VITAMIN C, SEPSIS AND SEPSIS-INDUCED ARDS

Vitamin C - an antioxidant and a stress hormone

Askorbic acid (Vitamin C) is synthesized from glucose in the liver. It is transported intracellularly by a protein called SVCT2 (Sodium-dependent Vitamin C Transporter 2), mainly to the suprarenal glands, the hypophysis, neurons, neutrophil leucocytes, lymfocytes and macrophages [81] where it is stored at concentrations one hundred times higher than in the plasma. 

Almost all animals are capable of producing large amounts of Vitamin C due to the metabolite being the body’s most important antioxidant and stress hormone. It is a misconception that Vitamin C only functions as a vitamin. In fact, animal production of ascorbic acid is often significantly augmented at higher stress levels [82]. A frightened goat can easily double (2x) its production of ascorbic acid and under extreme conditions produce levels as high as 100 grams per day.  

In order to understand the importance of the Vitamin C in sepsis and sepsis-induced ARDS it is crucial to know that the presence of Vitamin C in the suprarenal glands, the hypophysis and in neurons is an absolute prerequisite for these organs to be able to synthesize dopamine, norepinephrine, epinephrine, vasopressin (i.e.antidiuretic hormone, ADH) and neurotransmitters [83]. Ascorbic acid is actually an essential co-factor for the synthesis of two copper-containing enzymes, ”dopamine-hydroxylase” and ”peptidylglycine alfa-amidating monooxygenase”. Without Vitamin C the body’s stress mechanisms,  immune system and nervous system will not properly function.    

Humans (as well as many primates, bats, and a few other mammals) are not capable of synthesizing their own Vitamin C due to a mutation in the human genome and are entirely dependent on obtaining it from dietary sources. However, there are strict limitations to the amount of Vitamin C that humans can obtain from the diet because of the low capacity of the special transport protein, SVCT1, to transport the Vitamin C from the gut into the blood. The amount of ascorbic acid absorbed and transported by an individual will not exceed 350-500 mg/day regardless of the amount of fruit, berries or Vitamin C tablets consumed. Normally this amount of Vitamin C is enough when a patient is in a healthy state and there is no need for supplementary intakes. 

However, for patients in an unhealthy state the amount of Vitamin C can become critically low and even catastrophically low if sepsis or sepsis-induced ARDS are present. The body’s need for antioxidants under life-threatening conditions is greatly increased and the body’s store of Vitamin C, in particular, is rapidly used up. 

For over twenty years it has been known that acute illness, endotoxemia and sepsis cause an acute deficiency in Vitamin C, as measured by low serum- and intracellular levels [84]. In one study on 14 critically ill surgical patients, including two with septic shock, Vitamin C/s was as low as (6,1±1,7 micromol/L) [85], which is clearly below the level of causing scurvy. In four other studies on critically ill septic patients Vitamin C levels were extremely low and in some patients undetectable [84]. 

            Multiorgan failure 

Humans with severe sepsis will often suffer from multiorgan failure (MOF). It is unknown what causes MOF but evidence suggests that oxidative metabolites, associated with the body’s inflammatory response (i. e. Reactive Oxygen Species, ROS) are involved. These oxidative metabolites steal critical electrons from enzymes and other  intra- and extracellular biomolecules. The huge lack of anti-oxidants found in septic patients may be a factor associated with increased death rates. It is well known that septic patients - for reasons unknown - have augmented mixed venous oxygen saturation levels, SvO2 of 80-85% as compared to normal levels of 75% - sometimes despite low arterial saturation levels, SaO2. This suggests that cell mitochondria are not efficiently  using available oxygen;  perhaps an indication of  a non-optimally functioning Krebs cycle or electron transport chain. Furthermore, these skewed oxygen saturation levels could possibly explain why the patient’s energy production is failing at a cellular level and there is not enough ATP being produced that ultimately may result in multiorgan failure. 

The basis for the mitochondrial electron transport chain in the mitochondria is an oxidation/reduction process from 2+ to 3+ iron and back to 2+ iron again in the different cytochromes. When the lost electron cannot be regained due to the damaging presence of oxidative metabolites, the process can not be repeated and the energy production will be terminated. The ascorbic acid molecule may play an essential and ameliorative role in this biochemical process by donating two (2) free electrons.    

As an example, the following placebo-controlled, randomised, double-blind study involving 28 surgical ICU-patients is in line with the above-referenced reasoning. In addition to conventional treatment with antibiotics, cristalloid fluids and norepinephrine infusion half of the patients were given Vitamin C ( 7 g/day) and the other half was given a placebo for 3 days. Patients receiving the placebo required more than twice as much of norepinephrine-infusion, mcg/min (p<0.0004) and over a longer time span (p<0,007). Furthermore, in the placebo-group 64% (9/14) died within 28 days, whereas only 14% (2/14) in the treatment group (p<0,009) [86]. This is a large difference which is highly statistically significant.  

