ACE Inhibitors: Treating Delirium in ICU Patients

Delirium is defined as a disturbance in mental state that can result in reduced awareness and impaired thinking.¹ According to some estimates, over 2/3 of intensive care unit (ICU) patients experience delirium,² most of whom undergo a combination of its hyperactive (characterized by agitation and restlessness) and hypoactive (lethargy, withdrawal) forms. Several factors predispose ICU patients in particular to delirium, including prolonged hospital stay,² heavy sedation,⁴ and postoperative complications.⁵ The pathophysiology of delirium is not entirely certain, but neurotransmitter imbalance, inflammation, and decreased cellular respiration in the brain have all been implicated.⁶ Recent research has explored angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers as treatments for delirium in ICU patients. 

The renin-angiotensin system regulates blood pressure via the two eponymous proteins.⁷ Renin cleaves angiotensin to form angiotensin I, which is then converted to angiotensin II by ACE. Angiotensin II binds to G-protein coupled receptors, causing vasoconstriction and a subsequent increase in blood pressure.⁸ ACE inhibitors and ACE-receptor blockers interfere with this pathway. Additionally, ACE inhibitors that can breach the blood-brain barrier have been found to lower the incidence of dementia and stroke.⁹ This observation inspired the hypothesis that ACE inhibitors could be used to treat delirium, another neurological disorder.  

To test this hypothesis, Farag et al.¹⁰ selected ICU patients who were diagnosed with delirium using the Confusion Assessment Method and who were scheduled to have an operation at some point during the five years over which the study was conducted. Participants received angiotensin system inhibitors, some before their operation and some immediately after. Compared to the control group, the patients who received either ACE inhibitors or ACE receptor blockers before their operations did not show any significant decrease in delirium. Patients who received angiotensin system inhibitors postoperatively, however, showed a 50% decrease in delirium symptoms and a later onset of delirium on average compared to the control group. The authors concluded that the preoperative use of ACE inhibitors was ineffective because the drugs were not active in the period following the surgery, when patients are at the greatest risk of developing delirium. 

Farag et al. also explain their data in light of recent discoveries in the molecular mechanism of the renin-angiotensin system (RAS). Inhibiting the traditional RAS system, recent research has shown, amplifies the production of slightly different angiotensin products, which have neuroprotective and anti-inflammatory effects.¹¹ It has also been found that angiotensin receptor blockers interact with the nuclear receptor peroxisome proliferator-activated receptor gamma, an interaction that in other contexts has been associated with improved cognition.¹² The authors suggest that these alternative pathways account, in part, for the reduction in delirium.  

There are, however, potential drawbacks to using ACE inhibitors to treat delirium. A contraindication for ACE inhibitors is renal dysfunction, which may be present in older patients, who are also more likely to develop delirium. Several cases of ACE inhibitors inducing hallucinations have been reported.¹³ However, current data suggests that ACE inhibitors are overall a safe and promising treatment for delirium. 

References 

1. “Delirium.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 1 Sept. 2020, www.mayoclinic.org/diseases-conditions/delirium/symptoms-causes/syc-20371386. 

2. “Patients and Families Overview.” CIBS Center, Accessed 30 Nov. 2020, www.icudelirium.org/patients-and-families/overview. 

3. Ely, E., et al. “The Impact of Delirium in the Intensive Care Unit on Hospital Length of Stay.” Intensive Care Medicine, vol. 27, no. 12, 2001, pp. 1892–1900., doi:10.1007/s00134-001-1132-2.  

4. McFarling, U. L. “Hospitals Struggle to Address Terrifying ‘ICU Delirium’.” STAT, 14 Oct. 2016, www.statnews.com/2016/10/14/icu-delirium-hospitals/. 

5. Whitlock, Elizabeth L., and Andrea Vannucci. “Postoperative Delirium.” Minerva Anesthesiology, vol. 77, no. 4, Apr. 2011, pp. 448–456. 

6. Ely, E. W. “Delirium in the Intensive Care Unit.” Yearbook of Intensive Care and Emergency Medicine 2005, 2005, pp. 721–734., doi:10.1007/0-387-26272-5_60. 

7. Klabunde, Richard E. “Renin-Angiotensin-Aldosterone System.” Cardiovascular Physiology Concepts, 8 Dec. 2016, www.cvphysiology.com/Blood%20Pressure/BP015. 

8. “The Renin-Angiotensin-Aldosterone-System.” TeachMePhysiology, 28 Apr. 2020, teachmephysiology.com/urinary-system/regulation/the-renin-angiotensin-aldosterone-system. 

9. Sink, K. M., et al. “Angiotensin-Converting Enzyme Inhibitors and Cognitive Decline in Older Adults With Hypertension.” Archives of Internal Medicine, vol. 169, no. 13, 2009, p. 1195., doi:10.1001/archinternmed.2009.175. 

10. Farag, E., et al. “Association between Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers and Postoperative Delirium.” Anesthesiology, vol. 133, no. 1, 2020, pp. 119–132., doi:10.1097/aln.0000000000003329. 

11. Farag, E., et al. “The Renin Angiotensin System and the Brain: New Developments.” Journal of Clinical Neuroscience, vol. 46, 2017, pp. 1–8., doi:10.1016/j.jocn.2017.08.055. 

12. Zanchetti, A., and D. Elmfeldt. “Findings and Implications of the Study on Cognition and Prognosis in the Elderly (SCOPE) – A Review.” Blood Pressure, vol. 15, no. 2, 2006, pp. 71–79., doi:10.1080/08037050600771583. 

13. Doane, J., and B. Stults. “Visual Hallucinations Related to Angiotensin-Converting Enzyme Inhibitor Use: Case Reports and Review.” The Journal of Clinical Hypertension, vol. 15, no. 4, 2013, pp. 230–233., doi:10.1111/jch.12063.