PRE-TREATMENT PROTOCOL FOR CRYONICS PATIENTS?

by Ben Best

Sometimes drugs and antioxidants are given to cryonics patients after declaration of death for the purpose of reducing ischemic damage (brain and blood vessel damage due to lack of oxygen and nutrient when blood flow stops) and reperfusion injury (brain and blood vessel damage inflicted when blood flow is restarted after an ischemic period of more than ten minutes).

Restarting blood flow after more than about ten minutes of ischemia is typically more damaging than the ischemia itself because the ischemia sets the stage for oxygen to generate free-radicals rather than contribute to cellular energy production. The acidity produced by ischemia greatly reduces the release of arachidonic acid from cell membranes by phospholipases, so phospholipase activity and arachidonic acid release is greatly increased upon reperfusion [BRAIN RESEARCH REVIEWS 44:13-47 (2004)].

Easily-measured isoeicosanoid products of arachidonic acid oxidation show distinctly high urine levels following reperfusion of myocardial infarction patients [CIRCULATION 96:3314-3320 (1997)].

For reperfusion, the focus of membrane damage is on endothelial cells as well as platelets, leucocytes and other cells in the blood stream -- rather than on organ tissue, which is the focus of ischemic damage. Eicosanoids generated by arachidonic acid (especially leukotrienes) greatly increase the adhesion of leukocytes & platelets to capillary walls --plugging them up. Superoxide also increases the adhesion of leucocytes to vessel walls. Eicosanoids (leukotrienes & prostaglandins) and associated oxygen free-radicals make capillary walls more "leaky", causing edema which narrows the channels. (Activated neutrophils also produce free radicals: superoxide and hypochlorous acid.) These effects quickly become pronounced enough in reperfusion to block capillaries entirely -- the no reflow phenomenon. But no reflow can occur even without leukocytes & platelets. Free-radical and other membrane damage can loosen or dislodge atherosclerotic plaque causing emboli upon reperfusion.

Nitric oxide normally functions to not only reduce platelet aggregation & leukocyte adhesion to the endothelium, but to promote vascular smooth muscle relaxation and reduce endothelial cell cytokine production. Nitric oxide inhibits the expression of pro-inflammatory genes by transcription factor NF-kappaB [TRANSPLANTATION PROCEEDINGS 30:4239-4243 (1998)]. In the presence of superoxide, however, nitric acid reacts with superoxide to form the potent free radical peroxynitrite. During reperfusion, abnormally high amounts of superoxide converts almost all available nitric oxide to perxoynitrite -- regarded as the agent causing most of the damage to brain capillary endothelial cells [NEUROSURGERY 43(3):577-584 (1998)]. Damage to the endothelium not only increases edema (tissue swelling due to "leakiness"), but causes endothelial protrusions ("blebs") which can block capillaries.

Ischemia in tissues and blood vessels results in large amounts of ATP being broken-down to xanthine. Reperfusion allows the endothelial enzyme xanthine oxidase to convert xanthine plus oxygen to superoxide & uric acid. Liberated iron & zinc ions further increase free radical damage. In contrast to the vasculature, mitochondria in tissues rather than xanthine oxidase are the primary source of oxygen free radicals during reperfusion injury [JOURNAL OF CLINICAL INVESTIGATION 91:456-464 (1993)]. There is a linear correlation between the amount of reperfusion injury and disruption of the blood-brain barrier. Water flow into the brain due to blood-brain barrier disruption can lead to edema.

Agents such as Vitamin E, nifedipine, PBN and local anesthetics have shown promising results in animal experiments on ischemia/reperfusion, but are still not used in stroke therapy because they have all failed to pass clinical trials. DiHydroPyridine (DHP) derivatives, such as nimodipine, block L-type calcium channels. But the main benefit of DHPs in ischemia seems to be through arteriole dilatation rather than neuron calcium-channel blocking. Pre-treatment of dogs with nimodipine prior to ten minutes of ischemia led to an 80% normal recovery rate, as compared with an 86% death rate in untreated controls. Treatment 2 minutes post-ischemia had a negligible effect. [PHARMACOLOGY OF CEREBRAL ISCHEMIA, Joseph Krieglstein, Editor, p.65-73 (1988)].

For the terminal cryonics patient it can be asked, why wait until after declaration of legal death before using antioxidants or other agents that can reduce ischemic damage? Higher blood and tissue levels of some antioxidants can be achieved if administered in the days or weeks before legal death than if administered after the event. For antioxidants that are legal and safe, a treatment protocol makes a great deal of sense, although there have been few controlled studies on such pretreatment by cryonics researchers or anyone else. Relevant experiments in the literature generally involve pretreatment within one hour prior to induction of ischemia.

Intravenous injection of the alpha-tocopherol form of Vitamin E (20 mg/kg or 9 mg/pound) 30 minutes prior to ischemia has been shown to significantly reduce lipid peroxidation and neurological damage [STROKE 14(6):977-982 (1983)]. A better experiment would have included both alpha-tocopherol and gamma-tocopherol because gamma-tocopherol removes peroxynitrite whereas alpha-tocopherol does not [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA) 94(7):3217-3222 (1997)].

Vitamin E pretreatment for cryonics patients has the additional advantage of reducing blood clotting -- and does not have the risk of gastric bleeding associated with aspirin. Many fish oils (especially salmon oil) afford the same benefit, in addition to reducing the risk of cardiac arrest [MOLECULAR AND CELLULAR BIOCHEMISTRY 116:19-25 (1992)]. Reduced clotting in a cryonics patient is a great benefit -- and is reason for heparin injection after legal death. For patients undergoing surgery, however, Vitamin E and fish oils may be prohibited because clotting is desired.

Unlike Vitamin E, melatonin acts as an antioxidant through endogenous electron donation, which does not have the same potential for a pro-oxidant side effect [JOURNAL OF PINEAL RESEARCH 32:135-142 (2002)]. The capacity of melatonin to scavenge hydroxyl radicals is three orders of magnitude greater than Vitamin E [THE JOURNAL OF BIOLOGICAL CHEMISTRY 274(31):21937-21942 (1999)]. Pretreatment of gerbils with melatonin (10 mg/kg or 4.5 mg/pound) 30 minutes before reperfusion significantly reduced ischemic brain injury [JOURNAL OF PINEAL RESEARCH 29:217-227 (2000)]. Similar effects were achieved with rats [JOURNAL OF PINEAL RESEARCH 34:110-118 (2003)].

Pretreatment of gerbils with deprenyl (0.25 mg/kg or 0.11 mg/pound) two weeks before ischemia reduced damage to neurons in the hippocampus [JOURNAL OF NEURAL TRANSMISSION 107:779-786 (2000)]. N-acetylcysteine (15 grams) infused in human myocardial infarction patients over a 24-hour period significantly reduced ischemic damage [CIRCULATION 92:2855-2862 (1995)]. Curry powder contains curcumin, which is an antioxidant several times more potent than Vitamin E [THE JOURNAL OF NEUROSCIENCE 21(21):8370-8377 (2001)]. Meals with curry dishes might therefore be a good idea for cryonics patients anticipating near-term deanimation.

The evidence for pretreatment protocols to reduce ischemic and reperfusion damage in cryonics patients is sketchy and indirect. Appropriate dosage levels is guesswork. But it does seem that for antioxidants which have few side effects, a terminal cryonics patient would benefit by taking dosages which are several times what would be considered normal for a person taking supplements.