British Journal of Ophthalmology, 1985, 69, 108-116

A randomised prospective study* on treatmentof central retinal vein occlusion by isovolaemichaemodilution and photocoagulationLUTZ L HANSEN,' PETERIS DANISEVSKIS,l HANS-R ARNTZ,2GERD HOVENER,' AND MICHAEL WIEDERHOLT'3

From the departments of 'Ophthalmology, 2Medicine, and 3Clinical Physiology, Klinikum Steglitz derFreien Universitat Berlin, Berlin

SUMMARY Thirty eight patients with ischaemic and non-ischaemic central retinal vein occlusionwere evaluated for the effect of isovolaemic haemodilution. They were allocated at random to ahaemodilution group (19 patients, panretinal photocoagulation and isovolaemic haemodilution)and a control group (19 patients, panretinal photocoagulation). Haematocrit was lowered in stepsto 30 to 35% in the haemodilution group by repeated exchanges of whole blood for plasma anddextran (MW 40 000) and kept at this level for a period of six weeks. The haemodilution did notlead to serious complications. Three months after starting the treatment eight of 19 patients withhaemodilution showed a better visual acuity, whereas only one of 19 control patients hadimproved. Seven of 17 patients with haemodilution, but only one of 17 control patients, retained abetter visual acuity after one year. In the haemodilution group there were fewer patients withmacular fibrosis and more with only minor foveal changes. The haemodilution seems to be moreeffective in patients with ischaemic than with non-ischaemic central retinal vein occlusion. It isconcluded that isovolaemic haemodilution improves the visual outcome of patients with centralretinal vein occlusion, probably mediated by enhanced retinal blood flow.

There has been little change in the prognosis forvisual acuity (VA) of the eye after central retinal veinocclusion (CRVO) during the past decades. Definitetherapeutic effects have been achieved with the useof panretinal photocoagulation to prevent neo-vascular glaucoma in ischaemic CRVO. '1- An effec-tive medical treatment is lacking.4 The promisingfibrinolytic therapy5 6 has been abandoned byKohner7 because of its risk of vitreous haemorrhage,but it is still applied by others.8The pathogenesis of CRVO is still not completely

clear. There is controversy as to the primary event9-"of whether CRVO alone, or a transitory centralretinal artery occlusion, leads to outflow obstructionwith a rise in intravascular pressure, leakage of

*Preliminary results werc presented at the 80th mecting of theDeutschc Ophthalmologische Gcselischaft and at the 1983 ARVOMccting in Sarasota, USA.

Correspondence to Dr L L Hanscn, Augcnklinik und Poliklinik derFreicn Univcrsitat Bcrlin, Klinikum Stcglitz, Hindcnburgdamm 30,1()00 Bcrlin 45, FRG.

108

retinal capillaries, and expulsion of red cells. Thismight cause a local increase in blood viscosity byenhanced haematocrit and low shear rates, thusstrengthening the vicious circle to stasis until at least aprogressive ischaemic capillaropathy is produced.Furthermore, Ring et al.'2 detected a higher wholeblood and plasma viscosity in patients with CRVO.This finding was corroborated by Trope et al. 3

If increased viscosity is a factor promotingischaemia, then reducing viscosity to normal or lowerlevels for weeks or months after the onset of venousocclusion might at least moderate retinal ischaemiaand other sequelae of CRVO.

Recent work in man has shown that, after reduc-tion of haematocrit values (and thus reduction inviscosity), cerebral blood flow can be improved.'4Studies on retinal blood flow in pigs have shown anincrease in blood flow when whole blood viscositywas reduced by isovolaemic haemodilution.'516 Apilot open study on isovolaemic haemodilution inCRVO by one of US17 yielded very promising results

copyright. on S

eptember 30, 2021 by guest. P

rotected byhttp://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.2.108 on 1 F

ebruary 1985. Dow

nloaded from

A randomisedprospective study on treatment ofcentral retinal vein occlusion

concerning visual acuity. However, the new thera-peutic regimen did not prevent neovascularglaucoma. Panretinal photocoagulation has been aroutine procedure in our hospital in most patientswith CRVO, I and, since it is a well known procedurefor prevention of retinal neovascularisation,'-3 wedecided to combine isovolaemic haemodilution withphotocoagulation.The study was designed as a prospective random-

ised trial to evaluate the efficacy of isovolaemichaemodilution in patients with ischaemic and non-ischaemic CRVO after panretinal photocoagulation.

