69.6 (5.0)	0 (0)		-2.6% (-9.4, 4.3)
	39	Dex			69.8 (5.1)	1 (2.6)		0.0% (-7.0, 7.0)
Turan 2020	387	Plac	Cardiac	1234	62.0 (12.0)	1 (0.3)		—
	391	Dex			63.0 (11.0)	1 (0.3)		-0.0% (-0.7, 0.7)
Soh 2020	53	Plac	Cardiac	NR	65.0 [37-83]	1 (1.9)		—
	50	Dex			65.0 [23-82]	1 (2.0)		0.1% (-5.2, 5.4)
Momeni 2021	203	Plac	Cardiac	NR	70.0 {59-81}	10 (4.9)		—
	205	Dex			71.0 {61-81}	1 (0.5)		-4.4% (-7.6, -1.3)
Chitnis 2022	33	Prop	Cardiac	NR	78.8	0 (0)		—
	33	Dex			78.7	0 (0)		0.0% (-5.7, 5.7)
Qu 2023	206	Plac	Cardiac	NR	70.0 {65-75}	1 (0.5)		—
	188	Dex			67.5 {63-73}	3 (1.6)		1.1% (-0.9, 3.1)
30-day
Li 2017	135	Plac	Cardiac	234	67.5 (5.3)	4 (3.0)		—
	139	Dex			66.4 (5.4)	2 (1.4)		-1.5% (-5.0, 2.0)
Li 2020b	310	Plac	Various	123	69.0 (6.4)	1 (0.3)		—
	309	Dex			69.0 (6.6)	0 (0)		-0.3% (-1.2, 0.6)
Hong 2021	354	Plac	Ortho	1234	71.0 (5.0)	0 (0)		—
	356	Dex			71.0 (5.0)	0 (0)		0.0% (-0.6, 0.6)
Lu 2021	331	Plac	GI/Abd	123	70.4 (6.5)	0 (0)		—
	344	Dex			70.1 (5.8)	1 (0.3)		0.3% (-0.5, 1.1)
Lv 2022	157	Plac	Various	NR	68.4 (6.6)	7 (4.5)		—
	152	Dex			67.9 (5.9)	5 (3.3)		-1.2% (-5.5, 3.1)
Qu 2023	206	Plac	Cardiac	NR	70.0 {65-75}	1 (0.5)		0.0% (-1.3, 1.3)
	188	Dex			67.5 {63-73}	3 (1.6)		1.1% (-0.9, 3.1)
Xie 2023	119	Plac	GI/Abd	NR	68.6 (5.5)	2 (1.7)		—
	117	Dex			67.9 (5.6)	1 (0.9)		-0.8% (-3.7, 2.0)
90-day
van Norden 2021	32	Plac	Various	1234	70.5 (6.2)	5 (15.6)		—
	28	Dex			70.4 (7.1)	0 (0)		-15.6% (-29.2, -2.1)
Qu 2023	206	Plac	Cardiac	NR	70.0 {65-75}	1 (0.5)		0.0% (-1.3, 1.3)
	188	Dex			67.5 {63-73}	4 (2.1)		1.6% (-0.6, 3.9)
ASA PS: American Society of Anesthesiologists Physical Status; RD: risk difference; GI: gastrointestinal; Abd: abdominal (includes hepatic); Ortho: orthopedic; Various: more that one procedure category; Dex: Dexmedetomidine; Ulin: Ulinastatin; MS: morphine sulfate; Plac; placebo.
^a Mean Med (SD)[Range]{IQR}.

Ketamine

No studies

Melatonin/Ramelteon

Table 38. Reported in-hospital, 30-day, 90-day, and 1-year mortality in melatonin and ramelteon studies by comparator and surgical category.

