New Aussie research suggests intranasal insulin may reduce delirium in select groups of older adults.
Two sprays of insulin a day may be enough to shorten the duration of delirium.
There are few, if any, effective treatments for delirium. But a recent double-blind, randomised, placebo-controlled trial conducted in Sydney reports intranasal insulin reduced delirium duration by a median of three days in certain dementia patients. The findings have been published in Age and Ageing.
“Delirium has been recognised since Hippocrates in 500 BCE, yet despite that and the significant complications that can arise, we still have no proven treatments,” said Dr Anita Nitchingham, a geriatrician from Neuroscience Research Australia and the Prince of Wales Hospital in Sydney, in a statement. Dr Nitchingham was the lead author on the new research.
“Antipsychotics and benzodiazepines are sometimes used, off-label, to manage distressing symptoms, but studies have shown they do not improve outcomes and may cause harm. That’s why we need to look at other options to treat delirium and improve outcomes for patients.”
Researchers recruited 97 patients over the age of 64 who had prevalent delirium on admission to hospital and were being treated by geriatricians on a geriatric medical ward. Patients deemed to be haemodynamically unstable or likely to die within seven days were excluded from the current study. There were no exclusion criteria for patients with mild cognitive impairment or dementia.
Forty-eight patients received insulin (20 international units administered twice daily via an intranasal spray) and 49 patients received the placebo. Treatment was administered from enrolment in the study until the delirium resolved. Reasons for ceasing treatment included the patient was discharged from hospital, the presence of “unacceptable side effects” and the treatment having no effect after seven days.
There was a greater proportion of females in the placebo group compared to the insulin group (78% compared to 48%) but the two groups were otherwise well matched with respect to age, frailty and comorbidities. The average age of included patients was 87.6 years, while 82% of patients had either a hypoactive or mixed delirium motoric subtype.
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There was no difference between the insulin and placebo groups on the study’s primary outcome, delirium duration (median [interquartile range] 4.8 [2.9-9.2] and 6.8 [4.0-9.8] days, respectively). There was also no effect of intranasal insulin on delirium duration (adjusted hazard ratio and 95% confidence interval 0.7, 0.43-1.15) after controlling for the effects of age, sex, frailty, cognition, place of residence, comorbidities and acute illness severity.
Preplanned subgroup analyses revealed an association between age and the effect of insulin. Patients aged 88 years and younger who received insulin had a significant reduction in their delirium duration compared to patients who received placebo (3.9 [2.9-6.9] days versus 7.0 [4.7-9.7] days, aHR [95% CI] 0.34 [0.16-0.74]). However, there was no effect in patients older than 89 years (5.4 [2.9-11.1] days versus 4.9 [2.6-12.9] days, aHR [95% CI] 0.87 [0.39-1.94]). There were no sex-specific effects of insulin in delirium duration.
“In the brain, insulin facilitates glucose transport via glucose transporter type 4 and may also activate glucose transporter type 3, thereby supporting neuronal energy supply,” the authors explained, highlighting that using an intranasal delivery route meant the insulin could bypass the blood-brain barrier without causing other unwanted effects.
The authors were not surprised to see differences regarding the effects of insulin across age groups.
“As brain insulin resistance increases with age, it is plausible that higher doses of insulin may be required in an older population. We used 20 IU of intranasal insulin; however, studies have demonstrated that higher doses can be given without inducing clinically significant hypoglycaemia,” they noted.
The researchers offered several other potential explanations for their findings.
“In preclinical and human studies, intranasal insulin has been shown to modulate neuroinflammation by reducing proinflammatory cytokines such as TNF-alpha and interleukin-6 in the cortex, hippocampus, CSF and serum, while increasing the anti-inflammatory cytokine IL-10 and attenuating microglial activation – mechanisms relevant to interrupting the neuroinflammatory cascade implicated in delirium pathogenesis,” they wrote.
“Intranasal insulin also regulates hypothalamic-pituitary-adrenal axis activity by lowering stress-induced cortisol responses in human studies. Additionally, intranasal insulin enhances functional network connectivity, including increased resting-state connectivity between the hippocampus and the default mode network.
“Collectively, these findings highlight intranasal insulin’s potential to target multiple converging mechanisms implicated in delirium, particularly in a heterogeneous older population.”
Patients in the insulin group had a shorter acute length of stay compared to patients in the placebo group (7.9 [4.6-14.5] versus 12.9 [6.9-16.8], adjusted HR [95% CI] 0.56 [0.35-0.89]). There were no other differences between groups with respect to the remaining secondary outcomes (delirium severity, inpatient and 30-day mortality, new admissions to residential aged care facilities and antipsychotic use).
Treatment adherence was high in both groups (91.0% for insulin and 90.9% for placebo), with adverse events occurring in similar rates between the active and control groups (41% of patients receiving insulin, 43% of patients receiving placebo). Most adverse events were mild (e.g., falls, pneumonia and urinary tract infections). Only three adverse events were deemed to be related to the insulin treatment; none of these were considered serious.
“This study provides the first real step toward solving a 2500-year mystery, showing intranasal insulin is safe and feasible, and provides the evidence base we need to go to larger trials,” Dr Nitchingham concluded.
“The next step is to test intranasal insulin in larger, multi-centre trials to confirm whether it improves delirium outcomes across the health system and also to explore if it could be used to prevent delirium in high-risk patients.”
