Potentially Inappropriate Medications

Key Question

Among older patients undergoing surgery and anesthesia, do medications with potential central nervous system effects (i.e., benzodiazepines, antipsychotics, anticholinergics, ketamine, corticosteroids, gabapentin, or NSAIDs) administered during the perioperative period increase the risk of postoperative delirium or other adverse outcomes?

(Original Question: Among older patients undergoing surgery and anesthesia, do commonly used potentially inappropriate medications administered during the perioperative period increase the risk of postoperative delirium or other adverse outcomes?)

Outcomes Reported

Table 2. Dichotomous and count outcomes.

Outcome	RCT, N = 41	Crossover, N = 1	NR Trial, N = 1	Quasi-exp, N = 2	Prosp Coh, N = 6	Retro Coh, N = 36	Case-Cont, N = 2
ADL	1 (2.4%)	—	—	—	—	—	—
Complications	20 (49%)	—	—	—	—	1 (2.8%)	1 (50%)
DNCR/POCD	10 (24%)	—	—	—	—	—	—
Delirium	26 (63%)	1 (100%)	1 (100%)	2 (100%)	6 (100%)	35 (97%)	2 (100%)
Delirium duration	1 (2.4%)	—	—	—	—	—	—
Discharge location	1 (2.4%)	—	—	—	—	1 (2.8%)	—
Mortality	10 (24%)	1 (100%)	—	—	—	3 (8.3%)	1 (50%)
Opioid use	—	—	—	—	—	—	—
Pain	—	—	—	—	—	—	—
QoR	1 (2.4%)	—	—	—	—	—	—
Readmission	—	—	—	—	—	—	—
Satisfaction	—	—	—	—	—	—	—
RCT: randomized clinical trial; Crossover: crossover trial; NR Trial: non-randomized trial; Quasi-exp: before-after or time series; Prosp Coh: prospective cohort; Retro Coh: retrospective cohort; Case-Cont: case-control.

Table 3. Publications reporting continuous outcomes (not necessarily unique studies).

Outcome	RCT, N = 41	Crossover, N = 1	NR Trial, N = 1	Quasi-exp, N = 2	Prosp Coh, N = 6	Retro Coh, N = 36	Case-Cont, N = 2
Delirium duration	6 (15%)	—	—	—	1 (17%)	—	—
Length of stay	13 (32%)	1 (100%)	—	—	—	2 (5.6%)	1 (50%)
Opioid use	2 (4.9%)	—	—	—	—	—	—
RCT: randomized clinical trial; Crossover: crossover trial; NR Trial: non-randomized trial; Quasi-exp: before-after or time series; Prosp Coh: prospective cohort; Retro Coh: retrospective cohort; Case-Cont: case-control.

Table 4. Likert and ordinal outcomes.

Outcome	RCT, N = 41	Crossover, N = 1	NR Trial, N = 1	Quasi-exp, N = 2	Prosp Coh, N = 6	Retro Coh, N = 36	Case-Cont, N = 2
ADL	1 (2.4%)	—	—	—	—	—	—
DNCR/POCD	15 (37%)	—	—	—	—	—	—
Delirium	6 (15%)	—	—	1 (50%)	—	—	—
Complications	—	—	—	—	—	—	—
Pain	3 (7.3%)	—	—	—	—	1 (2.8%)	—
Quality of life	—	—	—	—	—	—	—
QoR	1 (2.4%)	—	—	—	—	—	—
Satisfaction	1 (2.4%)	—	—	—	—	—	—
RCT: randomized clinical trial; Crossover: crossover trial; NR Trial: non-randomized trial; Quasi-exp: before-after or time series; Prosp Coh: prospective cohort; Retro Coh: retrospective cohort; Case-Cont: case-control.

Included Studies

Table 5. Number of studies by design.

Design	Studies
Randomized Clinical Trial	39
Randomized Cluster Crossover Trial	1
Nonrandomized Trial	1
Before-After/Time Series	2
Prospective Cohort	6
Retrospective Cohort	14
Case-Control	2
Total	65
Studies with multiple publications counted only once (applies to 3 trials with 2 publications [see next table]).

Design, centers, country, surgery

Table 6. Study design, enrollment, centers, country, and surgery (see References for citations).

ID	Study	Centers	Enrolled	Country^a	Drug Class	Surgery
Randomized Clinical Trial
1505	Hongyu 2019	1	90	China^a	Anticholinergics	Thoracic
8574	Kalisvaart 2005	1	430	Netherlands	Antipsychotics	Ortho
16607	Prakanrattana 2007	1	126	Thailand	Antipsychotics	Cardiac
7098	Larsen 2010	1	495	USA	Antipsychotics	Ortho
4824	Hakim 2012	1	101	Egypt^a	Antipsychotics	Cardiac
9196	Wang 2012	2	457	China^a	Antipsychotics	GI/Abdominal Neuro Ortho Thoracic
8864	Fukata 2014	5	121	Japan	Antipsychotics	GI/Abdominal Ortho
7309	Fukata 2017	3	201	Japan	Antipsychotics	GI/Abdominal Hepatic Ortho
1937	Hollinger 2021	2	143	Switzerland	Antipsychotics	Various^b
9620	Aizawa 2002	1	42	Japan	Benzodiazepine (la)	GI/Abdominal
17055	Dianatkhah 2015	1	145	Iran^a	Benzodiazepine (la)	Cardiac
5164	Sultan 2010	1	152	Egypt^a	Benzodiazepine (sa)	Ortho
13731	Yu 2017	1	92	China^a	Benzodiazepine (sa)	Thoracic
13579	Azeem 2018	1	70	Egypt^a	Benzodiazepine (sa)	Cardiac
13568	He 2018	1	90	China^a	Benzodiazepine (sa)	Thoracic
1117	Mansouri 2019	1	150	Iran^a	Benzodiazepine (sa)	Ophtho
742	Li 2019	1	164	China^a	Benzodiazepine (sa)	Ortho
1625	Wang 2020a	1	44	China^a	Benzodiazepine (sa)	Oralmax
9157	Tan 2022	1	99	China^a	Benzodiazepine (sa)	GI/Abdominal
18582	Liao 2023	1	104	China^a	Benzodiazepine (sa)	GI/Abdominal
18346	Deng 2023	2	108	China^a	Benzodiazepine (sa)	Ortho
18820	Sun 2023b	1	120	China^a	Benzodiazepine (sa)	Ortho
18927	Yang 2023	1	320	China^a	Benzodiazepine (sa)	Ortho
18548	Kuang 2023	1	88	China^a	Benzodiazepine (sa)	Thoracic
20898	Kowark 2024	9	616	Germany	Benzodiazepine (sa)	Various^b
16533	Dieleman 2012	8	4,494	Netherlands	Corticosteroids	Cardiac
14006	Mardani 2013	1	110	Iran^a	Corticosteroids	Cardiac
10036	Sauer 2014	1	737	Netherlands	Corticosteroids	Cardiac
10075	Ottens 2014 (Dieleman 2012)	3	291	Netherlands	Corticosteroids	Cardiac
10515	Whitlock 2015	80	7,507	Canada	Corticosteroids	Cardiac
20581	Valentin 2016	1	140	Brazil^a	Corticosteroids	GI/Abdominal
2778	Glumac 2017	1	169	Croatia	Corticosteroids	Cardiac
3250	Royse 2017 (Whitlock 2015)	3	555	Australia	Corticosteroids	Cardiac
7686	Xiang 2022	1	174	China^a	Corticosteroids	GI/Abdominal
17365	Brondum 2022	1	39	Denmark	Corticosteroids	GI/Abdominal
18178	Zeng 2022	1	60	China^a	Corticosteroids	Ortho
18474	Huang 2023a	1	160	China^a	Corticosteroids	Ortho
2730	Leung 2017	1	750	USA	Gabapentin	Ortho Spine
5765	Zhu 2018	1	178	China^a	NSAIDs	Ortho
5809	Zhou 2019a	1	180	China^a	NSAIDs	Ortho
17987	Shen 2022	1	120	China^a	NSAIDs	Thoracic
Randomized Cluster Crossover Trial
5365	Spence 2020	2	800	Canada	Benzodiazepine (sa)	Cardiac
Before-After/Time Series
9464	Ushida 2009	1	122	Japan	Corticosteroids	Ortho
10090	Yamasaki 2019	1	21	Japan	H2 blockers	GI/Abdominal
Nonrandomized Trial
750	Van Grootven 2016	5	86	Belgium	Benzodiazepine (ns)	Ortho
Prospective Cohort
2985	Pipanmekaporn 2021	1	429	Thailand	Benzodiazepine (ns)	Various^b
7722	Duprey 2022	2	566	USA	Benzodiazepine (ns) Antipsychotics NSAIDs Anticholinergics	Non-cardiac
1332	Wang 2021	1	1,266	USA	Benzodiazepine (sa)	Various^b
7522	Leigheb 2022	1	83	Italy	Benzodiazepine (sa)	Ortho
6840	Ke 2022a	4	98	Singapore	Benzodiazepine (sa)	Other
16970	Aoki 2023	1	222	Japan	Benzodiazepine (sa)	Cardiac
Retrospective Cohort
17141	Slor 2011b (Kalisvaart 2005)	1	526	Netherlands	Anticholinergics	Ortho
17142	Mueller 2020b (Mueller 2020a)	2	651	Germany	Antipsychotics	Gyn GI/Abdominal Thoracic Urol
18984	Poeran 2020g (Poeran 2020a)		527,254	USA	Benzodiazepine (any)	Ortho
5163	Memtsoudis 2019 THA	4,400	564,226	USA	Benzodiazepine (any) Benzodiazepine (sa) Benzodiazepine (la) Corticosteroids NSAIDs	Ortho
17134	Memtsoudis 2019 TKA	4,400	1,130,569	USA	Benzodiazepine (any) Benzodiazepine (sa) Benzodiazepine (la) Corticosteroids NSAIDs	Ortho
20892	Memtsoudis 2019k (Memtsoudis 2019a)	4,400	564,226	USA	Benzodiazepine (any) Benzodiazepine (sa) Benzodiazepine (la) Corticosteroids NSAIDs	Ortho
20893	Memtsoudis 2019l (Memtsoudis 2019a)	4,400	1,130,569	USA	Benzodiazepine (any) Benzodiazepine (sa) Benzodiazepine (la) Corticosteroids NSAIDs	Ortho
18983	Poeran 2020f (Poeran 2020a)		527,254	USA	Benzodiazepine (la)	Ortho
17140	Slor 2011a (Kalisvaart 2005)	1	526	Netherlands	Benzodiazepine (ns)	Ortho
3727	Mangusan 2015a	1	656	USA	Benzodiazepine (ns)	Cardiac
4888	Weinstein 2018a	1	41,766	USA	Benzodiazepine (ns)	Ortho
17143	Weinstein 2018b (Weinstein 2018a)	1	41,766	USA	Benzodiazepine (ns)	Ortho
8003	Fuchita 2019a	1	84	USA	Benzodiazepine (ns)	Thoracic
20896	Ishibashi-Kanno 2020b (Ishibashi-Kanno 2020a)	1	69	Japan	Benzodiazepine (ns)	Headneck
118	Mueller 2020a	2	651	Germany	Benzodiazepine (sa)	Gyn GI/Abdominal Thoracic Urol
17228	Poeran 2020a		527,254	USA	Benzodiazepine (sa)	Ortho
18509	Kaneko 2023	1	98	Japan	Benzodiazepine (sa)	Cardiac
18938	Yoshimura 2023	1,730	16,185	Japan	Benzodiazepine (sa)	Cardiac
17038	Liu 2023a	1	195	China^a	Benzodiazepine (sa)	Urol
16961	Koch 2023	1	1,058	Germany	Benzodiazepine (sa)	Various^b
18945	Zarour 2023	1	1,973	Israel	Benzodiazepine (sa)	Various^b
17148	Fuchita 2019b (Fuchita 2019a)	1	84	USA	Corticosteroids	Thoracic
18976	Poeran 2020b (Poeran 2020a)		527,254	USA	Corticosteroids	Ortho
17006	Burfeind 2022	1	1,627	USA	Corticosteroids H2 blockers Benzodiazepine (sa)	Various^b
16714	Park 2022	900	237,872	USA	Gabapentin	Various^b
20897	Ishibashi-Kanno 2020c (Ishibashi-Kanno 2020a)	1	69	Japan	H2 blockers	Headneck
20894	Mangusan 2015b (Mangusan 2015a)	1	656	USA	NSAIDs	Cardiac
18977	Poeran 2020c (Poeran 2020a)		527,254	USA	NSAIDs Benzodiazepine (any)	Ortho
20895	Mangusan 2015c (Mangusan 2015a)	1	656	USA	Nonbenzodiazepine hypnotics	Cardiac
18985	Poeran 2020h (Poeran 2020a)		527,254	USA	Nonbenzodiazepine hypnotics	Ortho
Case-Control
9279	Nandi 2014	1	463	USA	Benzodiazepine (ns)	Ortho
9977	Choi 2019	1	58	South Korea	Corticosteroids	Thoracic
Antichol: anticholinergics; Antipsych: antipsychotics; la: long-acting; sa: short-acting; ns: not stated; GI: gastrointestinal; Ortho: orthopedic; Neuro: neurological; Oralmax: oral maxillofacial; Vasc: vascular.
^a Non very-high Human Development Index country.
^b Described as various or more than 4 different types of surgery.