Patients and methods

All patients over 40 years old with recent centralvenous occlusion (less than four months durationof symptoms) referred to our hospital between 1November 1980 and 12 December 1982 were con-sidered for the randomised, controlled, prospectivetrial.

Patients with systemic diseases (congestive heartfailure despite treatment, renal and respiratory in-sufficiency of the pink puffer type, anaemia below38% packed cell volume (PCV), thrombocytosisabove 450x 109/1, insufficient clarity of media, pre-existing macular disease, and psychosocial problems,which would not allow long term follow up, wereexcluded from the study (Table 1). In addition we didnot treat patients with mild non-ischaemic CRVOwithout macular oedema whose visual acuity wasabove 6/7*5.One of us (H.R.A.) took a thorough medical

history and made a clinical examination of allpatients. They were then referred for systemicevaluation including ECG, x-ray of the chest, andDoppler sonography of the supra-aortic vessels. Ifnecessary an extended cardiovascular assessment(that is, 24 h ECG, echocardiogram, etc.) was done.Blood was collected by standard laboratory

Table 1 Exclusion criteria for patients with CRVO

No ofpatients

Patients presenting with CRVO 53Total excluded 15Anacmia ICongestive hcart failurc 2Rcspiratory insufficicncy INo follow up possiblc 3Ophthalmological reasons* 4Agc <40 years 2Premature terminationst 2

Patients finally cntcring thestudy 38

*Cataract 1, pre-existing maculopathy 1, mild non-ischaemic CRVO 2.tPatients who discontinued thcrapy after two wecks.

methods to determine the values for the following:haemoglobin, haematocrit (PCV), blood film, ESR,platelet count, partial thromboplastin time, pro-thrombin time, serum creatinine, Na, K, bloodglucose, serum cholesterol and triglyceridelevels, uric acid, liver function, and serum proteinelectrophoresis.During the initial ophthalmological evaluation the

following examinations were done: visual acuity(Snellen chart at 6 m, fully refracted), slit lamp exam-ination of the anterior segment, gonioscopy andfundus biomicroscopy (direct and indirect), applana-tion tonometry, visual fields (Goldmann), colourphotography of the fundus, and fluorescein angio-graphy. Fundus fluorescein angiograms wererepeated after three and 12 months. The visual acuitytest was done weekly during the first three weeks andagain, along with all other procedures mentioned,after six weeks and three, six, and 12 months.To reduce variance all visual acuity determinations

were done by two of us (L.L.H. and P.D.), and thefundus was examined by one of us (L.L.H.).Concerning the fundus biomicroscopy we paid

special attention to the extent and character of retinalhaemorrhages (deep, superficial, subhyaloid), andoedema. The macula was carefully examined formicrocysts, cystoid degeneration, premacular gliosis,and serous detachments or degenerative changes ofthe pigment epithelium. The number and region ofcotton wool spots was recorded. Opticociliary veinsand collaterals were noted.

Fluorescein angiograms of the posterior pole wereused to evaluate areas of retinal capillary non-perfusion, completeness of the perifocal arcade,leakage from capillaries and main veins, and, in latestages, intraretinal microvascular abnormalities andnew vessel formation. Arteriovenous transit time wasestimated from the appearance of the dye in theretinal arteries until the complete filling of the majorand central retinal veins.

After complete medical and ophthalmologicalexamination each patient was randomly assigned(lottery system) to either a control group (photo-coagulation) or a haemodilution group (photocoagu-lation and haemodilution). Patients were not treatedin a blind manner because it is not possible to hide thepaleness of a patient with haemodilution from theinvestigator.

Panretinal photocoagulation (xenon-arc, Zeiss,Oberkochen) was done within two days afteradmission. After retrobulbar anaesthesia 200 to 250burns were placed in a scattered manner outside thetemporal arcades, and a distance of one or two discdiameters was kept from the papilla. The centralburns were 30, and those placed more peripherally4.5°, both of 1 s duration.

