Sepsis in the Hospital and High-Dose Intravenous Ascorbic Acid: Interview with Alpha A. Fowler III, MD

by Kirk Hamilton

Kirk Hamilton: Can you please share with us your educational background and current position?

Alpha A Fowler, III, MD:

• Medical School: Medical College of Georgia, Augusta, Georgia (1971–1975)
• Internal Medicine Residency: Virginia Commonwealth University, Richmond, Virginia (1975–1979)
• Fellowship in Pulmonary Disease and Critical Care Medicine: University of Colorado Health Science Center, Denver, Colorado (1979–1982)
• Current Position: Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University School of Medicine; Director, VCU Johnson Center for Critical Care and Pulmonary Research (1982–present)

KH: What got you interested in studying the role of intravenous ascorbic acid (AA) in sepsis patients?

Alpha A. Fowler: I and my colleagues have had a 30-year research interest in sepsis and the acute lung injury which occurs following the onset of sepsis. Approximately 5 years ago, we discovered using experimental animals of sepsis and lung injury that ascorbic acid would dramatically attenuate the extent of the inflammatory response in these animals and would significantly improve survival of the animals. Due to the inability to achieve significant blood levels of AA when AA is administered by the oral route, we administered AA to the animals “parenterally” (non-oral) by injecting the AA into the peritoneum of the animals. AA was rapidly absorbed into the circulation achieving high blood levels. The very significant experimental work we performed in the laboratory all pointed to AA’s effects being very powerful and potently anti-inflammatory. We summarized AA’s effects in several research publications. We then proposed to VCU’s Institutional Review Board to perform a trial in critically ill patients who had developed bacterial sepsis. As you know from reviewing our Journal of Translational Research publication, the trial was highly successful.¹

KH: What is the morbidity and mortality of septic patients in hospitals generally?

AAF: Patients with severe sepsis suffer higher mortality rates compared to patients with organ failure but no sepsis. Despite over 15,000 patients studied and over $1 billion in study costs, effective sepsis therapy remains elusive. The average mortality rate from bacterial sepsis is approximately 45%. Patients who survive sepsis have a very high morbidity rate with persisting organ failure (i.e., renal failure, myocardial infarction, stroke, liver injury, persisting lung fibrosis, and the need for oxygen therapy).

KH: What is the biochemistry of AA that might alter the pathophysiology of sepsis? Anti-inflammatory? Anti-infective? Prooxidant? Antioxidant?

AAF: My research colleagues and I have extensively documented the potent effects of AA. Importantly, AA “downregulates” or attenuates the extent of the inflammatory response that occurs in sepsis. Critical pro-inflammatory proteins that are released into the bloodstream following the onset of sepsis are very significantly attenuated. AA does this by blocking the activation of an important transcription factor (nuclear factor-kappa B) that drives the “expression” of the genes which lead to surges of the various inflammatory proteins in the bloodstream after sepsis starts. We have demonstrated in experimental animals that AA is anti-infective. We determined this by sampling the blood of septic animals who received AA. Blood was cultured from animals who did not receive AA or animals who received AA. The treated animals had a much lower incidence of positive blood cultures. AA is well known to be a potent antioxidant.

KH: Where did you come up with a daily dose of 50 mg/kg/24 h and 200 mg/kg/24 h? For a 70 kilogram person, that is 3500 mg and 14,000 mg of AA intravenously over a 24-hour period respectively. Is that correct? And then, if I understand correctly, that dose was split into 4 doses (1 every 6 hours) and each one of those doses of AA was put in a 50 ml bag of D5W kept in the refrigerator and administered with light protected tubing? Am I getting this therapy picture correctly?

AAF: Yes, that’s correct. I would also add that the 50 ml bag containing the drug was kept hooded from the time the drug left the refrigerator until all the drug was infused; the hood stayed on to prevent any oxidation of the AA. We determined/approximated the daily effective dosage from our animal studies. When we took AA into our clinical trials, we really did not know what exact dosage would be effective. We selected the two dosages by what we expected the resulting drug level to be. We didn’t really have any guidance, we literally just experimented to arrive at the top dosage level. The total daily dosage of AA was divided into 4 aliquots and administered IV every 6 hours. So each patient who received AA received 4 infusions daily for 4 days.

KH: Were blood levels of AA or other biochemical markers taken before, during, or after

the intervention? If so did they correlate with symptoms and supplementation with AA?

