Vitamin C, Hydrocortisone and Thiamine: Q/A.

We have received hundreds of e-mails (and a few letters to the Editor) in response to the publication of our paper. Below is a compilation of the most common questions together with our best answers.

 Q. Why was the mortality rate in your control group so high relative to world averages?

A.  When we began using this “cocktail” we were unsure of its benefits (and risks) and we therefore only used the cocktail in patients at highest risk of dying and at the highest risk of developing progressive organ failure. In order to be treated with the cocktail patients required to have been admitted via our Emergency Room with severe sepsis or septic shock AND an initial procalcitonin (PCT) > 2 ng/ml (we routinely measure PCT in all our patients suspected of having sepsis). The median procalcitonin in the treatment and control groups were 25 ng/ml and 15 ng/ml respectively. The median PCT in the MOSES study, the largest study to date to evaluate the time course of PCT in patients with severe sepsis and septic shock was 5 ng/ml.[1] In the MOSES study nearly 50% of patients had a PCT < 2. PCT is a very good quantitative marker of sepsis severity. We therefore selected out a subgroup of patients with sepsis at highest risk of complications and death, i.e. we include the sickest half of patients with sepsis. When we performed the retrospective case-controlled study we matched the control group patients based on PCT and severity of illness; i.e. we used the same selection criteria for the treatment and control groups (This is indicated in the manuscript).

After completing the study and once we analyzed the data (for efficacy and safety) we changed our indications for use; WE NOW treat EVERY patient with sepsis who is sick enough to be admitted to our ICU. The cocktail is started in the ER at the same time as antibiotics are ordered. This broad use of the cocktail may explain the progressive decline in sepsis mortality at our hospital from Jan 2016 to Jan 2017, which has been reported by an independent data analytics company (see accompanying PowerPoint lecture).

The exact incidence and mortality of sepsis in the US (or elsewhere) is difficult to determine. This depends on the selection criteria used and whether the data is severity adjusted. Administrative databases have been shown to be notoriously unreliable. In addition, one cannot extrapolate from the mortality reported in clinical trials; due to the large number of exclusion criteria they do not represent real world practice. It is noteworthy that in the Surviving Sepsis Campaign Database (over 130 000 patients) the overall mortality was 34.8%.

Q.  I wanted to ask if you all still use this cocktail in treatment of all of your sepsis patients?  Do you have a Sepsis protocol at your hospital that is standardized?  I didn’t read about a standard protocol in the article so I was curious.  At our institution we have an order set for sepsis.

A.  When we started this exercise we were not sure of the treatment effect so we restricted the use to the sickest 50% of septic patients.. i.e those with a procalcitonin > 2 ng.ml (first 47 patients- see above). Once we analyzed the data and did the retrospective matching we extended the protocol to all patients admitted to our ICU with the diagnosis of sepsis. At present the protocol is started in the ER at the same time we start antibiotics. We have now treated over 300 patients ….the findings are reproducible time over time over time.

We don’t have a standard protocol per se. We believe in the “Precision Medicine Approach” (see Blog on SEP-1) … treatment is individualized for every patient. Sepsis is the most complex of all diseases and the notion that a simple algorithm (Not-Surviving Sepsis Campaign) can treat all patients is absurd. That being said we follow a number of treatment principles that are outlined in “the Steps to the Cure” as well as my publications on this topic. Our nurses, residents  and attendings are so tuned-in to this approach that it is part of our  “culture.”  When I tell folks that in our ICU patients simply do not die from sepsis.. they don’t believe me. However, this is the truth.. and our CEO and CMO would bear witness to this statement.

Q. How do you mix and administer the Vitamin C and what’s its shelf-life and cost.

A. Vitamin C is provided by the manufacturer (Mylan Institutional LLC) as a 50 ml vial at a concentration of 500mg/ml. Three (3) ml of vitamin C is placed in a 50ml bag of Normal Saline (1500mg vitamin C in 50ml bag) which is infused over 1 hour. The dosing schedule is 1500mg every 6 hours for 4 days or until discharge from the ICU.

