Since the launch in 1998 of the anti-impotence drug sildenafil (viagra), the American food and drug administration has identified 50 cases of drug-related blindness, the so-called nonarteritic anterior ischemic optic neuropathy. This, very serious, side effect frequently leads to sudden, mostly irreversible loss of vision, and there is no proven effective treatment to cure patients or to prevent recurrence. The mechanism of ischemic optic neuropathy is not clear, but it could be related to the fact that the ophthalmic and central retinal arteries have an autoregulation of their own blood flow without any autonomic nerve supply; vasoreactivity could be lower albeit efficient, and therefore more vulnerable to systemic modifications of the circulation.

Visual adverse events have been reported after ingestion of sildenafil (viagra), the anti-impotence drug prescribed to more than 27 million men worldwide _[1]. These side effects include nonarteritic anterior ischemic optic neuropathy (NAION), an ischemic infarction of the optic nerve head, frequently leading to sudden, mostly irreversible loss of vision _[2], and for which there is no proven effective treatment to cure patients or to prevent recurrence _[3].

The American Food and Drug Administration has identified several cases of this condition _[4]. However, epidemiological data suggest that one case of NAION might be expected in a cohort of 8893 sildenafil users _[5].

Clinical data
The mechanism by which this medication might damage the optic nerve is not well understood. One hypothesis is vascular insufficiency at the optic nerve head. This insufficiency and the resulting ischemia may be more frequent in people with certain anatomical characteristics (for example, small physiological cup) _[6]. It has been theorized that sildenafil, which works through the nitric oxide-cyclic GMP pathway, may alter the perfusion of the optic nerve head by modifying nitric oxide levels _[4]. In fact, the drug increases nitric oxide levels, which in turn cause reduced perfusion _[4]. Sildenafil also has a weaker inhibitory action on PDE6, located in the rod and cone photoreceptors. This could explain the modest, transient visual symptoms, as well as typically blue tinge to vision, increased brightness of lights and blurry vision, reported with sildenafil use, and occurring more frequently at higher doses _[1].

However, recent reports have raised the question of whether such a sildenafil–NAION association might exist. Early studies suggested that, although ocular side effects are rare, sildenafil may be associated with NAION _[6], and the drug may be considered potentially blinding _[7]. Hayreh _[8] stated that the nature of optic nerve head blood flow and the various factors that influence it, the systemic vascular effects of the drug, and the clinical features of NAION lead us to believe that sildenafil is a contributory factor.

Nevertheless, other studies suggest that a causal relationship is difficult to establish, since the possible mechanism of interaction between the anti-impotence drug and NAION is unclear _[9]. Moreover, many subjects frequently have vascular risk factors that may, per se also put them at increased risk for NAION _[1]. In accordance with this, McGwin et al. _[4] observed that for men with a history of myocardial infarction or hypertension, the use of viagra may increase the risk of NAION. This should provide support, albeit indirect, that should an association exist between viagra and NAION, it may be limited to individuals with a history of cardiovascular disease _[4]. Similarly, just a few months ago, in a previous issue of the American Journal of Ophthalmology, Lee and Newman _[10] suggested that in light of the possible, but as of yet still unproven association between NAION and anti-impotence drugs, informed consent regarding the possible but likely low risk of NAION for these drugs might be useful for high-risk individuals (for example, older aged subjects, with vasculopathic risk factors, and small cup-to-disk ratios). In the same issue, Fraunfelder _[11] concluded his study stating that since millions have taken these medications with risk factors for NAION, this may be an expected coincidence. Nevertheless, in a previous report, Pomeranz et al. _[6] considered that four of their five patients experiencing NAION had no vascular risk factors for ischemic optic neuropathy. Therefore, the role of these agents in the ischemic optic neuropathy continues to be controversial.

Decreased visual acuity and loss of visual ability are also, although uncommon, surgical and anesthesiological complications. Surgery may contribute, with an estimated incidence after non-ocular surgery of 0.01–1% _[12] greater following ophthalmologic operations _[13]. In fact, the incidence of NAION after cataract extraction is approximately one every 2000 cases _[14], but acute visual loss related to ischemic optic neuropathy has been well documented after neurosurgery, nephrectomy, ENT or general surgery, liposuction, prostatectomy, and particularly cardiopulmonary bypass or spine surgery. Patients with pre-existing hypertension, diabetes, elevated cholesterol, hyperlipidemia, sickle cell anemia, renal failure, gastrointestinal ulcer, narrow-angle glaucoma, vascular or cardiac disease, arteriosclerosis, polycythemia vera, and collagen vascular disorders are at increased risk _[3], _[15] and _[16]. This is of importance, considering that 58% of men aged 50–69 under pharmaceutical management for erectile dysfunction, had more comorbidities associated _[17], and half of all people reaching the age of 65, for one reason or another, have one or more surgical operations _[18]. The mechanism of perioperative ischemic optic neuropathy is not clear, but it could be related to the fact that the ophthalmic and central retinal arteries have an autoregulation of their own blood flow without any autonomic nerve supply; vasoreactivity could be lower, albeit efficient, and therefore more vulnerable to systemic modifications of the circulation _[19] and _[20]. In accordance with this possible mechanism, precipitating perioperative factors for ischemic optic neuropathy include prolonged hypotension _[21], anemia, surgery trauma, hemorrhage, shock _[22], direct pressure on the ocular globe and long operative times _[16].

Anesthesia has been also associated with ischemic optic neuropathy, with regard to anesthetic agent effects on retrobulbar circulation. High alveolar concentrations of volatile anesthetics may enhance alterations in ophthalmic artery blood flow, since end diastolic velocity in ophthalmic artery decreased to 70%, whereas mean arterial pressure decreased only to 4% _[23]. Carbon dioxide may play an important role in the etiology of ischemic optic neuropathy, and the resulting recommendation should be to respect the patients’ carbon dioxide concentration keeping it in a normal range _[24].

The hypothesis

These data are consistent with the hypothesis that viagra, surgery and anesthesia, taken together, could be a potentially dangerous cocktail of risk factors for sudden, irreversible loss of vision. To reduce the risk, sildenafil use should be avoided at least one week before surgical operations, since the reported cases of blindness developed soon after drug ingestion, namely within 24–36 h _[15]. Physicians should inform the users about the potential risk of associating the drug to surgery and anesthesia, avoiding the prescription of viagra to their patients, if scheduled for future operations. Moreover, anesthesia providers should be informed up front of this assumption to allow the use of prevention strategies.

Since studies supporting or denying this hypothesis are not yet available and the existing data do not seem to shed light on this topic, these precautions should be applied until this conundrum has been satisfactorily elucidated.

References

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V. Fodale_a, R. Di Pietro_b and S. Santamaria_c
a Anesthesia Intensive Care, Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina, School of Medicine, Policlinico Universitario ‘G. Martino’, via C. Valeria, 98125 Messina, Italy
_b Department of Surgical Specialties, Section of Ophthalmology and Refractive Surgery, University of Messina, School of Medicine, Policlinico Universitario ‘G. Martino’, via C. Valeria, 98125 Messina, Italy
_c Section of Ophthalmology and Refractive Surgery, Rome American Hospital, Roma, Italy