Country Summary

Table 7. Summary of studies by country where conducted.

	N = 65^a
Country
China	19 (29%)
USA	12 (18%)
Japan	9 (14%)
Egypt	3 (4.6%)
Germany	3 (4.6%)
Iran	3 (4.6%)
Netherlands	3 (4.6%)
Thailand	2 (3.1%)
Australia	1 (1.5%)
Belgium	1 (1.5%)
Brazil	1 (1.5%)
Canada	1 (1.5%)
Croatia	1 (1.5%)
Denmark	1 (1.5%)
Israel	1 (1.5%)
Italy	1 (1.5%)
Singapore	1 (1.5%)
South Korea	1 (1.5%)
Switzerland	1 (1.5%)
^a n (%)

Drugs by Study

Benzodiazepines

Table 8. Studies examining benzodiazepines, dose, and timing according to study design.

Study	N	Drug	ASA	Anesthetic				Age^b	MMSE^b	Dosing	Timing^c	Surgery
Benzodiazepines (short-acting)
Study	N	Drug	PS^a	Vol	TIVA	Reg	Sed	Age^b	MMSE^b	Dosing	Timing^c	Surgery
Randomized Clinical Trial
Sultan 2010	49	None	123			✓		72.3 (6.4)				Ortho
	53	Melatonin	123			✓		70.4 (7.1)
	50	Midazolam	123			✓		69.9 (8.2)		7.5mg (qd×2d)	▆▁▁
Yu 2017	46	Dexmedetomidine	12		✓			68.7 (4.3)	29.8 (0.7)			Thoracic
	46	Midazolam	12		✓			69.1 (4.9)	29.8 (0.7)	0.05ug/kg (bid×1d)	▁▆▁
He 2018	30	Placebo	123	✓	✓			83.2 (5.1)				Thoracic
	30	Dexmedetomidine	123	✓	✓			82.5 (5.4)
	30	Midazolam	123	✓	✓			81.9 (6.2)		0.03mg/kg (qd×1d)	▆▁▁
Azeem 2018	30	Dexmedetomidine	NR		✓			65.3 (4.8)				Cardiac
	30	Midazolam	NR		✓			66.7 (5.6)		0.05mg/kg
Li 2019	55	Propofol	123			✓		68.2 (6.4)				Ortho
	55	Dexmedetomidine	123			✓		69.3 (7.1)
	54	Midazolam	123			✓		66.9 (6.6)		^d	▁▆▁
Mansouri 2019	50	Placebo	12		✓			64.0 (7.2)				Ophtho
	50	Dexmedetomidine	12		✓			66.5 (1.6)
	50	Midazolam	12		✓			63.6 (8.3)		0.1mg/kg (qd×1d)	▁▆▁
Wang 2020a	20	Dexmedetomidine	NR		✓			60.0 (10.1)				Oralmax
	20	Midazolam	NR		✓			60.5 (8.2)		0.03mg/kg (1d)
Tan 2022	33	Propofol	12				✓	66.2 (5.0)				GI/Abd
	33	Remimazolam	123				✓	66.4 (4.8)		0.1mg/kg (qd×1d)	▁▆▁
	33	Remimazolam	123				✓	65.5 (5.2)		0.2mg/kg (qd×1d)	▁▆▁
Deng 2023	53	Dexmedetomidine	23			✓		71.8 (5.5)				Ortho
	52	Remimazolam	23			✓		70.8 (4.4)		0.025mg/kg (qd×1d)	▁▆▁
Kuang 2023	42	Propofol	12		✓			65.2 (4.4)				Thoracic
	42	Remimazolam	12		✓			65.4 (3.9)		0.3mg/kg (qd)	▁▆▁
Liao 2023	35	Placebo	NR		✓			69.7 (2.5)	27.7 (1.9)			GI/Abd
	35	Dexmedetomidine	NR		✓			71.3 (3.6)	27.8 (2.1)
	34	Remimazolam	NR		✓			70.1 (3.6)	27.7 (1.7)	0.2mg/kg (qd)	▁▆▁
Sun 2023b	51	None	123		✓			72.4 (5.7)				Ortho
	53	Remimazolam	123		✓			71.8 (6.2)		0.1mg/kg	▁▆▁
Yang 2023	153	Placebo	123		✓			68.0	26.0			Ortho
	147	Remimazolam	123		✓			68.0	26.0	0.25mg/kg (qd×1d)	▁▆▁
Kowark 2024	303	Placebo	1234					72.3 (4.4)				Various
	304	Midazolam	1234					71.5 (4.4)		3.75mg (qd×1d)	▆▁▁
Randomized Cluster Crossover Trial
Spence 2020	389	Midazolam (liberal)^e	NR					67.2 (10.0)		5.2mg ^f	▆▆▆	Cardiac
	411	Midazolam (restricted)^e	NR					66.7 (11.3)		4.6mg ^f	▆▆▆
Prospective Cohort
Wang 2021	357	None	1234					74.5 (6.6)				Various
	357	Midazolam	1234					74.1 (4.2)		1.99mg ^f	▆▁▁
Ke 2022a	91	None	NR									Other
	7	Midazolam	NR								▁▆▁
Leigheb 2022	36	None	1234									Ortho
	47	Midazolam	1234							0.5-1.0mg	▆▁▁
Aoki 2023	124	None	23	✓	✓			77.2 (5.9)	28.0 (1.7)			Cardiac
	76	Remimazolam	23		✓			77.7 (6.1)	28.0 (1.5)	NR	▁▆▁
Retrospective Cohort
Memtsoudis 2019 THA	107,736	None	NR									Ortho
	373,219	Benzodiazepine (any sa)	NR							NR	▁▆▆
	15,329	Benzodiazepine (any la)	NR							NR	▁▆▆
	67,942	Benzodiazepine (any sa/la)	NR							NR	▁▆▆
Memtsoudis 2019 TKA	175,288	None	NR									Ortho
	778,956	Benzodiazepine (any sa)	NR							NR	▁▆▆
	25,667	Benzodiazepine (any la)	NR							NR	▁▆▆
	150,658	Benzodiazepine (any sa/la)	NR							NR	▁▆▆
Mueller 2020a	82	None	1234					71.8 (4.9)	28.6 (4.9)			Various
	529	Midazolam	1234					71.8 (4.9)	28.6 (4.9)	6.1mg	▆▁▁
Poeran 2020a	338,015	None	NR	✓	✓	✓						Ortho
	167,137	Midazolam	NR	✓	✓	✓					▆▁▆
Koch 2023	1,001	None	1234					69.7 (6.3)	28.9 (1.4)			Various
	57	Midazolam	1234					69.7 (6.3)	28.9 (1.4)	NR	▆▁▁
Liu 2023a	50	None	1234					68.0 [66-72]				Urol
	145	Midazolam	1234					68.0 [66-72]		NR	▁▆▁
Kaneko 2023	58	Placebo	NR		✓			84.0 {81-87}	26 {23-27}			Cardiac
	40	Remimazolam	NR		✓			84.0 {81-88}	25 {24-28}	3mg/kg (1d)	▁▆▁
Yoshimura 2023	5,552	None	NR									Cardiac
	10,633	Midazolam	NR								▆▁▁
Zarour 2023	1,191	None	1234					77.0 {73-82}				Various
	782	Midazolam	1234					74.0 {72-78}			▆▁▁
PS: physical status; Vol: volatile; TIVA: total intravenous anesthesia; Reg: regional; Sed: sedation; MMSE: Mini-Mental State Exam; THA: total hip arthroplasty; TKA: total knee arthroplasty.
^a ASA Physical Status of patients included (proportions can be found here[link to table add]).
^b Mean Med (SD)[Range]{IQR}.
^c Bars indicate adminstration times from left to right: preoperative, induction/intraoperative, and postoperative (includes PACU).
^d Dose adjusted to maintain light sedation.
^e Liberal or restricted administration relevant to intraoperative period.
^f Mean intraoperative dose.

Study	N	Drug	ASA	Anesthetic				Age^b	MMSE^b	Dosing	Timing^c	Surgery
Benzodiazepines (long-acting)
Study	N	Drug	PS^a	Vol	TIVA	Reg	Sed	Age^b	MMSE^b	Dosing	Timing^c	Surgery
Randomized Clinical Trial
Aizawa 2002	20	None	NR	✓	✓			76.2 (4.1)				GI/Abd
	20	Flunitrazepam	NR	✓	✓			75.9 (4.5)		0.4mg/kg (qd×3d)	▆▁▁
Dianatkhah 2015	66	Melatonin	NR					60.0 (10.2)				Cardiac
	71	Oxazepam	NR					61.7 (9.9)		10mg (qd×10d)	▆▁▆
Retrospective Cohort
Memtsoudis 2019 THA	107,736	None	NR									Ortho
	373,219	Benzodiazepine (any sa)	NR							NR	▁▆▆
	15,329	Benzodiazepine (any la)	NR							NR	▁▆▆
	67,942	Benzodiazepine (any sa/la)	NR							NR	▁▆▆
Memtsoudis 2019 TKA	175,288	None	NR									Ortho
	778,956	Benzodiazepine (any sa)	NR							NR	▁▆▆
	25,667	Benzodiazepine (any la)	NR							NR	▁▆▆
	150,658	Benzodiazepine (any sa/la)	NR							NR	▁▆▆
Poeran 2020f	450,479	None	NR	✓	✓	✓						Ortho
	54,673	Benzo_long	NR	✓	✓	✓					▆▁▆
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 Bars indicate adminstration times from left to right: preoperative, induction/intraoperative, and postoperative (includes PACU).

