HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Electronic Letters to:

Retina: Quan Dong Nguyen, Syed Mahmood Shah, Elizabeth Van Anden, Jennifer U. Sung, Susan Vitale, and Peter A. Campochiaro Supplemental Oxygen Improves Diabetic Macular Edema: A Pilot Study Invest. Ophthalmol. Vis. Sci. 2004; 45: 617-624 [Abstract] [Full text] [PDF]

eLetters: Submit a response to this article

Electronic letters published:

Oxygen and Diabetic Retinopathy

Geoffrey B. Arden   (4 January 2005)

Author Response: Oxygen and Diabetic Retinopathy

Peter A. Campochiaro   (4 January 2005)

Oxygen and Diabetic Retinopathy 4 January 2005
Geoffrey B. Arden Send letter to journal: Re: Oxygen and Diabetic Retinopathy g.arden{at}city.ac.uk Geoffrey B. Arden	Nguyen et al.1 have shown diabetic maculopathy regresses after continuous oxygen inhalation. Here we explain why the small amount of additional oxygenation can have therapeutic value, how the regime may be improved, and suggest other related means of treating diabetic retinopathy (DR). It is known2,3 that inhalation of oxygen partially, rapidly and transiently reverses losses of retinal function in diabetic persons with very early retinopathy, but the pilot study by Nguyen et al.1 is the first to show that long term administration of oxygen can reverse the structural changes associated with DR. These authors gave oxygen by nasal tube and increased the arterial oxygen saturation from 94-99% in various patients to 100%. The percentage of alveolar oxygen achieved by this method of administration is <70%, so the total increase in the quantity of oxygen carried by the blood by hemoglobin and plasma would be 5-10%. The increase in the oxygen delivered to the retina cannot be precisely calculated, but assuming that all autoregulation has been lost, and no additional blood retinal barrier occurs in DR, it cannot be higher than 10%. It would therefore appear that this small increase in oxygen delivery relieved retinal anoxia and reversed the changes of diabetic maculopathy, which at first glance may seem unlikely. In fact, the large dual blood supply of the retina has in the past suggested to those interested in DR that anoxia was not a direct cause of the condition. However, the retina has a very high metabolic demand, so that even in the normal eye the pO2 of the outer retina drops to zero in dark adaptation. In animal experiments, the pO2 in the diabetic retina is reduced, even in regions where there is no capillary drop-out.4,5 However, the oxygen requirement of the retina is not constant. In dark adaptation it doubles,4 and it is therefore evident that the therapeutic effect of oxygen reported1 must be largely (if not totally) occurring while the patients sleep in darkness. This consideration would be important in further such trials, because continuous oxygen inhalation is unpleasant and hinders mobility. However, the result also emphasizes the possible importance of another method of treatment of DR,6,7,8 that is, the prevention of dark-adaptation in sleep, which could best be achieved by wearing a simple device that shone light through the closed lids during sleep. The evidence that such a method of treatment should be effective has been reviewed,6 and, in experimental diabetes in rats, it has been shown that after 24 hours of darkness the retinal expression level of VEGF (the cytokine implicated in causation of DR) doubles (Chibber R, Sriharan M, Bahaedin M, Ben-Mahmud M, Arden GB, Kohner M, unpublished data). Geoffrey B. Arden1 and Reinier O. Schlingemann2 1Applied Vision Research Centre, City University, London 2Ocular Angiogenesis Group, Department of Ophthalmology, Academic Medical Center, Amsterdam References 1. Nguyen QD, Shah, SM, van Anden E, Sung JU, Vitale E and Campochiaro P. Supplemental oxygen improves diabetic macular edema: a pilot study. Invest Ophthalmol Vis Sci. 2004;45:617-624. 2. Dean FM, Arden GB, Dornhorst A. Partial reversal of protan and tritan colour defects with inhaled oxygen in insulin dependent diabetic subjects. Brit J Ophthalmol. 1997;81:27-30. 3. Drasdo N, Chiti Z, Owens DR, North RV. Effect of darkness on inner retinal hypoxia in diabetes. Lancet. 2002;29:2251-2253. 4. Linsenmeier RA. The effect of light and darkness on oxygen distribution and consumption in the cat retina. J Gen Physiol. 1986;88:521-542. 5. Linsenmeier RA, Braun RD, McRipley MA, et al. Retinal hypoxia in long-term diabetic cats. Invest Ophthalmol Vis Sci. 1998;39:1647-1657. 6. Arden GB, Wolf JE, Tsang Y. Does dark adaptation exacerbate diabetic retinopathy? Evidence and a linking hypothesis. Vision Res. 1998;38:1723-1739. 7. Arden GB, Wolf JE, Collier, J Wolff, C, Rosenberg M. Dark adaptation is impaired in diabetics before photopic visual losses can be seen. Can hypoxia of rods contribute to diabetic retinopathy? In: Hollyfield JG, Anderson RE, LaVail MM, eds. Retinal Degenerative Diseases and Experimental Therapy. Proceedings of the XIII International Symposium on Retinal Degeneration. New York: Kluwer Academic/Plenum; 1999:305-316. 8. Arden GB. The absence of diabetic retinopathy in patients with retinitis pigmentosa: implications for pathophysiology and possible treatment. Br J Ophthalmol. 2001;85:366-370.
Author Response: Oxygen and Diabetic Retinopathy 4 January 2005
Peter A. Campochiaro Send letter to journal: Re: Author Response: Oxygen and Diabetic Retinopathy pcampo{at}jhmi.edu Peter A. Campochiaro	Drs. Arden and Schlingemann bring up some interesting points. Supplemental inspired oxygen may result in only small increments in tissue oxygen levels in patients with diabetic macular edema as they suggest, but the key question is, are the alterations in retinal oxygenation (whatever they are) sufficient to alter expression of hypoxia-regulated genes, such as VEGF. We predicted that the changes in retinal oxygenation would be sufficient to downregulate VEGF based upon experiments in mice, which show that hyperoxia reduces constitutive expression and ischemia-induced expression of VEGF. The findings in patients support that prediction and suggest that VEGF and/or other hypoxia-regulated genes play a role in DME. The suggestion that since the metabolic activity of photoreceptors increases during dark adaptation, it may be possible to get essentially equal benefit by providing supplemental oxygen only during sleep or illuminating the retinas through the closed eyelids during sleep or both, is intriguing. We agree that the demonstration that VEGF expression is increased in the retinas of diabetic rats during dark adaptation supports the hypothesis, and we look forward to reading this study when it is published. As Drs. Arden and Schlingemann surmise, the biggest impediment to patient entry into an ongoing clinical trial investigating the effect of supplemental oxygen in DME is patient concern regarding the inconvenience of being constantly attached to an oxygen tank. Providing supplemental oxygen only at night would greatly improve convenience and patient acceptance. At the outset of our studies, our motivation was not to identify a new treatment for DME, but rather to determine if hypoxia participates in the pathogenesis of DME. However, unexpectedly some patients who had improvement in retinal thickness into or very near the normal range during 3 months of supplemental oxygen, maintained improvement after oxygen was stopped. We postulate that once retinal thickening was improved, a hypoxia-driven feedback loop was broken, allowing pre-existent focal and grid laser to maintain stability. If this finding is confirmed in the ongoing clinical trial, then contrary to our original expectations, supplemental oxygen may serve as an adjunct to other treatments for DME. If this is the case, making its use more palatable will be an important consideration, and the suggestions of Drs. Arden and Schlingemann may prove extremely valuable in this regard. Quan Dong Nguyen Mahmood Shah Peter A. Campochiaro Johns Hopkins School of Medicine, Baltimore, Maryland