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Oxygen Inhalation in Retinal Arterial Occlusion
OXYGEN IN RETINAL ARTERIAL OCCLUSION
789
8. Bacon, H . E., Sherman, L. F., and Campbell, W . N . : Hemangiopericytoma: An unusual extrarectal tumor. Minn. Med., 33 :683-4 (July) 19S0. 9. Forrester, J. S., and Houston, R. Α . : Hemangiopericytoma with metastases; report of a case with autopsy. Arch. Path., 51:651-6S7 (June) 1951. 10. Ault, G. VV., Smith, R. S., and Castro, A. F.: Hemangiopericytoma of the sigmoid colon: report of a case. Surgery, 30:523-527 (Sept.) 1951. 11. Forman, I., and Campbell, W . N . : Hemangiopericytoma, an unusual pelvic tumor. Am. J. Obstet. & Gynec, 63:929 (Apr.) 1952. 12. Wise, R. Α . : Hemangiopericytoma, surgical considerations. Arch. Surg., 65:201-210 (July) 1952. 13. Fisher, E. R., Kaufman, N., and Mason, E. J.: Hemangiopericytoma; histologic and tissue culture studies. Am. J. Path., 28:653-661 (July-Aug.) 1952. 14. Smith, W . P., and Swenson, R. E . : Hemangiopericytoma of the ileum. Am. J. Surg., 87:143 (Jan.) 1954. 15. Greene, R. R., and Gerbie, A . B.: Hemangiopericytoma of the uterus. Obstet. & Gynec, 3:150-159 (Feb.) 1954. 16. Pedowitz, P., Felmus, L. B., and Grayzel, D. G.: Hemangiopericytoma of the uterus. Am. J. Obst. & Gynec, 67 :549 (Mar.) 1954. 17. McCormack, L. J., and Gallivan, W . F.: Hemangiopericytoma. Cancer, 7:595-601 (May) 1954. 18. Begg, C. F., and Garrett, R . : Hemangiopericytoma in the meninges. Cancer, 7 :607 (May) 1954. 19. Ferguson, F. O., Claggett, O. T., and McDonald, D. R . : Hemangiopericytoma (glomus tumor) of the mediastinum. Surgery, 36:320 (Aug.) 1954. 20. Zimmerman, K. W . : Der feinere Bau der Blutcapillaren. Ztschr. f. Anat. u. Entwcklngsgesch. 6 8 : 29, 1923. 21. Reese, A. B.: Tumors of the Eye. New York, Hoeber, 1953, p. 354.
OXYGEN
I N H A L A T I O N IN R E T I N A L A R T E R I A L A
PRELIMINARY ARNALL
OCCLUSION
REPORT
PÄTZ,
M.D.
Baltimore, Maryland
Observations made in studies on the role
Even the ganglion cells which are
farthest
of o x y g e n in retrolental fibroplasia^'^ raised
removed from the choroid appeared normal
the possibility that o x y g e n inhalation may be
(fig. 1 ) .
a beneficial adjunct in the therapy o f clinical retinal arterial occlusion. briefly
summarized:
These
When
data are
young
mice,
rats, kittens, or puppies were exposed to 80-
Apparently o x y g e n inhalation elevated the choroidal blood o x y g e n tension the
range
avascular
increasing
o f diffusion o f o x y g e n to
the
inner retinal layers. These data
percent oxygen for four days or longer, the
suggested that in clinical retinal arterial o c -
retinal vessels were totally
as
elusion in adults, the inhalation o f oxygen
seen in flat retinal preparations and in cross
might diminish the anoxic damage that re
obliterated
sections o f India-ink injected specimens. All
suits from
other vessels o f the eye and in particular the
layers.
choroidal vessels were imaffected. A picture
retinal ischemia in these
inner
T o determine if increased choroidal diffu-
analogous to clinical retinal arterial occlusion
sion actually occurs, the o x y g e n
was thus produced. In several experiments,
across the avascular retina was measured di-
diffusion
the animals were maintained in high c o n -
rectly with the o x y g e n electrode. A recording
centrations o f oxygen continuously f o r 10
o f the o x y g e n tension at the vitreal surface
days o r longer. In many of these animals
of the retina was made in five eyes of three
complete retinal vessel obliteration persisted
anesthetized adult cats using a specially con-
until the animals were killed. Although c o m -
structed electrode. A platinum electrode in-
pletely avascular for this prolonged period,
sulated
the retinas appeared normal on cross section,
through a Ziegler-knife scleral incision over
by a capillary tube
was
inserted
790
ARNALL PATZ
these
observations
demonstrated
that
the
range of diffusion of oxygen from the cho roid could be extended by the inhalation o f oxygen. A
controlled experiment was next
per
formed to determine the effects o f o x y g e n inhalation occlusion
on experimental retinal arterial in
the
adult
rat.