Study	N	Drug	ASA	Anesthetic				Age^b	MMSE^b	Dosing	Timing^c	Surgery
Benzodiazepine (any or not specified)
Study	N	Drug	PS^a	Vol	TIVA	Reg	Sed	Age^b	MMSE^b	Dosing	Timing^c	Surgery
Retrospective Cohort
Slor 2011a	96	None	NR									Ortho
	430	Benzodiazepine (ns sa/la)	NR							NR	^d Unspecified
Mangusan 2015a	424	None	NR					66.5 (10.8)				Cardiac
	232	Benzodiazepine (ns sa/la)	NR					66.5 (10.8)		NR	▁▁▆
Weinstein 2018a	2,643	None	NR			✓						Ortho
	33,223	Benzodiazepine (ns sa/la)	NR			✓					▁▆▁
Weinstein 2018b	33,500	None	NR			✓						Ortho
	3,451	Benzodiazepine (ns sa/la)	NR			✓					▁▁▆
Memtsoudis 2019 THA	107,736	None	NR									Ortho
	373,219	Benzodiazepine (any sa)	NR							NR	▁▆▆
	15,329	Benzodiazepine (any la)	NR							NR	▁▆▆
	67,942	Benzodiazepine (any sa/la)	NR							NR	▁▆▆
Fuchita 2019a	3	None	NR					61.7 (10.5)				Thoracic
	81	Benzo_ns	NR					61.7 (10.5)			▁▆▁
Memtsoudis 2019 TKA	175,288	None	NR									Ortho
	778,956	Benzodiazepine (any sa)	NR							NR	▁▆▆
	25,667	Benzodiazepine (any la)	NR							NR	▁▆▆
	150,658	Benzodiazepine (any sa/la)	NR							NR	▁▆▆
Memtsoudis 2019k	428,543	None	NR									Ortho
	135,683	Benzodiazepine (any sa/la)	NR							NR	▁▆▆
Memtsoudis 2019l	861,439	None	NR									Ortho
	269,130	Benzodiazepine (any sa/la)	NR							NR	▁▆▆
Poeran 2020g	455,116	None	NR	✓	✓	✓						Ortho
	50,036	Benzodiazepine (any sa/la)	NR	✓	✓	✓					▆▁▆
Ishibashi-Kanno 2020b	33	None	NR					62.9 (11.9)				Headneck
	36	Benzo_ns	NR					62.9 (11.9)			▁▁▆
Case-Control
Nandi 2014	376	None	NR									Ortho
	87	Benzodiazepine (ns sa/la)	NR								▁▆▆
Nonrandomized Trial
Van Grootven 2016	62	None	NR					80.1 (6.8)				Ortho
	24	Benzodiazepine (ns sa/la)	NR					80.1 (6.8)		NR	^d Unspecified
Prospective Cohort
Pipanmekaporn 2021	173	None	NR									Various
	256	Benzodiazepine (ns sa/la)	NR								▆▁▁
Duprey 2022	^e	Antipsychotic (any)	NR					76.6 (5.0)		NR	▁▁▆	Various
	^e	Benzodiazepine (ns sa/la)	NR					76.6 (5.0)		NR	▁▁▆
PS: physical status; Vol: volatile; TIVA: total intravenous anesthesia; Reg: regional; Sed: sedation; MMSE: Mini-Mental State Exam; THA: total hip arthroplasty; TKA: total knee arthroplasty.
^a ASA Physical Status of patients included (proportions can be found here[link to table add]).
^b Mean Med (SD)[Range]{IQR}.
^c Bars indicate adminstration times from left to right: preoperative, induction/intraoperative, and postoperative (includes PACU).
^d Not specified.
^e Reported only results from proportional hazards models.

Antipsychotics

Table 9. Studies examining antipsychotics, dose, and timing according to study design.

Study	N	Drug	ASA	Anesthetic				Age^b	MMSE^b	Dosing	Timing^c	Surgery
Antipsychotics
Study	N	Drug	PS^a	Vol	TIVA	Reg	Sed	Age^b	MMSE^b	Dosing	Timing^c	Surgery
Randomized Clinical Trial
Kalisvaart 2005	218	Placebo	NR					79.6 (6.3)	24.5 (4.2)			Ortho
	212	Haloperidol	NR					78.7 (6.0)	25.0 (6.8)	0.5mg (tid×5d)	▆▁▁
Prakanrattana 2007	63	Placebo	NR	✓	✓			60.7 (9.8)				Cardiac
	63	Risperidone	NR	✓	✓			61.3 (9.7)		1mg (qd×1d)
Larsen 2010	204	Placebo	123	✓		✓		74.0 (6.2)				Ortho
	196	Olanzapine	123	✓		✓		73.4 (6.1)		5mg (bid×1d)	▆▁▁
Hakim 2012	50	Placebo	NR	✓								Cardiac
	51	Risperidone	NR	✓						0.5mg (bid)
Wang 2012	228	Placebo	234					74.4 (7.0)				Various
	229	Haloperidol	234					74.0 (5.8)		5mg (qd×1d)
Fukata 2014	62	None	NR					80.2 (3.9)	23.0 (5.4)			Various
	59	Haloperidol	NR					80.5 (3.8)	23.3 (6.4)	2.5mg (qd×3d)
Fukata 2017	100	None	NR					81.3 (4.3)	25.1 (5.6)			Various
	101	Haloperidol	NR					82.0 (4.4)	24.6 (5.2)	5mg (qd×6d)
Hollinger 2021	44	Placebo	NR					74.8 (6.6)	28.3 (2.3)			Various
	47	Ketamine	NR					73.4 (6.1)	27.7 (1.7)
	45	Haloperidol	NR					73.4 (6.3)	28.0 (1.3)	5ug/kg (qd×1d)	▁▆▁
Retrospective Cohort
Mueller 2020b	558	None	1234					71.8 (31.5)	28.6 (4.9)			Various
	92	Haloperidol	1234					71.8 (4.9)	28.6 (4.9)		▁▁▆
Prospective Cohort
Duprey 2022	^d	Antipsychotic (any)	NR					76.6 (5.0)		NR	▁▁▆	Various
	^d	Benzodiazepine (ns sa/la)	NR					76.6 (5.0)		NR	▁▁▆
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 Bars indicate adminstration times from left to right: preoperative, induction/intraoperative, and postoperative (includes PACU).
^d Reported only results from proportional hazards models.

Anticholinergics

Table 10. Studies examining anticholinergics, dose, and timing according to study design.

Study	N	Drug	ASA	Anesthetic				Age^b	MMSE^b	Dosing	Timing^c	Surgery
Anticholinergic drugs
Study	N	Drug	PS^a	Vol	TIVA	Reg	Sed	Age^b	MMSE^b	Dosing	Timing^c	Surgery
Retrospective Cohort
Slor 2011b	480	None	NR									Ortho
	46	Anticholinergic (any)	NR							NR	^d Unspecified
Randomized Clinical Trial
Hongyu 2019	30	Placebo	123	✓				69.1 (8.3)	27.1 (2.6)			Thoracic
	30	Penehyclidine	123	✓				72.4 (5.7)	27.8 (2.1)	0.01mg/kg (qd×1d)	▆▁▁
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 Bars indicate adminstration times from left to right: preoperative, induction/intraoperative, and postoperative (includes PACU).
^d Not specified.

Corticosteroids

Table 11. Studies examining corticosteroids, dose, and timing according to study design.

Study	N	Drug	ASA	Anesthetic				Age^b	MMSE^b	Dosing	Timing^c	Surgery
Corticosteroids
Study	N	Drug	PS^a	Vol	TIVA	Reg	Sed	Age^b	MMSE^b	Dosing	Timing^c	Surgery
Before-After/Time Series
Ushida 2009	81	Methylprednisolone	NR	✓	✓			69.8 [53-84]		2500mg	▁▆▁	Ortho
	41	Methylprednisolone	NR	✓	✓			68.1 [52-86]		2000mg	▁▆▆
Randomized Clinical Trial
Dieleman 2012	2,247	Placebo	NR	✓	✓			66.1 (10.7)				Cardiac
	2,235	Dexamethasone	NR	✓	✓			66.2 (11.0)		1mg/kg (qd×1d)	▁▆▁
Mardani 2013	50	Placebo	NR					60.0 (12.8)	27.8 (3.1)			Cardiac
	43	Dexamethasone	NR					64.5 (11.1)	28.6 (3.1)	8mg (tid×3d)	▆▁▁
Sauer 2014	370	Placebo	NR					66.0 (12.0)				Cardiac
	367	Dexamethasone	NR					67.0 (12.0)		1mg/kg (qd×1d)	▁▆▁
Ottens 2014	138	Placebo	NR	✓	✓			65.4 (11.5)				Cardiac
	140	Dexamethasone	NR	✓	✓			63.4 (12.3)		1mg/kg (qd×1d)	▁▆▁
Whitlock 2015	3,752	Placebo	NR					67.3 (13.8)				Cardiac
	3,755	Methylprednisolone	NR					67.5 (13.6)		250mg (bid×1d)	▁▆▁
Valentin 2016	40	None	NR		✓			67.2 (5.2)	23.5 (3.2)			GI/Abd
	36	Dexamethasone	NR		✓			68.0 (6.3)	25.2 (3.0)	8mg (qd×1d)	▁▆▁
Glumac 2017	81	Placebo	NR	✓				64.2 (9.4)	28.3 (1.2)			Cardiac
	80	Dexamethasone	NR	✓				63.7 (9.0)	28.1 (1.2)	0.1mg/kg (qd×1d)	▆▁▁
Royse 2017	246	Placebo	NR					74.3 (9.3)				Cardiac
	236	Methylprednisolone	NR					73.4 (10.5)		250mg (bid×1d)	▁▆▁
Xiang 2022	84	Placebo	23		✓	✓		70.0 {68-73}	23 {22-24}			GI/Abd
	84	Methylprednisolone	23		✓	✓		71.0 {68-74}	22 {22-24}	2mg/kg (qd×1d)	▆▁▁
Brondum 2022	16	Placebo	123	✓	✓			60.0 (15.0)				GI/Abd
	17	Methylprednisolone	123	✓	✓			62.0 (9.2)		125mg (qd)	▁▆▁
Zeng 2022	30	Placebo	123		✓	✓		65.4 (7.6)				Ortho
	30	Dexamethasone	NR	✓		✓		67.9 (8.6)		5mg (qd×1d)	▁▆▁
Huang 2023a	80	Placebo	1234	✓				85.0 {80-90}	16 {14-23}			Ortho
	80	Dexamethasone	1234	✓				84.5 {79-89}	18 {13-22}	10mg (qd×1d)	▆▁▁
Case-Control
Choi 2019	16	Methylprednisolone > 72h	1234					71.0 {63-74}		1.5mg/kg (qd×28d)		Thoracic
	42	Methylprednisolone ≤ 72h	1234					70.0 {61-72}		1.5mg/kg (qd×28d)
Retrospective Cohort
Memtsoudis 2019 THA	542,536	None	NR									Ortho
	21,690	Corticosteroid (any)	NR							NR	▁▆▆
Memtsoudis 2019 TKA	1,082,854	None	NR									Ortho
	47,715	Corticosteroid (any)	NR							NR	▁▆▆
Fuchita 2019b	77	None	NR					61.7 (10.5)				Thoracic
	7	Dexamethasone	NR					61.7 (10.5)			▁▆▁
Poeran 2020b	480,056	None	NR	✓	✓	✓						Ortho
	25,096	Methylprednisolone	NR	✓	✓	✓					▆▁▆
Burfeind 2022	74	None	1234	✓	✓	✓		76.9 (6.7)				Various
	417	None	1234	✓	✓	✓		76.9 (6.7)
	104	Famotidine/Midzolam/Dexamethasone	1234	✓	✓	✓		72.3 (5.6)			▁▆▆
	1,006	Famotidine/Midzolam/Dexamethasone	1234	✓	✓	✓		72.3 (5.6)			▁▆▆
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 Bars indicate adminstration times from left to right: preoperative, induction/intraoperative, and postoperative (includes PACU).

