Efficacy and safety of guanfacine in hospitalized patients with delirium: A scoping review

Abstract

Objective

To assess current evidence regarding guanfacine use in hospitalized patients with delirium.

Introduction

Delirium is a common and important complication of critical illness. Central alpha-2 agonists are often used for symptomatic management. Guanfacine is an enteral central alpha-2 agonist approved for the treatment of attention deficit hyperactivity disorders. However, its use for delirium treatment has not been systematically assessed.

Inclusion criteria

All studies of guanfacine to treat patients with delirium during hospitalization. We excluded reviews, letters, commentaries, correspondence, conference abstracts, expert opinions or editorials.

Methods

We performed a systematic search of the literature using: MEDLINE (Ovid), Embase (Ovid), CENTRAL and SCOPUS (Elsevier) from inception until 29 February, 2024. Two independent reviewers assessed the identified citations and abstracts. Data on study and patient characteristics, as well as efficacy and safety outcomes, were extracted. Efficacy was defined by guanfacine's ability to relieve delirium and improve clinical outcomes, including intensive care unit (ICU) length of stay (LOS), hospital LOS, and mortality. Safety was assessed for hemodynamic stability or other reported side effects.

Results

We screened 908 articles and included two case reports, one case series, two retrospective descriptive cohorts, and one retrospective analytic cohort. Guanfacine therapy was associated with delirium attenuation and a reduction in the use of sedative agents. Median dosage was 1.5 mg daily, with a median time to delirium improvement of 3 days. However, guanfacine therapy was not associated with decreased ICU or hospital LOS. The most frequently reported adverse events were mild hypotension and bradycardia.

Conclusion

There is limited data on the efficacy of guanfacine for the treatment of delirium. However, given its pharmacologic properties and its available safety data, controlled investigations may be justified.

1. Introduction

Delirium is the most common neurological complication among patients admitted to the intensive care unit (ICU).[1], [2], [3] Delirium is also a risk factor for increased hospital length of stay (LOS) and decreased chance of home discharge.⁴

Although pharmacological management appears attractive, most clinical trials have yielded negative or mixed results.[5], [6], [7], [8], [9], [10], [11] Nonetheless, despite lack of strong evidence, they are commonly used to treat delirium among ICU patients in Australia and New Zealand.¹² Among these, dexmedetomidine, a central alpha-2A adrenergic receptor agonist, has shown positive results in some studies and current guidelines suggest it should be considered in mechanically ventilated patients with delirium where the level of agitation precludes extubation.¹³

Guanfacine is an enteral selective alpha-2A adrenergic receptor agonist.¹⁴ (Appendix I). Guanfacine was originally studied as an anti-hypertensive agent in 1975.¹⁵ It was registered in the USA in 1986 as Tenex®, an immediate-release form, for the treatment of hypertension. An extended-release formulation of guanfacine (Intuniv®) was later approved by the FDA in 2009 for the treatment of paediatric and adult attention deficit hyperactivity disorder (ADHD), a condition with phenotypical features, such as inattention, which partly overlap with those of delirium.¹⁶

Delirium and ADHD may share anatomical and pathophysiological mechanisms, both involving functional abnormalities in the dorsolateral prefrontal cortex.[17], [18], [19], [20] ADHD appears characterized by dopaminergic and noradrenergic activity abnormalities,^21,22 while delirium appears characterized by increased noradrenergic activity originating in the locus coeruleus, which impairs attention and cognitive performance.[23], [24], [25], [26] These theoretical models of the mechanisms behind ADHD and delirium are summarized in Appendix II. Thus, guanfacine could potentially offer benefits for delirium treatment, by binding to the alpha-2A receptor in the locus coeruleus and causing presynaptic inhibition of norepinephrine release as shown in Fig. 1.^27,28

Fig. 1.