Study	N	Drug	Surgery	ASA	Age^a	Mortality		RD (95% CI)
Study	N	Drug	Surgery	PS	Age^a	N (%)	0 - 100%	RD (95% CI)
Hospital
de Jonghe 2014^b	192	Plac	Ortho	NR	83.4 (7.5)	4 (2.1)		—
	186	Mel			84.1 (8.0)	4 (2.2)		0.1% (-2.8, 3.0)
Jaiswal 2019^b	58	Plac	Thoracic	NR	56.1 (15.8)	4 (6.9)		—
	59	Ram			58.1 (14.1)	3 (5.1)		-1.8% (-10.4, 6.8)
30-day
Shi 2021^b	149	Plac	Cardiac	NR	71.6 (6.6)	21 (14.1)		—
	148	Mel			71.5 (6.7)	18 (12.2)		-1.9% (-9.6, 5.7)
Hokuto 2020^c	186	None	GI/Abd	123	69.0 [30-88]	0 (0)		—
	120	Ram			71.0 [34-85]	0 (0)		0.0% (-1.4, 1.4)
90-day
de Jonghe 2014^b	192	Plac	Ortho		83.4 (7.5)	41 (21.4)		19.3% (13.1, 25.4)
	186	Mel			84.1 (8.0)	39 (21.0)		18.9% (12.7, 25.1)
ASA PS: American Society of Anesthesiologists Physical Status; RD: risk difference; GI: gastrointestinal; Abd: abdominal (includes hepatic); Ortho: orthopedic; Various: more that one procedure category; Ram: ramelteon; Mel: melatonin; Plac; placebo.
^a Mean Med (SD)[Range]{IQR}.
^b Randomized clinical trial.
^c Before-after design.

Pooled

Dexmedetomidine

Figure 51. Risk ratio for hospital and 30-day mortality – dexmedetomidine compared with placebo or no intervention.

Dex: dexmedetomidine; Plac: placebo.
*Trials conducted in China with RR 0.69 (95% CI, 0.41–1.15); others RR 0.59 (95% CI, 0.10–3.37).

Figure 52. Risk difference for hospital and 30-day mortality – dexmedetomidine compared with placebo or no intervention.

Dex: dexmedetomidine; Plac: placebo.
*Trials conducted in China.

Figure 53. Mortality for dexmedetomidine compared with placebo or no intervention small study effects — funnel plot.

Melatonin/Ramelteon

Figure 54. Risk difference for hospital and 30-day mortality – melatonin or ramelteon compared with placebo or no intervention.

Mel: melatonin; Ram: ramelteon; Plac: placebo.

Risk of Bias

Randomized

Figure 55. Summary risk of bias assessment for randomized clinical trials.

Figure 56. Risk of bias assessments for randomized clinical trials.

Nonrandomized

Figure 57. Summary risk of bias assessment for nonrandomized studies.

Figure 58. Risk of bias assessments for nonrandomized studies.

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34.

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35.

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36.

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38.

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39.

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42.

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43.

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Key Question

Balance Tables

Dexmedetomidine

Outcomes Reported

Included Studies

Design, centers, country, and surgery

Country Summary

Interventions & Comparators

Dexmedetomidine

Ketamine

Melatonin/Ramelteon

Delirium Incidence

Dexmedetomidine

Ketamine

Melatonin/Ramelteon

Pooled

Dexmedetomidine

Subgroups

Ketamine

Melatonin/Ramelteon

Network

Neurocognitive Disorder <30 days

Dexmedetomidine

Ketamine

Melatonin/Ramelteon

Pooled

Dexmedetomidine

Ketamine

Network

Neurocognitive Disorder 30 days to 1 year

Dexmedetomidine, Ketamine, and Melatonin

Pooled

Dexmedetomidine

Ketamine

Network (exploratory)

Physical Function

Complications

Dexmedetomidine

Bradycardia

Pooled

Hypotension

Pooled

Other

Pooled

Ketamine

Ramelteon

Length of Stay

Dexmedetomidine

Ketamine

Melatonin or ramelteon

Pooled

Dexmedetomidine

Melatonin/Ramelteon

Mortality

Dexmedetomidine

Ketamine

Melatonin/Ramelteon

Pooled

Dexmedetomidine

Melatonin/Ramelteon

Risk of Bias

Randomized

Nonrandomized

References

Neurocognitive Disorder
<30 days

Neurocognitive Disorder
30 days to 1 year