Neurocritical Care

, Volume 30, Issue 2, pp 307–315 | Cite as

Effects of Osmotic Therapy on Pupil Reactivity: Quantification Using Pupillometry in Critically Ill Neurologic Patients

  • C. OngEmail author
  • M. Hutch
  • M. Barra
  • A. Kim
  • S. Zafar
  • S. Smirnakis
Original Article



Osmotic therapy is a critical component of medical management for cerebral edema. While up to 90% of neurointensivists report using these treatments, few quantitative clinical measurements guide optimal timing, dose, or administration frequency. Its use is frequently triggered by a qualitative assessment of neurologic deterioration and/or pupil size, and anecdotally appears to improve pupil asymmetry suggestive of uncal herniation. However, subjective pupil assessment has poor reliability, making it difficult to detect or track subtle changes. We hypothesized that osmotic therapy reproducibly improves quantitative pupil metrics.


We included patients at two centers who had recorded quantitative pupil measurements within 2 h before and after either 20% mannitol or 23.4% hypertonic saline in the neurosciences intensive care unit. The primary outcome was the Neurologic Pupil Index (NPi), a composite metric ranging from 0 to 5 in which > 3 is considered normal. Secondary outcomes included pupil size, percent change, constriction and dilation velocity, and latency. Results were analyzed with Wilcoxon signed-rank tests, Chi-square and multi-level linear regression to control for other edema-reducing interventions.


Out of 72 admissions (403 paired pupil observations), NPi significantly differed within 2 h of osmotic therapy when controlling for other commonly used interventions in our whole cohort (β = 0.08, p = 0.0168). The effect was most pronounced (β = 0.57) in patients with abnormal NPi prior to intervention (p = 0.0235).


Pupil reactivity significantly improves after osmotic therapy in a heterogenous critically ill population when controlling for various other interventions. Future work is necessary to determine dose-dependent effects and clinical utility.


Cerebral edema Mannitol Hypertonic saline 


Author Contribution

CO was responsible for study design, analysis, interpretation of results, and the writing of the manuscript. MH assisted in statistical analysis of results and entering demographic and clinical data for patients. MB provided pharmacological expertise regarding osmotic therapy and manuscript review. AK was responsible for collecting pupillometry smart guards, entering demographic and clinical data, manuscript review and administrative duties regarding IRB submission process. SZ assisted in study design and collection, manuscript review. SS oversaw study design and provided expertise regarding analysis and interpretation of results.

Source of Support

American Brain Foundation.

Conflict of interest

Dr. Ong reports grants from American Brain Foundation, during the conduct of the study. All other authors have nothing to disclose.

Supplementary material

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Supplementary material 1 (DOCX 160 kb)
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Supplementary material 2 (DOC 108 kb)
12028_2018_620_MOESM3_ESM.docx (30 kb)
Supplementary material 3 (DOCX 30 kb)
12028_2018_620_MOESM4_ESM.docx (16 kb)
Supplementary material 4 (DOCX 16 kb)


