13.1.2Systemic Thrombolytic Therapy

Systemic thrombolysis has been successfully used to treat acute myocardial infarction, pulmonary embolism, ischemic stroke, deep vein thrombosis, and acute arterial occlusions of the lower limbs. Therefore, its attempted use in CRVO was expected. Unfortunately, it proved to be ineffec-

tive or too risky.69,74,140,253,318

Kohner and colleagues performed a prospective randomized study in 41 patients with CRVO with symptoms for less than 7 days. Patients were randomized to receive 3 days of intravenous streptokinase followed by anticoagulation for 6 months or observation. Final VA was better in the treatment group, but severe intraocular hemorrhage in three patients was responsible for its poor reception and absence of follow-up study of this approach.140

Elman reported a prospective study of 96 patients with CRVO who received a regimen that changed intrastudy, but was based around an intravenous infusion of tissue plasminogen activator for 3Ð8 h followed by anticoagulation with heparin, warfarin, and aspirin.69 In his study, patients received systemic intravenous infusion of tissue plasminogen activator 100 mg at an average of 21 days after onset of CRVO. At 6 months follow-up, 42% of patients had recovered at least three lines of vision, but one patient died of a hemorrhagic stroke associated with the treatment.69 Because of this catastrophe, the therapy was not adopted.

To avoid the systemic side effects, superselective ophthalmic artery Þbrinolytic therapy with urokinase 300,000 IU infused over 1 h was used in 26 patients.213 Six eyes were reported to signiÞcantly improve, but it is not possible to determine the meaning of the result in the absence of a control group. Two patients developed vitreous hemorrhage requiring vitrectomy.213 Use of systemic thrombolytic drugs for CRVO has been abandoned because of the risk of life-threatening complications such as intracerebral and gastrointestinal hemorrhage associated with treatment for a nonfatal malady.74,318

Another randomized trial studied patients with CRVO and ME reducing VA to 20/50 or less and with onset of symptoms within 11 days of presentation. It randomized 41 patients to intravenous tissue plasminogen activator (TPA) (50 mg) or isovolumic hemodilution (IH). At 1 year, there was an improved visual outcome in the TPA group.98 Patients under the age of 70 were excluded to reduce the risk of systemic hemorrhagic events. The proportion of patients improving three lines of more was 45% in the TPA group compared to 21% for the IH group.98 Median 1 year VA was 20/60 in the TPA group compared to 20/400 in the IH group.98 The regimen was expensive with 8 days of hospitalization. The Þrst day the patients receiving TPA were given 50 mg of recombinant TPA intravenously over 60 min with concomitant heparinization that continued for the 8 days in the hospital. Patients also were treated with aspirin 100 mg/day for 12 weeks. No systemic adverse events occurred, but one subretinal hemorrhage did. Perhaps because of the inpatient nature and aggressiveness of the intervention, this treatment approach has not been adopted.98

13.1.3 Isovolumic Hemodilution

The Þnding that some patients with CRVO have increased blood viscosity from several possible causes, such as elevated hematocrit, elevated Þbrinogen, and abnormal erythrocyte aggregation, led to trials of isovolumic hemodilution (IH) with replacement of blood by plasma expanders. By decreasing blood viscosity, IH is thought to improve retinal circulation and oxygenation.94,235,286 The general aim of this treatment is to increase the ßuidity of the blood, thus improving the microcirculation and oxygen delivery to the retina.84,94 The targeted level of hematocrit varies from 30% to 38% rather than the normal 38Ð42%, and it is important to maintain the lowered hematocrit for 6 weeks rather than 2Ð3 weeks.94 It appears that intervention within the Þrst 2 weeks is more effective than later intervention.84 Treated eyes have had mean changes in

VA ranging from a mean loss of 1.3 lines to a mean gain of 1.5 lines.84,300 In addition, some evidence suggests that the rate of conversion from nonischemic to ischemic CRVO is reduced, although the comparisons were made with historicalandnotconcurrentcontrols.84Hemodilution for CRVO reduces the resistive index of the central retinal artery, but does not change central venous blood ßow velocity as determined by color Doppler imaging.285 Many patients undergo the treatment and do not beneÞt, requiring that other treatments be tried.74 The ßuid used for replacement of the removed blood matters. In a study using normal saline rather than dextran replacement ßuid, the IH group had worse outcomes than the control group.168 In some studies, IH has been combined with laser panretinal photocoagulation because IH alone did not prevent some cases of subsequent neovascular glaucoma.94

Despite level 1 evidence of the efÞcacy of IH, and beneÞcial effects documented regarding VA,

retinal circulation time, and rheological variables, isovolumic hemodilution has never been used in the United States to an appreciable extent and appears to be used primarily in a few European centers (Table 13.3). Even in Europe, its use is in decline since the advent of intravitreal injection of anti-VEGF drugs.318 Reasons for its nonadoption are speculative, but may include evidence based on studies of small sample size; reluctance of ophthalmologists to engage in systemic treatments requiring phlebotomies, infusions, and systemic hazards; the chronic nature of the disease for which recurrent use of hemodilution is impractical; the conßicting evidence that patients with CRVO have hyperviscosity; logistical problems in arranging for internists and family doctors to administer these systemic treatments; and reimbursement issues. Not all patients with CRVO are eligible. In published studies, 28% of patients with CRVO were not eligible for reasons including anemia, congestive heart failure, renal disease, and pulmonary disease.94,108,161,231,253