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Ascorbic Acid: Evidence-Based Health Information Related to COVID-19

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By Jennifer L. Richardson, PharmD, BCPS, CACP

Hello and welcome to review of pertinent drug information for tsarskoe b2 from the society of infectious diseases pharmacists my name is jan richardson and i am an antimicrobial stewardship pharmacist and clinical coordinator at mercy health athenian hospital in toledo ohio today i will be discussing ascorbic acid and its potential therapeutic role in severe ovid 19 the

Dead are updated as of april 17 2020 because of little available data concerning any individual agents effectiveness in treating ovid 19 my plan for this presentation is to piece together information to tell the story of ascorbic acid we’ll talk about roles of ascorbic acid in the body deficiency in sceptic states discuss proposed improvements in disease biomarkers

Or clinical condition and any role specifically relating to viruses to end up with an overall recommendation for its use in kovat 19 ascorbic acid or vitamin c is a water soluble cofactor involved in a variety of essential biochemical reactions within the human body its effectiveness as an antioxidant is due to its ability to readily donate electrons shifting between

Two primary forms it can reduce metals such as copper and iron and has been shown to regenerate other antioxidants such as vitamin e under normal physiological conditions and ascorbate radical may be formed but it seems this free radical is comparatively unreactive and can be easily reduced back to the l-ascorbic acid form ascorbic acid is also required for the

Synthesis of collagen carnitine and endogenous catecholamines such as norepinephrine and dopamine these processes and more have been primarily demonstrated in vitro but precise roles that vitamin c plays in vivo is uncertain unlike many animals humans cannot synthesize this essential nutrient and it must be obtained exitus li due to its water-soluble nature it

Is not effectively stored signs of vitamin c deficiency due to little or no intake can occur within four weeks reference ranges vary slightly but less than approximately eleven point four micro moles per liter or less than 0.2 milligrams per deciliter is deemed to indicate deficiency reduced levels of ascorbic acid and critically ill and septic patients have been

Described in multiple publications this depletion appears to occur from the role of scavenging free radicals and reactive oxygen species that are over produced during immune activation and inflammation of critical illness and by inhibition of the reduction of dehydroascorbic acid back to ascorbic acid experimental models describe extensive involvement of a pick

Acid throughout the body and certainly deficiency in shock states could describe some of the things we see in these patients for example its antioxidant role at the molecular level provides reasoning for capillary leak its role in college information and role in catecholamine synthesis may lead to decrease vascular tone and hypotension immunosuppression is also

Suggested in states of deficiency cells of the immune system have very high concentrations of vitamin c and during sepsis ascorbic acid is thought to potentially mitigate the cytokine surge consequence of accumulating neutrophils in the lung thus working to prevent the destruction of alveolar capillaries septic shock is characterized by resistant hypotension and

Abnormalities in cellular metabolism and it continues to be postulated that the therapy addition of vitamin c should approve these conditions dosing frequency and duration of ascorbic acid is not specifically determined for any prophylactic or treatment regimen of any condition iv doses of 2 to 3 grams per day have been shown to normalize plasma concentrations in

Critically ill patients iv dosing has been shown to produce much higher levels an oral or ntral administration additionally rapid renal clearance of iv therapy lens to the rationale of multiple daily dosing schedules i included some pharmacokinetic data reported by patti eddy and colleagues showing plasma concentration differences in iv and pio dosing in healthy

Subjects oral is listed on top and iv is on the bottom and take a second to see where one gram dose falls for each note that the y-axis is micro moles for oral and millimoles for iv for those who hate math one millimole is 1000 micro moles systemic dose finding during critical illness has not been performed high doses such as 10 to 200 grams per infusion have

Been administered to oncology and burn patients and malignancy studies suggest maximal radical scavenging at levels perhaps as high as 10 times normal but regarding ideal dosing of ascorbic acid for septic patients we have more questions and answers at this point to provide some dose answers wang and colleagues performed at meta-analysis published in 2019 the

Predefined primary outcome included all cause mortality at final follow-up the authors concluded that iv ascorbic acid doses of 3 to 10 grams per day significantly reduced the mortality of critical illness and doses above herbal this had no mortality benefit i think worthy of mentioning is that mortality was measured at whatever endpoint the original study defined

Twelve studies here included 1210 patients with about 1/2 receiving ascorbic acid of these 12 studies 5 trials were randomized with an additional 3 listed as quasi randomized and only 4 evaluated severe sepsis or septic shock additionally only one cepsa study had a mortality head mortality as a primary endpoint which was the marik 2017 study in which patients also

Received hydrocortisone and biman or the hat protocol as it may be referred to initial analysis of the data showed that receipt of ascorbic acid did not affect mortality regardless of indication they then separated the data by dose and found overall mortality benefit in the medium dose group which was not indication specific they then performed another subgroup

