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Effects of Enzymatic Sterilization Detergents on the Corneal Endothelium
Chirag Parikh, BA;
Brian D. Sippy, MD, PhD;
Daniel F. Martin, MD;
Henry F. Edelhauser, PhD
Arch Ophthalmol. 2002;120:165-172.
ABSTRACT
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Objective To evaluate the potential of enzymatic detergents to cause endothelial
damage and anterior segment inflammation.
Methods Paired rabbit corneas were mounted in an in vitro specular microscope.
Endothelia were perfused either with the sterile irrigating solution BSS Plus
(Alcon Laboratories Inc, Ft Worth, Tex) (control) or 0.1%, 0.4%, or 1.0% Medline
Enzymatic Detergent (Medline Industries Inc, Mundelein, Ill) in BSS Plus.
Swelling rates were determined by regression analysis. Human endothelia were
perfused using 1.56% detergent. All corneas were fixed for scanning electron
microscopy (SEM) and transmission electron microscopy (TEM). Endothelial permeability
was determined following perfusion of 0.78% detergent. Finally, in vivo intracameral
injections with 1.56% or 3.9% detergent were performed to evaluate clinical
changes and to correlate with histopathologic analysis.
Results Dose-related corneal swelling rates were observed. Digital specular
micrographs revealed greater endothelial cell damage when perfused with 1.0%
detergent. The TEM of endothelia exposed to 1.0% solutions demonstrated abnormal
vacuolization and dilated extracellular spaces, which manifested as an increased
corneal permeability to 3 to 4 times that of controls. Human corneas swelled
comparably to rabbit corneas but demonstrated increased sensitivity when evaluated
by TEM and SEM. Histopathologic analysis after intracameral injection revealed
thickened corneas with fewer endothelial cells and irises with increased inflammatory
and fibrinous responses compared with controls.
Conclusions Medline Enzymatic Detergent causes a dose-dependent corneal swelling,
ultrastructural damage, increased corneal permeability, and increased inflammatory
response in the iris after intracameral injection.
Clinical Relevance Failure to adequately rinse the detergent from surgical instruments
may result in corneal edema and intraocular inflammation.
INTRODUCTION
POSTOPERATIVE endophthalmitis continues to be a complication following
intraocular surgery. The differential diagnosis of acute postoperative endophthalmitis
includes infection, preexisting uveitis, iris trauma, and sterile uveitis,
which is usually due to retained lens fragments or foreign materials introduced
intraoperatively. Sterile uveitis has been reported to occur in as many as
2% of patients following cataract extraction. This phenomenon is rarely associated
with long-term visual loss, but it may manifest with worrisome acute signs,
including a sterile hypopyon.1
Toxic endothelial cell destruction (TECD) syndrome is another important
complication after intraocular surgery with an undetermined incidence, since
it is a relatively new disease recognized by Breebaart et al.2
Several different causes have been associated with the development of TECD
syndrome after cataract surgery.2-3
This syndrome is characterized by profound corneal edema less than 24 hours
after surgery. Toxins implicated in TECD syndrome include topical antiseptic
solutions4-5 and intraocular medications
and preservatives.6-10
Kim11 and Breebaart et al2
showed for the first time that the development of acute corneal decompensation
following cataract surgery could be related to a toxic product formed when
detergent residue comes in contact with viscoelastic material or from the
residue itself. Nuyts et al3 correlated laboratory
data with the clinical data by Breebaart and colleagues by demonstrating that
a dose-dependent corneal swelling occurred after cleaning reusable cannulas
with an increasing concentration of the same detergent. They also showed that
residual detergent perfused to the endothelium of isolated rabbit and human
corneas damaged the endothelial barrier function, leading to immediate corneal
swelling.
Smith et al12 reported another type of
TECD syndrome caused by a new sterilization procedure and the use of reusable
cannulas. The small lumen of these cannulas had oxidized metal residues on
their internal surfaces, and on reuse, the residue was irrigated into the
eye during surgery. In a related article, Duffy et al13
described cases of TECD syndrome associated with this new sterilization method,
which used acetic acid, peracetic acid, and hydrogen peroxide, that caused
the reduction of hydrogen peroxide to water and the oxidation of brass to
zinc and copper ions, leading to heavy metal toxicity when the residue was
irrigated into the anterior chamber.