109

copyright. on S

eptember 30, 2021 by guest. P

rotected byhttp://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.2.108 on 1 F

ebruary 1985. Dow

nloaded from

Lutz L Hansen, Peteris Danisevskis, Hans-R Arntz, Gerd Hovener, and Michael Wiederholt

Haemodilution was induced as described before.On the first day 500 ml of whole blood was taken(Biopack P double plasmaphorese bag, containing 75ml ACD stabilisator according to USP per 500 ml ofblood, Biotest-Serum-Institut, Frankfurt/M, FRG)and centrifuged at 3500 rpm for 10 min. Then theplasma was separated (including the buffy coat) andslowly retransfused into the patient. During and aftercentrifugation approximately 150-250 ml of lowmolecular weight dextran (MW 40000) was infusedto keep the patient in an almost perfect isovolaemicbalance. Possible anaphylactic reactions induced bydextran-reactive IgG antibodies were prevented byintravenous injection of 20 ml of small dextranmolecules (MW 1000, Promit, Knoll AG, Ludwig-shafen, FRG) once a week.The same procedure was repeated three to six

times within the next 10 days until a haematocrit levelof 30-35% was reached. Thereafter, until a period ofsix weeks' treatment had been reached, haemodilu-tion was done whenever the PCV exceeded 35%.Only during the first 10 days did the patients stay inthe hospital.

Statistical variation of the results is expressed asstandard deviation of the mean (mean±SD) if nototherwise mentioned. Significance of the differencesbetween corresponding values was tested by the ttest. Visual acuity changes were tested by Fisher'sexact test,'9 based on the x2 distribution (2x2 table).

Results

Of 53 patients with either ischaemic or non-ischaemicCRVO referred to our clinic 15 had to be excludedfor various reasons (Table 1), so that a total of 38patients was left. These patients were randomlyassigned to either the haemodilution (photocoagula-tion and isovolaemic haemodilution) or controlgroup (photocoagulation only). Thirty four patientscould be followed up for one year, two for sixmonths, and two for only three months.Table 2 shows the coincidental medical and oph-

thalmological diseases. The high incidence of athero-sclerosis, systemic hypertension, and hyperlipaemiawas evident. Only four of 19 patients in each groupdid not show cardiovascular risk factors. We foundone patient with stenosis of the ophthalmic artery asshown by Doppler sonography though there were nosigns of carotid occlusive disease. Three patients inthe control group and five in the haemodilution groupreceived medical therapy for newly detected con-gestive heart failure or systemic hypertension. Pre-existing cardiac or antihypertensive therapy wasmaintained. Treatment with pentoxyfylline oracetylsalicyclic acid was discontinued.Some general medical data and the ophthalmo-

Table 2 Medical and coincidental ophthalmologicaldiseases

Disease Photocoagula- Photocoagulationtion, no ofpatients and haemodilution,

no ofpatients

Atherosclerosis vasculardiseases* 11 6

Systemic hypertension 8 11Diabetes mellitus 2 1Hyperlipaemia 5 4Supra-aortic artery stenosis 1 0Glaucoma 3 3Old retinal vein occlusion

of the other eye 1 2

*Angina and/or history of myocardial infarction, cercbrovascularinfarction, peripheral arterial occlusive disease.

logical features of both patient groups at the time ofentrance into the study are depicted in Table 3. Nosignificant differences existed between the twogroups with respect to age, haematocrit, andduration of occlusion before entering the trial. Thesame holds true for ophthalmological findings beforethe start of therapy. Taking into account visualacuity, visual fields, biomicroscopy of the fundus,and fluorescein angiograms,2'-22 13 patients showedischaemic CRVO (haemorrhagic retinopathy)-arather high proportion of about 34%. This might bedue to the fact that mild cases of non-ischaemicCRVO are often not referred to our clinic for in-patient treatment.

Table 3 Entrance data ofpatients

Photocoagulation

No of patients 19Age (years) 71-3±8+9Haematocrit (%) 43-4±3-0Duration of occlusion

(days) 36±30Visual acuity:

>6/15 76/20-6/60 7-6/120 5

Visual fields (Goldmann):Absolute centralscotoma (14e) 9

Peripheral defects(12e) 13

No defects (12e) 4Biomicroscopy of fundus:

Cystoid macularoedema 15No of cotton wool spots>10 6

No of cotton wool spots<10 4

Ischaemic CRVO 6

Haemodilution andphotocoagulation

1967-6±8-5*44-5±3-8*

44±35*

658

10

92

15

7

57

*Not significantly differcnt from photocoagulation group.

110

copyright. on S

eptember 30, 2021 by guest. P

rotected byhttp://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.2.108 on 1 F

ebruary 1985. Dow

nloaded from

A randomisedprospective study on treatment ofcentral retinal vein occlusion

Follow up time (months)0 15 3 6

Fig. 1 Course ofVA changes inpatients after a haemodilution andphotocoagulation. The individualsteps ofimprovement or

deterioration are given in Fig. 3.