NSAIDs

Table 12. Studies examining NSAIDs, dose, and timing according to study design.

Study	N	Drug	ASA	Anesthetic				Age^b	MMSE^b	Dosing	Timing^c	Surgery
NSAIDs
Study	N	Drug	PS^a	Vol	TIVA	Reg	Sed	Age^b	MMSE^b	Dosing	Timing^c	Surgery
Retrospective Cohort
Mangusan 2015b	369	None	NR					66.5 (10.8)				Cardiac
	287	Ketoprofen	NR					66.5 (10.8)		NR	▁▁▆
Memtsoudis 2019 THA	309,921	None	NR									Ortho
	254,305	NSAID (any)	NR							NR	▁▆▆
Memtsoudis 2019 THA	344,467	None	NR									Ortho
	219,759	COX-2 inhibitor	NR							NR	▁▆▆
Memtsoudis 2019 TKA	569,339	None	NR									Ortho
	561,230	NSAID (any)	NR							NR	▁▆▆
Memtsoudis 2019 TKA	710,381	None	NR									Ortho
	420,188	COX-2 inhibitor	NR							NR	▁▆▆
Poeran 2020c	436,131	None	NR	✓	✓	✓						Ortho
	69,021	NSAID (any)	NR	✓	✓	✓					▆▁▆
Randomized Clinical Trial
Zhu 2018	82	Placebo	NR		✓			70.8 (5.2)	27.6 (2.7)			Ortho
	81	Celocoxib	NR		✓			71.4 (5.6)	28.1 (3.2)	200mg (bid×7d)	▆▁▁
Zhou 2019a	60	None	12	✓				75.2 (5.3)	28.9 (1.2)			Ortho
	60	Flurbiprofen	12	✓				78.3 (6.1)		50mg (qd×1d)	▆▁▁
	60	Flurbiprofen	12	✓				76.1 (5.9)	28.1 (1.4)	50mg (qd×1d)	▁▆▁
Shen 2022	60	Placebo	23	✓				68.4 (3.1)	27.5 (2.0)			Thoracic
	60	Flurbiprofen	23	✓				68.6 (2.9)	27.2 (2.0)	100mg (qd×1d)	▁▆▁
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 Bars indicate adminstration times from left to right: preoperative, induction/intraoperative, and postoperative (includes PACU).

Gabapentin

Table 14. Studies examining gabapentin, dose, and timing according to study design.

Study	N	Drug	ASA	Anesthetic				Age^b	MMSE^b	Dosing	Timing^c	Surgery
Gabapentin
Study	N	Drug	PS^a	Vol	TIVA	Reg	Sed	Age^b	MMSE^b	Dosing	Timing^c	Surgery
Randomized Clinical Trial
Leung 2017	347	Placebo	1234		✓	✓		73.0 (6.0)				Various
	350	Gabapentin	1234		✓	✓		73.0 (6.0)		900mg (tid×3d)	▆▁▆
Retrospective Cohort
Park 2022	118,936	None	NR					74.4 (6.8)				Various
	118,936	Gabapentin	NR					74.5 (6.7)			▆▁▆
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 Bars indicate adminstration times from left to right: preoperative, induction/intraoperative, and postoperative (includes PACU).

Delirium Incidence

Benzodiazepines

Table 15. Delirium incidence and ascertainment during hospitalization in studies examining benzodiazepines.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR (95% CI)	Surgery
Benzodiazepines (short-acting) — randomized designs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR (95% CI)	Surgery
Randomized Clinical Trial
Sultan 2010	49	None	Other	3	16 (32.7)		—	Ortho
	53	Melatonin			5 (9.4)		0.29 (0.11-0.73)
	50	Midazolam			22 (44.0)		1.35 (0.81-2.24)
Yu 2017	46	Dexmedetomidine	CAM	3	3 (6.5)		—	Thoracic
	46	Midazolam			10 (21.7)		3.33 (0.98-11.33)
Azeem 2018	30	Dexmedetomidine	CAM	7	1 (3.3)		—	Cardiac
	30	Midazolam			2 (6.7)		2.00 (0.19-20.90)
He 2018	30	Placebo	CAM	Note^b	15 (50.0)		—	Thoracic
	30	Dexmedetomidine			7 (23.3)		0.47 (0.22-0.98)
	30	Midazolam			17 (56.7)		1.13 (0.70-1.82)
Wang 2020a	20	Dexmedetomidine	unspecified	Stay	1 (5.0)		—	Oralmax
	20	Midazolam			9 (45.0)		9.00 (1.25-64.59)
Yang 2023	153	Placebo	CAM	3	19 (12.4)		—	Ortho
	147	Remimazolam			23 (15.6)		1.26 (0.72-2.21)
Kowark 2024	303	Placebo	CAM	30	3 (1.0)		—	Various
	304	Midazolam			4 (1.3)		1.33 (0.30-5.89)
Randomized Cluster Crossover Trial
Spence 2020	389	Midazolam (liberal)	CAM	Stay	55 (14.1)		—	Cardiac
	411	Midazolam (restricted)			72 (17.5)		1.24 (0.90-1.71)
RR: risk ratio; CAM: Confusion Assessment Method; NR: not reported.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.
^b Maximum of reported daily incidence.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR aOR (95% CI)	Surgery
Benzodiazepines (short-acting) — nonrandomized designs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR aOR (95% CI)	Surgery
Retrospective Cohort
Memtsoudis 2019 THA	107,736	None	Other^b	Stay	2,844 (2.6)		—	Ortho
	373,219	Benzodiazepine (any sa)			7,068 (1.9)		0.79 (0.72-0.87)
	15,329	Benzodiazepine (any la)			1,075 (7.0)		2.10 (1.82-2.42)
	67,942	Benzodiazepine (any sa/la)			3,798 (5.6)		1.74 (1.56-1.94)
Memtsoudis 2019 TKA	175,288	None	Other^b	Stay	4,783 (2.7)		—	Ortho
	778,956	Benzodiazepine (any sa)			16,603 (2.1)		0.82 (0.77-0.88)
	25,667	Benzodiazepine (any la)			1,928 (7.5)		2.24 (2.01-2.49)
	150,658	Benzodiazepine (any sa/la)			9,070 (6.0)		1.78 (1.64-1.92)
Mueller 2020a	82	None	CAM	7	11 (13.4)		—	Various
	529	Midazolam			51 (9.6)		0.72 (0.39-1.32)
Poeran 2020a	338,015	None	Other^b	Stay	60,462 (17.9)		—	Ortho
	167,137	Midazolam			19,085 (11.4)		0.64 (0.63-0.65)
Kaneko 2023	58	Placebo	CAM	3	15 (25.9)		—	Cardiac
	40	Remimazolam			3 (7.5)		0.29 (0.09-0.94)
Koch 2023	1,001	None	DSM	7	184 (18.4)		—	Various
	57	Midazolam			14 (24.6)		1.34 (0.83-2.15)
Liu 2023a	50	None	Other^b	Stay	5 (10.0)		—	Urol
	145	Midazolam			14 (9.7)		0.97 (0.37-2.54)
Zarour 2023	1,191	None	CAM/other	2	187 (15.7)		—	Various
	782	Midazolam			115 (14.7)		0.94 (0.76-1.16)
Prospective Cohort
Wang 2021	357	None	CAM	Note^c	89 (24.9)		—	Various
	357	Midazolam			83 (23.2)		0.93 (0.72-1.21)
Ke 2022a	91	None	Other^b	Stay	10 (11.0)		—	Other
	7	Midazolam			1 (14.3)		1.30 (0.19-8.75)
Leigheb 2022	36	None	DRS	Stay	5 (13.9)		—	Ortho
	47	Midazolam			12 (25.5)		1.84 (0.71-4.75)
Aoki 2023	124	None	CAM	5	33 (26.6)		—	Cardiac
	76	Remimazolam			23 (30.3)		1.14 (0.73-1.78)
RR: risk ratio; aOR: adjusted odds ratio; ns: not specified; sa: short-acting; la: long-acting; CAM: Confusion Assessment Method; THA: total hip arthroplasty; TKA: total knee arthroplasty.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.
^b Claims-based algorithm.
^c Maximum of reported daily incidence.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR aOR (95% CI)	Surgery
Benzodiazepine (any or not specified) — nonrandomized designs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR aOR (95% CI)	Surgery
Retrospective Cohort
Slor 2011a	96	None	CAM/DSM	5	24 (25.0)		—	Ortho
	430	Benzodiazepine (ns sa/la)			36 (8.4)		0.73 (0.35-1.51)
Mangusan 2015a	424	None	unspecified	Stay	90 (21.2)		—	Cardiac
	232	Benzodiazepine (ns sa/la)			71 (30.6)		1.44 (1.10-1.88)
Weinstein 2018a	2,643	None	Other	Stay	161 (6.1)		—	Ortho
	33,223	Benzodiazepine (ns sa/la)			636 (1.9)		0.31 (0.27-0.37)
Weinstein 2018b	33,500	None	Other	Stay	620 (1.9)		—	Ortho
	3,451	Benzodiazepine (ns sa/la)			164 (4.8)		2.57 (2.17-3.04)
Fuchita 2019a	3	None	CAM	Stay	1 (33.3)		—	Thoracic
	81	Benzo_ns			26 (32.1)		0.96 (0.19-4.92)
Memtsoudis 2019 THA	107,736	None	Other^b	Stay	2,844 (2.6)		—	Ortho
	373,219	Benzodiazepine (any sa)			7,068 (1.9)		0.79 (0.72-0.87)
	15,329	Benzodiazepine (any la)			1,075 (7.0)		2.10 (1.82-2.42)
	67,942	Benzodiazepine (any sa/la)			3,798 (5.6)		1.74 (1.56-1.94)
Memtsoudis 2019 TKA	175,288	None	Other^b	Stay	4,783 (2.7)		—	Ortho
	778,956	Benzodiazepine (any sa)			16,603 (2.1)		0.82 (0.77-0.88)
	25,667	Benzodiazepine (any la)			1,928 (7.5)		2.24 (2.01-2.49)
	150,658	Benzodiazepine (any sa/la)			9,070 (6.0)		1.78 (1.64-1.92)
Memtsoudis 2019k	428,543	None	Other^b	Stay	10,796 (2.5)		—	Ortho
	135,683	Benzodiazepine (any sa/la)			3,989 (2.9)		1.17 (1.13-1.21)
Memtsoudis 2019l	861,439	None	Other^b	Stay	23,096 (2.7)		—	Ortho
	269,130	Benzodiazepine (any sa/la)			9,288 (3.5)		1.29 (1.26-1.32)
Ishibashi-Kanno 2020b	33	None	DSM	Stay	10 (30.3)		—	Headneck
	36	Benzo_ns			13 (36.1)		1.19 (0.61-2.34)
Poeran 2020g	455,116	None	Other	Stay	68,846 (15.1)		—	Ortho
	50,036	Benzodiazepine (any sa/la)			10,701 (21.4)		1.41 (1.39-1.44)
Case-Control
Nandi 2014	376	None	Other	Stay	57 (15.2)		—	Ortho
	87	Benzodiazepine (ns sa/la)			41 (47.1)		9.68 (4.30-21.8)
Prospective Cohort
Pipanmekaporn 2021	173	None	CAM	Stay	12 (6.9)		—	Various
	256	Benzodiazepine (ns sa/la)			11 (4.3)		0.62 (0.28-1.37)
Duprey 2022		Antipsychotic (any)	CAM	Stay			1.48 (0.75-2.93)^c	Various
		Benzodiazepine (ns sa/la)					3.03 (1.97-4.67^c
RR: risk ratio; aOR: adjusted odds ratio; ns: not specified; sa: short-acting; la: long-acting; THA: total hip arthroplasty; TKA: total knee arthroplasty.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.
^b Claims-based algorithm.
^c Hazard ratio compared with not given drug.

