Consensus 4

4th Consensus Meeting:
Intraocular Pressure

Fort Lauderdale, FL, May 5, 2007

Consensus 4

edited by Robert N. Weinreb, James D. Brandt, David Garway-Heath and Felipe A. Medeiros
2007. xviii and 128 pages with 57 figures, of which 7 in full color, and 7 tables. Hardbound.
ISBN-10: 90 6299 213
ISBN-13: 978-90-6299-213 3
Published by Kugler Publications.
Click here for more information on all publications in the Consensus series.

See meeting photos

Consensus statements

Basic Science of Intraocular Pressure


Aqueous flow

  1. IOP is determined by contributions from aqueous humor production (measured
    as aqueous flow), trabecular outflow, uveoscleral outflow and episcleral venous
    pressure.
  2. Aqueous flow has a distinctive circadian rhythm, being lower at night than
    during the day.
    Comment: Aqueous flow is not affected by exfoliation syndrome, pigment
    dispersion syndrome, primary open angle glaucoma, or ocular hypertension.
    Comment: Aqueous flow is reduced by diabetes mellitus and myotonic dystrophy.
  3. The best technique to measure aqueous flow in humans is by fluorophotometry.
    Comment: Limitations and assumptions associated with fluorophotometry
    include:
  • a rate of diffusion of fluorescein into the iris, limbal vessels and
    tear film is assumed;
  • fluorescein is distributed uniformly throughout the anterior chamber and
    cornea;
  • a lens-iris barrier is present to block the egress of the tracer into
    the posterior chamber;
  • Short-term fluctuations in aqueous flow of less than 30 minutes are
    not detectable.

Trabecular outflow

  1.  The trabecular outflow pathway is comprised of the trabecular
    meshwork, the juxtacanalicular connective tissue (JCT), the endothelial
    lining of Schlemm’s canal, the collecting channels and aqueous veins.

Comment: Normal outflow resistance resides in the inner wall region of
Schlemm’s canal (SC), including JCT and inner endothelial lining of SC. Cells in
trabecular meshwork influence the hydraulic conductivity of the inner wall region
and outflow resistance by modulating extracellular matrix turnover and/or by actively
changing cell shape.
Comment: Trabecular outflow is under the influence of ciliary muscle tone.

  1. Outflow facility in healthy human eyes is the range of 0.1
    to 0.4 µl / min / mmHg.

Comment: Outflow facility is reduced in primary open angle glaucoma, ocular
hypertension, and exfoliation and pigment dispersion syndromes with accompanying
ocular hypertension.
Comment: In chronic open-angle glaucoma there is an increase in extracellular
material in the juxtacanalicular connective tissue and decrease in number of pores
in Schlemm’s canal endothelium.

  1. Outflow facility can be measured with tonography and fluorophotometry.
    Both methods have inherent limitations associated with their use.

Uveoscleral outflow

  • The uveoscleral outflow pathway is comprised of the ciliary muscle, supraciliary
    space, suprachoroidal space, sclera and other less defined areas.
  • Uveoscleral outflow is 25-57% of total outflow in young healthy humans and
    uveoscleral outflow decreases with aging.
    Comment: Uveoscleral outflow is reduced in ocular hypertension with an
    without exfoliation syndrome, increased in uveitis, and unchanged in pigment
    dispersion syndrome with ocular hypertension.
  • In clinical studies, uveoscleral outflow is calculated from the modified
    Goldmann equation.
    Comment: Inherent variability is great and reproducibility is fair. Invasive
    methods to measure uveoscleral outflow are:

    • 1. The tracer collection method;
    • 2. The indirect isotope method

Episcleral venous pressure

  1. Episcleral venous pressure in healthy humans is 8 to 10 mmHg.
    Comment: It is affected by body position, inhalation of O2, application of cold
    temperature and treatment with vasoactive drugs.
    Comment: Episcleral venomanometry is used in clinical studies. This measurement
    is difficult to make and highly variable.
    Comment: Direct cannulation is used in animal studies. This is an accurate
    but invasive method.