Panretinal photocoagulation was quite similar instrength with 222±27 burns in haemodiluted patientsand 221±23 burns in controls.A therapeutic low level of PCV could be main-

tained for at least six weeks after cessation of haemo-dilution. In some cases the patient did not reach thepretherapeutic level until after four to five months(Table 4). Isovolaemic haemodilution was a welltolerated therapeutic procedure in most patients. Nopatient suffered from serious complications. One ofthe two patients who refused further treatment had a

short fainting spell during the third haemodilutionthat was interpreted as a vagovasal syncope. Two orthree of the patients complained of being easilyfatigued by physical exertion. Three patients who feltdisturbed by restricted physical activity due to

FOLLOW UP TIME (MONTHS0 1,5 3 6

+4 -

C-)gx + 3 -

+2-1--

I +1-

L Z< O O40

D Z -1-

> LL

-2-0 2-

z -3-I

-4-

dyspnoea were all more than 75 years old. ECG inthese patients remained unchanged.The course of the visual acuity (VA) over the

Table 4 Haematocrit and thrombocytes of haemodilutedpatients

No of Packed cell Thrombocytespatients volume (%) 1000 cells/ml

Before treatment 19 44-5±3-8 214±546 weeks 19 31-7±2-1* 299+49t3 months 18 38-4±5-6t 251±596 months It) 434±3-4 -

12 months 15 42-9±5-1

*p<0-Ol compared with pretreatment level.tp<O05 compared with pretreatment level.

12

Fig. 2 Course ofVA changes inpatients afterphotocoagulationonly. Individualsteps ofimprovement or deterioration are

given in Fig. 3.

12

C

0Lov)

1-

o6

._

.5-_D

ill

copyright. on S

eptember 30, 2021 by guest. P

rotected byhttp://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.2.108 on 1 F

ebruary 1985. Dow

nloaded from

Lutz L Hansen, Peteris Danisevskis, Hans-R Arntz, Gerd Hovener, and Michael Wiederholt

whole follow up period is depicted in Figs. 1 and 2. Itwas obvious that the main increase in VA. in thehaemodiluted patients occurred during the first sixweeks, with only a few patients improving up to threeor six months later (Fig. 1). If there is no improve-ment starting within the first four weeks of haemo-dilution, no substantial gain in VA can be expected.A true relapse with deterioration of fundus signs,visual fields, and fundus fluorescein angiogramsoccurred in four patients, in two despite an alreadylow haematocrit level of 35%.The development of VA in patients treated with

photocoagulation only (Fig. 2) was somewhat dif-ferent from that of haemodiluted patients. Morepatients suffered from a visual loss during the firstthree months. However, most of them recoveredeven after the sixth month, so that the final visualoutcome was not significantly different from theinitial VA.VA results three months after commencement of

therapy are shown in Fig. 3. This is at the time when,in most haemodiluted patients, a normal haematocritis reached again, and a rheogenic effect can no longerbe expected. A change in visual acuity was con-

sidered to be present when the patient could read atleast two lines more on the text card. Among thehaemodiluted patients seven improved by two to four

NPL

PL

HM

Fig. 3 Visual acuity before andthree months after the start oftherapy. Closed symbols markphotocoagulation. Open symbolsmean photocoagulation andhaemodilution. Circles standfornon-ischaemic CRVO, trianglesforischaemic CRVO.

,-

C)

-J

Li)

-J

z

CF

6/120

6/60

6/30

6/20

6/12

6/9

6/6

6/4

0

4' (

(.0 (

lines on the Snellen chart; 12 remained unchanged;no patient deteriorated. On the other hand, in thecontrol group only one patient improved, 12remained unchanged, and five became worse.

Statistical analysis by the exact Fisher test for 2x2tables showed statistical significance (p<0-05) for theimprovement of the haemodiluted patients.

Fig. 4 indicates that one year after starting thetherapy there was no fundamental change in thevisual outcome compared with the three-monthresults, though one haemodiluted patient deterio-rated by four lines. In five of 17 patients in thehaemodilution group visual acuity was still better bytwo or more lines, whereas none of the controlpatients had improved (p<005).

