Outcome pRognostication of Acute Brain Injury With the NeuroloGical Pupil indEx

NCT04490005 | Completed DMC

• 1 other identifier: ORANGE
• Study Type: observational
• Target: 118
• Locations: 8 countries
• Sites: 14

Brief Summary

The use of quantitative, automated, infrared technology for pupillary examination has long been used in ophthalmology and anesthesiology research. Its interest in neurocritical care has progressively grown, in parallel with the advancements in device technology. In this regard, the use of the noninvasive NPi®-200 pupillometer (Neuroptics, Laguna Hills, California, USA) allows the measurement of a series of dynamic pupillary variables (including the percentage pupillary constriction, latency, constriction velocity, and dilation velocity), which can be integrated into an algorithm, to compute the Neurological Pupil index (NPi). The NPi is a proprietary scalar index with values between 0 and 5 (with a 0.1 decimal precision), an NPi value \< 3 indicating an abnormal pupillary reactivity. Importantly, the NPi is not influenced by sedation-analgesia, at the doses used in neurocritical care practice, and by mild hypothermia. Preliminary single-center data recently demonstrated that abnormal NPi is associated with worse outcome in patients with traumatic and hemorrhagic ABI, and can be a useful adjunct for ICP monitoring and therapy. There is currently a great need for quantitative tools to predict early prognostication in ABI patients, and the NPi appears of potential great value. We hypothesize that:

1. 1.Abnormal NPi (defined as NPi \<3) are strongly predictive of poor GOS-E (1-4) at 6 months after the acute event.
2. 2.NPi=0 is strongly predictive of mortality (GOS 1).
3. 3.Abnormal NPi is predictive of a higher ICP 20 index (number of end-hourly measures of ICP \>20 mm Hg divided by the total number of measurements, multiplied by 100) and a greater burden of interventions needed to control ICP (measured by the Therapy Intensity Level scale for ICP management, Therapy Intensity Level (TIL) 4).

Conditions

Acute Brain Injury; Pupillary Reflex Impaired

Keywords

acute brain injury; pupillometry; intracranial hypertension; neurological outcome

Outcome Measures

Primary Outcomes (1)

• Correlation between abnormal Neurological Pupil index (NPi) and long-term outcome

  To evaluate the association between abnormal Neurological Pupil index (NPi) and long-term outcome (6-month mortality and neurological recovery, measured with the extended Glasgow Outcome Score, GOS-E) in patients with ABI.

  6 months

Secondary Outcomes (1)

• Correlation between intracranial hypertension and abnormal NPI values

  6 months

Study Arms (1)

Acute brain injury

Intensive care unit (ICU) admission after ABI, including traumatic brain injury (TBI), aneurysmal subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH) • Age 18 years old.

Other: pupillometry

Interventions

pupillometry OTHER

evaluation of pupillary reflex by using the Neuroptics Pupillometer every 4 hours during ICU stay

Acute brain injury

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

No formal sample size calculation has been performed due to the exploratory nature of the study. However, we expect to recruit a total of 420 patients, 140 per pathology for whom GOSE will be performed (i.e. TBI, ICH, SAH), over a 12-months period. Therefore, the six participating centres will contribute, based on their potentiality of recruitment, with a minimum of 20 patients for each of the three pathologies, for a total of 60.

You may qualify if:

• Intensive care unit (ICU) admission after ABI, including traumatic brain injury (TBI), aneurysmal subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH)
• Age \> 18 years old.
• Pupillometry available as standard evaluation tool.

You may not qualify if:

• ABI not admitted to the ICU.
• Facial trauma not allowing pupils' evaluation.
• Age \< 18 years

Sponsors & Collaborators

• University of Milano Bicocca: lead
• University of Lausanne: collaborator
• Université Libre de Bruxelles: collaborator

Study Sites (14)

Department of Neurology, University of California

San Francisco, California, 94110, United States

Location

Parnassus Hospital UCSF

San Francisco, California, 94143, United States

Location

John Hopkins

Baltimore, Maryland, 21218, United States

Location

Harborview Medical Center

Seattle, Washington, 98104, United States

Location

Erasme Hospital, Université Libre de Bruxelles

Brussels, Belgium

Location

Department Anesthesia and Critical Care, University Hospital

Grenoble, France

Location

Universitätsklinikum

Erlangen, Germany

Location

Spedali Civili

Brescia, BS, 25121, Italy

Location

ASST-MONZA San Gerardo Hospital

Monza, MB, 20900, Italy

Location

Policlinico Gemelli

Roma, RM, 00168, Italy

Location

Oslo Universitary Hospital

Oslo, Norway

Location

Ramón Y Cajal University Hospital

Madrid, Spain

Location

Hospital Clinic Universitari de València, University of Valencia

Valencia, Spain

Location

Centre Hospitalier Universitaire Vaudois (CHUV), University Hospital and University of Lausanne

Lausanne, Switzerland

Location

Related Publications (25)

• Sharshar T, Citerio G, Andrews PJ, Chieregato A, Latronico N, Menon DK, Puybasset L, Sandroni C, Stevens RD. Neurological examination of critically ill patients: a pragmatic approach. Report of an ESICM expert panel. Intensive Care Med. 2014 Apr;40(4):484-95. doi: 10.1007/s00134-014-3214-y. Epub 2014 Feb 13.