The
rat
was
chosen because of the similarity between the rat and human retinal circulations. A s occurs in the human retina, the inner retinal layers o f the rat are nourished by the retinal ves sels and the outer layers primarily by the choroid. In both humans and rats, there are t w o distinct capillary nets in the inner ret inal
layers
with
the
outer
layers
being
totally devoid o f vessels. EXPERIMENTAL
SUBJECTS
Fig. 1 (Pätz). Section of retina of 21-day Indiaink injected mouse raised in 70-percent oxygen since birth. Note that there is no ink in the retina. Arrow points to cords of endothelial cells but no canalized vascular channels exist. A l though the retina is avascular, the ganglion cells (g) appear normal. (Hematoxylin-eosin, X400.)
A N D
OBSERVATIONS
METHODS
Seventy-two adult white rats were divided into pairs. Under light ether anesthesia, the left eye o f each animal was operated. The conjunctiva
was dissected and the
lateral
rectus muscle severed. Under direct visuali zation under the dissecting microscope, the left central retinal vessels were coagulated
the pars plana of the ciliary body. Under
by diathermy or severed with a Ziegler knife
direct
just posterior to the globe.
ophthalmoscopic vizualization,
the
electrode was passed across the vitreous to
One-half o f the animals were placed with
the inner surface of the retina on the o p
in five minutes into incubators containing
posite side. T h e oxygen tension was meas
95-percent oxygen, and the other half serv
ured and recorded on a continuous recording
ing as controls were placed in room
air.
galvanometer. (Details of this technique will
(Five
re
appear in a later report.)
quired to suture the lids securely to protect
In two eyes the central retinal vessels were
minutes
was the average time
the globe.) T h e animals in each group were
occluded by direct coagulation o f the optic
killed at two, four, 12, 18, and 48 hours, and
cup. T h e oxygen tension at the retinal sur
eight days after
face abruptly dropped to near zero. Although
receiving oxygen for longer than 48 hours
retinal blood
flow
ministration
of
was eliminated, on ad 100-percent
oxygen
by
tracheal cannula, there was noted a measur
operation. T h o s e animals
were removed to room air for 24 hours on the second, fourth, and sixth day in o x y g e n to prevent pulmonary o x y g e n toxicity.
able increase in oxygen tension at the inner
Both eyes were enucleated—the right nor
retinal surface. These preliminary observa
mal eye serving as a control o n technique.
tions with the electrode were essentially a
T h e horizontal meridians were labeled with
pilot study intended to investigate the feasi
sutures and all eyes after paraffin embedding
bility o f the technique. Although limited,
were sectioned exactly horizontally at six
O X Y G E N IN R E T I N A L A R T E R I A L O C C L U S I O N
microns thickness. Routine and special nerve stains were employed. These included Nissl, Gomori's reticulum, Bodian, phosphotungstic acid hematoxylin, periodic-acid Schiff, and hematoxylin and eosin. The amount o f retinal edema was quantitated by measuring the thickness o f the inner layers with a mi crometer scale; ganglion cell and bipolar cell counts per high-power field were recorded. RESULTS
In the eight-day specimens there was no difference between oxygen treated and con trols. In the 48-hour specimens there was equivocal protection o f the inner retinal lay ers by oxygen. In specimens up to 18 hours, however, a varying degree o f pro tection resulted from o x y g e n administration. The oxygen-treated animals showed much less edema and coagulation necrosis. Degen eration o f the ganglion cells and bipolars was appreciably less in the oxygen-treated
791
animals when compared with their controls in r o o m air (figs. 2 to 4 ) . In no case, h o w ever, did the o x y g e n administration result in total protection o f the inner retinal layers as some slight degenerative change was pres ent in all. Complete details o f these data with tables showing a quantitative appraisal o f the amount o f retinal edema and necrosis, ganglion cell and bipolar cell counts, and the results o f special staining techniques are omitted from this preliminary report. T h e y will appear subsequently. CLINICAL
OBSERVATIONS
In t w o cases o f early retinal arterial o c clusion, o x y g e n has been administered with an apparent beneficial effect as an adjunct to routine therapy. In two cases first seen two days after occlusion, o x y g e n therapy had no effect. These cases are briefly sum marized :
Fig. 2 (Pätz). Section of normal retina of one-year-old control rat. Note normal thickness of inner retinal layers (brackets). ( N F ) Nerve-fiber layer, ( g ) Ganglion cells. ( I P ) Inner plexiform layer. ( I N ) Inner nuclear layer. ( O N ) Outer nuclear layer. ( R C ) Rods and cones. (Hematoxylin-eosin, x400.)
ARNALL PATZ
792
Fig. 3 (Patz). Section of rat retina 18 hours in room air after occlusion of retinal vessels. Note massive edema of nerve fiber layer (NF) and inner nuclear layer ( I N ) . Thickness of inner layers of normal retina (brackets) is shown for comparison. Note coagulation necrosis in inner plexiform layer. Loss of ganglion cell and inner nu clear layer populations is promi nent. Note pyknotic nuclei and cell ghosts in these layers. The outer retinal layers are normal. (Hema toxylin-eosin, X400.)