Comparative illustration of a hypothesized model of neuronal activity in the layer 3 pyramidal neuron at dorsolateral prefrontal cortex (dlPFC) during delirium and guanfacine administration. Fig. 1A. According to this model, in delirium, stress leads to an increase in norepinephrine (NE) signaling. NE binds to alpha1A receptor (α1-AR) and increases Inositol Triphosphate (IP3) that stimulates calcium efflux from smooth endoplasmic reticulum. Increased intracellular calcium activates adenylyl cyclase (AC) that promotes cAMP synthesis. cAMP stimulates phosphokinase A (PKA) activity that opens K family channels including Hyperpolarization-activated cyclic nucleotide–gated channels (HCN)and voltage-gate potassium channel subfamily Q (KCNQ). Opening both channels causes efflux of K⁺ out of cell and leads to neuron hyperpolarization. This state reduces the excitability of layer 3 pyramidal neurons in the dlPFC. Reduced firing of neuronal activity in layer 3 pyramidal neuron impairs working memory and may contribute to delirium. Fig. 1B. Current pharmacological understanding is that Guanfacine binds to alpha2A receptor (α2-AR) of the presynaptic NE releasing axon (blue color) and reduces NE release. Additionally, guanfacine also binds to alpha 2A receptor of post synaptic neuron in the dlPFC. This causes inhibition of AC and lowers the level of cAMP and PKA activity. Consequently, potassium channels are closed, restoring normal dlPFC neuronal activity. α-1AR: Alpha-1A adrenergic receptors, AC: Adenylyl cyclase, cAMP: Cyclic adenosine monophosphate, HCN: Hyperpolarization-activated cyclic nucleotide–gated channels, IP3: Inositol Triphosphate, KCNQ: Voltage-gate potassium channel subfamily Q, NE: Norepinephrine, NMDA: N-methyl-d-aspartate,PKA: Phosphokinase A.

Accordingly, this scoping review aimed to evaluate current knowledge on the clinical efficacy and safety of guanfacine for managing delirium. Efficacy was assessed based on symptom relief, ICU LOS, hospital LOS, and mortality. Safety focused on hemodynamic instability.

2. Methodology

We conducted a scoping review according to the Cochrane Database of Systematic Reviews and Joanna Briggs Institute (JBI) methodology for scoping reviews²⁹ and reported using Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping reviews (PRISMA-ScR).³⁰ The objective of this scoping review was to provide information on data regarding the clinical efficacy and safety of guanfacine use for the treatment of delirium in hospitalized patients with particular focus on ICU patients. A protocol for this review was registered on an Open Science Framework (OSF) and is accessible at https://osf.io/m98hv.

3. Eligibility criteria

The inclusion criteria for this scoping review were defined based on participants, concept, context, and evidence sources.²⁹ Studies involving delirium were included. The concept focused on the use of guanfacine for symptomatic management of delirium. The context of interest was hospitalized adult patients. The types of evidence included randomized controlled trials, prospective cohort studies, retrospective cohort studies, case series and case reports. Articles not published in English, reviews, letters, commentaries, correspondence, conference abstracts, expert opinions and editorials were excluded. Animal studies and in vitro or ex vivo studies were also excluded.

4. Information sources

Databases searched included MEDLINE Ovid ALL <1974 to February 29, 2024>, Embase Ovid Classic <1974 to February 29, 2024 >, Cochrane Central Register of Controlled Trials (CENTRAL) < 2000 to February 29, 2024> and SCOPUS(Elsevier) < 1982 to February 29, 2024>.

5. Search strategy

The search process was conducted in three stages by the lead author (NP). The initial stage involved running preliminary searches in MEDLINE (OVID) and Embase (OVID). From these preliminary searches, relevant studies were identified and analyzed for appropriate indexing terms (e.g. Medical Subject heading (MeSH)) and the titles and abstracts were examined for relevant keywords for our two main concepts: delirium AND guanfacine. In the second stage, a comprehensive search followed, incorporating all indexed terms and keywords across all selected databases. No limits or filters were used to refine the search. The keywords for this step included (Confusion OR Psychomotor Agitation OR bewilderment OR disorientation OR delirium OR delirious OR agitation OR restlessness) AND (Guanfacine OR Estulic OR Tenex). Detailed search syntax included is in Appendix III. In the final stages, the references for included studies were reviewed but no new studies were identified through this process.

6. Selection of sources of evidence

Following the search, all identified citations were collated and uploaded into COVIDENCE, a web-based collaboration software platform that streamlines the production of systematic and other literature reviews. The duplicate articles were removed by the program. Titles and abstracts were screened by two or more independent reviewers for assessment against the inclusion criteria for the review. The full text of selected citations was assessed in detail against the inclusion criteria by two independent reviewers (NP, AP). Any disagreements between the reviewers at each stage of the selection process were resolved through discussion, or by an additional reviewer. The results of the search and the study inclusion process were reported and presented in a PRISMA flow diagram as shown in Fig. 2.