Synergism between Vitamin C and Cortisone  

In sepsis, pro-inflammatory cytokines are generated that block and down-regulate the transport of Vitamin C over the cell membrane, SVCT2  [87]. This means that the insufficient amount of Vitamin C that has actually been resorbed from the intestine by SVCT1 has increased difficulties entering the cells through SVCT2 [88], thus reducing the production of dopamine, epinephrine, norepinephrine, cortisol, vasopressin and neurotransmitters. By binding to certain glucocorticoid receptors, the glucocorticoids normally increase the sensitivity of blood vessels for catecholamines and reinforce its effect mainly by inhibiting the endothelial NO- and prostacyclin synthesis, but also by augmenting the inflow of calcium in the smooth muscle cell of the vessel wall [89]. 

In sepsis these glucocorticoid receptors are oxidized (i.e. losing electrons). Cortisone can then no longer bind to these receptors and cannot interact with catecholamines to stabilize the blood pressure [90]. 

However, if Vitamin C is given intravenously there will be a ’reduction’ of the glucocorticoid receptors (i.e. electrons are given back), which will restore its function [90]. Furthermore, the blockade and the down regulation of SVCT2 is broken, at which point the transport of intracellular Vitamin C and the synthesis of catecholamines, vasopressin and neurotransmitters is resumed [87], concomitantly with the strengthening of the immune system. 

Thus, there is a synergism between glucocortiocoids and Vitamin C, in which these metabolites reciprocally support and reinforce the effect of one another, as there is also a synergism between catecholamines and glucocorticoids and between Vitamin C and catecholamines. These synergistic effects are inhibited in septic patients but are restored by intravenous Vitamin C and Solu-Cortef. This is the rational behind giving both together and not only one or the other. Therefore in conjunction it is interesting to note that hypophyseal adreno-cortical stimulation by ACTH normally releases both cortisol and ascorbic acid from the suprarenal gland, a fact has known since 1960, that emphasizes the need for both corticosteroids and ascorbic acid [91]. 

                    Thiamine

   

In a double-blind, placebo-controlled randomised study in 79 patients with sepsis 28 of these patients had Thiamin deficiency (≈35%) [92]. Half the patients were given a supplement of Thiamine 200 mg x 2 over 7 days. The mortality rate during these days was 46% in the placebo-group but only 13% in the group given Thiamine, a 72% reduction in mortality [92]. Thus, by administration of Thiamin alone the potential to reduce mortality by 2/3 in patients with sepsis (p<0.05) was observed. In another randomised double-blind, placebo-controlled study in 70 patients with sepsis, 8/35 of patients in the placebo-group developed renal failure and needed dialysis (=21%), whereas only 1/35 of patients (=3%) receiving Thiamine (200 mg x 2 IV. for 7 days) needed dialysis (p<0.04) [93]. 

These results may be further explained by the fact that Thiamine is essential and very important for aerobic metabolism, since it acts as a co-enzyme for pyruvate dehydrogenase. If Thiamine is missing then pyruvate can not be converted to Acetyl-coenzyme A and there will be no energy production through the Krebs Cycle and the electron transport chain. This means that puryvate will be converted to lactic acid instead causing a decrease in pH and a heavy burden on respiration, which might be devastating for patients with pneumonia [94, 95, 97-101]. This mechanism of lactic acid production has been misunderstood as ”hypoperfusion” for decades and is still misunderstood by many doctors. This blockade of the Krebs cycle leads to anaerobic metabolism in which one glucose molecule only produces 2 ATPs instead of 38 ATPs through the normal Krebs cycle and electron transport chain. This represents an enormous reduction of the energy production (=1/17), simultaneously with the production of lactic acid thus jeopardizing patient breathing and the patient’s life. In view of this reduction of energy production, there is little wonder why sepsis very often leads to multiorgan failure. And this is the reason for adding Thiamine IV. to our septic and sepsis-induced ARDS-patients.  

Combination of Vitamin C, Solu-Cortef and Thiamine

In 2016 a study of  94 patients with sepsis was published by Marik et al. [96] Forty-seven (47) patients admitted to Intensive Care Medicine during av 7 month-period got conventional treatment with fluids and antibiotics. The following 7 months period 47 consecutive sepsis patients were given intravenous Vitamin C (1,5 g x 4) + Solu-Cortef  (50 mg x 4) + Thiamin (200 mg x 2) for four days. Nineteen of the 47 patients given conventional treatment died during the hospital stay (=40,4%), which is concordant with international numbers for mortality rate in these patients. In the group given the treatment combination only 4 out of 47 died (8,5%) which was highly significant (p<0.001). However, none of these developed organ failure and the 4 patients who died in this group died of diseases unrelated to the septic condition [96].    

Sture Blomberg, Assoc. Prof.

Anesthesiology & Intensive Care Medicine

REFERENCES:

[81] Anderson R., Vitamin C and Cellular Immune Functions, Protection 

Against Hypochlorous Acid‐Mediated Inactivation of Glyceraldehyde‐3‐Phosphate 

Dehydrogenase and ATP Generation in Human Leukocytes as A Possible Mechanism 

of Ascorbate‐Mediated Immunostimulation.” Ann N Y Acad Sci. 1990; 587:34-48. 