The importance of this information stems from the fact that ethylene
oxide is considered an occupational carcinogen and reproductive toxin by the
National Institute for Occupational Safety and Health, Centers for Disease
Control and Prevention.14-15 It
is currently the sterilization method of choice for ophthalmic instruments.
However, as more information becomes available about the effects of this gas,
there is a greater demand for better and safer alternatives. To fill this
demand, enzymatic detergents, which have the ability to clean instruments
of blood and tissue material, have been formulated. Medline Enzymatic Detergent
(Medline Industries Inc, Mundelein, Ill), a brand of enzymatic detergent,
which contains subtilisin, an exotoxin, and  -amylase, can be used for
instrument sterilization by soaking in a 0.78% solution followed by an adequate
rinse to remove residue and ending with an autoclave cycle. The autoclaving
process does not deactivate these enzymes because they are stable until the
temperature reaches and exceeds 140°C. This makes the rinsing stage crucial
because the autoclaves in use today reach maximum temperatures between 120°C
and 130°C.
The purpose of this study is to evaluate the direct effect on the corneal
endothelium of a currently used enzymatic detergent and to determine the acute
anterior chamber reaction following intracameral injection of this detergent.
This study describes another potential cause of sterile uveitis and TECD syndrome
that is related to the use of these new enzymatic detergents. With the current
emphasis on decreasing the use of ethylene oxide, the potential for sterile
uveitis and TECD to occur in the future after intraocular surgical procedures
is a major concern. The possibility of such complications occurring is compounded
if reusable cannulas are used because of the chance that detergent residue
may build up inside the small lumens and may then be irrigated into the eye
at the end of the intraocular procedure when the anterior chamber is reformed.
MATERIALS AND METHODS
New Zealand white rabbits (1.5-2.5 kg) were anesthetized with an intramuscular
injection of 0.6 mL of ketamine hydrochloride (100 mg/mL) and 0.6 mL of xylazine
hydrochloride (20 mg/mL). They were then euthanized with an intracardiac overdose
of sodium pentobarbital solution (324 mg/mL, Euthenasia-5; Henry Schein, Port
Washington, NY). The eyes were enucleated and the corneas excised and mounted
in a dual-chamber in vitro specular microscope for endothelial perfusion.
All animals were handled according to the Association for Research in Vision
and Ophthalmology statement for the use of animals in ophthalmology and vision
research.
Both corneal endothelia of each pair were initially perfused with the
sterile irrigating solution BSS Plus (Alcon Laboratories Inc, Ft Worth, Tex)
at a rate of 0.07 mL/min for a 1-hour stabilization period. After the stabilization
period, one cornea was perfused with a 0.1%, 0.4%, or 1.0% solution of Enzymatic
Detergent in BSS Plus for 1 hour followed by a washout phase with BSS Plus
for 2 hours. The paired control cornea was continually perfused with BSS Plus
for the entire experiment. Corneal thickness measurements were taken every
15 minutes, and corneal swelling rates were calculated by linear regression
analysis. Serial specular photographs of the rabbit endothelium were taken
with an Olympus DP10 digital camera (Olympus America Inc, Melville, NY) inserted
into the eyepiece slot on the in vitro specular microscope. At the end of
each experiment, the paired corneas were fixed in 2.5% glutaraldehyde in 0.1M
cacodylate buffer and processed for scanning electron microscopy (SEM) and
transmission electron microscopy (TEM).
Four paired human corneas were received from the Georgia Eye Bank. The
mean ± SD tissue parameters for these human eyes included a donor age
of 54.8 ± 5.7 years, death-to-enucleation time of 5.5 ± 1.3
hours, and enucleation-to-experiment time of 4.2 ± 1.1 days. The corneas
were transported in corneal storage media (Optisol GS; Bausch & Lomb,
Irvine, Calif) and stored at 4°C. The paired human corneas were mounted
in the same dual-chambered in vitro specular microscope as the rabbit corneas.
After mounting, the epithelium was removed from each human cornea using a
corneal Gill knife. The rest of the perfusion experiment was similar to rabbit
endothelial perfusions except that we tested the effect of 1.56% detergent,
which is twice the recommended concentration for instrument sterilization.
At the end of each experiment, the paired corneas were fixed for electron
microscopy.