In both groups final VA was certainly worse forischaemic than non-ischaemic CRVO. However, as

regards the increase in VA the most markedimprovements were reached with haemodilution inpatients with ischaemic CRVO, of whom four of sixstill had better VA one year after treatment. Not one

of the six control patients with ischaemic CRVOshowed improved VA. This finding had not reachedstatistical significance, as the numbers of patientswere too small for testing, so it should be an

important point in further studies on haemodilution.One year after starting therapy the appearance of

A~~~~

AA

ft A~/

o hR8A * A

* S

/ * 0

UI I I I I I I--

-ft. "ft . .n u.a.. a.D~~~% --fseOO R u 2XVISUAL A Z3"ftVISUAL ACUITY AT 3 MONTHS

112

copyright. on S

eptember 30, 2021 by guest. P

rotected byhttp://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.2.108 on 1 F

ebruary 1985. Dow

nloaded from

A randomisedprospective study on treatment ofcentral retinal vein occlusion

Table 5 Appearance ofposterior pole after one year

Photocoagulation Haemodilutionand photo-coagulation

Total No of patients 17 17Macular findings:Normal 2 2Minor pigment epithelial

changes 1 4Persistent macular oedema 7 6Major pigment epithelial

changes and/or rctinalatrophy 1 2

Macular fibrosis 6 3Intraretinal microvascular

abnormalities (postcriorpole) 15 11

Collaterals on disc 8 9Preretinal vessels 0 0

the retina (Table 5) was quite similar in both groupswhether haemodiluted or not. No preretinal vesselscould be observed, and no neovascular glaucoma haddeveloped. About half of the patients had collateralson the disc, but none ofthem had real neovascularisa-tions as determined by fluorescein angiography.Intraretinal microvascular abnormalities werecommon, but less so in the haemodilution group.

NPL

PL

HM

1-54

In-i

-i

z

CF

6/120

6/60

6/30

6/20

6112

6/9

6/6

6/4

The macular findings in the two groups did notdiffer very much. In the haemodilution group therewere more patients with minor macular changes andfewer patients with macular fibrosis, which explainswhy this group had a better overall visual outcomethan the control group.

Discussion

Isovolaemic haemodilution was used as a newtherapeutic concept to treat patients with CRVO.The general aim was to increase the fluidity of blood.Blood viscosity can easily be decreased by loweringthe haematocrit level and replacing the lost circula-tion cell volume with low molecular weight dextranor other substitutes. Microcirculation, and thusoxygen supply, are improved. Oxygen pressure with-in the tissue is constant or even higher than normal,until a haematocrit level of some 20-25% is reached.The compensatory increase in cardiac output ismainly achieved by an increased arteriovenous 02-difference and stroke volume.23 24The rationale for doing such an invasive therapy in

patients with CRVO is twofold: (1) Independent ofthe primary event in CRVO the blood flow decreasesin venules and capillaries, leading to vascular leakageand lower shear rates. The resulting increase in local

A

'A A

0

A

* 0 0/ O

A

aL

.

0

Fig. 4 Visual acuity before andone year after the start oftherapy.Closedsymbols markphotocoagulation. Open symbolsmean photocoagulation andhaemodilution. Circles standfornon-ischaemic CRVO, trianglesforischaemic CRVO.

0

tw CD C a

0)C Ix XVU ACU AT1tC z

VISUAL ACUITY AT 1 YEAR

113

copyright. on S

eptember 30, 2021 by guest. P

rotected byhttp://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.2.108 on 1 F

ebruary 1985. Dow

nloaded from

Lutz L Hansen, Peteris Danisevskis, Hans-R Arntz, Gerd Hovener, and Michael Wiederholt

blood viscosity certainly strengthens the vicious circlethat may ultimately produce progressive ischaemiccapillaropathy. (2) In two laboratories patients withCRVO have been shown to have higher than normalwhole blood and plasma viscosity values.'2 '3 Studieson cerebral and retinal blood flow have reported anincrease in blood flow when whole blood viscositywas reduced by haemodilution. 14 1'

Uncontrolled studies of hypervolaemic&- and iso-volaemic haemodilution 17 in 10 patients with CRVOwere quite promising. However, haemodilutionalone did not prevent neovascular glaucoma. There-fore in the present study panretinal photocoagulationwas done in all patients before haemodilution wasstarted. We applied fewer burns compared withLaatikainen et al.,' but it has been shown by May etal.2 that a total of 120-300 burns prevented neo-vascular glaucoma. It is questionable whether this is anecessary procedure in all patients with CRVO,because it has been shown that only widespreadcapillary occlusion leads to rubeosis iridis and/orneovascular glaucoma. 221)2' 2627 However, somepatients who initially present non-ischaemic types ofCRVO may later develop ischaemicCRVO. Hayreh22noted 7% such patients. In addition, estimates ofabout 10% to 27% have been made322211 for thosepatients who cannot be classified in either groupduring the first weeks of their presentation. We thinkthat carefully performed panretinal photocoagula-tion is a relatively safe procedure compared to therisk of neovascularisation in patients with an un-known course of CRVO. The only complication wesaw in 38 patients was a transient choroidal effusionin one patient.There were two methodological drawbacks in our

