TY - JOUR

T1 - Brimonidine eye drops reveal diminished sympathetic pupillary tone in comatose patients with brain injury

AU - Jakobsen, Elisabeth Waldemar

AU - Nersesjan, Vardan

AU - Albrechtsen, Simon Sander

AU - Othman, Marwan H.

AU - Amiri, Moshgan

AU - Knudsen, Niels Vendelbo

AU - Larson, Merlin D.

AU - Hassager, Christian

AU - Møller, Kirsten

AU - Kjaergaard, Jesper

AU - Kondziella, Daniel

N1 - Publisher Copyright: © 2023, The Author(s).

PY - 2023

Y1 - 2023

N2 - Background: There is an urgent need for easy-to-perform bedside measures to detect residual consciousness in clinically unresponsive patients with acute brain injury. Interestingly, the sympathetic control of pupil size is thought to be lost in states of unconsciousness. We therefore hypothesized that administration of brimonidine (an alpha-2-adrenergic agonist) eye drops into one eye should produce a pharmacologic Horner’s syndrome if the clinically unresponsive patient is conscious, but not if the patient is unconscious. Here, in a first step to explore this hypothesis, we investigated the potential of brimonidine eye drops to distinguish preserved sympathetic pupillary function in awake volunteers from impairment of sympathetic tone in patients in a coma. Methods: We enrolled comatose patients admitted for acute brain injury to one of the intensive care units (ICU) of a tertiary referral center, in whom EEG and/or neuroimaging for all practical purposes had ruled out residual consciousness. Exclusion criteria were deep sedation, medications with known drug interactions with brimonidine, and a history of eye disease. Age- and sex-matched healthy and awake volunteers served as controls. We measured pupils of both eyes, under scotopic conditions, at baseline and five times 5–120 min after administering brimonidine into the right eye, using automated pupillometry. Primary outcomes were miosis and anisocoria at the individual and group levels. Results: We included 15 comatose ICU patients (seven women, mean age 59 ± 13.8 years) and 15 controls (seven women, mean age 55 ± 16.3 years). At 30 min, miosis and anisocoria were seen in all 15 controls (mean difference between the brimonidine-treated pupil and the control pupil: − 1.31 mm, 95% CI [− 1.51; − 1.11], p < 0.001), but in none (p < 0.001) of the 15 ICU patients (mean difference: 0.09 mm, 95% CI [− 0.12;0.30], p > 0.99). This effect was unchanged after 120 min and remained robust in sensitivity analyses correcting for baseline pupil size, age, and room illuminance. Conclusion: In this proof-of-principle study, brimonidine eye drops produced anisocoria in awake volunteers but not in comatose patients with brain injury. This suggests that automated pupillometry after administration of brimonidine can distinguish between the extremes of the spectrum of consciousness (i.e., fully conscious vs. deeply comatose). A larger study testing the “intermediate zone” of disorders of consciousness in the ICU seems warranted.

AB - Background: There is an urgent need for easy-to-perform bedside measures to detect residual consciousness in clinically unresponsive patients with acute brain injury. Interestingly, the sympathetic control of pupil size is thought to be lost in states of unconsciousness. We therefore hypothesized that administration of brimonidine (an alpha-2-adrenergic agonist) eye drops into one eye should produce a pharmacologic Horner’s syndrome if the clinically unresponsive patient is conscious, but not if the patient is unconscious. Here, in a first step to explore this hypothesis, we investigated the potential of brimonidine eye drops to distinguish preserved sympathetic pupillary function in awake volunteers from impairment of sympathetic tone in patients in a coma. Methods: We enrolled comatose patients admitted for acute brain injury to one of the intensive care units (ICU) of a tertiary referral center, in whom EEG and/or neuroimaging for all practical purposes had ruled out residual consciousness. Exclusion criteria were deep sedation, medications with known drug interactions with brimonidine, and a history of eye disease. Age- and sex-matched healthy and awake volunteers served as controls. We measured pupils of both eyes, under scotopic conditions, at baseline and five times 5–120 min after administering brimonidine into the right eye, using automated pupillometry. Primary outcomes were miosis and anisocoria at the individual and group levels. Results: We included 15 comatose ICU patients (seven women, mean age 59 ± 13.8 years) and 15 controls (seven women, mean age 55 ± 16.3 years). At 30 min, miosis and anisocoria were seen in all 15 controls (mean difference between the brimonidine-treated pupil and the control pupil: − 1.31 mm, 95% CI [− 1.51; − 1.11], p < 0.001), but in none (p < 0.001) of the 15 ICU patients (mean difference: 0.09 mm, 95% CI [− 0.12;0.30], p > 0.99). This effect was unchanged after 120 min and remained robust in sensitivity analyses correcting for baseline pupil size, age, and room illuminance. Conclusion: In this proof-of-principle study, brimonidine eye drops produced anisocoria in awake volunteers but not in comatose patients with brain injury. This suggests that automated pupillometry after administration of brimonidine can distinguish between the extremes of the spectrum of consciousness (i.e., fully conscious vs. deeply comatose). A larger study testing the “intermediate zone” of disorders of consciousness in the ICU seems warranted.

KW - Automated pupillometry

KW - Cardiac arrest

KW - Coma

KW - Consciousness

KW - Disorders of consciousness

KW - Prognosis

KW - Traumatic brain injury

U2 - 10.1007/s00701-023-05569-8

DO - 10.1007/s00701-023-05569-8

M3 - Journal article

C2 - 37014450

AN - SCOPUS:85151527684

VL - 165

SP - 1483

EP - 1494

JO - Acta Neurochirurgica

JF - Acta Neurochirurgica

SN - 0001-6268

IS - 6

ER -