  1. 1.
    Cadena R, Shoykhet M, Ratcliff JJ. Emergency neurological life support: intracranial hypertension and herniation. Neurocrit Care. 2017;27:82–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Hays AN, Lazaridis C, Neyens R, Nicholas J, Gay S, Chalela JA. Osmotherapy: use among neurointensivists. Neurocrit Care. 2011;14:222–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA. Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions. Crit Care Med. 2000;28:1556–64.CrossRefPubMedGoogle Scholar
  4. 4.
    Koenig MA, Bryan M, Lewin JL 3rd, Mirski MA, Geocadin RG, Stevens RD. Reversal of transtentorial herniation with hypertonic saline. Neurology. 2008;70:1023–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Francony G, Fauvage B, Falcon D, Canet C, Dilou H, Lavagne P, et al. Equimolar doses of mannitol and hypertonic saline in the treatment of increased intracranial pressure. Crit Care Med. 2008;36:795–800.CrossRefPubMedGoogle Scholar
  6. 6.
    Ropper AH. The opposite pupil in herniation. Neurology. 1990;40:1707–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Mcnealy DE, Plum F. Brainstem dysfunction with supratentorial mass lesions. Arch Neurol. 1962;7:10–32.CrossRefGoogle Scholar
  8. 8.
    Ropper AH. Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. N Engl J Med. 1986;314:953–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Ropper AH, Cole D, Louis DN. Clinicopathologic correlation in a case of pupillary dilation from cerebral hemorrhage. Arch Neurol. 1991;48:1166–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Fisher CM. Brain herniation: a revision of classical concepts. Can J Neurol Sci. 1995;22:83–91.CrossRefPubMedGoogle Scholar
  11. 11.
    Olson DM, Stutzman S, Saju C, Wilson M, Zhao W, Aiyagari V. Interrater reliability of pupillary assessments. Neurocrit Care. 2016;24:251–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Couret D, Boumaza D, Grisotto C, Triglia T, Pellegrini L, Ocquidant P, et al. Reliability of standard pupillometry practice in neurocritical care: an observational, double-blinded study. Crit Care. 2016;20:99.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Meeker M, Du R, Bacchetti P, Privitera CM, Larson MD, Holland MC, et al. Pupil examination: validity and clinical utility of an automated pupillometer. J Neurosci Nurs. 2005;37:34–40.CrossRefPubMedGoogle Scholar
  14. 14.
    R Development Core Team. R: a language and environment for statistical computing. 2016.Google Scholar
  15. 15.
    Papangelou A, Zink EK, Chang WW, Frattalone A, Gergen D, Gottschalk A, et al. Automated pupillometry and detection of clinical transtentorial brain herniation: a case series. Mil Med. 2018;183:e113–21.CrossRefPubMedGoogle Scholar
  16. 16.
    Cruz J, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupillary widening: a randomized trial. Neurosurgery. 2002;51:628–37 (discussion 637-628).CrossRefPubMedGoogle Scholar
  17. 17.
    Roberts I, Smith R, Evans S. Doubts over head injury studies. BMJ. 2007;334:392–4.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Diringer MN, Zazulia AR. Osmotic therapy: fact and fiction. Neurocrit Care. 2004;1:219–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Alvarez B, Ferrer-Sueta G, Radi R. Slowing of peroxynitrite decomposition in the presence of mannitol and ethanol. Free Radic Biol Med. 1998;24:1331–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Wise BL, Chater N. The value of hypertonic mannitol solution in decreasing brain mass and lowering cerebrospinal-fluid pressure. J Neurosurg. 1962;19:1038–43.CrossRefPubMedGoogle Scholar
  21. 21.
    Grande PO, Romner B. Osmotherapy in brain edema: a questionable therapy. J Neurosurg Anesthesiol. 2012;24:407–12.CrossRefPubMedGoogle Scholar
  22. 22.
    Rudehill A, Gordon E, Ohman G, Lindqvist C, Andersson P. Pharmacokinetics and effects of mannitol on hemodynamics, blood and cerebrospinal fluid electrolytes, and osmolality during intracranial surgery. J Neurosurg Anesthesiol. 1993;5:4–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Bentsen G, Breivik H, Lundar T, Stubhaug A. Hypertonic saline (7.2%) in 6% hydroxyethyl starch reduces intracranial pressure and improves hemodynamics in a placebo-controlled study involving stable patients with subarachnoid hemorrhage. Crit Care Med. 2006;34:2912–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Brophy GM, Human T, Shutter L. Emergency neurological life support: pharmacotherapy. Neurocrit Care. 2015;23(Suppl 2):S48–68.CrossRefPubMedGoogle Scholar
  25. 25.
    Suarez JI, Qureshi AI, Bhardwaj A, Williams MA, Schnitzer MS, Mirski M, et al. Treatment of refractory intracranial hypertension with 23.4% saline. Crit Care Med. 1998;26:1118–22.CrossRefPubMedGoogle Scholar
  26. 26.
    Ropper AH. Management of raised intracranial pressure and hyperosmolar therapy. Pract Neurol. 2014;14:152–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Paczynski RP. Osmotherapy. Basic concepts and controversies. Crit Care Clin. 1997;13:105–29.CrossRefPubMedGoogle Scholar
  28. 28.
    Nau R. Osmotherapy for elevated intracranial pressure: a critical reappraisal. Clin Pharmacokinet. 2000;38:23–40.CrossRefPubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kamel H, Navi BB, Nakagawa K, Hemphill JC 3rd, Ko NU. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials. Crit Care Med. 2011;39:554–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Brown DA, Wijdicks EF. Decompressive craniectomy in acute brain injury. Handb Clin Neurol. 2017;140:299–318.CrossRefPubMedGoogle Scholar
  32. 32.
    Shirozu K, Setoguchi H, Tokuda K, Karashima Y, Ikeda M, Kubo M, et al. The effects of anesthetic agents on pupillary function during general anesthesia using the automated infrared quantitative pupillometer. J Clin Monit Comput. 2017;31:291–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Larsen RS, Waters J. Neuromodulatory correlates of pupil dilation. Front Neural Circuits. 2018;12:21.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ropper AH, Shafran B. Brain edema after stroke. Clinical syndrome and intracranial pressure. Arch Neurol. 1984;41:26–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Diggle PJ, Heagerty P, Liang K-Y, Zeger SL. Analysis of longitudinal data. Oxford: Oxford University Press; 2002. p. 31.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society 2018

Authors and Affiliations

  • C. Ong
    • 1
    • 3
    • 4
    Email author
  • M. Hutch
    • 1
  • M. Barra
    • 2
    • 4
  • A. Kim
    • 3
    • 4
  • S. Zafar
    • 2
    • 4
  • S. Smirnakis
    • 3
    • 4
    • 5
  1. 1.Boston University School of MedicineBostonUSA
  2. 2.Massachusetts General HospitalBostonUSA
  3. 3.Brigham and Women’s HospitalBostonUSA
  4. 4.Harvard Medical SchoolBostonUSA
  5. 5.Jamaica Plain VA HospitalBostonUSA

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