trial. First, it was not possible to do a double-blindstudy, because 'placebo haemodilution' is notpossible. Second, the important determinations ofVA could not be done by anyone not involved in thestudy. This certainly is a disadvantage that could bepartly overcome by standardising these examinations(same examiners, same room, daytime).However, we think that the main point of com-

parability, well matched general and ophthalmo-logical entrance data, is excellently fulfilled (Tables2,3).Only 8% of our patients with CRVO had to be

excluded for medical reasons. Until now the onlytreatment that seems to be of benefit for the visualoutcome is fibrinolytic therapy.568 However, fibrin-olysis has some important shortcomings that limit itsapplication to relatively young people with a shortduration ofsymptoms. These limitations do not applyfor isovolaemic dilution, and one has to take intoaccount that CRVO is predominantly a disease of theelderly.

Visual prognosis of CRVO is strongly dependenton the degree of retinal capillary occlusion. Thevisual outcome of the ischaemic CRVO is always verypoor, whereas the non-ischaemic type often runs abenign course. However, analysis of data in theliterature shows a wide range of final visual acuities inthe latter form. For example, Hayreh29 claimed thatabout 50% of the non-ischaemic cases would endwith 6/6 or 6/9 without any therapy. On the otherhand Laatikainen et al. ' showed that, in serious formsof non-ischaemic CRVO, only one out of 25 patientshad a final VA of more than 6/60. This again stressesthe importance of well comparable entrance data inrandomised trials of CRVO. In our study haemo-diluted patients had a better visual outcome thancontrol patients. The course of visual acuity change(Figs. 1, 2) shows an impressive difference betweenthe two groups, especially during the first six weeks.While the VA of the majority of haemodilutedpatients rises above the entrance level, the opposite istrue of the controls. A comparison on the basis of atwo-line improvement yields statistical significanceafter three months. Although afew relapses occurred,the visual outcome of haemodiluted patients was stillsignificantly better after one year. This shows that aonce achieved visual improvement can be maintainedwithout further haemodilution in most responsivepatients. Our results are supported by a preliminaryreport by Brunner et al. `' Kohner et al.7 found noeffects from a haemodilution. However, theirpatients had obviously been treated for only two orthree weeks, and the haematocrit levels had beenlowered to only 38-42%. In our experience this is notsufficient to yield an improvement.

Thirteen patients in our study had ischaemicCRVO: seven in the haemodilution group, and six inthe control group. These numbers were too small forsignificant conclusions to be drawn from the courses.It is interesting that five of seven patients respondedto haemodilution, of whom only one relapsed (Figs.3, 4), whereas no control patient with ischaemicCRVO had a better final VA. It seems that a decreasein blood viscosity and an improvement of retinalperfusion are of particular importance in ischaemicCRVO. This finding would support the results ofTrope et al.," who found increased whole blood andplasma viscosity only in patients with ischaemiccentral and branch vein occlusion. Future studiesmust show whether this tendency is statisticallysignificant. If it is haemodilution could be used as aspecial tool to improve the hitherto very poor visualprognosis of this disease.Haemodilution reduces, but does not prevent, the

serious sequelae on the posterior pole. Persistence ofoedema and macular scarring were the main causes ofpoor vision. In the haemodilution group there were

114

copyright. on S

eptember 30, 2021 by guest. P

rotected byhttp://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.2.108 on 1 F

ebruary 1985. Dow

nloaded from

A randomisedprospective study on treatment ofcentral retinal vein occlusion

Fig. 5A Fluorescein angiogram ofa patient with ischaemicCRVO. Early arteriovenous phase with strong retinaloedema, haemorrhages, and areas ofcapillary occlusionbefore therapy.