Antipsychotics

Table 16. Delirium incidence and ascertainment during hospitalization in studies examining antipsychotics.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR (95% CI)	Surgery
Antipsychotics — randomized designs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR (95% CI)	Surgery
Randomized Clinical Trial
Kalisvaart 2005	218	Placebo	CAM/DSM	14	36 (16.5)		—	Ortho
	212	Haloperidol			32 (15.1)		0.91 (0.59-1.42)
Prakanrattana 2007	63	Placebo	CAM	Stay	20 (31.7)		—	Cardiac
	63	Risperidone			7 (11.1)		0.35 (0.16-0.77)
Larsen 2010	204	Placebo	CAM/DSM	Stay	82 (40.2)		—	Ortho
	196	Olanzapine			28 (14.3)		0.36 (0.24-0.52)
Hakim 2012	50	Placebo	DSM	Stay	17 (34.0)		—	Cardiac
	51	Risperidone			7 (13.7)		0.40 (0.18-0.89)
Wang 2012	228	Placebo	CAM	7	53 (23.2)		—	Various
	229	Haloperidol			35 (15.3)		0.66 (0.45-0.97)
Fukata 2014	60	None	neecham	7	20 (33.3)		—	Various
	59	Haloperidol			25 (42.4)		1.27 (0.80-2.02)
Fukata 2017	100	None	neecham	10	32 (32.0)		—	Various
	99	Haloperidol			18 (18.2)		0.57 (0.34-0.94)
Hollinger 2021	44	Placebo	ICDSC/other	3	4 (9.1)		—	Various
	47	Ketamine			3 (6.4)		0.70 (0.17-2.96)
	45	Haloperidol			5 (11.1)		1.22 (0.35-4.25)
RR: risk ratio; CAM: Confusion Assessment Method; DSM: Diagnostic and Statistical Manual of Mental Disorders; NEECHAM: Neelon and Champagne confusion scale; ICDSC: Intensive Care Delirium Screening Checklist.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		HR (95% CI)	Surgery
Antipsychotics — nonrandomized designs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	HR (95% CI)	Surgery
Retrospective Cohort
Mueller 2020b	558	None	CAM	7	51 (9.1)		—	Various
	92	Haloperidol			14 (15.2)		1.66 (0.96-2.88)
Prospective Cohort
Duprey 2022		Antipsychotic (any)	CAM	Stay			1.48 (0.75-2.93)^b	Various
		Benzodiazepine (ns sa/la)					3.03 (1.97-4.67^b
RR: hazard ratio; CAM: Confusion Assessment Method; DSM: Diagnostic and Statistical Manual of Mental Disorders; NEECHAM: Neelon and Champagne confusion scale; ICDSC: Intensive Care Delirium Screening Checklist.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.
^b Hazard ratio compared with not given drug.

Anticholinergics

Table 17. Delirium incidence and ascertainment during hospitalization in studies examining anticholinergics.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR (95% CI)	Surgery
Anticholinergics — randomized designs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR (95% CI)	Surgery
Randomized Clinical Trial
Hongyu 2019	30	Placebo	CAM	Note^b	5 (16.7)		—	Thoracic
	30	Penehyclidine			16 (53.3)		3.20 (1.34-7.62)
RR: risk ratio; CAM: Confusion Assessment Method.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.
^b Maximum of reported daily incidence.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR (95% CI)	Surgery
Anticholinergics — nonrandomized designs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR (95% CI)	Surgery
Retrospective Cohort
Slor 2011b	480	None	CAM/DSM	5	52 (10.8)		—	Ortho
	46	Anticholinergic (any)			8 (17.4)		1.61 (0.81-3.17)
RR: odds ratio; CAM: Confusion Assessment Method; DSM: Diagnostic and Statistical Manual of Mental Disorders.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.

Corticosteroids

Table 18. Delirium incidence and ascertainment during hospitalization in studies examining corticosteroids.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR (95% CI)	Surgery
Corticosteroids — randomized designs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR (95% CI)	Surgery
Randomized Clinical Trial
Dieleman 2012	2,247	Placebo	unspecified	Stay	262 (11.7)		—	Cardiac
	2,235	Dexamethasone			205 (9.2)		0.79 (0.66-0.94)
Mardani 2013	50	Placebo	DSM	Note^b	13 (26.0)		—	Cardiac
	43	Dexamethasone			4 (9.3)		0.36 (0.13-1.02)
Sauer 2014	370	Placebo	CAM	4	55 (14.9)		—	Cardiac
	367	Dexamethasone			52 (14.2)		0.95 (0.67-1.35)
Whitlock 2015	3,752	Placebo	CAM	Note^b	289 (7.7)		—	Cardiac
	3,755	Methylprednisolone			295 (7.9)		1.02 (0.87-1.19)
Xiang 2022	84	Placebo	CAM	Note^b	7 (8.3)		—	GI/Abd
	84	Methylprednisolone			3 (3.6)		0.43 (0.11-1.60)
Huang 2023a	80	Placebo	Other	5	21 (26.2)		—	Ortho
	80	Dexamethasone			9 (11.2)		0.43 (0.21-0.88)
RR: odds ratio; CAM: Confusion Assessment Method; DSM: Diagnostic and Statistical Manual of Mental Disorders; NR: not reported.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.
^b Maximum of reported daily incidence.

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR aOR (95% CI)	Surgery
Corticosteroids — nonrandomized designs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR aOR (95% CI)	Surgery
Before-After/Time Series
Ushida 2009	81	Methylprednisolone	DOS	Stay	23 (28.4)		—	Ortho
	41	Methylprednisolone			3 (7.3)		0.26 (0.08-0.81)
Case-Control
Choi 2019	16	Methylprednisolone > 72h	CAM	Stay	10 (62.5)		—	Thoracic
	42	Methylprednisolone ≤ 72h			10 (23.8)		0.38 (0.20-0.74)
Retrospective Cohort
Fuchita 2019b	77	None	CAM	Stay	27 (35.1)		—	Thoracic
	7	Dexamethasone			0 (0)		Not estimated
Memtsoudis 2019 THA	542,536	None	Other	Stay	14,146 (2.6)		—	Ortho
	21,690	Corticosteroid (any)			639 (2.9)		0.95 (0.81-1.11)
Memtsoudis 2019 TKA	1,082,854	None	Other	Stay	31,013 (2.9)		—	Ortho
	47,715	Corticosteroid (any)			1,371 (2.9)		0.96 (0.86-1.06)
Poeran 2020b	480,056	None	Other	Stay	75,409 (15.7)		—	Ortho
	25,096	Methylprednisolone			4,138 (16.5)		1.05 (1.02-1.08)
RR: relative risk; aOR: adjusted odds ratio; CAM: Confusion Assessment Method; DOS: delirium observation screening; THA: total hip arthroplasty; TKA: total knee arthroplasty.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.

NSAIDS

Table 19. Delirium incidence and ascertainment during hospitalization in studies examining NSAIDs

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR aOR (95% CI)	Surgery
NSAIDs
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR aOR (95% CI)	Surgery
Retrospective Cohort
Memtsoudis 2019 THA	309,921	None	Other^b	Stay	9,316 (3.0)		—	Ortho
	254,305	NSAID (any)			5,469 (2.2)		0.85 (0.79-0.91)
Memtsoudis 2019 THA	344,467	None			10,052 (2.9)		—	Ortho
	219,759	COX-2 inhibitor			4,733 (2.2)		0.82 (0.77-0.89)
Memtsoudis 2019 TKA	569,339	None	Other^b	Stay	18,812 (3.3)		—	Ortho
	561,230	NSAID (any)			13,572 (2.4)		0.84 (0.80-0.88)
Memtsoudis 2019 TKA	710,381	None			21,502 (3.0)		—	Ortho
	420,188	COX-2 inhibitor			10,882 (2.6)		0.83 (0.79-0.88)
Poeran 2020c	436,131	None	Other	Stay	70,339 (16.1)		—	Ortho
	69,021	NSAID (any)			9,208 (13.3)		0.83 (0.81-0.84)
Mangusan 2015b	369	None	unspecified	Stay	104 (28.2)		—	Cardiac
	287	Ketoprofen			57 (19.9)		0.70 (0.53-0.94)
RR: relative risk; aOR: adjusted odds ratio; CAM: Confusion Assessment Method; DOS: delirium observation screening; THA: total hip arthroplasty; TKA: total knee arthroplasty.
^a Day(s) over which incidence proportion assessed. Stay indicates duration of hospitalization.
^b Claims-based algorithm.

Gabapentin

Study	N	Arm	Scale	Day(s)^a	Incidence Proportion		RR aOR (95% CI)	Surgery
Gabapentin
Study	N	Arm	Scale	Day(s)^a	N (%)	0 – 100%	RR aOR (95% CI)	Surgery
Randomized Clinical Trial
Leung 2017	347	Placebo	CAM	3	72 (20.7)		—	Various
	350	Gabapentin			84 (24.0)		1.16 (0.88-1.53)
Retrospective Cohort
Park 2022	118,936	None	CAM	2	3,148 (2.6)		—	Various
	118,936	Gabapentin			4,040 (3.4)		1.28 (1.23-1.34)
RR: relative risk.
^a Day(s) over which incidence proportion assessed.

Study Primary Aim

Delirium Prevention

Table 20. Studies examining delirium prevention.