Evaluation and after removing an outlier trial now leaving just three determined that a mortality benefit was seen in sepsis patients who received ascorbic acid these two results are illustrated on this slide with the left side of each graph favoring ascorbic acid administration secondary information presented in this meta-analysis is not discussed here because

This really was a heterogeneous mixture of patient populations using small studied studies with varied methods and treatments one study in the wang meta-analysis provided the impetus for the citrus le trial that we will discuss shortly in 2014 fowler and colleagues performed a small safety study of 26 patients to evaluate potential adverse reactions in severely

Septic patients receiving iv ascorbic acid this was a safety trial to look at incidents of hypotension tachycardia hypernatremia and nausea and vomiting in septic patients receiving iv ascorbic acid they looked at doses of 50 milligrams for kilograms and 200 milligrams per kilogram for 24 hours for 4 days no patients were withdrawn due to adverse events and the

Authors concluded that low and high doris dose ascorbic acid therapy is safe they collected additional data and subsequently reported trends and c-reactive protein procalcitonin as well as change in sofa scores which favored this vitamin c group reaching numeric statistical significance differences in thrombomodulin was not found lack of adjustment of co-founding

Factors such as timing of appropriate and other patient characteristics is an important factor that must be considered when evaluating these results another hypothesis was tested by zappa and colleagues that administration of high-dose ascorbic acid would reduce vasopressin requirements and surgical critically ill patients compared with placebo this was a small single

Center randomized double-blind prior trial of 28 patients with about half receiving treatment high-dose was defined as 25 milligrams for kilogram iv every six hours for 72 hours vasopressin dose and duration were the primary outcomes which are shown here the authors reported that patients in the treatment group had a significantly lower mean and total norepinephrine

Dose within the first 24 hours as well as a lower duration of norepinephrine use although not a primary endpoint they also found a significant reduction of 28-day mortality in the treatment group dr. fowler and his colleagues attempted to add to the data pool and investigated if ascorbic acid infusion effects organ failure or bore biomarkers of inflammation and

Vascular injury in the citrucel ii trial published in jama in 2019 this randomised trial was double-blind placebo-controlled multi-centered and included 167 icu patients with sepsis and rds with the primary outcome of determining if ascorbic acid infusion would reduce sofa scores at 96 hours or c-reactive protein or thrombomodulin levels at 168 hours their sofa

Scores were calculated without bilirubin patients with sepsis who developed acute respiratory failure in the preceding 24 hours were randomized to receive ascorbic acid 15 milligrams per kilogram iv every six hours or placebo for 96 hours the results showed no significant difference in any of the primary endpoints all with numeric values matching almost completely

Between the groups they did go on to report on 46 secondary outcomes 43 of these 46 outcomes were not significantly different but the investigators did report significant improvements in mortality at 28 days ic free days at 28 and hospital three days at 60 days although the investigators performed a good study to add to our pool of data the secondary outcomes

Just mentioned must be viewed as hypothesis-generating without adjusting for co-founding factors the possibility of errors of chance are quite high and can influence each other for example the mortality endpoint was a likely driver of icu and hospital points from a purist standpoint this is a negative study as the primary end points were not met so far we have

Not seen any scenario where the administration of ascorbic acid alone has proven clinical benefit and critically ill septic patients it’s use in combination with thiamine and hydrocortisone or a hat therapy was reported by american colleagues in a retrospective before and after a single senator study published in chest in 2017 the primary outcome was hospital

Survival treatment group patients with a primary diagnosis of sepsis or septic shock and a procalcitonin of two or greater were treated with hat within 24 hours of icu admission 7 months of the treatment group with the added therapy were compared against a control group of patients treated in the preceding 7 months with their standard care the control group did

Not receive iv vitamin c or thiamine there were 47 patients in each group the treatment group received usual care plus iv vitamin c 1.5 grams iv every six hours for four days or until i see you discharged hydrocortisone 50 milligrams every six hours for seven days or until i see you discharged and thiamine 200 milligrams iv every 12 hours for four days or until i

See you discharged the authors reported that hospital mortality was 8.5% the treatment group versus forty point four percent in the control group the propensity adjusted odds of mortality in the patients treated with the vitamin c protocol was zero point one three and thus the primary endpoint was met although much hard work was done here also many weaknesses are

Present such as a small size and retrospective nature the investigators were also keenly aware of the patient’s being studied with the new therapy also 59.6 of the patients in the control group were treated with hydrocortisone they did report some additional secondary findings that were numerically significant but these were also not adjusted and unfortunately