fewer patients with macular fibrosis and more withonly minor foveal changes. The smaller number ofpatients with intraretinal microvascular abnormalities(Table 5) as seen by fluorescein angiography alsopoints to the beneficial effect of haemodilution (Fig.5). However, the limited prevention of fundussequelae and the final visual outcome make it clearthat the increase in blood fluidity does not eliminatethe cause of CRVO, which is an imbalance betweeninflow and outflow of blood in the retina. It probablyjust partially relieves retinal hypoperfusion during acritical time of serious outflow obstruction. We donot know how this outflow obstruction is overcome insome patients. The visible collaterals on the papillado not characterise patients with better VA, and inour study no difference was found between the twogroups (Table 5).One should expect that the efficacy of higher blood

fluidity would be the better the shorter the time lapsebetween visual disturbance and the start of therapy.Table 6 compares some data of patients with differenteffects on their VA. Only the occlusion time, that isthe duration of symptoms before therapy, is signifi-cantly shorter in patients with visual improvement.Age and haematocrit levels do not differ. Neverthe-less it has to be mentioned that one patient who hadhaemodilution on the third day could read only oneline more on the test card after one year. Anotherpatient suffering from mild venostasis retinopathy for

Fig. 5B Three months after the start ofisovolaemichaemodilution the retinal oedema and haemorrhages haveprofoundly decreased. Intraretinal microvascularabnormalities have developed at theposteriorpole, and thereis stillsome leakage ofplasma at thefoveal arcade. Visualacuity increasedfrom 6/60 to 6124.

about four months had an initial VA of 6/9 with mildnon-cystoid oedema of the posterior pole. His VAwas enhanced to 6/6 under haemodilution, which,however, was not regarded as a significant increaseunder our conditions. Thus probably milder caseswith longstanding macular oedema without cystoiddegeneration may be amenable to haemodilutioneven later than six to eight weeks after first appear-ance of symptoms.

Isovolaemic haemodilution may constitute a newtherapeutic regimen in CRVO. The chance fora better visual outcome is improved, probablymediated by enhanced retinal blood flow 16 and pre-vention of stasis. This method does not eliminate thecause of outflow obstruction and hence has its limita-

Table 6 Comparison between patients with improved andnon-improved VA after haemodilution

VA improved VA unchanged Significanceor decreased

No of patients 7 12Agc (years) 65-7±69 68-8±9- 11 NSHacmatocrit (%) 43-9±4-7 44-9±3-0 NSOcclusion time:Days 25±11 55±4(0 p<t)-)1Range (10-40)) (3-120)

115

copyright. on S

eptember 30, 2021 by guest. P

rotected byhttp://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.2.108 on 1 F

ebruary 1985. Dow

nloaded from

Lutz L Hansen, Peteris Danisevskis, Hans-R Arntz, Gerd Hovener, and Michael Wiederholt

tions. Isovolaemic haemodilution is a safe and welltolerated therapy even in elderly patients with signsof cardiovascular disease, when obvious cardiac andrespiratory insufficiency have been excluded. Ifpossible, rheological measurements should gobeyond the determination of the PCV.3'

We are grateful to M Helmchen for organising haemodilution ofthe outpatients; to G Broskamp and H Kraus for photographicassistance; and to M Koch for preparing the illustrations.

References

1 Laatikainen L, Kohner EM, Khoury D, Blach RK. Panretinalphotocoagulation in central retinal vein occlusion: a randomisedcontrolled clinical study. BrJ Ophthalmol 1977; 61: 741-53.

2 May DR, Klein MR, Peyman GA, Raichand M. Xenon arc

panretinal photocoagulation for central retinal vein occlusion: arandomised prospective study. Br J Ophthalmol 1979; 63:725-34.

3 Magargal LE, Brown GE, Augsburger JJ, Donoso LA. Efficacyof panretinal photocoagulation in preventing neovascularglaucoma following ischemic central retinal vein occlusion. Oph-thalmology 1982; 89: 780-4.

4 Sedney SS. Photocoagulation in retinal vein occlusion. Doc Oph-thalmol 1976; 40: 1-226.

S Kohner EM, Petitt JE, Hamilton AM, Bulpitt CJ, Dollery CT.

Streptokinase in central retinal vein occlusion: a controlledclinical trial. Br MedJ 1976, i: 550-3.

6 Weigelin E. Fibrinolysebehandlung bci venosen Verschlussender Netzhaut. Fortschr Ophthalmol 1982; 79: 218-22.

7 Kohner EM, Laatikainen LL, Oughton J. The managementof central retinal vein occlusion. Ophthalmology 1983; 90:484-7.

8 Ohrloff C, Trubestein G, Volker B, Weigelin E. Zur Fibrinolysebei Venenverschlussen der Retina. Fortschr Ophthalmol 1983;80:162-5.