CASE
1
A 62-year-old white man with a history o f hypertension of six years' duration noted a sudden blurring o f vision in his left eye. O n covering his right eye, he noted that the en tire lower half of his left field o f vision was blind. H e reported fo r examination four hours later. T h e right eye was normal with the excep tion of prominent retinal arteriosclerosis. The visual acuity in the left eye was reduced to 4/200. T h e upper retina showed a diffuse
faint pallor and an absolute scotoma in volved the lower field of vision including the fixation point. Preparations were made for a cervical sympathetic block. During this period an oxygen mask was fittd on the patient. A ventura was connected in the s y s t e i T i so that oxygen o r air could be
alternated without the patient's knowledge. The oxygen mask was applied and the ven tura set so that the patient was breathing room air for 15 minutes. T h e absolute lower field defect remained constant. T h e ventura
Fig. 4 (Pätz). Section of rat retina 18 hours after occlusion of central vessels. The animal was maintained in oxygen during the entire 18-hour period. Compare with animal of Figure 3 which re ceived no oxygen and note much less edema and necrosis of inner retinal layers. Surviving cells in both ganglion and inner nuclear layers greatly outnumber those in the nonoxygenated animal. Brackets show normal thickness of inner retinal layers for comparison. (Hematoxylin and eosin, X400.)
O X Y G E N IN
RETINAL ARTERIAL
OCCLUSION
793
was then turned to administer pure o x y g e n .
improved to 2 0 / 5 0 . T h e lower field o f vision
A f t e r three minutes the patient reported,
remained normal. T h e visual status has re
"there is a
flickering
in the central blind
mained stable for 14 months with no residual
area and I can for the first time see m y
defect detected in the lower field and
knees and the
central vision remaining at 2 0 / 5 0 .
floor."
A field check showed
that the absolute scotoma was n o w relative and was only detected with a 3/1,000 white target. T h e visual acuity improved to 2 0 / 7 0 . The ventura was then turned to deliver r o o m air. In approximately three minutes the cen tral vision faded, and the lower field o f vision disappeared. O x y g e n was started after
15 minutes on
air and a similar improvement was noted. On
stopping oxygen, the lower field faded
(figs. 5 A and 5 B ) . A
left sympathetic block was then per
formed with Xylocaine and massage o f the globe
was
performed.
Oxygen
inhalation
was continued for four hours. O n stopping oxygen after four hours, the lower field re mained open and central vision stabilized at about 2 0 / 7 0 . The
sympathetic block was repeated
24
hours later and the patient was maintained on Priscoline, 25 mg. every four hours, f o r five days. The retinal edema in the upper half o f the retina gradually subsided. T h e central vision
CASE
A
the
2
72-year-old white woman with a
five-
year history o f mild hypertension noted the sudden appearance o f a "veil" over her left eye while watching television. Examination one hour and 15 minutes later revealed the vision in the left eye to be reduced to no light perception. Ophthalmoscopic examination
showed a
faint mild gray haze over the entire retina. There was stasis o f the retinal circulation and
the
classic "cattle car" effect
of
the
blood cells in the vessels was noted. Vision in the right
eye was normal and the eye-
grounds were negative except for moderate hypertensive vascular changes. A ventura and o x y g e n mask was used as in the first case. T h e patient breathed room air through the mask for 10 minutes show ing no light perception repeatedly. Without her knowledge, the ventura deliver
100-percent
oxygen.
was turned to After
three
minutes, light perception returned in the en tire peripheral field. A f t e r five minutes, she counted fingers at t w o feet accurately just temporal to the fixation point. T h e ventura
Fig. 5A (Pätz). Case 1. Tangent screen field prior to oxygen inhalation (S/1,000 white tar get).
was turned to deliver air and the vision dropped within one and one-half minutes to bare light perception. After
10 minutes
on air,
a change to
o x y g e n elicited the same response as before and, on reverting
back to air, the vision
again was reduced to light perception only (figs. 6 A and 6 B ) . A cervical sympathetic block with (Pätz). Fig. SB Case 1. Tangent screen field 1 0 minUtes after oxygen inhalation (S/1,000 white t a r g e t ) .
Xylo
caine was done and massage o f the globe followed. T h e patient was started on P r i s c o line 25 mg. every four hours by mouth. O x y g e n was administered by mask for three hours. T h e peripheral field remained full and normal. T h e central scotoma persisted. A f t e r a four-month follow-up the peripheral field
794
ARNALL PATZ
glucose and other metabolites. Likewise, the resulting Fig. 6A (Patz). Case 2. Visual field, left eye, prior to oxy gen inhalation (15/ 1,000 white target).
cessation
of
blood
flow
should
favor an accumulation o f carbon dioxide and other
breakdown products. Therefore, in
creasing
choroidal o x y g e n
tension to
en
hance diffusion across the retina aids
the
ischemic tissue only in its oxygenation with out supplying other metabolites. O n e would anticipate vessel
that
in total
occlusion,
in
permanent spite
of
retinal adequate
oxygenation, the ischemic adult retina, lack Fig. 6B (Patz). Case 2. Visual field, left eye, 10 minutes after oxygen inhala tion (15/1,000 white target).
ing other metabolites, would ultimately de generate.
These
animal
occlusion
experi
ments support this premise. Restitution of retinal blood flow is, there fore,
fundamental
in
the
treatment
of
retinal occlusion. O x y g e n inhalation can be considered as an adjunct to oxygenate the has remained normal. A central scotoma has persisted, however, with vision remaining at 20/200.
ischemic tissues until circulation is restored. It is fortunate, however, that, in many pa tients, cessation of blood flow is either tem porary or partial, as is evidenced by a return of varying levels o f vision after
DISCUSSION
The
use
of
oxygen
therapy
in
many
occlusion.