Fig. 2.

PRISMA flow diagram.

7. Data extraction

Two reviewers collaborated to create a data-charting form to determine which variables to extract. In the case report and case series study, we extracted data including patient characteristics, data on delirium and its prior treatment before guanfacine initiation, guanfacine treatment, and its outcome. For cohort studies, we also extracted data including patient characteristics, guanfacine treatment, and efficacy and safety outcome of treatment. Efficacy was assessed based on symptom relief, ICU LOS, hospital LOS and mortality. Safety focused on hemodynamic instability. Data charting forms are shown in Appendix IV.

8. Results

8.1. Search results and included studies

The search strategy identified 908 articles. After the removal of 232 duplicates, the title and abstracts of 676 studies were screened. After screening, 32 papers were selected for full-text review. In the end, six articles were included. There were two case reports, one case series (n = 7), two retrospective descriptive cohort studies (n = 254) and one retrospective analytic cohort study (n = 187). The extracted data from case series and case reports are shown in Table 1, while extracted data from cohort studies are shown in Table 2.

Table 1.

Characteristics of patients, intervention, and outcome in case reports and case series.

Author/Year	no	Age/Sex	Diagnosis	Underlying Disease	Day diagnosisdelirium andguanfacine start	Guanfacineprescribe.(Dose, form)	Concomitantmedication	Outcome	Time toimprovement(Days)
Bauer, 202134	1	17,M	COVID-19 delirium	Autism, anxiety	1, 10	1 mg OD, ER	Quetiapine	Resolution of delirium	3
Jiang, 202132	2	40,M	Acute stroke	None	3, 8	0.5 mg BID, IR	Dexmedetomidine Quetiapine	ICDSC 7 to 3	2.5
	3	74,F	Rupture thoracic aortic aneurysm	NA	4, 5	NA	Haloperidol	ICDSC 8 to 4	3
	4	63,M	pneumothorax, pulmonary contusions	NA	2, 5	NA	Haloperidol	ICDSC 9 to 3	2
	5	33,M	Polysubstance withdrawal	NA	2, 2	NA	Chlorpromazine	ICDSC 11to 4	3
	6	80,M	post total hip replacement	OA, HT	1, 3	1 mg BID, IR	Haloperidol	4AT 12 to 5	2.5
	7	68,F	Urinary tract infection, groin cellulitis	NA	3, 4	NA	Risperidone	4AT 11 to 5	2.5
	8	52,F	Spinal surgery complicated by HAP	NA	2, 4	NA	Quetiapine Haloperidol	4AT 12 to 4	2
Sher, 202031	9	70, F	COVID-19 pneumonia	None	26, 29	0.5–1 mg BID, IR	Melatonin Valproic acid Haloperidol	Resolution of delirium	5

4AT: 4AT delirium assessment tool, BID: twice daily, COVID-19: Coronavirus Disease of 2019, ER: Extended-release form, HAP: Hospital acquired pneumonia, HT: Hypertension, ICDSC: ICU delirium screening checklist, IR: Immediate-release form, NA: No available data, OA: Osteoarthritis, OD: once daily, Und. Disease: underlying disease.

Table 2.

Characteristics of patients, intervention, and outcome in retrospective cohort studies.

Author, year	Na	Age (years)	Comorbidity	Reason for admission n (%)		MV use	Guanfacine prescription	Outcome
Boncyk, 202136	187b	61 (48–72)b	NA	Medical disorder	41.6%	80%	Dose:	- Delirium on day after Prescription OR 1.12 (0.72–1.70)
				Trauma	23.6%		2 (1–4) mgc	-Mortality HR 0.61 (0.22–1.67)
				Surgery	18.4%		Duration:	-ICU free day −0.31(-2.61 – 1.99)
				Cardiovascular	15.9%		3 (2–7) dc	-Hospital free day −0.61 (-3.04–1.81)
Fetters, 202235	105	59 (41–72)b	COVID-19 32% Depression 2% Psychiatric 7%	Post surgery	24%	41%	Dose: 1.5 (1–2) mgc	- Discontinue dexmedetomidine
				Respiratory failure	21%			-at 48 h 58 %
				Cardiogenic shock	18%			-at 72 h 71 %
				ICH, Stroke	11%			-Mortality rate 11 %
				Sepsis	10%			-ICU LOS 13 (8–22) dc
				Trauma	11%			-Hospital LOS 24 (14–36.5) dc
				Others	11%
Jiang, 202333	149	58.12 ±16.67c	Depression 27.5% Neuro 20.8% Anxiety 20.1% COVID-19 14 %	Cardiovascular	15.4%	NA	Initial dose: 1.82 ± 0.55 mgd Max dose: 2.61 ± 0.88 mgd	- Time to 25% reduction of acute sedative agent 71.59 ± 38.88 hoursd
				Respiratory	14%
				Neuro	13.4%
				Hepatic	12%
				Sepsis	10.7%
				Renal	10%
				Gastrointestinal	8.7%