In another rabbit corneal endothelial perfusion experiment, endothelial
carboxyfluorescein permeability was measured using the method of Watsky et
al16 and Kim et al.17
The value of corneal endothelial permeability is expressed as centimeters
per minute. In this study, one cornea served as a control and was perfused
with BSS Plus for the entire experiment. Its pair was initially stabilized
with BSS Plus, then exposed to 0.78% detergent in BSS Plus for another hour,
and finally exposed to BSS Plus for 1 hour as a washout. After this, the permeability
protocol was followed. Significance was determined using a 2-tailed t test for paired values.
In vivo experiments were conducted with another group of New Zealand
white rabbits. In these experiments, the rabbits were deeply anesthetized
with an intramuscular injection of 0.6 mL of ketamine hydrochloride and 0.6
mL of xylazine hydrochloride. The rabbits were positioned under an operating
microscope, and a speculum was used to retract the lids. One drop of 0.3%
ciprofloxacin was placed in the eye for antimicrobial prophylaxis, and one
drop of 0.5% proparacaine hydrochloride was used for topical anesthesia. Using
a 30-gauge needle on a 1-mL tuberculin syringe, approximately 50 to 150 µL
of aqueous humor was removed from the anterior chamber. The anterior chamber
of one eye was reformed through a new injection tract using either 1.56% or
3.9% detergent in BSS Plus, whereas the contralateral eye's anterior chamber
was reformed with BSS Plus alone as a control. All solutions were filtered
through a 0.2-µm filter before injection into the anterior chamber.
A small air bubble was intentionally injected into the anterior chamber to
help seal the wound and, thus, prevent extrusion of fluid during the immediate
postoperative period. During the surgery, BSS Plus was used to keep the rabbit's
cornea moist, and cellulose sponges were used to check wound integrity at
the completion of the injection. Subsequently, each eye was examined biomicroscopically
at 1, 3, and 5 hours for the 3.9% solution and additionally at 24 hours for
the 1.56% solution. At the end of each experiment, the rabbits were euthanized,
and the eyes were enucleated and fixed in formalin for histologic processing.
RESULTS
Corneal swelling rates were determined to establish that a dose-response
relationship existed when various concentrations of detergent solutions were
perfused to the endothelium (Figure 1).
The arrows indicate the times at which the endothelium was first exposed to
the detergent and the time at which the washout with BSS Plus was begun. The
mean ± SD corneal swelling rate of endothelia perfused with 0.1% detergent
solution is 21.3 ± 3.3 µm/h. The corneas swell at a rate of 25.5
± 5.7 µm/h when the endothelia are perfused with 0.4% detergent
and at a rate of 40.7 ± 9.6 µm/h when perfused with 1.0% detergent.
These values are compared with the cumulative swelling rate of 5.94 ±
1.23 µm/h for all BSS Plus paired controls.
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Figure 1. Corneal thickness curves for Medline
Enzymatic Detergent (Medline Industries Inc, Mundelein, Ill) and BSS Plus
(Alcon Laboratories Inc, Ft Worth, Tex) perfusions. Error bars indicate ±SEM.
Arrows indicate start and end of detergent perfusion. Swelling rates are as
follows: 21.3 ± 3.3 µm/h for 0.1% detergent, 25.5 ± 5.7
µm/h for 0.4% detergent, and 40.4 ± 21.2 µm/h for 1.0%.
BSS Plus (control)–perfused corneas swell at a rate of 5.94 ±
1.23 µm/h.
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Digital specular micrographs of the rabbit corneal endothelium were
taken during the endothelial perfusion experiments. The specular micrographs
show that the endothelial cells perfused with 0.1% detergent look similar
to those perfused with BSS Plus except that they were slightly swollen. At
the 1.0% concentration, there is a loss of endothelial cell structure and
visualization, indicating endothelial and stromal edema (Figure 2).
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Figure 2. Digital specular micrographs of
endothelia perfused with BSS Plus (Alcon Laboratories Inc, Ft Worth, Tex)
and 0.1%, 0.4%, and 1.0% Medline Enzymatic Detergent (Medline Industries Inc,
Mundelein, Ill) solutions. Endothelia perfused with lower concentrations are
swollen but look similar to control. Endothelia perfused with 1.0% detergent
become edematous and damaged. T indicates time.