Study	N	Drug Class	Study Aim
Randomized Clinical Trial
Aizawa 2002	42	Benzodiazepine (la)	“We attempted to control disturbances of the sleepwake cycle by medication after surgery as a mean of preventing POD, but bearing in mind there was a risk that artificial regulation of the sleep rhythm would have significant side effects that outweighed its benefits.”
Kalisvaart 2005	430	Antipsychotics	“This was a randomized, placebo-controlled, doubleblind, clinical trial of low-dose haloperidol prophylaxis for postoperative delirium in elderly hip-surgery patients who were at intermediate or high risk for this complication. The aim was to assess the effectiveness of 1.5 mg of haloperidol daily versus placebo on the primary (incident delirium) and secondary (deterioration of delirium) prevention of postoperative delirium in hip-surgery patients.”
Prakanrattana 2007	126	Antipsychotics	“This study was primarily aimed to evaluate the potential of a single dose of risperidone to prevent postoperative delirium in adult patients undergoing cardiac surgery with cardiopulmonary bypass.”
Larsen 2010	495	Antipsychotics	“Our study sought to evaluate the impact of the perioperative administration of olanzapine on the prevention of postoperative delirium in elderly patients undergoing elective joint-replacement surgery. Secondary objectives included the length of stay, medical complications, the severity and duration of delirium, and disposition after hospital discharge.”
Hakim 2012	101	Antipsychotics	“The aim of this trial was to test the hypothesis that administration of risperidone to elderly patients who developed subsyndromal delirium after cardiac surgery would result in reduction of the incidence of clinical delirium.”
Wang 2012	457	Antipsychotics	“The purpose of this study was to determine the efficacy and safety of short-term administration of low-dose intravenous haloperidol in preventing delirium in critically ill elderly patients after noncardiac surgery.”
Dieleman 2012	4,494	Corticosteroids	“We conducted a large randomized clinical trial to quantify the effect of a single intraoperative dose of dexamethasone on the incidence of major adverse events in patients undergoing cardiac surgery.” Delirium was specified as a secondary outcome (adverse event).
Mardani 2013	110	Corticosteroids	“Therefore, this study was conducted with aim of evaluation of DEX effects on post‑operative delirium and complications after cardiac surgery.” Posited potential beneficial effects.
Fukata 2014	121	Antipsychotics	“[T]o investigate the efficacy and safety of the daily postoperative administration of low-dose haloperidol on postoperative delirium in 75-year-old or older patients who underwent abdominal or orthopedic surgery.”
Sauer 2014	737	Corticosteroids	“The objective of the present study was to investigate in detail whether the intraoperative administration of high-dose dexamethasone to patients undergoing cardiac surgery affects the incidence of postoperative delirium during the first 4 postoperative days. We hypothesized that dexamethasone administration would reduce the incidence of delirium at any time point during the first 4 postoperative days.”
Ottens 2014	291	Corticosteroids	“In this study, we assessed the effect of an intraoperative high dose of dexamethasone on cognitive outcome of patients who underwent cardiac surgery with the use of CPB. We hypothesized that the incidence of POCD at 1 month after surgery would be lower in patients who received dexamethasone compared with those who received placebo.” Preplanned substudy of Dieleman 2012.
Valentin 2016	140	Corticosteroids	This study aimed to evaluate the effect of dexamethasone on the incidence of postoperative cognitive dysfunction in elderly patients.
Leung 2017	750	Gabapentin	postoperative delirium within 3 days of surgery
Glumac 2017	169	Corticosteroids	“The aim of the current study was to assess the effects of preoperative dexamethasone on cognitive outcomes on the 6th day after surgery and also on the inflammatory response in patients who had undergone cardiac surgery. We hypothesised that the incidence of early POCD and the magnitude of the inflammatory response would be reduced in patients who received dexamethasone compared with those who received placebo.”
Royse 2017	555	Corticosteroids	“Our goal was to determine whether high-dose methylprednisolone improves the quality of postoperative recovery and reduces the incidence of delirium after cardiac surgery involving cardiopulmonary bypass. Specifically, we tested the primary hypothesis that high-dose methylprednisolone improves the quality of recovery compared to placebo. Secondarily, we tested the hypothesis that high-dose methylprednisolone reduces the incidence of delirium during the initial three postoperative days.”
Fukata 2017	201	Antipsychotics	“The aim of this study was to evaluate the safety and efficacy of the early administration haloperidol in preventing the aggravation of postoperative delirium in elderly patients.”
Zhu 2018	178	NSAIDs	“This study was conducted to investigate the effect of celecoxib in POCD incidence in geriatric patients undergoing total knee arthroplasty (TKA).”
Mansouri 2019	150	Benzodiazepine (sa)	“[T]he present study aims to compare the effects of preoperative intravenous administration of midazolam and dexmedetomidine on the prevention of POCD among the elderly candidates for cataract surgery.”
Zhou 2019a	180	NSAIDs	“The aims of this study were to evaluate the postoperative pain, cognitive function and serum levels of pro-inflammatory cytokines in patients undergoing hip arthroplasty surgery with pre- or intraoperative flurbiprofen.” Posited that flurbiprofen preventive for dNCR.
Hollinger 2021	143	Antipsychotics	“This randomised, double-blinded, placebo-controlled study aimed to compare haloperidol and ketamine separately and in combination to prevent the incidence of postoperative delirium.”
Xiang 2022	174	Corticosteroids	“This randomized, double-blind, placebo-controlled trial was designed to evaluate whether a single preoperative dose of methylprednisolone reduced the rate of POD in older patients undergoing gastrointestinal surgery and its association with the shedding of endothelial glycocalyx markers.”
Shen 2022	120	NSAIDs	Per registry, primary outcome was mortality; per article, primary outcome was delirium
Kuang 2023	88	Benzodiazepine (sa)	effect of remimazolam on neurocognitive outcomes
Liao 2023	104	Benzodiazepine (sa)	we hypothesized that remimazolam might reduce the incidence of POCD in older patients by decreasing intraoperative neuroinflammatory reactions, improving hemodynamic stability, and lowering perioperative opioid usage
Sun 2023b	120	Benzodiazepine (sa)	Remimazolam combined with general anesthesia in improving stress and cognitive performance.
Yang 2023	320	Benzodiazepine (sa)	NA
Retrospective Cohort
Poeran 2020a	527,254	Benzodiazepine (sa)	NA
Poeran 2020b	527,254	Corticosteroids	NA
Poeran 2020c	527,254	NSAIDs Benzodiazepine (any)	NA
Poeran 2020f	527,254	Benzodiazepine (la)	NA
Poeran 2020g	527,254	Benzodiazepine (any)	NA
Poeran 2020h	527,254	Nonbenzodiazepine hypnotics	NA

Other Studies

Table 21. Studies with aim including examining adverse effects of a potentially inappropriate medication outside a delirium prevention trial.

Study	N	Drug Class	Study Aim
Randomized Clinical Trial
Sultan 2010	152	Benzodiazepine (sa)	“The incidence of postoperative delirium will be tested if affected by three different sedative drugs including melatonin.” But included midazolam as comparator without hypothesized impact on delirium.
Whitlock 2015	7,507	Corticosteroids	“We aimed to assess whether prophylactic steroids benefit patients at high risk of morbidity and mortality undergoing cardiac surgery with cardiopulmonary bypass.” Delirium was included as a safety outcome.
Dianatkhah 2015	145	Benzodiazepine (la)	“Based on the above-affirmed data, the present study sought to evaluate the effect of melatonin on postoperative sleep in patients undergoing CABG.”
Yu 2017	92	Benzodiazepine (sa)	“Therefore, the comparison of the post-anesthesia delirium of elderly patients treated with thoracic surgery between Dexmedetomidine and Midazolam Maleate was discussed in this paper, expecting to provide clinical references.” Midazolam noted only as comparator without posited effect on delirium.
He 2018	90	Benzodiazepine (sa)	“To study the preventive effect of dexmedetomidine (DEX) on the postoperative delirium (POD) in elderly patients aged over 75 years old after vertebral fracture operation, and its regulating effect on the depth of anesthesia during operation.”
Azeem 2018	70	Benzodiazepine (sa)	“This study was designed to compare dexmedetomidine with morphine and midazolam‑based regimen after cardiac surgery at equivalent levels of sedation and analgesia to decrease the incidence of postoperative delirium.”
Li 2019	164	Benzodiazepine (sa)	“The primary aim of this study was to evaluate the short-term (1 week postoperatively) and long-term (1 year postoperatively) incidence of POCD after elective joint replacement surgery in patients aged ≥65 years.” Delirium prevention trial included benzodiazepines as a comparator, with authors noting its potential to cause delirium.
Hongyu 2019	90	Anticholinergics	“Pentanethaquine hydrochloride (PHC) is a novel, selective anticholinergic drug. Due to its strong anti-cholinergic effect on the central and peripheral nerves and no side effect of accelerated heart rate, it has been increasingly used in general anesthesia recently. However, studies have shown that PHC may increase the incidence of POCD and PD and may decrease the concentration of inflammatory cytokines, but there is no clear evidence to confirm either the pros and cons of this drug. Therefore, the elderly patients with lung cancer undergoing thoracoscopic surgery under general anesthesia were selected to determine whether PHC is suitable for use in elderly patients.”
Wang 2020a	44	Benzodiazepine (sa)	“… [R]etrospectively compare[d] the effects of hydromorphone plus midazolam and hydromorphone plus dexmedetomidine as sedatives following oral and maxillofacial surgery.”
Tan 2022	99	Benzodiazepine (sa)	“[W]e aimed to evaluate the effect of RT [remimazolam tosilate] on the early cognitive function of elderly patients undergoing upper GI endoscopy.”
Brondum 2022	39	Corticosteroids	effects of methylprednisolone on postop pain, nausea, and recovery after open hernia repair
Zeng 2022	60	Corticosteroids	effect of dexamethasone on pain and quality of recovery
Deng 2023	108	Benzodiazepine (sa)	effect of remimazolam on sleep quality
Kowark 2024	616	Benzodiazepine (sa)	Primary outcome is patient satisfaction
Randomized Cluster Crossover Trial
Spence 2020	800	Benzodiazepine (sa)	“[W]e designed a pragmatic randomised cluster crossover trial to test whether an institutional policy of restricted use of benzodiazepines during surgery (compared with liberal use) reduces postoperative delirium.”
Nonrandomized Trial
Van Grootven 2016	86	Benzodiazepine (ns)	“The aim of the present secondary data analysis was therefore to investigate if preoperative state anxiety is a risk factor for postoperative delirium in older hip fracture patients.”
Before-After/Time Series
Ushida 2009	122	Corticosteroids	“The aim of the present study was to investigate factors contributing to the development of postoperative delirium in cervical surgery.”
Yamasaki 2019	21	H2 blockers	“The present study evaluated and compared the incidence rates and severities of postoperative delirium between the famotidine and omeprazole groups in patients receiving hepatectomy who were over 65 years of age.”
Prospective Cohort
Wang 2021	1,266	Benzodiazepine (sa)	“[T]he aim of this study is to assess the effect of intravenous midazolam as a premedication on the incidence of postoperative delirium in older adults.”
Pipanmekaporn 2021	429	Benzodiazepine (ns)	risk factors of delirium
Ke 2022a	98	Benzodiazepine (sa)	Risk factor study aimed to do a pragmatic observational study using Nu-DESC to understand the incidence of PACU delirium in patients aged 65 years and older after major non-cardiac surgery
Leigheb 2022	83	Benzodiazepine (sa)	risk factors for delirium
Duprey 2022	566	Benzodiazepine (ns) Antipsychotics NSAIDs Anticholinergics	“To better understand the important potential role of presurgical and postsurgical medication use on postoperative delirium and PND [postoperative neurocognitive disorder] in older adults undergoing major surgery, we sought to investigate 3 associations: (1) presurgical medication use and postoperative delirium; (2) inpatient, postsurgical medication use and postoperative delirium; and (3) the delirium-independent relationship between inpatient, postsurgical medication use and cognition 1 month after surgery.”
Aoki 2023	222	Benzodiazepine (sa)	“[W]e conducted a prospective observational study to investigate whether general anesthesia with remimazolam is associated with the development of postoperative delirium when compared with other anesthetic agents.”
Retrospective Cohort
Slor 2011a	526	Benzodiazepine (ns)	This study examined the effect of general anesthesia on postoperative delirium in a large homogeneous participant group. Study outcomes were also stratified for delirium risk factors, examining risk of delirium associated with general anesthesia in individuals undergoing hip surgery with and without cognitive impairment. Effects of classes of medications on postoperative delirium were explored. Understanding the role of anesthetic technique and perioperative medications as risk factors for postoperative delirium may further increase knowledge of potential methods to prevent postoperative delirium.
Mangusan 2015a	656	Benzodiazepine (ns)	“The purpose of this study was to examine the effect of postoperative delirium on 5 outcome measures in patients who had cardiovascular surgery with use of cardiopulmonary bypass: length of postoperative hospital stay, prevalence of falls, discharge to a nursing facility (skilled nursing facility, long-term acute care facility, rehabilitation center), discharge to home with home health services, and use of inpatient physical therapy.”
Mangusan 2015b	656	NSAIDs	“The purpose of this study was to examine the effect of postoperative delirium on 5 outcome measures in patients who had cardiovascular surgery with use of cardiopulmonary bypass: length of postoperative hospital stay, prevalence of falls, discharge to a nursing facility (skilled nursing facility, long-term acute care facility, rehabilitation center), discharge to home with home health services, and use of inpatient physical therapy.”
Mangusan 2015c	656	Nonbenzodiazepine hypnotics	“The purpose of this study was to examine the effect of postoperative delirium on 5 outcome measures in patients who had cardiovascular surgery with use of cardiopulmonary bypass: length of postoperative hospital stay, prevalence of falls, discharge to a nursing facility (skilled nursing facility, long-term acute care facility, rehabilitation center), discharge to home with home health services, and use of inpatient physical therapy.”
Weinstein 2018a	41,766	Benzodiazepine (ns)	risk factors of delirium
Weinstein 2018b	41,766	Benzodiazepine (ns)	risk factors of delirium
Memtsoudis 2019 THA	564,226	Benzodiazepine (any) Benzodiazepine (sa) Benzodiazepine (la) Corticosteroids NSAIDs	“We hypothesized that the incidence of postoperative delirium and its risk factors among joint arthroplasty patients would be reduced over time and that modifiable risk factors could be identified.”
Fuchita 2019a	84	Benzodiazepine (ns)	Risk factor study.
Fuchita 2019b	84	Corticosteroids	Risk factor study.
Memtsoudis 2019k	564,226	Benzodiazepine (any) Benzodiazepine (sa) Benzodiazepine (la) Corticosteroids NSAIDs	“We hypothesized that the incidence of postoperative delirium and its risk factors among joint arthroplasty patients would be reduced over time and that modifiable risk factors could be identified.”
Memtsoudis 2019l	1,130,569	Benzodiazepine (any) Benzodiazepine (sa) Benzodiazepine (la) Corticosteroids NSAIDs	“We hypothesized that the incidence of postoperative delirium and its risk factors among joint arthroplasty patients would be reduced over time and that modifiable risk factors could be identified.”
Mueller 2020a	651	Benzodiazepine (sa)	risk factors for delirium
Mueller 2020b	651	Antipsychotics	risk factors for delirium
Burfeind 2022	1,627	Corticosteroids H2 blockers Benzodiazepine (sa)	“[O]ur objective was to assess whether perioperative PIM administration was associated with poor outcomes in geriatric patients with preexisting frailty or cognitive impairment.”
Koch 2023	1,058	Benzodiazepine (sa)	depth of anesthesia and cognitive outcomes
Liu 2023a	195	Benzodiazepine (sa)	risk factors for delirium
Yoshimura 2023	16,185	Benzodiazepine (sa)	The association between the administration of midazolam and the incidence of postoperative delirium was evaluated using extensive data to assess the safety of the intraoperative administration of midazolam during cardiac surgery.
Zarour 2023	1,973	Benzodiazepine (sa)	We therefore aimed to evaluate the independent association between midazolam premedication and postoperative delirium, as well as other postoperative complications, in elderly surgical patients.
Case-Control
Nandi 2014	463	Benzodiazepine (ns)	“The aim of this study was to explore if administration of specific anesthetic agents, opiate pain medications, or benzodiazepines increases the risk of post-operative delirium following total hip and knee arthroplasty.”
Choi 2019	58	Corticosteroids	“The objective of this study was to investigate the beneficial effects of early (within 72 h) treatment with corticosteroids in patients with postoperative ALI [acute lung injury] compared with late treatment. Our hypothesis was that fibroproliferation, which is an early response to lung injury, would be inhibited by early corticosteroid treatment without serious adverse events.”