d: day, LOS: Length of stay, MV: Mechanical ventilator, NA: No available data.

^aNumber of guanfacine use/comparator group.

^bComparator was non-pharmacological management of guanfacine.

^cMedian and interquartile range.

^dMean and standard deviation.

8.2. Efficacy of guanfacine

Most studies provided detailed information on the formulation and dosage of guanfacine use. The intermediate release form was commonly utilized across studies,[31], [32], [33] although extended-release formulations were also employed.³⁴ Initial doses typically ranged from 1 to 2 mg per day.[31], [32], [33], [34], [35], [36]

Resolution of delirium was observed in case series and case reports. Bauer et al. and Sher et al. documented two case reports where guanfacine was beneficial for delirium resolution. In both reports, guanfacine was added to the existing antipsychotic regimen, which included quetiapine and haloperidol.^31,34 Additionally, Jiang et al. presented a case series of eight patients, demonstrating that guanfacine improved delirium symptoms.³² According to these case reports and series, improvements in delirium typically occurred 2–5 days after administration.^31,32,34 However, the measurement of symptom improvement was conducted using the Intensive Care Delirium Screening Checklist (ICDSC) and the 4A's (Alertness, Attention, Acute change or fluctuation course, and Age-date of birth-place-current year) test, which are screening tools for delirium rather than for follow-up.³²

Some studies indicated that adding guanfacine to the current symptomatic management of delirium can facilitate the reduction of intravenous sedative agents. Fetter et al. demonstrated that the addition of guanfacine at a median dose of 1.5 mg daily enabled the discontinuation of dexmedetomidine in 58% and 71% of patients at 48 and 72 h, respectively.³⁵ Similarly, Jiang et al. reported that adding guanfacine at doses of 1–2 mg daily resulted in a 25% reduction in sedative agents within 72 h.³³ However, these studies did not provide data on other concurrent sedative agents, and the lack of a comparative group means we cannot exclude the possibility that these effects were due to other agents or the natural course of delirium.

There is limited data on clinical outcomes related to guanfacine treatment for delirium. Only one cohort study by Boncyk et al. provides such data.³⁶ This single-centre retrospective cohort study involved 8521 delirious adult ICU patients. The study compared clinical outcomes among patients who did not receive any pharmacologic treatment for delirium and those who received haloperidol, olanzapine, quetiapine, valproic acid, or guanfacine. Only 187 patients received guanfacine. Compared to non-pharmacologic therapy, guanfacine did not show improvements in ICU LOS, hospital LOS, or hospital mortality. However, this study may have been underpowered and was not well controlled.

8.3. Safety of guanfacine

Only two cohort studies addressed the safety outcomes of guanfacine usage.^33,35 Within these studies, a total of 24 cases of hypotension were observed among 254 patients. Among these cases, only eight were attributed to guanfacine.³⁵ Additionally, bradycardia was reported in 4 patients’ cases.^33,35 Four patients necessitated intubation during guanfacine therapy.³⁵

9. Discussion

9.1. Key findings

In this scoping review, out of 905 studies assessed, only six, involving more than 400 patients, focused on guanfacine for delirium treatment. Notably, all of these were observational studies. Among them, there were two case reports, one case series, and two retrospective descriptive cohort studies, all suggesting that guanfacine may alleviate delirium symptoms within a time frame of two to three days post-administration. However, a single retrospective analytic cohort study compared the outcomes of guanfacine treatment to non-pharmacological approaches to delirium management, revealing no significant difference in mortality rates, duration of stay in the ICU, or overall hospitalization length. Furthermore, adverse effects associated with guanfacine were reported in only two descriptive cohort studies, predominantly manifesting as isolated incidents of hypotension and bradycardia.