It is in these patients that oxygen
inhala
ischemic processes and especially in acute
tion should be beneficial by reducing
coronary vessel occlusion is well established
severity o f anoxic damage during the tem
in general medicine. In many ocular dis
porary ischemia.
orders, Bietti^ has advocated o x y g e n therapy
In
interpreting the animal
experiments,
to improve general ocular nutrition. In ret
it is significant that o x y g e n therapy
inal arterial occlusion a singularly favorable
started
five
minutes
was after
avascular
retinal occlusion. Experiments are in prog
retina lies in direct apposition to the vascular
ress to determine the maximum time follow
choroid, the circulation of which is intact.
ing experimental occlusion at which o x y g e n
choroidal oxygen tension by
inhalation may be expected to have a bene
situation
exists.
Increasing
Here
the
thin
approximately
the
oxygen inhalation permits an extension o f the normal range of diffusion o f oxygen to reach When
the the
avascular central
inner
retinal
layers.
retinal artery was o c
ficial effect on the ischemic retina. There was no difference histologically in the retinal occlusion produced by diathermy coagulation and cutting o f the retinal vessels.
cluded in rats, apparently an increase in ret
The
inal oxygenation via the choroid delayed the
changes c o n f o r m closely to those described
onset o f irreversible degenerative changes.
by TurnbuU* and confirm his careful studies.
rate
of
appearance
of
the
retinal
In a limited clinical trial oxygen inhalation markedly improved the function o f surviv ing retinal elements. In total retinal arterial occlusion it is ap
RECOMMENDATIONS
A t this preliminary stage, the recommendations
seem
justified.
following When
a
parent that all blood-borne constituents di
diagnosis o f relatively recent retinal arterial
rected to the inner retinal layers are de
occlusion is made, attempts to
pleted. This not only includes oxygen, but
blood flow should be vigorously pursued as
re-establish
O X Y G E N IN R E T I N A L A R T E R I A L O C C L U S I O N
an emergency procedure. T h e choice o f therapy may be one or preferably a combi nation o f some of the following procedures: Cervical sympathetic block, massage o f the globe, paracentesis, retrobulbar block and vasodilators. Inhalation o f oxygen by a tightly fitting mask or nasal catheter is ad vised. O x y g e n should be administered at a flow rate o f at least eight liters per minute during the initial trial. A working suggestion is that if no ap preciable change in the patient's visual acuity o r field is noted after 30 minutes, o x y g e n therapy should be discontinued. I f a signifi cant improvement is noted, oxygen inhala tion should be continued for about two to four hours along with other measures to re establish retinal circulation. There need be no concern for pulmonary oxygen toxicity here. However, when oxygen concentrations of over 70 percent are given continuously for 24 hours or longer, pulmonary oxygen toxicity may result. Cases o f retinal occlusion o f short dura tion are seen relatively infrequently b y a single investigator. It would be appreciated and extremely helpful in obtaining an ade quate clinical appraisal of oxygen inhalation in early occlusion if ophthalmologists giving this a trial would either publish their results or communicate with me.
795
S U M M A R Y
1. Previous animal studies on the role o f o x y g e n o n the immature retina and experi ments cited here on retinal arterial occlusion in the adult rat suggest that oxygen inhala tion may be beneficial in cases o f early retinal arterial occlusion. A preliminary clinical trial supports these experimental data. 2. T h e results o f the animal experiments are briefly summarized. T h e responses to o x y g e n inhalation in four clinical cases are presented. ADDENDU Μ
Since this paper was prepared, one addi tional case o f retinal occlusion was seen six hours after the vision blurred. T h e visual field opened partially after oxygen inhalation. A second case seen four hours after onset o f symptoms showed no improvement what soever in the visual field or visual acuity after oxygen inhalation. 920 St. Paul Street
(2).
ACKNOWLEDGEMENTS
Mr. Don H . Higginbotham, graduate student in biochemistry, Georgetown University, assisted in the animal experiments and Mrs. Ann Eastham prepared the histologic sections. The preliminary experiments measuring the retinal oxygen ten sion were done in collaboration with Dr. Martin Larrabee, Department of Biophysics, Johns Hop kins University.
REFERENCES
1. Pätz, Α., Hoeck, L. E., and De La Cruz, E . : Studies on the effect of high oxygen administration in retrolental fibroplasia: I. Nursery observations. Am. J. Ophth., 35:1248-1253 (Sept.) 1952. 2. Pätz, Α., Eastham, Α., Higgenbotham, D. H., and Kleh, T . : Oxygen studies in retrolental fibroplasia: II. The production of the microscopic changes of retrolental fibroplasia in experimental animals. Am. J. Ophth., 36:1511-1522 (Nov.) 1953. 3. Bietti, G.: Effects of experimentally decreased or increased oxygen supply in some ophthalmic diseases. Arch. Ophth., 49:491-513 (May) 1953. 4. Turnbull, W . : Experimental retinal anemia in rats. Arch. Ophth., 43:9-31 (Jan.) 1950.