Risk of Bias

Randomized

Figure 1. Summary risk of bias assessment for randomized clinical trials.

Figure 2. Risk of bias assessments for randomized clinical trials.

Nonrandomized

Figure 3. Summary risk of bias assessment for nonrandomized studies.

Figure 4. Risk of bias assessments for nonrandomized studies.

Causal Model

Figure 5. Causal model for the relationship between potentially inappropriate medications and outcomes. Likely mediators include anesthetics, other drugs, pain, hypotension, clinical instability, infection, electrolytes, and sleep deprivation.

PIM: potentially inappropriate medications; dNCR: delayed neurcognitive recovery (<30 days); POCD: postoperative cognitive disorder (30 days to 1 year); NCD: neurocognitive disorders (> 1 year).

References

Aizawa K, Kanai T, Saikawa Y, Takabayashi T, Kawano Y, Miyazawa N, Yamamoto T: A novel approach to the prevention of postoperative delirium in the elderly after gastrointestinal surgery. Surg Today 2022; 32:310–4

Aoki Y, Kurita T, Nakajima M, Imai R, Suzuki Y, Makino H, Kinoshita H, Doi M, Nakajima Y: Association between remimazolam and postoperative delirium in older adults undergoing elective cardiovascular surgery: A prospective cohort study. J Anesth 2023; 37:13–22

Azeem TMA, Yosif NE, Alansary AM, Esmat IM, Mohamed AK: Dexmedetomidine vs morphine and midazolam in the prevention and treatment of delirium after adult cardiac surgery; a randomized, double-blinded clinical trial. Saudi Journal of Anaesthesia 2018; 12:190–7

Brøndum TL, Leerhøy B, Jensen KK: Effect of preoperative, high-dose glucocorticoid on early cognitive function after abdominal wall reconstruction –a randomized controlled trial. International Journal of Surgery Open 2022; 48 C7 - 100567

Burfeind KG, Zarnegarnia Y, Tekkali P, O’Glasser AY, Quinn JF, Schenning KJ: Potentially inappropriate medication administration is associated with adverse postoperative outcomes in older surgical patients: A retrospective cohort study. Anesth Analg 2022; 135:1048–56

Choi H, Shin B, Yoo H, Suh GY, Cho JH, Kim HK, Choi YS, Kim J, Zo JI, Shim YM, Jeon K: Early corticosteroid treatment for postoperative acute lung injury after lung cancer surgery. Ther Adv Respir Dis 2022; 13:1753466619840256

Deng CM, Meng ZT, Yang J, Zhang CJ, Lu M, Wang YX, Mu DL: Effect of intraoperative remimazolam on postoperative sleep quality in elderly patients after total joint arthroplasty: A randomized control trial. Journal of Anesthesia 2023; 37:511–21

Dianatkhah M, Ghaeli P, Hajhossein Talasaz A, Karimi A, Salehiomran A, Bina P, Jalali A, Ghaffary S, Shahmansouri N, Vejdani S: Evaluating the potential effect of melatonin on the post-cardiac surgery sleep disorder. J Tehran Heart Cent 2015; 10:122–8

Dieleman JM, Nierich AP, Rosseel PM, Maaten JM van der, Hofland J, Diephuis JC, Schepp RM, Boer C, Moons KG, Herwerden LA van, Tijssen JG, Numan SC, Kalkman CJ, Dijk D van, Dexamethasone for Cardiac Surgery Study G: Intraoperative high-dose dexamethasone for cardiac surgery: A randomized controlled trial. JAMA 2012; 308:1761–7

10.

Duprey MS, Devlin JW, Griffith JL, Travison TG, Briesacher BA, Jones R, Saczynski JS, Schmitt EM, Gou Y, Marcantonio ER, Inouye SK: Association between perioperative medication use and postoperative delirium and cognition in older adults undergoing elective noncardiac surgery. Anesth Analg 2022; 134:1154–63

11.

Fuchita M, Khan SH, Perkins AJ, Gao S, Wang S, Kesler KA, Khan BA: Perioperative risk factors for postoperative delirium in patients undergoing esophagectomy. Ann Thorac Surg 2022; 108:190–5

12.

Fukata S, Kawabata Y, Fujishiro K, Kitagawa Y, Kuroiwa K, Akiyama H, Takemura M, Ando M, Hattori H: Haloperidol prophylaxis for preventing aggravation of postoperative delirium in elderly patients: A randomized, open-label prospective trial. Surg Today 2022; 47:815–26

13.

Fukata S, Kawabata Y, Fujisiro K, Katagawa Y, Kuroiwa K, Akiyama H, Terabe Y, Ando M, Kawamura T, Hattori H: Haloperidol prophylaxis does not prevent postoperative delirium in elderly patients: A randomized, open-label prospective trial. Surg Today 2022; 44:2305–13

14.

Glumac S, Kardum G, Sodic L, Supe-Domic D, Karanovic N: Effects of dexamethasone on early cognitive decline after cardiac surgery: A randomised controlled trial. Eur J Anaesthesiol 2017; 34:776–84

15.

Hakim SM, Othman AI, Naoum DO: Early treatment with risperidone for subsyndromal delirium after on-pump cardiac surgery in the elderly: A randomized trial. Anesthesiology 2012; 116:987–97

16.

He F, Shen L, Zhong J: A study of dexmedetomidine in the prevention of postoperative delirium in elderly patients after vertebral osteotomy. International Journal of Clinical and Experimental Medicine 2018; 11:4984–90

17.

Hollinger A, Rüst CA, Riegger H, Gysi B, Tran F, Brügger J, Huber J, Toft K, Surbeck M, Schmid HR, Rentsch K, Steiner L, Siegemund M: Ketamine vs. Haloperidol for prevention of cognitive dysfunction and postoperative delirium: A phase IV multicentre randomised placebo-controlled double-blind clinical trial. J Clin Anesth 2021; 68:110099

18.

Hongyu X, Qingting W, Xiaoling S, Liwu Z, Ailing Y, Xin L: Penehyclidine hydrochloride on postoperatively cognitive function. Med Hypotheses 2019; 129:109246

19.

Huang JW, Yang YF, Gao XS, Xu ZH: A single preoperative low-dose dexamethasone may reduce the incidence and severity of postoperative delirium in the geriatric intertrochanteric fracture patients with internal fixation surgery: An exploratory analysis of a randomized, placebo-controlled trial. J Orthop Surg Res 2023; 18:441

20.

Ishibashi-Kanno N, Takaoka S, Nagai H, Okubo-Sato M, Fukuzawa S, Uchida F, Yamagata K, Yanagawa T, Bukawa H: Postoperative delirium after reconstructive surgery for oral tumor: A retrospective clinical study. International Journal of Oral and Maxillofacial Surgery 2020; 49:1143–8

21.

Kalisvaart KJ, Jonghe JF e, Bogaards MJ, Vreeswijk R, Egberts TC, Burger BJ, Eikelenboom P, Gool WA van: Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: A randomized placebo-controlled study. J Am Geriatr Soc 2022; 53:1658–66

22.

Kaneko S, Morimoto T, Ichinomiya T, Murata H, Yoshitomi O, Hara T: Effect of remimazolam on the incidence of delirium after transcatheter aortic valve implantation under general anesthesia: A retrospective exploratory study. Journal of Anesthesia 2023; 37:210–8

23.

Ke Y, Chew S, Seet E, Wong WY, Lim V, Chua N, Zhang J, Lim B, Chua V, Loh NHW, Ti LK: Incidence and risk factors of delirium in post-anaesthesia care unit. Ann Acad Med Singap 2022; 51:87–95

24.

Koch S, Blankertz B, Windmann V, Spies C, Radtke FM, Röhr V: Desflurane is risk factor for postoperative delirium in older patients’ independent from intraoperative burst suppression duration. Front Aging Neurosci 2023; 15:1067268

25.

Kuang Q, Zhong N, Ye C, Zhu X, Wei F: Propofol versus remimazolam on cognitive function, hemodynamics, and oxygenation during one-lung ventilation in older patients undergoing pulmonary lobectomy: A randomized controlled trial. J Cardiothorac Vasc Anesth 2023; 37:1996–2005

26.

Larsen KA, Kelly SE, Stern TA, Bode RH, Jr. P, L. L. H, D. J. G, D. B, B. E. S, G. A. H, K. A. C, J. J. P: Administration of olanzapine to prevent postoperative delirium in elderly joint-replacement patients: A randomized, controlled trial. Psychosomatics 2022; 51:409–18

27.

Leigheb M, De Sire A, Zeppegno P, Forni F, Sgreccia M, Gagliardi VP, Pogliacomi F, Sabbatini M: Delirium risk factors analysis post proximal femur fracture surgery in elderly. Acta Biomed 2022; 92:e2021569

28.