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Representative SEM and TEM of endothelia perfused with BSS Plus and
1.0% detergent are shown in Figure 3
and Figure 4, respectively. The
SEM of a corneal endothelium perfused with BSS Plus shows confluent hexagonal
endothelial cells and intact intercellular junctions (Figure 3A). The TEM illustrates normal subcellular organelles, preserved
endothelial junctions, and little evidence of cellular swelling (Figure 3B). The SEM of a cornea perfused
with 1.0% detergent solution shows swollen hexagonal cells and raised junctional
flaps (not shown). Higher magnification of the junctional area shows swelling
and suggests junctional damage (Figure 4A).
The TEM reveals an irregular plasma membrane, abnormal vacuolization between
and within the endothelia, disrupted intracellular organelles, and damaged
intercellular junctions (Figure 4B).
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Figure 3. A, Scanning electron micrograph
of endothelia perfused with BSS Plus (Alcon Laboratories Inc, Ft Worth, Tex)
shows an undisrupted monolayer and intact intercellular junctions (original
magnification x1000). B, Transmission electron micrograph shows normal
intracellular organelles and a regular plasma membrane (original magnification
x4350).
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Figure 4. A, Scanning electron micrograph
of endothelia perfused with 1.0% Medline Enzymatic Detergent (Medline Industries
Inc, Mundelein, Ill) solution shows swollen intercellular regions and disrupted
intercellular junctions (original magnification x2000). B, Transmission
electron micrograph shows increased intracellular vacuolization, abnormal
subcellular organelles, and a slightly irregular plasma membrane (original
magnification x4350).
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Perfusion of donor human corneal endothelia with 1.56% detergent yielded
an average swelling rate of 60.1 ± 14.5 µm/h, which is comparable
to that of rabbits (Figure 5). Paired
controls perfused with BSS Plus swell at a rate of 8.8 ± 5.1 µm/h.
The SEM for the endothelia perfused with 1.56% detergent solution shows that
many cells have detached from the basement membrane, leaving a less confluent
endothelial cell monolayer (Figure 6A) than controls (Figure 7A). The TEM
for the same cornea reveals cells with considerable damage. The cells have
detached from the basement membrane and contracted, intracellular organelles
are damaged, and cell membranes are disrupted (Figure 6B). The TEM for the control endothelia looks normal, with
a regular plasma membrane and intact subcellular organelles (Figure 7B).
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Figure 5. Corneal swelling curves for donor
human endothelia perfused with 1.56% Medline Enzymatic Detergent (Medline
Industries Inc, Mundelein, Ill) and BSS Plus (Alcon Laboratories Inc, Ft Worth,
Tex). Error bars indicate ±SEM. The corneal swelling rate is 60.1 ±
14.5 µm/h when endothelia are perfused with detergent vs 8.8 ±
5.1 µm/h when perfused with BSS Plus.
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Figure 6. A, Scanning electron micrograph
of human corneal endothelia perfused with 1.56% Medline Enzymatic Detergent
(Medline Industries Inc, Mundelein, Ill) shows a disrupted endothelial monolayer
and destroyed intercellular junctions (original magnification x1000).
B, Transmission electron micrograph of the endothelium reveals detached and
contracted cells. Intracellular organelles are damaged, and vacuolization
is increased (original magnification x4350).
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Figure 7. A, Scanning electron micrograph
of human corneal endothelia perfused with BSS Plus (Alcon Laboratories Inc,
Ft Worth, Tex) shows a normal mosaic and intact intercellular junctions (original
magnification x1000). B, Transmission electron micrograph of the endothelium
reveals normal cells with intact subcellular organelles and a regular plasma
membrane (original magnification x4350).
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To assess damage to the endothelial barrier function caused by the Enzymatic
Detergent, corneal permeability experiments were performed. Control rabbit
corneal endothelia perfused with BSS Plus have an average permeability (mean
± SEM) of 6.25 x 10-4± 0.58 cm/min, whereas
the corneal endothelia perfused with 0.78% detergent solution have an average
permeability of 22.74 x 10-4± 6.83 cm/min (P = .04).
Finally, in vivo experiments demonstrate that the 1.56% solutions injected
into the anterior chamber of rabbits cause mild corneal edema clinically and
a mild-to-moderate fibrinous exudate in the anterior chamber. Additionally,
the results of the clinical examination up to 24 hours for both eyes were
normal (ie, no photophobia, apparent pain, conjunctival injection, or hypopyon).