AAF: Great question. We took baseline AA blood levels and baseline inflammatory biomarker levels before AA was administered. The study we conducted in human subjects was a double-blind, placebo-controlled trial, so we did not know what the patient was receiving. We repeatedly sampled blood for AA blood levels and inflammatory biomarkers at 12, 24, 36, 48, and 96 hours. When we unblinded the data we had gathered on each patient, we found that there was a very significant correlation with blood AA levels. The patients who received AA exhibited rapid improvement in organ failure that had been caused by sepsis. The high dose of AA produced the most dramatic effects and resulted in the rapid correction of organ failure that was assessed by the Sequential Organ Failure Assessment (SOFA) score. Patient who received placebo (sugar water) had no change in the extent of their organ failure. We also observed that patients who received AA exhibited prompt reduction in the inflammatory biomarker levels.

KH: Can you tell us about your study and the basic results?

AAF: The study examined patients with severe sepsis in the Medical Respiratory Intensive Care Unit at Virginia Commonwealth University Medical Center. The patients we studied were all critically ill with severe sepsis. We studied 24 patients with 8 patients being randomized to placebo, 8 patients randomized to low dose AA (50 mg/kg/day for 4 days), and 8 patients randomized to high-dose AA (200 mg/kg/day for 4 days). The study was a double-blinded, placebo-controlled trial. The “blind” was maintained by VCU Health System’s Investigational Pharmacy. The trial was a huge success due in large part to VCU’s Critical Care Nursing. They assured that “study drug” would be administered every 6 hours for the 4-day treatment protocol.

KH: Did the low dose of AA at 50 mg/kg/day arm of the study have as much positive anti-inflammatory effects from biochemical marker change and reduce SOFA scores as the higher dose of 200 mg/kg/day did? In other words, if the 200 mg/kg/day arm resulted in better clinical and biochemical results in these septic patients, would more vitamin C in mg/kg/day work better, or at least be warranted as a therapeutic trial to see if there is a greater clinical effect? Because I can assure you that a higher dose of intravenous AA can be given safely from the 1000s of anecdotal clinician infusions over the last 75 years since the time of Dr. Frederick Klenner, who pioneered IV vitamin C?

AAF: As you know, we tested two different dosages of AA. With the 200 mg/kg/day, we saw a very significant impact on the SOFA score. The 50 mg/kg/day AA dosage had an impact on the SOFA score as well. SOFA scores on the lower-dosage AA dropped but not to the same statistical extent. The high-dosage AA reduced SOFA scores significantly at days 1 through 4. Low-dose AA infusions also reduced the SOFA score each day but not to the same extent. We tested three biomarkers. C-reactive protein and procalcitonin are markers of inflammation. Both the high- and low-dosage AA significantly reduced these biomarkers. Low- and high-dose AA significantly reduced C-reactive protein to the same extent. It was the high-dose AA that had the most profound effect on the inflammatory biomarker procalcitonin, reducing the blood level significantly by day 2. But very importantly, we quantified a protein called thrombomodulin. Thrombomodulin is a protein normally bound to the surface of endothelial cells and not found free in the circulation. If the blood level of thrombomodulin rises, this is a surrogate marker of vascular injury. In this study, we found that thrombomodulin blood levels in patients randomized to placebo began to rise 24 hours after entering the study. The rising blood levels of thrombomodulin indicated severe vascular injury in the placebo patients. The thrombomodulin levels in both low- and high-dose AA-treated patients never rose. This indicated that both low- and high-dose AA protected the vasculature in patients with severe sepsis.

The question, would more vitamin C in mg/kg/day work better, or at least be warranted as a therapeutic trial to see if there is a greater clinical effect? may be answered in time. However, performing clinical trials in critically ill human subjects is an arduous task. The regulatory steps that one has to proceed through in our current environment when studying humans seem to be never ending. This is understandable, due in very large part to concerns for patient safety. We are excited by our results and are very pleased that we were able to reduce the SOFA score and biomarker levels with 200 mg/kg/day AA infusions. Although our study was not powered to examine mortality, we did see mortality fall from 62.5% in placebo patients to 38% in vitamin C treated patients. Some researchers have noted that extremely high doses of AA are prooxidative rather than being antioxidative. We are for the present going to stick with the high-dose AA we reported.

KH: Were there any side effects with the AA therapy? How was the patient compliance?

AAF: No adverse events occurred in critically ill patients who received AA. Patients who were critically ill were studied. Compliance was not an issue. Study drug was administered on time by Critical Care Nursing.

KH: Who is a candidate for AA therapy? All subjects with heart failure? All subjects with diseases of the heart where there is a reduced ejection fraction?

AAF: AA can be administered to all patients with sepsis. Heart failure was present in several patients who received AA. No adverse event occurred.

KH: I am thrilled about your work and have been waiting a long time to see larger doses of ascorbate used intravenous for acute illness, but you are probably well aware while these are very large doses for conventional medical care, these are small doses of intravenous vitamin C for those practitioners who used it regularly. AA at 30 to 100 grams IV are “not uncommon” intravenous doses in integrative medicine practices? Can you comment, please?