Measurement of Intraocular Pressure

  1.  On average, greater central corneal thickness (CCT) results in
    overestimation of intraocular pressure (IOP) as measured by Goldmann applanation
    tonometry (GAT).
    Comment: The extent to which CCT contributes to the measurement error
    (in relation to other factors) in individual patients under various conditions
    has yet to be established.
  2. Compared to GAT, CCT has a lesser effect on IOP measured by dynamic
    contour tonometry (DCT) and the ocular response analyzer (ORA) (corneal
    compensated IOP). CCT has a greater effect on IOP measured by NCT and Rebound
    Tonometry.
  3. Currently we have insufficient evidence comparing different tonometers
    in the same population. However, there are some data to suggest that Goldmann
    applanation tonometry is more precise (lowest measurement variability),
    compared to other methods.
  4. Precision and agreement of tonometry devices should be reported in a
    standardized format:

    • Coefficient of repeatability (for intra-observer variation)
    • Mean difference (or difference trend over range) and 95% limits
      of agreement (for inter-observer and inter-instrument differences)

    Comment: Under ideal circumstances for measurement, precision figures
    reported for GAT are:

    • Intraobserver variability: 2.5 mmHg (two readings by the same observer
      will be within this figure for 95% of subjects)
    • Interobserver variability: ± 4 mmHg (95% confidence limits either
      side of mean difference between observers)
    • In clinical practice these figures may be considerably higher •
      Intra-class correlation coefficients are not clinically useful
  5. Currently there are no data to support a specific frequency of calibration
    verification for GAT.
    Comment: The frequency for verification of GAT calibration of at
    least twice yearly is suggested.

For clinical research, a verification error > ± 1 mmHg should be the threshold
to send the tonometer for recalibration; the threshold for clinical practice
may be higher and requires a cost-benefit analysis.

  1. Correction nomograms that adjust GAT IOP based solely on CCT are neither
    valid nor useful in individual patients.
    Comment: A thick cornea gives rise to a greater probability of an
    IOP being over-estimated (and a thin cornea of an IOP being under-estimated),
    but the extent of measurement error in individual patients cannot be ascertained
    from the CCT alone.
  2. Measurement of CCT is important in assessing risk for incident glaucoma
    among ocular hypertensives in the clinical setting, though the association
    between CCT and glaucoma risk may be less strong in the population at large.
  3. The corneal modulus of elasticity likely has a greater effect on GAT
    IOP measurement error than CCT, especially with corneal pathology and after
    corneal surgery.
    Comment: The corneal modulus of elasticity increases with age, thus
    generating artifactual increases in Goldmann tonometry with age.
    Comment: A higher modulus of elasticity is associated with greater
    stiffness.
  4. Consideration of corneal visco-elasticity is essential for determining
    the ocular mechanical resistance to tonometry and hence improving the accuracy
    of IOP measurement.
    Comment: Corneal aging affects the visco-elasticity of the tissue
    and adds another layer of complexity to determining the mechanical resistance
    of the cornea to tonometry.
  5. Large amounts of corneal edema produce an underestimation of IOP when
    measured by applanation tonometry.

Small amounts of corneal edema (as induced by contact lens wear) probably
cause an overestimation of IOP.

  1. To obtain a GAT measurement, which is relatively unaffected by daytime
    changes in CCT, the patient should desirably have been awake with his/her
    eyes open for at least two hours prior to the measurement being made.
  2. The wearing of contact lenses on the day when tonometry is performed
    may lead to an artifactually raised IOP as measured by GAT. Comment:
    Contact lens wearing patients should have tonometry performed after having
    been awake, without contact lenses, for at least two hours for contact lens-induced
    and diurnal corneal edema to resolve.
  3. There are changes in corneal biomechanics following many forms of keratorefractive
    surgery, associated with a mean fall in IOP as measured by applanation tonometry.
    Comment: Although there is a mean fall across patients in measured
    IOP, there is a wide variability in response.
  4. DCT and ORA (corneal compensated IOP) may both be less sensitive to
    changes in corneal biomechanics following keratorefractive surgery and have
    less variance than standard applanation tonometry.
  5. The use of a lid speculum, sedatives and general anesthetics can significantly
    affect IOP measurement in children, and tonometers vary in their accuracy
    in pediatric eyes.
    Comment: The clinician should adopt a consistent protocol for the
    measurement of IOP in children so that through experience the ‘normal’ range
    for their protocol can be determined.