Further experiments using a 3.9% detergent concentration demonstrate a marked
response 1 hour after injection. The eyes become hyperemic and edematous,
develop a hyphema, and are photophobic. No hypopyon develops in this model.
However, rabbits were euthanized soon after development of hyphema and photophobia.
Histopathologic analysis reveals the average thickness for the corneas
of the eyes injected with detergent solution to be 510 vs 388 µm (P = .04) for the corneas of the eyes injected with BSS
Plus. The endothelial cell count is decreased to 17 cells per high-power field
on the detergent-injected eye vs 20 cells per high-power field (P = .04) on the BSS Plus–injected eye. Williams et al18 showed that there was a relationship between cell
density and number of cells per high-power field. For human tissue, the formula
for determining cell density is as follows:
Since cell densities of humans and rabbits are similar, it is likely
that this relationship is comparable. Histologic analysis of the control eye
provided evidence of mild inflammation in the iris with lymphocytes and polymorphonuclear
leukocytes (PMNs) and a slight fibrinous exudate in the anterior chamber containing
a few PMNs (Figure 8A). The iris
of the detergent-treated eye is infiltrated with an increased number of lymphocytes
and PMNs and demonstrates perivascular fibrinous exudates around anterior
iris vessels and evidence of hemorrhage, whereas the fibrinous exudate in
the anterior chamber contains numerous PMNs (Figure 8B).
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Figure 8. A, Histologic analysis of a rabbit
eye injected with BSS Plus (Alcon Laboratories Inc, Ft Worth, Tex) demonstrates
mild inflammation and a slight fibrinous exudate containing few polymorphonuclear
leukocytes. B, The paired eye injected with 3.9% Medline Enzymatic Detergent
(Medline Industries Inc, Mundelein, Ill) demonstrates an increased inflammatory
and fibrinous response. Additionally, there is evidence of hemorrhage and
perivascular fibrinous exudates around anterior iris vessels.
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COMMENT
Since the enzymes, subtilisin, an exotoxin, and -amylase contained
in the Medline Enzymatic Detergent cannot be deactivated until temperatures
reach and exceed 140°C, we did an experiment (data not shown) in which
the detergent was autoclaved at 120°C and subsequently diluted to 1.0%
in BSS Plus before being perfused to the rabbit corneal endothelium. The corneal
swelling rate was identical to the corneal endothelial perfusions with the
nonautoclaved detergent (Figure 1).
This experiment confirmed that autoclaving would not deactivate the enzymes
in this detergent. We continued our evaluation of this detergent by hypothesizing
that inadequate rinsing of the reusable cannulas could allow residue buildup
in the lumen, as described by Nuyts et al.3
It was further theorized that this residue would lead to variable concentrations
of this detergent being irrigated into the anterior chamber when it is reformed
at the end of intraocular procedures.
By direct exposure to the rabbit corneal endothelium with multiple concentrations
of the detergent in BSS Plus vs BSS Plus (control), we discovered a dose-related
response (Figure 1). In the anterior
chamber, subtilisin, a serine protease, has the ability to damage multiple
intraocular structures. Kim et al19 showed
that subtilisin had a direct toxic effect on corneal endothelial cell structure,
function, and viability. The SEM, TEM, and swelling rates support the findings
of Kim and coauthors. Suzuki et al20 demonstrated
that serine proteases will cause stratum corneum desquamation via degradation
of hemidesmosomes. The carboxyfluorescein endothelial permeability experiments
illustrate that these enzymes also may be involved in the breakdown of corneal
endothelial tight junctions that compromise the barrier function that is crucial
for the maintenance of corneal transparency. Although it is probable that
higher concentrations of detergent could increase the endothelial permeability
to a greater extent, it is not possible to accurately evaluate this with the
current experimental procedure, since light scattering due to stromal edema
occurs earlier in the perfusion experiment, causing the corneal thickness
readings later in the experiment to be unreliable.
In addition to the increased permeability of rabbit corneas, we found
that donor human corneas perfused with 1.56% detergent solution also displayed
a marked corneal swelling rate (Figure 5) and extensive endothelial damage on SEM and TEM (Figure 6). Although the corneal endothelia perfused with BSS Plus
maintained an intact endothelial monolayer (Figure 7A) with normal intracellular organelles (Figure 7B), the paired human cornea perfused with the detergent
had a disrupted endothelial monolayer (Figure
6A) and detached endothelial cells (Figure 6B). This was probably caused by a breakdown of adherens-type
junctions and desmosomes or hemidesmosomes that bind the endothelial cells
to each other and to the Descemet membrane.