AAF: We are well aware of the literature and the dosages of AA that have been reported by physicians engaged in various studies (i.e., cancer). The AA dosage protocol we administered to septic patients emerged out of carefully performed scientific investigation. You can refer to the scientific papers we have published using the dosage we arrived at.^2–7

KH : What was the solution with vitamin C? D5W, sterile water? Were there any added nutrients as well to the ascorbate solution?

AAF: AA (vitamin C) was prepared by VCU Medical Center’s Investigational Pharmacy in 50 ml aliquots. AA was mixed with dextrose 5% and water. Once the AA solution was prepared, the aliquots to be administered were kept at 4 ºC in the dark. The 50 ml aliquots had a light protected hood placed over the bag. When AA was to be infused, the hooded AA aliquot was taken from the ICU refrigerator and infused into the patient in light-protected tubing over 30 minutes. All these measures were taken to prevent AA from spontaneously oxidizing, which it will do if these measures are not addressed. No nutrients were added to the AA solution.

KH: How can the public or health professionals use this information?

AAF: We feel that AA infusion into critically ill patients is a totally overlooked form of therapy. AA to treat bacterial and fungal sepsis is a form of therapy which has been “hiding in plain sight.” We are hopeful that AA infusion to treat severe sepsis will emerge into the standard of care for this patient population. We are currently conducting an NIH-sponsored double-blind, placebo-controlled trial examining specifically the effectiveness of AA to treat sepsis-induced acute respiratory distress syndrome (ARDS). This trial is a phase II trial in which Virginia Commonwealth University School of Medicine Pulmonary Disease and Critical Care Medicine Division is the lead center. Participating centers are Critical Care Medicine at Emory University, Critical Care Medicine at the Cleveland Clinic, and Critical Care Medicine at the Medical College of Wisconsin. The results of this trial will be published within the next two years.

KH: Do you have any further comments on this very interesting subject?

AAF: We currently are expanding our research with AA infusions further into human subjects. We have phase I trials using AA in patients post open heart surgery, patients with post closed head injury, and patients post cardiac arrest. We are at work designing a trial to examine AA infusion in patients post bone marrow transplant. All these various patient populations have a high incidence of organ injury.

KH: Can’t wait to see the research. Send the published results on any AA IV infusion in hospital care as soon as published and I would love to interview you or your colleagues on that topic. You are doing a great service putting this safe, cheap, and simple therapy to scientific rigor, which, in my opinion, would/will save thousands of lives and millions, if not billions, of dollars in health-care costs.

AAF: You are right about that. The US Food and Drug Administration 2½ years ago removed a product called activated protein C from the market. Activated protein C was used to treat patients with severe sepsis, the identical patients we used AA to treat. Virginia Commonwealth University Health System’s charge for a 96-hour infusion of activated protein C was greater than $30,000. Activated protein C, besides being expensive, was associated with a high incidence of adverse events. We calculated the cost of AA we used in the Phase I Sepsis Trial. We could treat the identical patients for less than $1000. So you are right. AA as a therapy for sepsis is safe and inexpensive compared with other drug costs in the ICU environment.

Alpha A Fowler, III, MD

Division of Pulmonary Disease and Critical Care Medicine

Department of Internal Medicine, School of Medicine

Virginia Commonwealth University

PO Box 980050, Richmond, VA 23298-0050, USA

804-828-9071; fax 804-828-2578

afowler@mcvh-vcu.edu

Notes

1. Fowler AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32.
2. Fisher BJ, Kraskauskas D, Martin EJ, et al. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am J Physiol Lung Cell Mol Physiol. 2012 Jul 1;303(1):L20–L32
3. Fisher BJ, Seropian IM, Kraskauskas D, et al. Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit Care Med. 2011 Jun;39(6):1454–1460.
4. Fisher BJ, Kraskauskas D, Martin EJ, et al. Attenuation of sepsis-induced organ injury in mice by vitamin C. JPEN J Parenter Enteral Nutr. 2014 Sep;38(7):825–839.
5. Fowler AA 3rd, Syed AA, Knowlson S, et al.; Medical Respiratory Intensive Care Unit Nursing, Fisher BJ, Natarajan R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014 Jan 31;12:32.
6. Mohammed BM, Fisher BJ, Huynh QK, et al. Resolution of sterile inflammation: role for vitamin C. Mediators Inflamm. 2014;2014:173403.
7. Mohammed BM, Fisher BJ, Kraskauskas D, et al. Vitamin C: a novel regulator of neutrophil extracellular trap formation. Nutrients. 2013 Aug 9;5(8):3131–3151.

Compliments of Tishcon Corp., makers of Q-Gel.

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