. 2022 Aug 27;26:258. doi: 10.1186/s13054-022-04131-9

Table 3.

Summary of evidence-based therapies, potentially useful therapies, and emerging therapies to prevent AKI-associated delirium

Direct evidence-based therapies [23]	Indirect evidence-based therapies [44, 100, 110, 113, 117]	Emerging therapies and future investigations [66, 96, 97, 116]
Study: Prospective cohort Siew et al. 2017 Findings: Renal replacement therapy is associated with a reduced odds of delirium in AKI Recommendations: Future studies are needed to examine the mechanisms underlying these associations and the effects renal replacement therapy may have on AKI-associated delirium. Consider the use of renal replacement therapy to reduce risk of delirium	Study: Systematic review and meta-analysis on dexmedetomidine Flükiger et al. 2018 Findings: Overall incidence of delirium in the dexmedetomidine group was significantly lower compared to placebo, standard sedatives, and opioids Recommendations: Preferential use of dexmedetomidine for sedation, which may also potentially be renally protective (Liu et al.)	Study: Study on the use of anti-IL-6 to reverse delirium-like phenotypes in mice model of UTI Rashid et al. 2021 Findings: Mice with UTI had significantly elevated plasma IL-6 and demonstrated behavioral impairments that were fully reversed with treatment with systemic anti-IL-6 Recommendations: Given that anti-IL-6 reversed UTI-induced delirium-like phenotypes in mice, future studies should examine if systemic or targeted IL-6 inhibition may also mitigate AKI-associated delirium
	Study: Systematic review of the risk of delirium with different opioids Swart et al. 2017 Findings: Significant risk of delirium from the use of meperidine, compared with other opioids. Decreased risk with hydromorphone and fentanyl Recommendations: Preferential use of fentanyl compared to other opioids in setting of renal impairment	Study: Study of the effects of GSA intrahippocampal injection in rats Pan et al. 1996 Finding: GSA-injected animals led to seizures and damage to the hippocampus that was prevented by the administration of the NMDA receptor antagonist ketamine Recommendations: Given that GSA is increased in the serum and CSF of patients with renal failure, future studies may examine the use of NMDA receptor antagonists to prevent delirium in AKI
	Study: Review paper on use of Drugs in End-Stage Kidney Disease Wilcock et al. 2017 Findings: Lower risk of accumulation with lorazepam compared to diazepam or clonazepam in ESRD Recommendations: When benzodiazepines are indicated, lorazepam may be preferred	Study: Retrospective cohort Murugan et al. 2021 Findings: Lower rates of ultrafiltration reduced organ dysfunction Recommendations: Future studies are needed to determine the effects of lower rates of ultrafiltration on delirium in patients with AKI
	Study: Case–control study Lieberman et al. 1985 Findings: For patients with chronic renal failure, use of tricyclic antidepressants leads to elevated serum levels of glucuronidated metabolites Recommendations: Given that glucuronidated metabolites of tricyclic antidepressants were reported to exert potent biologic effects peripherally and in the central nervous system (Lieberman et al.), a similar accumulation of metabolites may occur in AKI, potentially leading to delirium, although future research is needed to prove this. Minimizing the use of neuropathic agents, which may accumulate in the context of AKI, may decrease delirium risk

Direct evidence-based therapies [23]

Indirect evidence-based therapies [44, 100, 110, 113, 117]

Emerging therapies and future investigations [66, 96, 97, 116]

Study:

Prospective cohort

Siew et al. 2017

Findings:

Renal replacement therapy is associated with a reduced odds of delirium in AKI

Recommendations:

Future studies are needed to examine the mechanisms underlying these associations and the effects renal replacement therapy may have on AKI-associated delirium. Consider the use of renal replacement therapy to reduce risk of delirium

Study:

Systematic review and meta-analysis on dexmedetomidine

Flükiger et al. 2018

Findings:

Overall incidence of delirium in the dexmedetomidine group was significantly lower compared to placebo, standard sedatives, and opioids

Recommendations:

Preferential use of dexmedetomidine for sedation, which may also potentially be renally protective (Liu et al.)

Study:

Study on the use of anti-IL-6 to reverse delirium-like phenotypes in mice model of UTI

Rashid et al. 2021

Findings:

Mice with UTI had significantly elevated plasma IL-6 and demonstrated behavioral impairments that were fully reversed with treatment with systemic anti-IL-6

Recommendations:

Given that anti-IL-6 reversed UTI-induced delirium-like phenotypes in mice, future studies should examine if systemic or targeted IL-6 inhibition may also mitigate AKI-associated delirium

Study:

Systematic review of the risk of delirium with different opioids

Swart et al. 2017

Findings:

Significant risk of delirium from the use of meperidine, compared with other opioids. Decreased risk with hydromorphone and fentanyl

Recommendations:

Preferential use of fentanyl compared to other opioids in setting of renal impairment

Study:

Study of the effects of GSA intrahippocampal injection in rats

Pan et al. 1996

Finding:

GSA-injected animals led to seizures and damage to the hippocampus that was prevented by the administration of the NMDA receptor antagonist ketamine

Recommendations:

Given that GSA is increased in the serum and CSF of patients with renal failure, future studies may examine the use of NMDA receptor antagonists to prevent delirium in AKI

Study:

Review paper on use of Drugs in End-Stage Kidney Disease

Wilcock et al. 2017

Findings:

Lower risk of accumulation with lorazepam compared to diazepam or clonazepam in ESRD

Recommendations:

When benzodiazepines are indicated, lorazepam may be preferred

Study:

Retrospective cohort

Murugan et al. 2021

Findings:

Lower rates of ultrafiltration reduced organ dysfunction

Recommendations:

Future studies are needed to determine the effects of lower rates of ultrafiltration on delirium in patients with AKI

Study:

Case–control study

Lieberman et al. 1985

Findings:

For patients with chronic renal failure, use of tricyclic antidepressants leads to elevated serum levels of glucuronidated metabolites

Recommendations:

Given that glucuronidated metabolites of tricyclic antidepressants were reported to exert potent biologic effects peripherally and in the central nervous system (Lieberman et al.), a similar accumulation of metabolites may occur in AKI, potentially leading to delirium, although future research is needed to prove this. Minimizing the use of neuropathic agents, which may accumulate in the context of AKI, may decrease delirium risk

AKI, Acute kidney injury; ESRD, end-stage renal disease; CKD, chronic kidney disease; CNS, central nervous system; GSA, guanidinosuccinic acid; CSF, cerebrospinal fluid; and NMDA, N-methyl-d-aspartate