IOP as a Risk Factor for Glaucoma Development & Progression

  1. There is strong evidence to support higher mean IOP as a significant factor
    for the development of glaucoma.
  2. There is strong evidence to support higher mean IOP as a significant risk
    factor for glaucoma progression.
  3. IOP is more variable in glaucomatous than in healthy eyes, but both 24-hour
    IOP fluctuation and IOP variation over periods longer than 24 hours tends to
    be correlated with mean IOP.
  4. There is currently insufficient evidence to support 24-hour IOP fluctuation
    as a risk factor for glaucoma development or progression.
    Comment: 24 hour IOP measurements are comprised of day-time (diurnal)
    and night-time (nocturnal) periods.
    Comment: Diurnal IOP is generally highest after awakening and decreases
    during the day-time period.
    Comment: Posture is an important variable in the measurement of IOP;
    IOP in the sitting position is generally lower than in the supine position.
  5. There is currently insufficient evidence to support IOP variation over periods
    longer than 24 hours as a risk factor for glaucoma development and progression.
  6. Sufficiently low blood pressure, combined with sufficiently high IOP, generates
    low ocular perfusion pressure and is associated with increased OAG prevalence
    in cross-sectional studies.
    Comment: Physiologic IOP variation occurs in regular rhythmic cycles.
    Regular IOP peaks and valleys are normal, and compensatory mechanisms are in
    place to preserve the integrity of the tissue and the organism.
    Comment: The peaks and troughs in circadian IOP and blood pressure do
    not necessarily occur simultaneously.

Epidemiology of Intraocular Pressure

  1. Self-described race is a poor summary of human biodiversity.
    Comment: Self-described race still contains important information that
    both correlates well with genetic measures of ancestry and disease risk on a
    populations basis.
  2. Evidence for differences in IOP between blacks and white is contradictory
    from available populations-based studies.
  3. Evidence for a relationship between IOP and age is contradictory from available
    populations-based studies.
  4. Evidence for a relationship between IOP and gender is contradictory from
    available populations-based studies.
  5. Studies with similar methodology comparing differences in IOP between multiple
    racial groups allowing direct comparisons generally have not been performed.
    Comment: IOP appears lower in Asian populations than populations with
    European and African ancestry, however direct comparisons have not been made.
  6. Variations in study designs and IOP measurement techniques limit comparison
    of mean IOPs across racial, ethnic and regional strata. Comment: Very few population-based
    surveys have included important biomarkers such as CCT that may effect the measured
    IOP.
    Comment: IOP is higher in eyes with shorter axial anterior chamber depth
    as a result of pathological angle-closure.
    Comment: Corneal radius of curvature is a potential source of measurement
    error, and should be adjusted for when using an applanation tonometer.
  7. There is a strong positive relationship between IOP and OAG, although prevalent
    and incident OAG cases occur commonly at IOP < 22 mmHg.

Clinical Trials & Intraocular Pressure

  1. The type of clinical trial (i.e., Phase II, III, or IV) influences the study
    design and subsequent considerations of treatment groups, recruitment criteria,
    and power.
  2. An appropriately-designed clinical trial for efficacy of IOP reduction should
    specify a clinically significant treatment effect (delta); probability of a
    type 1 error (alpha), usually set at 5%, and a desired power (conventionally
    at least 80%).
  3. Clinical trials in related disease areas should strive to use similar designs
    and outcome measures to facilitate meta-analysis (i.e., a pooling of results
    of independent trials).
  4. Clinical trials comparing IOP-lowering efficacy of different treatment should
    provide 95% confidence intervals for the difference in IOP reduction.
  5. Efficacy trials should define a priori the clinically meaningful
    difference for that specific study.
    Comment: In addition to IOP-lowering, other factors such as safety and
    side-effects must be considered in defining a clinically-meaningful difference
    for that specific study.
  6. Protocols should include at least two post-screening IOP measurements acquired
    on at least two different days for calculating baseline IOP, prior
    to randomization    .
  7. Protocol analyses also should include measurement of baseline IOP, central
    corneal thickness and type of glaucoma to allow adjustment for these potentially
    confounding variables when comparing IOP-lowering interventions.

Target IOP in Clinical Practice

  1. The target IOP is the IOP range at which the clinician judges that progressive
    disease is unlikely to affect the patient’s quality of life.
    Comment: The burdens and risks of therapy should be balanced against
    the risk of disease progression.
  2. The determination of a target IOP is based upon consideration of the amount
    of glaucoma damage, the IOP at which the damage has occurred, and the life expectancy
    of the patient, and other factors including status of the fellow eye and family
    history of severe glaucoma.
    Comment: At present, the target IOP is estimated and cannot be determined
    with any certainty in a particular patient.
    Comment: There is no validated algorithm for the determination of a target
    IOP. This does not, however, negate its use in clinical practice.
  3. It is recommended that the target IOP be recorded so that it is accessible
    on subsequent patient visits.
  4. The use of a target IOP in glaucoma requires periodic re-evaluation.
    Comment: This entails examination of the optic nerve and assessment of
    visual function to detect glaucomatous progression, the effect of the therapy
    upon the patients quality of life, and whether the patient has developed any
    new systemic or ocular conditions that might affect the risk/benefit ratio of
    therapy.
    Comment: During the re-evaluation, it is essential to determine whether
    the IOP target is appropriate and should not be changed, or that it needs to
    be lowered or raised.