9.2. Relationship to previous studies

The potential efficacy of guanfacine in alleviating delirium and facilitating reduction in other sedative medications is consistent with guanfacine's pharmacology and its hypothesized effect on prefrontal cortex disorders.^27,37,38 Most studies included in our review utilized immediate-release guanfacine, this is primarily based on medication availability within each healthcare system. However, considering its pharmacological properties, both immediate-release and extended-release formulations exhibit similar time to peak concentration (1–4 h for immediate-release, 5–6 h for extended-release) and half-life (12–22 h for immediate-release, 13–23 h for extended-release). Consequently, the difference between the two formulations is not substantial.^14,16,[39], [40], [41]

In considering the putative therapeutic onset of guanfacine for delirium treatment, it is essential to acknowledge the pharmacokinetic properties of the medication. As most medications require approximately 4–5 half-lives to achieve steady-state concentrations, both immediate and extended-release formulations of guanfacine are anticipated to take around 2–3 days to demonstrate observable improvements in delirium symptoms or reduction in the use of acute sedative agents. This implies that guanfacine may not exert its full therapeutic effect within the span of a single day.[31], [32], [33], [34], [35]

As previously described, guanfacine's mechanism of action involves selective alpha-2A agonists. Thus, hypotension and bradycardia are the primary concerns for adverse events. Guanfacine immediate release was initially formulated as an antihypertensive medication.⁴² On the other hand, Guanfacine extended release was developed as an alternative medication for ADHD treatment and has been approved to be safe for adolescents and adults. However, our scoping review suggests that the incidence of hypotensive episodes attributed to guanfacine may not be as frequent as anticipated.

9.3. Study implications

Our findings imply that guanfacine has the typical pharmacological properties of an alpha-2A receptor agonist (like clonidine and dexmedetomidine) and may logically offer potential benefits in relieving delirium symptoms among hospitalized patients and potentially reducing the need for acute sedative agents. Moreover, it can be administered enterally, a route of administration not available for dexmedetomidine. However, a minority of patients may experience adverse effects such as hypotension or bradycardia (as is the case with clonidine and/or dexmedetomidine).

Furthermore, this agent has not yet been tested in randomized controlled trials, which makes drawing any conclusions challenging. Therefore, the risk-benefit ratio and comparative therapeutic efficacy of guanfacine relative to other sedative medications need to be carefully evaluated. Randomized controlled trials are needed to assess the efficacy and safety of guanfacine administration in hospitalized patients with delirium.

9.4. Strength and limitations

Our scoping review represents the first comprehensive examination of guanfacine's potential in the treatment of delirium among hospitalized patients, along with its safety profile for therapeutic purposes. We conducted this scoping review systematically, adhering to the standardized JBI methodology. This approach facilitated a comprehensive and unbiased assessment of current literature. This comprehensive review will serve as a cornerstone for directing future research.

This scoping review has several limitations. First, due to limited available data, only observational studies were included, which precluded the possibility of conducting a meta-analysis and providing pooled effect estimates for guanfacine treatment. Thus, a scoping review was regarded as a suitable method for assessment. Second, most of the studies included in our analysis were retrospective and relied solely on electronic medical records for data collection. This method may pose a risk of missing crucial information, particularly related to safety outcomes. Third, most of the studies were non-comparative observational studies. Consequently, it was not possible to assess the comparative therapeutic effects of guanfacine and its safety potential in comparison to other medications or placebo. Fourth, lack of standardized methods for delirium diagnosis and outcome measurement across studies introduces additional variability and potential bias.

9.5. Conclusion

Our review suggests that guanfacine may attenuate delirium or facilitate the reduction of other sedative agents, a finding in-line with its pharmacological properties. Moreover, only a minority of patients experienced side effects and such side effects were of limited clinical impact and typical of those seen with other central apha-2A receptor agonists currently used for the management of delirium. Given these observations, rigorous investigations, particularly through a program of randomized controlled trials are warranted to validate its efficacy and safety for the treatment of delirium.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Nuttapol Pattamin: conceptualisation, methodology, writing of the first draft; Atthaphong Phongphithakchai: assistance with data collection, data curation and data analysis, and preparation of first draft; Sofia Spano: assistance with data collection, data curation and data analysis, and preparation of first draft; Akinori Maeda: assistance with data collection, data curation and data analysis, and preparation of first draft; Anis Chaba: assistance with data collection, data curation and data analysis, and preparation of first draft and staticial supervision; Yukiko Hikasa: assistance with data collection, data curation and data analysis, and preparation of first draft; Rinaldo Bellomo: supervision, conceptualisation, methodology, review of manuscript versions, correction and editing.