789
8. Bacon, H . E., Sherman, L. F., and Campbell, W . N . : Hemangiopericytoma: An unusual extrarectal tumor. Minn. Med., 33 :683-4 (July) 19S0. 9. Forrester, J. S., and Houston, R. Α . : Hemangiopericytoma with metastases; report of a case with autopsy. Arch. Path., 51:651-6S7 (June) 1951. 10. Ault, G. VV., Smith, R. S., and Castro, A. F.: Hemangiopericytoma of the sigmoid colon: report of a case. Surgery, 30:523-527 (Sept.) 1951. 11. Forman, I., and Campbell, W . N . : Hemangiopericytoma, an unusual pelvic tumor. Am. J. Obstet. & Gynec, 63:929 (Apr.) 1952. 12. Wise, R. Α . : Hemangiopericytoma, surgical considerations. Arch. Surg., 65:201-210 (July) 1952. 13. Fisher, E. R., Kaufman, N., and Mason, E. J.: Hemangiopericytoma; histologic and tissue culture studies. Am. J. Path., 28:653-661 (July-Aug.) 1952. 14. Smith, W . P., and Swenson, R. E . : Hemangiopericytoma of the ileum. Am. J. Surg., 87:143 (Jan.) 1954. 15. Greene, R. R., and Gerbie, A . B.: Hemangiopericytoma of the uterus. Obstet. & Gynec, 3:150-159 (Feb.) 1954. 16. Pedowitz, P., Felmus, L. B., and Grayzel, D. G.: Hemangiopericytoma of the uterus. Am. J. Obst. & Gynec, 67 :549 (Mar.) 1954. 17. McCormack, L. J., and Gallivan, W . F.: Hemangiopericytoma. Cancer, 7:595-601 (May) 1954. 18. Begg, C. F., and Garrett, R . : Hemangiopericytoma in the meninges. Cancer, 7 :607 (May) 1954. 19. Ferguson, F. O., Claggett, O. T., and McDonald, D. R . : Hemangiopericytoma (glomus tumor) of the mediastinum. Surgery, 36:320 (Aug.) 1954. 20. Zimmerman, K. W . : Der feinere Bau der Blutcapillaren. Ztschr. f. Anat. u. Entwcklngsgesch. 6 8 : 29, 1923. 21. Reese, A. B.: Tumors of the Eye. New York, Hoeber, 1953, p. 354.
OXYGEN
I N H A L A T I O N IN R E T I N A L A R T E R I A L A
PRELIMINARY ARNALL
OCCLUSION
REPORT
PÄTZ,
M.D.
Baltimore, Maryland
Observations made in studies on the role
Even the ganglion cells which are
farthest
of o x y g e n in retrolental fibroplasia^'^ raised
removed from the choroid appeared normal
the possibility that o x y g e n inhalation may be
(fig. 1 ) .
a beneficial adjunct in the therapy o f clinical retinal arterial occlusion. briefly
summarized:
These
When
data are
young
mice,
rats, kittens, or puppies were exposed to 80-
Apparently o x y g e n inhalation elevated the choroidal blood o x y g e n tension the
range
avascular
increasing
o f diffusion o f o x y g e n to
the
inner retinal layers. These data
percent oxygen for four days or longer, the
suggested that in clinical retinal arterial o c -
retinal vessels were totally
as
elusion in adults, the inhalation o f oxygen
seen in flat retinal preparations and in cross
might diminish the anoxic damage that re
obliterated
sections o f India-ink injected specimens. All
suits from
other vessels o f the eye and in particular the
layers.
choroidal vessels were imaffected. A picture
retinal ischemia in these
inner
T o determine if increased choroidal diffu-
analogous to clinical retinal arterial occlusion
sion actually occurs, the o x y g e n
was thus produced. In several experiments,
across the avascular retina was measured di-
diffusion
the animals were maintained in high c o n -
rectly with the o x y g e n electrode. A recording
centrations o f oxygen continuously f o r 10
o f the o x y g e n tension at the vitreal surface
days o r longer. In many of these animals
of the retina was made in five eyes of three
complete retinal vessel obliteration persisted
anesthetized adult cats using a specially con-
until the animals were killed. Although c o m -
structed electrode. A platinum electrode in-
pletely avascular for this prolonged period,
sulated
the retinas appeared normal on cross section,
through a Ziegler-knife scleral incision over
by a capillary tube
was
inserted
790
ARNALL PATZ
these
observations
demonstrated
that
the
range of diffusion of oxygen from the cho roid could be extended by the inhalation o f oxygen. A
controlled experiment was next
per
formed to determine the effects o f o x y g e n inhalation occlusion
on experimental retinal arterial in
the
adult
rat.
The
rat
was
chosen because of the similarity between the rat and human retinal circulations. A s occurs in the human retina, the inner retinal layers o f the rat are nourished by the retinal ves sels and the outer layers primarily by the choroid. In both humans and rats, there are t w o distinct capillary nets in the inner ret inal
layers
with
the
outer
layers
being
totally devoid o f vessels. EXPERIMENTAL
SUBJECTS
Fig. 1 (Pätz). Section of retina of 21-day Indiaink injected mouse raised in 70-percent oxygen since birth. Note that there is no ink in the retina. Arrow points to cords of endothelial cells but no canalized vascular channels exist. A l though the retina is avascular, the ganglion cells (g) appear normal. (Hematoxylin-eosin, X400.)