  PMID: 24522878 RESULT

• Chen JW, Gombart ZJ, Rogers S, Gardiner SK, Cecil S, Bullock RM. Pupillary reactivity as an early indicator of increased intracranial pressure: The introduction of the Neurological Pupil index. Surg Neurol Int. 2011;2:82. doi: 10.4103/2152-7806.82248. Epub 2011 Jun 21.

  PMID: 21748035 RESULT

• Chen JW, Vakil-Gilani K, Williamson KL, Cecil S. Infrared pupillometry, the Neurological Pupil index and unilateral pupillary dilation after traumatic brain injury: implications for treatment paradigms. Springerplus. 2014 Sep 23;3:548. doi: 10.1186/2193-1801-3-548. eCollection 2014.

  PMID: 25332854 RESULT

• Larson MD, Behrends M. Portable infrared pupillometry: a review. Anesth Analg. 2015 Jun;120(6):1242-53. doi: 10.1213/ANE.0000000000000314.

  PMID: 25988634 RESULT

• Larson MD, Singh V. Portable infrared pupillometry in critical care. Crit Care. 2016 Jun 22;20(1):161. doi: 10.1186/s13054-016-1349-7.

  PMID: 27329287 RESULT

• Volpi PC, Robba C, Rota M, Vargiolu A, Citerio G. Trajectories of early secondary insults correlate to outcomes of traumatic brain injury: results from a large, single centre, observational study. BMC Emerg Med. 2018 Dec 5;18(1):52. doi: 10.1186/s12873-018-0197-y.

  PMID: 30518336 RESULT

• Han J, King NK, Neilson SJ, Gandhi MP, Ng I. External validation of the CRASH and IMPACT prognostic models in severe traumatic brain injury. J Neurotrauma. 2014 Jul 1;31(13):1146-52. doi: 10.1089/neu.2013.3003. Epub 2014 May 12.

  PMID: 24568201 RESULT

• Couret D, Boumaza D, Grisotto C, Triglia T, Pellegrini L, Ocquidant P, Bruder NJ, Velly LJ. Reliability of standard pupillometry practice in neurocritical care: an observational, double-blinded study. Crit Care. 2016 Mar 13;20:99. doi: 10.1186/s13054-016-1239-z.

  PMID: 27072310 RESULT

• Couret D, Simeone P, Freppel S, Velly L. The effect of ambient-light conditions on quantitative pupillometry: a history of rubber cup. Neurocrit Care. 2019 Apr;30(2):492-493. doi: 10.1007/s12028-018-0664-z. No abstract available.

  PMID: 30604030 RESULT

• Olson DM, Stutzman S, Saju C, Wilson M, Zhao W, Aiyagari V. Interrater Reliability of Pupillary Assessments. Neurocrit Care. 2016 Apr;24(2):251-7. doi: 10.1007/s12028-015-0182-1.

  PMID: 26381281 RESULT

• Hall CA, Chilcott RP. Eyeing up the Future of the Pupillary Light Reflex in Neurodiagnostics. Diagnostics (Basel). 2018 Mar 13;8(1):19. doi: 10.3390/diagnostics8010019.

  PMID: 29534018 RESULT

• Larson MD, Sessler DI. Pupillometry to guide postoperative analgesia. Anesthesiology. 2012 May;116(5):980-2. doi: 10.1097/ALN.0b013e318251d21b. No abstract available.

  PMID: 22433239 RESULT

• Morelli P, Oddo M, Ben-Hamouda N. Role of automated pupillometry in critically ill patients. Minerva Anestesiol. 2019 Sep;85(9):995-1002. doi: 10.23736/S0375-9393.19.13437-2. Epub 2019 Mar 29.

  PMID: 30938123 RESULT

• Shoyombo I, Aiyagari V, Stutzman SE, Atem F, Hill M, Figueroa SA, Miller C, Howard A, Olson DM. Understanding the Relationship Between the Neurologic Pupil Index and Constriction Velocity Values. Sci Rep. 2018 May 3;8(1):6992. doi: 10.1038/s41598-018-25477-7.

  PMID: 29725074 RESULT

• Jahns FP, Miroz JP, Messerer M, Daniel RT, Taccone FS, Eckert P, Oddo M. Quantitative pupillometry for the monitoring of intracranial hypertension in patients with severe traumatic brain injury. Crit Care. 2019 May 2;23(1):155. doi: 10.1186/s13054-019-2436-3.