Intracameral injections using higher concentrations of detergent, 1.56%
and 3.9%, caused a hyphema, corneal edema, conjunctival injection, and photophobia
1 hour after surgery. It is known that the rabbit inflammatory response in
the anterior chamber is different from the human response. Although humans
develop a hypopyon, rabbits will increase their aqueous humor protein and
form fibrinous coagulates. We observed this fibrin coagulate at the 1.56%
detergent concentration, but it was more difficult to observe at the higher
concentration since the hyphema and corneal edema impeded the view of the
anterior chamber and the iris.
Histopathologic examination revealed that the irises of the detergent-treated
eyes had a greater number of PMNs and lymphocytes (Figure 8B) when compared with the control eyes (Figure 8A). Additionally, the fibrinous coagulate that formed in
the anterior chamber of the eye injected with detergent also contained PMNs
(Figure 8B). This inflammatory picture
is similar to a sterile uveitis that could occur in humans if this enzymatic
cleaner was introduced into the anterior chamber during intraocular surgery.
At 3.9%, the highest concentration tested, there was a rapid breakdown of
the blood-aqueous barrier, leading to an increase in the number of red blood
cells (hyphema) in the anterior chamber (Figure 8B) when compared with controls (Figure 8A). Furthermore, the increased corneal thickness and decreased
endothelial cells per high-power field could manifest in humans as a picture
of TECD syndrome.
Richburg et al21 showed that rabbits
could develop a hypopyon if the anterior chamber was injected with Klebsiella endotoxin. They showed that when instruments were placed
in a 3-day-old ultrasonic bath contaminated with gram-negative bacteria, endotoxins
produced by these microorganisms could coat the instruments. Although the
bacteria themselves were eradicated by autoclaving, the endotoxin, a heat-stable
lipopolysaccharide, remained on the instruments. Introduction of endotoxin
into the anterior chamber may also cause a potentially serious case of endophthalmitis.
Other authors have attributed sterile hypopyons to numerous causes, including
intraocular lens polish and rough edges,22
reaction to lens proteins,23-25
intraocular lens sterilization techniques,26
laser iridotomy,27 leukemia,28
iridocyclitis, and other types of uveitis. Although we are not specifically
addressing the issue of endotoxin exposure, we believe it is advisable to
consider endotoxins as a source of sterile hypopyons.
The clinical implication of our study is that the use of reusable cannulas
can lead to unforeseeable complications that could be avoided by the use of
disposable cannulas. Also, if the bath in which surgical instruments are soaked
is prepared using a higher concentration of detergent, there is a possibility
that the cannulas and instruments used during intraocular surgery will be
coated with a thicker residue and/or higher concentration, allowing an avenue
for introduction into the eye. We maintain that the rinse phase of the cycle
is the most important step to prevent the consequences discussed. Use of these
enzymatic detergents is increasing because the US Department of Health and
Human Services has mandated the halt of ethylene oxide gas sterilization for
fear of its carcinogenicity. Therefore, it is possible that these complications
may become more prevalent. If any active enzymes enter the anterior chamber,
they could remain for several hours during aqueous turnover, causing damage
for the duration of their presence. Therefore, it is our recommendation that
surgeons restrict their use of reusable cannulas and be aware of the advantages
and disadvantages of the enzymatic detergents used for cleaning ophthalmic
instruments.
AUTHOR INFORMATION
Accepted for publication November 8, 2001.
This study was supported in part by National Eye Institute grant RO1-EY00933,
P30 EY06360, and an unrestricted grant from Research to Prevent Blindness,
New York, NY. Mr Parikh is a Research to Prevent Blindness medical student
fellow. Dr Sippy is supported by the American Ophthalmic Society-Knapp Ophthalmic
Pathology Fellowship.
Corresponding author and reprints: Henry F. Edelhauser, PhD, Emory
Eye Center, 1365-B Clifton Rd NE, Suite B2600, Atlanta, GA 30322 (e-mail: ophthfe{at}emory.edu).
From the Department of Ophthalmology, Emory Eye Center, Atlanta, Ga.
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