A N D
OBSERVATIONS
METHODS
Seventy-two adult white rats were divided into pairs. Under light ether anesthesia, the left eye o f each animal was operated. The conjunctiva
was dissected and the
lateral
rectus muscle severed. Under direct visuali zation under the dissecting microscope, the left central retinal vessels were coagulated
the pars plana of the ciliary body. Under
by diathermy or severed with a Ziegler knife
direct
just posterior to the globe.
ophthalmoscopic vizualization,
the
electrode was passed across the vitreous to
One-half o f the animals were placed with
the inner surface of the retina on the o p
in five minutes into incubators containing
posite side. T h e oxygen tension was meas
95-percent oxygen, and the other half serv
ured and recorded on a continuous recording
ing as controls were placed in room
air.
galvanometer. (Details of this technique will
(Five
re
appear in a later report.)
quired to suture the lids securely to protect
In two eyes the central retinal vessels were
minutes
was the average time
the globe.) T h e animals in each group were
occluded by direct coagulation o f the optic
killed at two, four, 12, 18, and 48 hours, and
cup. T h e oxygen tension at the retinal sur
eight days after
face abruptly dropped to near zero. Although
receiving oxygen for longer than 48 hours
retinal blood
flow
ministration
of
was eliminated, on ad 100-percent
oxygen
by
tracheal cannula, there was noted a measur
operation. T h o s e animals
were removed to room air for 24 hours on the second, fourth, and sixth day in o x y g e n to prevent pulmonary o x y g e n toxicity.
able increase in oxygen tension at the inner
Both eyes were enucleated—the right nor
retinal surface. These preliminary observa
mal eye serving as a control o n technique.
tions with the electrode were essentially a
T h e horizontal meridians were labeled with
pilot study intended to investigate the feasi
sutures and all eyes after paraffin embedding
bility o f the technique. Although limited,
were sectioned exactly horizontally at six
O X Y G E N IN R E T I N A L A R T E R I A L O C C L U S I O N
microns thickness. Routine and special nerve stains were employed. These included Nissl, Gomori's reticulum, Bodian, phosphotungstic acid hematoxylin, periodic-acid Schiff, and hematoxylin and eosin. The amount o f retinal edema was quantitated by measuring the thickness o f the inner layers with a mi crometer scale; ganglion cell and bipolar cell counts per high-power field were recorded. RESULTS
In the eight-day specimens there was no difference between oxygen treated and con trols. In the 48-hour specimens there was equivocal protection o f the inner retinal lay ers by oxygen. In specimens up to 18 hours, however, a varying degree o f pro tection resulted from o x y g e n administration. The oxygen-treated animals showed much less edema and coagulation necrosis. Degen eration o f the ganglion cells and bipolars was appreciably less in the oxygen-treated
791
animals when compared with their controls in r o o m air (figs. 2 to 4 ) . In no case, h o w ever, did the o x y g e n administration result in total protection o f the inner retinal layers as some slight degenerative change was pres ent in all. Complete details o f these data with tables showing a quantitative appraisal o f the amount o f retinal edema and necrosis, ganglion cell and bipolar cell counts, and the results o f special staining techniques are omitted from this preliminary report. T h e y will appear subsequently. CLINICAL
OBSERVATIONS
In t w o cases o f early retinal arterial o c clusion, o x y g e n has been administered with an apparent beneficial effect as an adjunct to routine therapy. In two cases first seen two days after occlusion, o x y g e n therapy had no effect. These cases are briefly sum marized :
Fig. 2 (Pätz). Section of normal retina of one-year-old control rat. Note normal thickness of inner retinal layers (brackets). ( N F ) Nerve-fiber layer, ( g ) Ganglion cells. ( I P ) Inner plexiform layer. ( I N ) Inner nuclear layer. ( O N ) Outer nuclear layer. ( R C ) Rods and cones. (Hematoxylin-eosin, x400.)
ARNALL PATZ
792
Fig. 3 (Patz). Section of rat retina 18 hours in room air after occlusion of retinal vessels. Note massive edema of nerve fiber layer (NF) and inner nuclear layer ( I N ) . Thickness of inner layers of normal retina (brackets) is shown for comparison. Note coagulation necrosis in inner plexiform layer. Loss of ganglion cell and inner nu clear layer populations is promi nent. Note pyknotic nuclei and cell ghosts in these layers. The outer retinal layers are normal. (Hema toxylin-eosin, X400.)