  PMID: 31046817 RESULT

• Aoun SG, Stutzman SE, Vo PN, El Ahmadieh TY, Osman M, Neeley O, Plitt A, Caruso JP, Aiyagari V, Atem F, Welch BG, White JA, Batjer HH, Olson DM. Detection of delayed cerebral ischemia using objective pupillometry in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 2020 Jan 1;132(1):27-32. doi: 10.3171/2018.9.JNS181928. Epub 2019 Jan 11.

  PMID: 30641848 RESULT

• Osman M, Stutzman SE, Atem F, Olson D, Hicks AD, Ortega-Perez S, Aoun SG, Salem A, Aiyagari V. Correlation of Objective Pupillometry to Midline Shift in Acute Stroke Patients. J Stroke Cerebrovasc Dis. 2019 Jul;28(7):1902-1910. doi: 10.1016/j.jstrokecerebrovasdis.2019.03.055. Epub 2019 Apr 25.

  PMID: 31031146 RESULT

• Ong C, Hutch M, Barra M, Kim A, Zafar S, Smirnakis S. Effects of Osmotic Therapy on Pupil Reactivity: Quantification Using Pupillometry in Critically Ill Neurologic Patients. Neurocrit Care. 2019 Apr;30(2):307-315. doi: 10.1007/s12028-018-0620-y.

  PMID: 30298336 RESULT

• Phillips SS, Mueller CM, Nogueira RG, Khalifa YM. A Systematic Review Assessing the Current State of Automated Pupillometry in the NeuroICU. Neurocrit Care. 2019 Aug;31(1):142-161. doi: 10.1007/s12028-018-0645-2.

  PMID: 30484008 RESULT

• Oddo M, Sandroni C, Citerio G, Miroz JP, Horn J, Rundgren M, Cariou A, Payen JF, Storm C, Stammet P, Taccone FS. Quantitative versus standard pupillary light reflex for early prognostication in comatose cardiac arrest patients: an international prospective multicenter double-blinded study. Intensive Care Med. 2018 Dec;44(12):2102-2111. doi: 10.1007/s00134-018-5448-6. Epub 2018 Nov 26.

  PMID: 30478620 RESULT

• Zuercher P, Groen JL, Aries MJ, Steyerberg EW, Maas AI, Ercole A, Menon DK. Reliability and Validity of the Therapy Intensity Level Scale: Analysis of Clinimetric Properties of a Novel Approach to Assess Management of Intracranial Pressure in Traumatic Brain Injury. J Neurotrauma. 2016 Oct 1;33(19):1768-1774. doi: 10.1089/neu.2015.4266. Epub 2016 Feb 11.

  PMID: 26866876 RESULT

• Wilson L, von Steinbuechel N, Menon DK, Maas AIR. Outcome assessment after traumatic brain injury - Authors' reply. Lancet Neurol. 2018 Apr;17(4):299-300. doi: 10.1016/S1474-4422(18)30045-0. Epub 2018 Mar 13. No abstract available.

  PMID: 29553376 RESULT

• Petrosino M, Gouvea Bogossian E, Rebora P, Galimberti S, Chesnut R, Bouzat P, Oddo M, Taccone FS, Citerio G; ORANGE Participants and Investigators. Neurological Pupil Index and Intracranial Hypertension in Patients With Acute Brain Injury: A Secondary Analysis of the ORANGE Study. JAMA Neurol. 2025 Feb 1;82(2):176-184. doi: 10.1001/jamaneurol.2024.4189.

  PMID: 39652324 DERIVED

• Oddo M, Taccone FS, Petrosino M, Badenes R, Blandino-Ortiz A, Bouzat P, Caricato A, Chesnut RM, Feyling AC, Ben-Hamouda N, Hemphill JC, Koehn J, Rasulo F, Suarez JI, Elli F, Vargiolu A, Rebora P, Galimberti S, Citerio G; ORANGE study investigators. The Neurological Pupil index for outcome prognostication in people with acute brain injury (ORANGE): a prospective, observational, multicentre cohort study. Lancet Neurol. 2023 Oct;22(10):925-933. doi: 10.1016/S1474-4422(23)00271-5. Epub 2023 Aug 28.

  PMID: 37652068 DERIVED

• Oddo M, Taccone F, Galimberti S, Rebora P, Citerio G; Orange Study Group. Outcome Prognostication of Acute Brain Injury using the Neurological Pupil Index (ORANGE) study: protocol for a prospective, observational, multicentre, international cohort study. BMJ Open. 2021 May 11;11(5):e046948. doi: 10.1136/bmjopen-2020-046948.

  PMID: 33980528 DERIVED

MeSH Terms

Conditions

Brain Injuries; Intracranial Hypertension

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Study Officials

• Giuseppe Citerio, MD, Prof

  University of Milano Bicocca

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 6 Months
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 1, 2020
• First Posted: July 28, 2020
• Study Start: November 2, 2020
• Primary Completion: April 2, 2022
• Study Completion: May 3, 2022
• Last Updated: January 25, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

ES (2); BE (1); DE (1); IT (3); CH (1); FR (1); US (4); NO (1)