[PMID:’2163229’]

[82] Kiwao Nakano, Seiji Suzuki. ”Stress-induced change in Tissue levels of Askorbinic 

Acid and Histamine in rats”. The Journal of Nutrition 1984;114 (9):1602-1608]

[83] Carr A. C., Shaw G.M., Fowler, A.A., Natarajan R. Ascorbate-dependent 

vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and 

septic shock? Critical Care 2015; 19: 418] [PMID: ’26612352’]

[84] Emma Borrelli; Pascale Roux-Lombard;Georges E. Grau; Eric Girardin;Bara Ricou; 

Jean-Michel Dayer;Peter M. Suter; ”Plasma concentrations of cytokines, their soluble 

receptors, and antioxidant vitamins can predict the development of multiple organ 

failure in patients at risk” Critical Care Medicine MAR 1996; 24(3):392-397. 

[PMID: ’8625625’]

[85] LLong C., et al. ”Ascorbic acid dynamics in the seriously ill and injured” 

Journal of Surgical Research 2003; 109(2): 144-148]

[86] Zabet M.H., Mohammadi M., Ramezani M., & Khalil H. ”Effect of high-dose 

ascorbic acid on vasopressor requirement in septic shock”. J Res Pharm Pract. 2016 

Apr-Jun;5(2):94-100] [PMID: ’27162802 ’]

[87] Fujita et al. ”Dexamethason induces sodium-dependant Vitamin C transporter in 

a mouse osteoblastic cell line MC3T3-E1”. Br J Nutrition 2001;86:145]

[88] Burzle M., & Hediger M.A. ”Functional and physiological role of Vitamin C 

Transporters” Current Topics in Membranes 2012; 70: 357-375

[89] Shumei Yang and Lubo Zhang. ”Glucocorticoids and Vascular Reactivity” Current 

Vascular Pharmacology, 2004; (2): 1-12]

[90] Okamoto K., Tanaka H., Makino Y., Makino I. Restoration of the Glucocorticoid 

Receptor Function by the Phosphodiester Compound of Vitamins C and E, EPC-K1 

(l-Ascorbic Acid 2-[3,4-Dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)

-2H-1-benzopyran-6-yl Hydrogen Phosphate] Potassium Salt), via a Redox-dependent 

Mechanism”. Biochemical Pharmacology 1998; 56(12):79-86

[91] Lahiri S. & LLoyd B.B. ”The Form of Ascorbic Acid Released by the rat adrenal”. 

Biochemical Journal 1962; 84:474-477] 

[92] Mark Donnino et al. ”Randomized, double-blind, placebo-controlled Trial of Thiamin 

as a Metabolic Resuscitator in Septic Shock: A pilot Study”.  Crit Care Medicine 2016; 44:360  

[93] Moskowitz A., Andersen L.W., Cocchi M. N., Karlsson M., Patel P.V., Donnino M.W. 

Thiamine as a Renal Protective Agent in Septic Shock. A Secondary Analysis of a 

Randomized, Double-Blind, Placebo-controlled Trial. Ann Am Thorac Soc. 2017 

May;14(5):737-741. [PMID: ’28207287’] 

[94] Frank RA, Leeper FJ, Luisi BF. Structure, mechanism and catalytic duality of 

thiamine-dependent enzymes. Cell Mol Life Sci. 2007;64:892–905. 

[95] Manzanares W, Hardy G. Thiamine supplementation in the critically ill. 

Curr Opin Clin Nutr Metab Care. 2011;14:610–617.

[96] Marik PE, Khangoora V, Rivera R, Hooper MH, CatravasJ. ”Hydrocortisone, 

Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: 

A Retrospective Before-After Study.”  Chest. 2017 Jun;151(6):1229-1238. Epub 2016 Dec 6.  

[97] Giacalone M, Martinelli R, Abramo A, Rubino A, Pavoni V, Jacconi P, Giunta F, 

Forfori F. ”Rapid reversal of severe lactic acidosis after thiamine administration in critically 

ill adults: a report of 3 cases.” Nutr Clin Pract. 2015 Feb;30(1):104-10. Epub 2014 Dec 16.

[98] Rémond C, Viard L, Paut O, Giraud P, Camboulives J. [Severe lactic acidosis and 

thiamine deficiency during parenteral nutrition in a child]. Ann Fr Anesth Reanim. 1999 

Apr;18(4):445-50. [Article in French]

[99] Teagarden AM, Leland BD. Rowan CM , and Lufti R. ”Thiamine Deficiency Leading 

to Refractory Lactic Acidosis in a Pediatric Patient.” Case Rep Crit Care 2017; 

[PMID: 29119026]

[100] Depeint F., Bruce W. R., Shangari N., Mehta R., O'Brien P. J. Mitochondrial 

function and toxicity: Role of the B vitamin family on mitochondrial energy 

metabolism. Chemico-Biological Interactions. 2006;163(1-2):94–112. 

[101] Luft F. C. Lactic acidosis update for critical care clinicians. Journal 

of the American Society of Nephrology : JASN. 2001;12, Supplement 17:S15–S19.