CASE
1
A 62-year-old white man with a history o f hypertension of six years' duration noted a sudden blurring o f vision in his left eye. O n covering his right eye, he noted that the en tire lower half of his left field o f vision was blind. H e reported fo r examination four hours later. T h e right eye was normal with the excep tion of prominent retinal arteriosclerosis. The visual acuity in the left eye was reduced to 4/200. T h e upper retina showed a diffuse
faint pallor and an absolute scotoma in volved the lower field of vision including the fixation point. Preparations were made for a cervical sympathetic block. During this period an oxygen mask was fittd on the patient. A ventura was connected in the s y s t e i T i so that oxygen o r air could be
alternated without the patient's knowledge. The oxygen mask was applied and the ven tura set so that the patient was breathing room air for 15 minutes. T h e absolute lower field defect remained constant. T h e ventura
Fig. 4 (Pätz). Section of rat retina 18 hours after occlusion of central vessels. The animal was maintained in oxygen during the entire 18-hour period. Compare with animal of Figure 3 which re ceived no oxygen and note much less edema and necrosis of inner retinal layers. Surviving cells in both ganglion and inner nuclear layers greatly outnumber those in the nonoxygenated animal. Brackets show normal thickness of inner retinal layers for comparison. (Hematoxylin and eosin, X400.)
O X Y G E N IN
RETINAL ARTERIAL
OCCLUSION
793
was then turned to administer pure o x y g e n .
improved to 2 0 / 5 0 . T h e lower field o f vision
A f t e r three minutes the patient reported,
remained normal. T h e visual status has re
"there is a
flickering
in the central blind
mained stable for 14 months with no residual
area and I can for the first time see m y
defect detected in the lower field and
knees and the
central vision remaining at 2 0 / 5 0 .
floor."
A field check showed
that the absolute scotoma was n o w relative and was only detected with a 3/1,000 white target. T h e visual acuity improved to 2 0 / 7 0 . The ventura was then turned to deliver r o o m air. In approximately three minutes the cen tral vision faded, and the lower field o f vision disappeared. O x y g e n was started after
15 minutes on
air and a similar improvement was noted. On
stopping oxygen, the lower field faded
(figs. 5 A and 5 B ) . A
left sympathetic block was then per
formed with Xylocaine and massage o f the globe
was
performed.
Oxygen
inhalation
was continued for four hours. O n stopping oxygen after four hours, the lower field re mained open and central vision stabilized at about 2 0 / 7 0 . The
sympathetic block was repeated
24
hours later and the patient was maintained on Priscoline, 25 mg. every four hours, f o r five days. The retinal edema in the upper half o f the retina gradually subsided. T h e central vision
CASE
A
the
2
72-year-old white woman with a
five-
year history o f mild hypertension noted the sudden appearance o f a "veil" over her left eye while watching television. Examination one hour and 15 minutes later revealed the vision in the left eye to be reduced to no light perception. Ophthalmoscopic examination
showed a
faint mild gray haze over the entire retina. There was stasis o f the retinal circulation and
the
classic "cattle car" effect
of
the
blood cells in the vessels was noted. Vision in the right
eye was normal and the eye-
grounds were negative except for moderate hypertensive vascular changes. A ventura and o x y g e n mask was used as in the first case. T h e patient breathed room air through the mask for 10 minutes show ing no light perception repeatedly. Without her knowledge, the ventura deliver
100-percent
oxygen.
was turned to After
three
minutes, light perception returned in the en tire peripheral field. A f t e r five minutes, she counted fingers at t w o feet accurately just temporal to the fixation point. T h e ventura
Fig. 5A (Pätz). Case 1. Tangent screen field prior to oxygen inhalation (S/1,000 white tar get).
was turned to deliver air and the vision dropped within one and one-half minutes to bare light perception. After
10 minutes
on air,
a change to
o x y g e n elicited the same response as before and, on reverting
back to air, the vision
again was reduced to light perception only (figs. 6 A and 6 B ) . A cervical sympathetic block with (Pätz). Fig. SB Case 1. Tangent screen field 1 0 minUtes after oxygen inhalation (S/1,000 white t a r g e t ) .
Xylo
caine was done and massage o f the globe followed. T h e patient was started on P r i s c o line 25 mg. every four hours by mouth. O x y g e n was administered by mask for three hours. T h e peripheral field remained full and normal. T h e central scotoma persisted. A f t e r a four-month follow-up the peripheral field
794
ARNALL PATZ
glucose and other metabolites. Likewise, the resulting Fig. 6A (Patz). Case 2. Visual field, left eye, prior to oxy gen inhalation (15/ 1,000 white target).
cessation
of
blood
flow
should
favor an accumulation o f carbon dioxide and other
breakdown products. Therefore, in
creasing
choroidal o x y g e n
tension to
en
hance diffusion across the retina aids
the
ischemic tissue only in its oxygenation with out supplying other metabolites. O n e would anticipate vessel
that
in total
occlusion,
in
permanent spite
of
retinal adequate
oxygenation, the ischemic adult retina, lack Fig. 6B (Patz). Case 2. Visual field, left eye, 10 minutes after oxygen inhala tion (15/1,000 white target).
ing other metabolites, would ultimately de generate.
These
animal
occlusion
experi
ments support this premise. Restitution of retinal blood flow is, there fore,
fundamental
in
the
treatment
of
retinal occlusion. O x y g e n inhalation can be considered as an adjunct to oxygenate the has remained normal. A central scotoma has persisted, however, with vision remaining at 20/200.
ischemic tissues until circulation is restored. It is fortunate, however, that, in many pa tients, cessation of blood flow is either tem porary or partial, as is evidenced by a return of varying levels o f vision after
DISCUSSION
The
use
of
oxygen
therapy
in
many
occlusion.