9 Hayreh SS, van Heuven WAJ, Hayreh MS. Experimental retinalvascular occlusion. I. Pathogenesis of central retinal veinocclusion. Arch Ophthalmol 1978; 96: 311-23.

10 McLeod D, Kohner EM. Hemorrhages after central retinal veinocclusion. Arch Ophthalmol 1978; 96: 1921.

11 Retinal vein occlusion (Editorial). Br J Ophthalmol 1979; 63:375-6.

12 Ring CP, Pearson TC, Sanders MD, Wetherley-Mein G.Viscosity and retinal vein thrombosis. BrJ Ophthalmol 1976; 60:397-410.

13 Trope GE, Lowe GDO, McArdle BM, et al. Abnormal bloodviscosity and haemostasis in longstanding retinal vein occlusion.BrJ Ophthalmol 1983; 67: 137-42.

14 Thomas DJ, Marshall J, Ross-Russell RW, et al. Effect of

haematocrit on cerebral blood-flow in man. Lancet 1977; ii:941-3.

15 Kohner EM, Barnes AB, Hill DW, Young S, Reid AC,Dormandy JH. Effect of viscosity on retinal blood flow. Proceed-ings of the 23rd International Congress of Ophthalmology 1978;172.

16 Oughton J, Chaine G, Barnes AJ, et al. Effect qf hemodilutionon retinal blood flow. Clin Hemorheol 1983; 3: 234.

17 Wiederholt M, Leonhardt H, Schmid-Schonbein H, Hager H.Die Behandlung von Zentralvenenverschlussen und Zentral-arterienverschlussen mit isovolamischer Hamodilution. KlinMonatsblAugenheilkd 1980; 177: 157-64.

18 Hovener G. Lichtkoagulation bci Zentralvenenverschluss. KlinMonatsbl Augenheilkd 1978; 173: 392-401.

19 Fisher RA. Statistical methods for research workers. London:Oliver and Boyd, 1950.

20 Hayreh SS. So-called 'central retinal vein occlusion'. I. Patho-genesis, terminology, clinical features. Ophthalmologica 1976;172:1-13.

21 Sinclair SH, Gragoudas ES. Prognosis for rubeosis iridis follow-ing central retinal vein occlusion. Br J Ophthalmol 1979; 63:735-43.

22 Hayreh SS. Classification of central retinal vein occlusion. Oph-thalmology 1983; 90: 458-74.

23 Messmer K, Sunder-Plassmann L, Klovekorn WP, Holper K.Circulatory significance of hemodilution: rheological changesand limitations. Adv Microcircul 1972; 4: 1-77.

24 Schmid-Schonbein H. Microrheology of erythrocytes, bloodviscosity, and the distribution of blood flow in the microcircula-tion. Int Rev Physiol 1976; 9: 1-62.

25 Radnot M, Follmann P. Rheomacrodex (dextran) in the treat-ment of the occlusion of the central retinal vein. Ann Ophthalmol1969; 1: 58-64.

26 Magargal LE, Donoso LA, Sanborn GE. Retinal ischemia andrisk of neovascularisation following central retinal vein obstruc-tion. Ophthalmology 1982; 89:1241-5.

27 Hayreh SS, Rojas P, Podhajsky P, Montague P, Woolson RF.Ocular neovascularisation with retinal vascular occlusion. III.Incidence ofocular neovascularisation with retinal vein occlusion.Ophthalmology 1983; 90: 488-506.

28 Sabates R, Hirose T, McMeel JW. Electroretinography in theprognosis and classification of central retinal vein occlusion.Arch Ophthalmol 1983; 101: 232-5.

29 Hayreh SS. So-called 'Central retinal vein occlusion' II. Venousstasis retinopathy. Ophthalmologica 1976; 172: 14-37.

30 Brunner R, Heinen H, Konen W, Gaethgens P, Hossmann V.Therapy of occlusive disease of retina by pentoxifyllin, iso-volemic hemodilution with albumine and hypervolemic hemo-dilution with dextran. A randomised double-blind study. ClinHemorrheol 1983; 3: 232.

31 Gallasch G. Neue Ansatze zur Diagnostik und Therapie vonGefaBverschlussen am Auge. Fortschr Ophthalmol 1983; 80:166-7.

116

copyright. on S

eptember 30, 2021 by guest. P

rotected byhttp://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.2.108 on 1 F

ebruary 1985. Dow

nloaded from