Leung JM, Sands LP, Chen N, Ames C, Berven S, Bozic K, Burch S, Chou D, Covinsky K, Deviren V, Kinjo S, Kramer JH, Ries M, Tay B, Vail T, Weinstein P, Chang S, Meckler G, Newman S, Tsai T, Voss V, Youngblom E: Perioperative gabapentin does not reduce postoperative delirium in older surgical patients: A randomized clinical trial. Anesthesiology 2017; 127:633–44

29.

Li WX, Luo RY, Chen C, Li X, Ao JS, Liu Y, Yin YQ: Effects of propofol, dexmedetomidine, and midazolam on postoperative cognitive dysfunction in elderly patients: A randomized controlled preliminary trial. Chin Med J (Engl) 2019; 132:437–45

30.

Liao YQ, Min J, Wu ZX, Hu Z: Comparison of the effects of remimazolam and dexmedetomidine on early postoperative cognitive function in elderly patients with gastric cancer. Frontiers in Aging Neuroscience 2023; 15

31.

Liu J, Li J, Gao D, Wang J, Liu M, Yu D: High ASA physical status and low serum uric acid to creatinine ratio are independent risk factors for postoperative delirium among older adults undergoing urinary calculi surgery. Clin Interv Aging 2023; 18:81–92

32.

Mangusan RF, Hooper V, Denslow SA, Travis L: Outcomes associated with postoperative delirium after cardiac surgery. Am J Crit Care 2015; 24:156–63

33.

Mansouri N, Nasrollahi K, Shetabi H: Prevention of cognitive dysfunction after cataract surgery with intravenous administration of midazolam and dexmedetomidine in elderly patients undergoing cataract surgery. Adv Biomed Res 2019; 8:6

34.

Mardani D, Bigdelian H: Prophylaxis of dexamethasone protects patients from further post-operative delirium after cardiac surgery: A randomized trial. Journal of Research in Medical Sciences 2013; 18:137–43

35.

Memtsoudis S, Cozowicz C, Zubizarreta N, Weinstein SM, Liu J, Kim DH, Poultsides L, Berger MM, Mazumdar M, Poeran J: Risk factors for postoperative delirium in patients undergoing lower extremity joint arthroplasty: A retrospective population-based cohort study. Reg Anesth Pain Med 2019 doi:10.1136/rapm-2019-100700

36.

37.

Mueller A, Spies CD, Eckardt R, Weiss B, Pohrt A, Wernecke KD, Schmidt M: Anticholinergic burden of long-term medication is an independent risk factor for the development of postoperative delirium: A clinical trial. J Clin Anesth 2020; 61:109632

38.

Nandi S, Harvey WF, Saillant J, Kazakin A, Talmo C, Bono J: Pharmacologic risk factors for post-operative delirium in total joint arthroplasty patients: A case-control study. J Arthroplasty 2022; 29:268–71

39.

Ottens TH, Dieleman JM, Sauer AM, Peelen LM, Nierich AP, Groot WJ e, Nathoe HM, Buijsrogge MP, Kalkman CJ, Dijk D van, Group DE for CSS: Effects of dexamethasone on cognitive decline after cardiac surgery: A randomized clinical trial. Anesthesiology 2022; 121:492–500

40.

Park CM, Inouye SK, Marcantonio ER, Metzger E, Bateman BT, Lie JJ, Lee SB, Levin R, Kim DH: Perioperative gabapentin use and in-hospital adverse clinical events among older adults after major surgery. JAMA Intern Med 2022; 182:1117–27

41.

Pipanmekaporn T, Punjasawadwong Y, Wongpakaran N, Wongpakaran T, Suwannachai K, Chittawatanarat K, Mueankwan S: Risk factors and adverse clinical outcomes of postoperative delirium in thai elderly patients: A prospective cohort study. Perspect Psychiatr Care 2021; 57:1073–82

42.

Poeran J, Cozowicz C, Zubizarreta N, Weinstein SM, Deiner SG, Leipzig RM, Friedman JI, Liu J, Mazumdar M, Memtsoudis SG: Modifiable factors associated with postoperative delirium after hip fracture repair: An age-stratified retrospective cohort study. European Journal of Anaesthesiology 2020; 37:649–58

43.

Prakanrattana U, Prapaitrakool S: Efficacy of risperidone for prevention of postoperative delirium in cardiac surgery. Anaesth Intensive Care 2007; 35:714–9

44.

Royse CF, Saager L, Whitlock R, Ou-Young J, Royse A, Vincent J, Devereaux PJ, Kurz A, Awais A, Panjasawatwong K, Sessler DI: Impact of methylprednisolone on postoperative quality of recovery and delirium in the steroids in cardiac surgery trial: A randomized, double-blind, placebo-controlled substudy. Anesthesiology 2017; 126:223–33

45.

Sauer AM, Slooter AJ, Veldhuijzen DS, Eijk MM van, Devlin JW, Dijk D van: Intraoperative dexamethasone and delirium after cardiac surgery: A randomized clinical trial. Anesth Analg 2022; 119:1046–52

46.

Shen L, Chen JQ, Yang XL, Hu JC, Gao W, Chai XQ, Wang D: Flurbiprofen used in one-lung ventilation improves intraoperative regional cerebral oxygen saturation and reduces the incidence of postoperative delirium. Frontiers in Psychiatry 2022; 13

47.

Slor CJ, Jonghe JF e, Vreeswijk R, Groot E, Ploeg TV, Gool WA van, Eikelenboom P, Snoeck M, Schmand B, Kalisvaart KJ: Anesthesia and postoperative delirium in older adults undergoing hip surgery. J Am Geriatr Soc 2011; 59:1313–9

48.

Spence J, Belley-Côté E, Jacobsohn E, Lee SF, Whitlock R, Bangdiwala S, Syed S, Sarkaria A, MacIsaac S, Lengyel A, Long S, Um K, McIntyre WF, Kavosh M, Fast I, Arora R, Lamy A, Connolly S, Devereaux PJ: Restricted versus liberal intraoperative benzodiazepine use in cardiac anaesthesia for reducing delirium (b-free pilot): A pilot, multicentre, randomised, cluster crossover trial. Br J Anaesth 2020; 125:38–46

49.

Sultan SS: Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth 2010; 4:169–73

50.

Sun Y, Zhang J, Feng S: Remimazolam supplemented to general anesthesia alleviates stress and cognitive impairment in elder patients after hip surgery. Psychiatry Investigation 2023; 20:301–6

51.

Tan Y, Ouyang W, Tang Y, Fang N, Fang C, Quan C: Effect of remimazolam tosilate on early cognitive function in elderly patients undergoing upper gastrointestinal endoscopy. J Gastroenterol Hepatol 2022; 37:576–83

52.

Ushida T, Yokoyama T, Kishida Y, Hosokawa M, Taniguchi S, Inoue S, Takemasa R, Suetomi K, Arai YC, McLaughlin M, Tani T: Incidence and risk factors of postoperative delirium in cervical spine surgery. Spine (Phila Pa 1976) 2022; 34:2500–4

53.

Valentin LSS, Pereira VFA, Pietrobon RS, Schmidt AP, Oses JP, Portela LV, Souza DO, Vissoci JRN, Da Luz VF, De Souza Trintoni LMDA, Nielsen KC, Carmona MJC: Effects of single low dose of dexamethasone before noncardiac and nonneurologic surgery and general anesthesia on postoperative cognitive dysfunction - a phase III double blind, randomized clinical trial. PLoS ONE 2016; 11

54.

Van Grootven B, Detroyer E, Devriendt E, Sermon A, Deschodt M, Flamaing J, Dubois C, Milisen K: Is preoperative state anxiety a risk factor for postoperative delirium among elderly hip fracture patients? Geriatr Gerontol Int 2016; 16:948–55

55.

Wang L, Zhang T, Huang L, Peng W: Comparison between dexmedetomidine and midazolam for sedation in patients with intubation after oral and maxillofacial surgery. Biomed Res Int 2020; 2020:7082597

56.

Wang ML, Min J, Sands LP, Leung JM: Midazolam premedication immediately before surgery is not associated with early postoperative delirium. Anesth Analg 2021; 133:765–71

57.

Wang W, Li HL, Wang DX, Zhu X, Li SL, Yao GQ, Chen KS, Gu XE, Zhu SN: Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: A randomized controlled trial*. Crit Care Med 2022; 40:731–9

58.

Weinstein SM, Poultsides L, Baaklini LR, Mörwald EE, Cozowicz C, Saleh JN, Arrington MB, Poeran J, Zubizarreta N, Memtsoudis SG: Postoperative delirium in total knee and hip arthroplasty patients: A study of perioperative modifiable risk factors. Br J Anaesth 2018; 120:999–1008

59.

Whitlock RP, Devereaux PJ, Teoh KH, Lamy A, Vincent J, Pogue J, Paparella D, Sessler DI, Karthikeyan G, Villar JC, Zuo Y, Avezum A, Quantz M, Tagarakis GI, Shah PJ, Abbasi SH, Zheng H, Pettit S, Chrolavicius S, Yusuf S, Investigators S: Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): A randomised, double-blind, placebo-controlled trial. Lancet 2022; 386:1243–53

60.

Xiang XB, Chen H, Wu YL, Wang K, Yue X, Cheng XQ: The effect of preoperative methylprednisolone on postoperative delirium in older patients undergoing gastrointestinal surgery: A randomized, double-blind, placebo-controlled trial. J Gerontol A Biol Sci Med Sci 2022; 77:517–23

61.

Yamasaki M, Fukuda Y, Tanimoto A, Narahara M, Kawaguchi Y, Ushiroda H, Fukuda S, Murakami T, Maeda Y: Reduction in the rate of postoperative delirium by switching from famotidine to omeprazole in japanese hepatectomized recipients. J Pharm Health Care Sci 2022; 5:10

62.

Yang JJ, Lei L, Qiu D, Chen S, Xing LK, Zhao JW, Mao YY, Yang JJ: Effect of remimazolam on postoperative delirium in older adult patients undergoing orthopedic surgery: A prospective randomized controlled clinical trial. Drug Design, Development and Therapy 2023; 17:143–53

63.

Yoshimura M, Hidaka Y, Morimoto Y: Association between the use of midazolam during cardiac anesthesia and the incidence of postoperative delirium: A retrospective cohort study using a nationwide database. Journal of Cardiothoracic and Vascular Anesthesia 2023 doi:10.1053/j.jvca.2023.08.147

64.

Yu DN, Zhu Y, Ma J, Sun Q: Comparison of post-anesthesia delirium in elderly patients treated with dexmedetomidine and midazolam maleate after thoracic surgery. Biomedical Research (India) 2017; 28:6852–5

65.

Zarour S, Weiss Y, Kiselevich Y, Iacubovici L, Karol D, Shaylor R, Davydov T, Matot I, Cohen B: The association between midazolam premedication and postoperative delirium - a retrospective cohort study. Journal of Clinical Anesthesia 2023 doi:10.1016/j.jclinane.2023.111113

66.

Zeng Y, Wang Q, Hu J, Yang J: Adding dexamethasone to adductor canal block combined with iPACK block improve postoperative analgesia of total knee arthroplasty. Clinical Journal of Pain 2022; 38:575–81

67.

Zhou ZJ, Tang J, Li WH, Tao WD: Preoperative intravenous flurbiprofen reduces postoperative pain and inflammatory cytokines in elderly patients after hip arthroplasty. Exp Ther Med 2019; 17:354–8

68.

Zhu Y, Yao R, Li Y, Wu C, Heng L, Zhou M, Yan L, Deng Y, Zhang Z, Ping L, Wu Y, Wang S, Wang L: Protective effect of celecoxib on early postoperative cognitive dysfunction in geriatric patients. Front Neurol 2018; 9:633