It is in these patients that oxygen
inhala
ischemic processes and especially in acute
tion should be beneficial by reducing
coronary vessel occlusion is well established
severity o f anoxic damage during the tem
in general medicine. In many ocular dis
porary ischemia.
orders, Bietti^ has advocated o x y g e n therapy
In
interpreting the animal
experiments,
to improve general ocular nutrition. In ret
it is significant that o x y g e n therapy
inal arterial occlusion a singularly favorable
started
five
minutes
was after
avascular
retinal occlusion. Experiments are in prog
retina lies in direct apposition to the vascular
ress to determine the maximum time follow
choroid, the circulation of which is intact.
ing experimental occlusion at which o x y g e n
choroidal oxygen tension by
inhalation may be expected to have a bene
situation
exists.
Increasing
Here
the
thin
approximately
the
oxygen inhalation permits an extension o f the normal range of diffusion o f oxygen to reach When
the the
avascular central
inner
retinal
layers.
retinal artery was o c
ficial effect on the ischemic retina. There was no difference histologically in the retinal occlusion produced by diathermy coagulation and cutting o f the retinal vessels.
cluded in rats, apparently an increase in ret
The
inal oxygenation via the choroid delayed the
changes c o n f o r m closely to those described
onset o f irreversible degenerative changes.
by TurnbuU* and confirm his careful studies.
rate
of
appearance
of
the
retinal
In a limited clinical trial oxygen inhalation markedly improved the function o f surviv ing retinal elements. In total retinal arterial occlusion it is ap
RECOMMENDATIONS
A t this preliminary stage, the recommendations
seem
justified.
following When
a
parent that all blood-borne constituents di
diagnosis o f relatively recent retinal arterial
rected to the inner retinal layers are de
occlusion is made, attempts to
pleted. This not only includes oxygen, but
blood flow should be vigorously pursued as
re-establish
O X Y G E N IN R E T I N A L A R T E R I A L O C C L U S I O N
an emergency procedure. T h e choice o f therapy may be one or preferably a combi nation o f some of the following procedures: Cervical sympathetic block, massage o f the globe, paracentesis, retrobulbar block and vasodilators. Inhalation o f oxygen by a tightly fitting mask or nasal catheter is ad vised. O x y g e n should be administered at a flow rate o f at least eight liters per minute during the initial trial. A working suggestion is that if no ap preciable change in the patient's visual acuity o r field is noted after 30 minutes, o x y g e n therapy should be discontinued. I f a signifi cant improvement is noted, oxygen inhala tion should be continued for about two to four hours along with other measures to re establish retinal circulation. There need be no concern for pulmonary oxygen toxicity here. However, when oxygen concentrations of over 70 percent are given continuously for 24 hours or longer, pulmonary oxygen toxicity may result. Cases o f retinal occlusion o f short dura tion are seen relatively infrequently b y a single investigator. It would be appreciated and extremely helpful in obtaining an ade quate clinical appraisal of oxygen inhalation in early occlusion if ophthalmologists giving this a trial would either publish their results or communicate with me.
795
S U M M A R Y
1. Previous animal studies on the role o f o x y g e n o n the immature retina and experi ments cited here on retinal arterial occlusion in the adult rat suggest that oxygen inhala tion may be beneficial in cases o f early retinal arterial occlusion. A preliminary clinical trial supports these experimental data. 2. T h e results o f the animal experiments are briefly summarized. T h e responses to o x y g e n inhalation in four clinical cases are presented. ADDENDU Μ
Since this paper was prepared, one addi tional case o f retinal occlusion was seen six hours after the vision blurred. T h e visual field opened partially after oxygen inhalation. A second case seen four hours after onset o f symptoms showed no improvement what soever in the visual field or visual acuity after oxygen inhalation. 920 St. Paul Street
(2).
ACKNOWLEDGEMENTS
Mr. Don H . Higginbotham, graduate student in biochemistry, Georgetown University, assisted in the animal experiments and Mrs. Ann Eastham prepared the histologic sections. The preliminary experiments measuring the retinal oxygen ten sion were done in collaboration with Dr. Martin Larrabee, Department of Biophysics, Johns Hop kins University.
REFERENCES
1. Pätz, Α., Hoeck, L. E., and De La Cruz, E . : Studies on the effect of high oxygen administration in retrolental fibroplasia: I. Nursery observations. Am. J. Ophth., 35:1248-1253 (Sept.) 1952. 2. Pätz, Α., Eastham, Α., Higgenbotham, D. H., and Kleh, T . : Oxygen studies in retrolental fibroplasia: II. The production of the microscopic changes of retrolental fibroplasia in experimental animals. Am. J. Ophth., 36:1511-1522 (Nov.) 1953. 3. Bietti, G.: Effects of experimentally decreased or increased oxygen supply in some ophthalmic diseases. Arch. Ophth., 49:491-513 (May) 1953. 4. Turnbull, W . : Experimental retinal anemia in rats. Arch. Ophth., 43:9-31 (Jan.) 1950.