Conflict of interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rinaldo Bellomo. MD, PhD, FRACP, FCICM - Editor in chief of Critical Care and Resuscitation If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix.

Appendix I. Supplementary table

Appendix tables I–1.

Pharmacokinetic and pharmacodynamic profile of agents used for delirium treatment (14,16,28,39,40,42).

	Guanfacine IR	Guanfacine ER	Dexmedetomidine	Clonidine
Mechanism	Selective central alpha 2A agonist	Selective central alpha 2A agonist	Central alpha 2 agonist	Central alpha 2 agonist
Pharmacodynamics
Kd (nM)
α2A	14–31	14–31	18	73–84
α2B	1850	1850	31	71
α2C	421	421	ND	81
Ki (nM)
α2A	50.3–93.3	50.3–93.3	0.015–2.1	35.48–61.65
α2B	1020–1380	1020–1380	ND	69.18–309.0
α2C	1120–3890	1120–3890	31	134.89–501.2
5-HT 2A	ND	ND	ND	ND
D1	ND	ND	ND	ND
D2	ND	ND	ND	ND
Pharmacokinetics
-Route	Oral	Oral	IV	Oral
-Bioavailability 80 %		80 %	100%	75–100%
-Tmax (hour)	1–4	5–6	0.17	2.07–5
-Protein binding	70 %	70 %	94 %	20–40 %
-Vd (L/kg)	6.3	6.3	0.85	2.1 L/kg
-Liver metabolism CYP3A5	CYP3A4	CYP3A4 CYP3A5	CYP2A6	CYP2D6 CYP1A2
-Renal excretion	50 %	50 %	95 %	40–60 %
-Fecal excretion	3–6 %	3–6 %	4 %	22 %
-Dialyzable	Poorly	Poorly	ND	Poorly
-T ½ (hour)	12.1–22.8	13–23	2.8	12.7–13.7

5HT: Serotonin receptor subtype, α: alpha adrenergic receptor agonist subtype, CYP: cytochrome p450 subtype, D: Dopamine receptor subtype, DexMed: dexmedetomidine, ER: Extended release, IR: Immediate release, Kd: equilibrium dissociation constant; ratio of drug concentration and receptor concentration to drug receptor complex concentration at equilibrium state in nanomole unit, lower Kd mean high receptor affinity, Ki: inhibitory constant; subtype of Kd which drug concentration occupy fifty percent of receptor, lower Ki mean high affinity, ND: No data, nM: nanomoles, T½: Half life, Tmax: Time to peak concentration, Vd: Volume distribution.

Appendix II. Supplementary figure

Appendix figure I-1.

Illustration of the comparative putative model of the mechanism of ADHD and delirium. Fig. 2A. Genetic predisposition along with environmental risk factors may promote abnormal brain activity in the dorsolateral prefrontal cortex (PFC), ventromedial PFC, anterior cingulate cortex, and parietal cortex via neurotransmitters derangement. Neurotransmitters abnormalities potentially responsible for this condition include dopamine, norepinephrine, serotonin, acetylcholine, GABA, and glutamate. The dopamine system may be responsible for planning and initiation of motor responses, reaction to novelty and processing of reward, while norepinephrine system may be responsible for arousal modulation and cognitive process. Derangement of dopamine and norepinephrine may then result in attention deficit and uncontrolled activity. Fig. 2B. Predisposing preexisting comorbidities along with precipitating risk factors from acute illness promote an increase in the arousal state and appear to trigger locus coeruleus activation to increase norepinephrine release. Norepinephrine release then exerts profound effects on the PFC and causes impairments in working memory and attention performance. ADHD:Attention deficit hyperactivity disorders,GABA:Gamma-aminobutyric acid,PFC:Prefrontal cortex.

Appendix III: Search strategy

Ovid MEDLINE(R) ALL <1946 to February 29, 2024>.

