Fitz-Roy Curry at UC Davis knows more about vascular permeability than I ever will, and I am pleased to say he has offered some thoughts on Paul Marik’s claims for the Norfolk Protocol. With a little text correcting by myself;
“Our lab has little experience with Vitamin C and vascular permeability regulation. In some investigations we used other antioxidants to attenuate acute inflammatory response but my impression was that their effectiveness varied with the type of inflammatory stimulus, so it would be hard to predict the effectiveness of a broad acting antioxidant like vitamin C on vascular permeability. Your question reminded me of grant proposals that I reviewed in the mid 1980’s that tested effects of vitamin C on vascular permeability in some animal models. I could not find any significant subsequent publications from these investigators to provide much new to the old observation that vitamin C tended to attenuate sepsis in some rodent models. However, since that time there has clearly been a re-emergence of investigations of vitamin C and endothelial dysfunction, many using endothelial cells in culture. I noticed a particularly active recent investigator (James May at Vanderbilt) who has worked on multiple possible mechanisms whereby vitamin C may act to limit microvascular dysfunction (both perfusion and permeability). These include inhibiting excessive production of NO and superoxide, the formation of peroxynitrite, PP2A activation, and occludin dephosphorylation. I would add possibly blocking endothelial glycocalyx break down, especially in the lung. Some of these mechanisms have been linked to sepsis in rat models. I would also like to see better evaluation of the acute effects of vitamin C on microvascular perfusion in such studies as I suspect that any action of vitamin C to improve microvascular perfusion may be as important as actions to modify permeability.”
“After reading the Marik paper I realize that many of these ideas form the basis for Marik’s approach. Nevertheless it is appropriate to question whether the above pre-clinical observation and Marik trial in particular are a sound basis for clinical interventions without much more careful evaluation in well designed clinical trials. For example I have my usual reservations about results from cultured endothelial cells which almost always express a pro-inflammatory phenotype. ECs in culture can be useful models of damaged endothelium but how well any particular in vitro model might relate to sepsis is not known. Rodent models of sepsis are a problem because of the very much lower susceptibility of rodents to LPS compared with human subjects. There are also issues associated with the distribution of vitamin C. With a MW of 176, vitamin C would distribute rapidly in the extracellular space and be readily filtered in the kidney. For example if 600mg of vitamin C distributed in 14 L of extracellular fluid, initial plasma Vitamin C levels could be as high as 4.3mg/dL. At normal GFR and renal function (reabsorption max about 1.7 mg/100ml filtered) close to half the vitamin C could be excreted within 2 hours. In sepsis both GFR and reabsorption are compromised so the kinetics of distribution and excretion might play important roles in dose response.”
To the last bit I would humbly add that Vit C is taken into cells by a sodium-dependent Vitamin C transporter, so there has to be urgent work on linking dose to extracellular and intracellular levels in the complex metabolic state of human sepsis. May & Harrison (2013) conclude that where there is endothelial dysfunction as a prelude to vascular dysregulation, leakage, or atherosclerosis;
“Supplementation to upper normal plasma ascorbate levels is clearly indicated in most diseases and conditions in which ascorbate is depleted [includes sepsis]. However, it is seldom a priority, because patients, physicians, and health authorities are unaware of the increasing evidence for multiple potentially important functions of ascorbate. With regard to the endothelium, it is worth emphasizing observations made more than 50 years ago that early scurvy generates endothelial disruption in guinea pigs, which resembles atherosclerosis and is fully and rapidly reversible with ascorbate repletion.”
Does anyone feel that ascorbate depletion, once documented, can be left untreated? Should we not at least be maintaining upper normal plasma ascorbate levels in patients with documented ascorbate deficiency? Consider our approach to glycaemia; Would an Ethics Committee allow us a Control Group with untreated hypoglycaemia or hypo-ascorbate-aemia?