The same limitations just discussed apply another study looking at combination therapy was published in jama in 2020 by fujian colleagues this was a multi-centered open-label randomized trial the compared ascorbic acid hydrocortisone and thiamine in the same doses as the just discussed marek study versus iv hydrocortisone 50 milligrams every six hours alone patients

Received therapy until shock resolution or up to 10 days patients septic shock definition were enrolled within 24 hours and randomized to therapy all patients were invasive pressors for at least two hours prior to enrollment 216 were enrolled and 211 were included for analysis the primary outcome of this trial was duration of time alive anaphase repressors up to

Day 7 the authors concluded that in patients with septic shock vitamin c hydrocortisone and thiamine did not significantly approve time alive or vasopressin over seven days compared with iv hydrocortisone alone they pre specified 10 secondary outcomes of which 9 showed no difference on day 3 there was a one-point difference in sofa scores that statistically favored

The treatment group no difference in other secondary outcomes such as vent free days or 28 or 90 day mortality were found the study had good protocol compliance and although still a small open label trial it seems to refute the extreme findings reported in the before and after america study i have not been able to show ascorbic acid provides mortality benefit or

That it improves biomarkers of inflammation or vascular injury in septic patients i thought it was worthy to look at any data talking specifically about vitamin c’s effects on viruses in general i’m sure you’re expecting inconclusive data here and i won’t disappoint you there has been some exploration to try to determine if vitamin c can directly protect or treat

Pneumonia caused by some influenza viruses but so far there’s been nothing to support the vitamin c is directly recital in vivo as you can imagine if we haven’t found an answer for disease states that we’ve encountered for years we have no answers for such a novel process such as severe kovat 19 disease based on the data we have it is unlikely that ascorbic acid is

Versatile against tsarskoe b2 and since we have a difficult time proving benefit in intending host responses in other clinical presentations of sepsis that we should likely not assume a benefit in severe kovan 19 illness we hope to get more of information within the air multiple studies are underway in investigating ascorbic acid in septic patients a china study

Is trialing 24 grams per day of iv vitamin c to treat patients with corona virus and severe respiratory complications many of these trials can be found on clinical trials gov because we want desperately to try something ascorbic acid is being used by some centers the argument may include some like it’s likely safe so why not so let’s briefly talk about that to

Date i’m unaware of any trials illustrating adverse effects with ascorbic acid and an administration at a wide range of doses items to consider include the potential for kidney stone formation in predisposed individuals unpredictable interference with point of care devices such as glucose devices leading to unreliable readings g6pd deficient individuals may have

An increased risk of hemolysis and reduced doses are recommended and drug interactions are rare but cyclosporine levels may be reduced regarding the cost of therapy a high dose regimen of 50 milligrams per kilogram iv every six hours for four days would incur medication cost of about $300 or more although not in the expense realm of therapies such as interleukin

6 receptor antagonists given the high prevalence of sepsis if protocol eyes use of this agent could result in significant spending overall so as i begin to wrap up the presentation i think it is prudent to also mention that societal guidelines do not comment on the use of ascorbic acid in sepsis with their wealth without a rds or with cova 19 with or without a

Rds so despite lack of societal support or great data i am asked to dose ascorbic acid what dose would i recommend if i could not convince the team that this is not a proven intervention i would likely respond as follows due to product availability and cost i think it is reasonable to suggest 1.5 grams iv q 6 hours for a total of 6 grams per day and i’m largely

Basing this on total body store estimation of 1.5 grams doses used to normalize levels in pharmacokinetic studies and the wang meta-analysis i do not feel air support for higher doses in septic shock or cova da illness my rationale is very weak but i would argue that there is no high dose data to hang one’s hat on either my goal is a restoration of normal levels

And not targeting massive plasma levels at this time i additionally would like to be mindful of drug supplies vitamin c is a nutrient involved in essential human processes that has shown to be depleted in critically ill patients the consequences of this depletion are mechanistically plausible but still in largely theoretical the hope that vitamin c may attenuate

The inflammation and vast injury associated with sepsis and a rds is yet unproven the complex condition of sepsis makes the study of individual agents very difficult and the perfect cocktail is yet unknown perhaps ascorbic acid studies need to evaluate different surrogate markers of inflammation and injury or maybe there’s a golden hour for therapy initiation what

Is a goal level in sepsis and does this need to be used in combination but in the end we must be cautious about putting too much emphasis on secondary outcomes or technically flawed small studies especially in consideration of global practice changes in conclusion from a purist standpoint the available data do not support the routine use of ascorbic acid for septic

Shock with or without a rds and there are no data to support its use in patients presenting with severe coronavirus disease with multiple studies currently underway we will hopefully soon have more pieces to this complicated puzzle thank you for your time

Transcribed from video
Ascorbic Acid: Evidence-Based Health Information Related to COVID-19 By The Society of Infectious Diseases Pharmacists