• 1.exp Confusion/
• 2.Psychomotor Agitation/
• 3.confusion.ti,ab,kf.
• 4.bewilderment.ti,ab,kf.
• 5.disorientation.ti,ab,kf.
• 6.delirium.ti,ab,kf.
• 7.delirious∗.ti,ab,kf.
• 8.agitation.ti,ab,kf.
• 9.restlessness.ti,ab,kf.
• 10.1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9
• 11.Guanfacine/
• 12.guanfacine.ti,ab,kf.
• 13.estulic.mp.
• 14.tenex.mp.
• 15.11 or 12 or 13 or 14
• 16.10 and 15

Ovid EMBASE <1946 to February 29, 2024>.

• 1.exp confusion/
• 2.exp delirium/
• 3.agitation/
• 4.confusion.ti,ab,kf.
• 5.bewilderment.ti,ab,kf.
• 6.disorientation.ti,ab,kf.
• 7.delirium.ti,ab,kf.
• 8.delirious∗.ti,ab,kf.
• 9.agitation.ti,ab,kf.
• 10.restlessness.ti,ab,kf.
• 11.1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10
• 12.guanfacine/
• 13.guanfacine.ti,ab,kf.
• 14.estulic.mp.
• 15.tenex.mp.
• 16.12 or 13 or 14 or 15
• 17.11 and 16

Cochrane Library (Wiley) < 2000 to February 29, 2024>.

ID	Search
#1	MeSH descriptor: [Confusion] explode all trees
#2	MeSH descriptor: [Psychomotor Agitation] explode all trees
#3	(confusion∗):ti,ab,kw (Word variations have been searched)
#4	(bewilder∗):ti,ab,kw (Word variations have been searched)
#5	(disorientation):ti,ab,kw (Word variations have been searched)
#6	(delirium):ti,ab,kw (Word variations have been searched)
#7	(delirious∗):ti,ab,kw (Word variations have been searched)
#8	(agitation):ti,ab,kw (Word variations have been searched)
#9	(restless∗):ti,ab,kw (Word variations have been searched)
#10	MeSH descriptor: [Guanfacine] explode all trees
#11	(guanfacine∗):ti,ab,kw (Word variations have been searched)
#12	(“Estulic"):ti,ab,kw (Word variations have been searched)
#13	(“Tenex"):ti,ab,kw (Word variations have been searched)
#14	{OR #1-#9}
#15	{OR #10-#13}
#16	{AND #14-#15}

SCOPUS(Elsevier).

(confusion OR delirium OR agitation OR bewilderment OR disorientation OR delirious∗ OR restlessness) AND (guanfacine OR estulic OR tenex)

Appendix IV. Case extraction form

Appendix tables IV–1.

Case extraction form for case series and case report.

Article characteristics	Article:
	Publication years:
	Authors:
	Study design:
Patient characteristics	Age:
	Sex:
	Comorbidity -COVID -Neuropsychiatry -Neurocognitive disorders
	Admission setting
	Reason of admission
	Mechanical ventilator use
Delirium data	Day of delirium diagnosis
	Medication prior guanfacine start
	Score assessment (CAM, 4AT)
Intervention	Day of guanfacine initiation
	Guanfacine dosage
	Guanfacine formulation
	Guanfacine duration
	Salvage medication
Efficacy outcome	Delirium resolved
	Duration of delirium resolved

Appendix tables IV–2.

Case extraction form for retrospective cohort study.

Article characteristics	Article:
	Publication years:
	Authors:
	Study design:
Patient characteristics	Number of patients
	Sex: male, %
	Comorbidity
	-COVID
	-Neuropsychiatry
	-Neurocognitive disorders
	Admission setting
	Reason of admission
	Mechanical ventilator use
Intervention and comparator	Guanfacine dosage
	Guanfacine formulation
	Guanfacine duration
	Salvage medication
Efficacy outcome	Primary outcome
	-Hazard ratio of mortality
	-Ratio of patient reduction of dexmedetomidine in 48 h
	-Time to reduction of acute sedative agent
	Secondary outcome
	-OR of delirium
	-Hospital LOS
	-ICU LOS or ICU free day
	-Time for delirium resolved
Safety outcome	Cardiovascular safety
	-Hypotension
	-Bradycardia
	-Arrhythmia