Once the vial is open, it is only “stable” for 4 hours. The resulting product is given 24 hours stability. When first ordered, 4 doses are made and then sent to the bed-side nurse. For the next day, the pharmacist will wait until 1 hour prior to the next dose to make the next batch. The acquisition cost of IV vitamin C as sold by Mylan Institutional LLC is $81 per vial. KRS Biotechnology (Boca Raton, FL) compounds a Vitamin C formulation (Tapioca) 500 mg/ml 50ml which has a 90 day shelf life from the time made and a 28 day “shelf life” after opening vial at a cost of $20 per vial.  With the KRS formulation one vial can be used for a patients entire 4 day course (16 doses).

Q. What about the use of vitamin C and spurious blood glucose levels using point-of-care glucose monitors?

A. Vitamin C and glucose have very similar molecular structures both being six-carbon molecules with glucose-6-phospate being the precursor molecule of vitamin C. Spuriously elevated POC glucose levels have been reported in patients with burns who have received large pharmacologic doses of vitamin C (in excess of 50g/day).[2,3] This phenomenon has been reported with vitamin C and other compounds with POC glucose devices that incorporate the glucose-dehydrogenase-pyrroloquinoline quinone (PQQ) amperometric method of testing. The pharmacologic doses of vitamin C used in patients with burns [2,3] and those with malignancy [4-6] result in mmolar concentrations of vitamin C. Our dosing strategy (1.5 g IV q 6 hourly) will results in blood vitamin C levels that are in the 200 umol/l range which should not cause significant cross-reaction with blood glucose concentrations which are in the mmolar range (6-11 mmol). To validate this we have measured blood glucose levels with POC testing (Accu-Chek Inform, Roche, Indianapolis, IN) and simultaneously with our central laboratory at the end of the vitamin C infusion and have noted minimal differences in the measured levels. We therefore believe that in the dosage used in our study, the interaction between vitamin C and POC glucose testing is not a clinically significant problem.

Q. Why did you apply a protocol that had not yet been tested?

A. As clinicians responsible for the care of patients that are at an exceedingly high risk of death one “has to think out of the box” as our current approach is unsatisfactory. The three agents which we combined in our “cocktail” are widely available, safe, cheap and have been used individually to treat sepsis and a wide range of disease. It should be noted that all patients with severe sepsis/septic shock have low or undetectable levels of vitamin C. The vitamin C was dosed according to the indications and dosage of the approved package insert (see below). We combined these three agents together on the presumption that the combined effect would be greater than that of the individual components.

Q. If our Intensivists begin using Vitamin C for our Sepsis patients, would the IRB need to oversee this as research? Did you obtain IRB approval for your study?

A. No, this is not required. As is clear from our paper, we performed a retrospective before-after study approved by our IRB. This treatment approach has now become standard of care in our ICU and in many ICU’s across the world (although the selection criteria may be different). The use of the cocktail in the clinical context is not research; the cocktail consists of three widely available and approved drugs with a long safety record.  Many of the drugs used in the ICU (in the USA) do not having supporting scientific data based on large RCTs nor do they have specific FDA labeling for that indication. Haloperidol is a good example. Haloperidol is not approved for the treatment of ICU delirium. The use of haloperidol for a patient with delirium in the ICU does not require IRB approval. It should be noted that haloperidol has significant risks and toxicity. However, when using “nonstandard” treatments or a drug for a non-approved indications the clinician must balance the potential benefits of the intervention, with the consequences of the disease (untreated) and with the safety of the proposed therapy.

It is our opinion based on an extensive review of the literature as well as our experience and that of others, that vitamin C, thiamine, and hydrocortisone are exceedingly safe and without known side effects (see below)  in the setting of a disease without alternative treatments and an exceedingly high mortality. When a clinician is confronted with a previously healthy patient who is at high risk of dying from sepsis, he/she has the duty to do whatever he/she can do to reduce the chances of his/her patient from dying. Some practitioners have argued that it is unethical to withhold an exceedingly safe and inexpensive intervention that is readily available and that has the potential to save the life of a patient with sepsis.  We believe that the balance of beneficence, non-maleficence and social justice clearly supports our treatment approach. However, randomized controlled trials are now being planned to determine the treatment effect of this novel intervention.

Q. Can you tell me if you are still seeing patients consistently responding well to your therapy?

A. We have now treated over 300 patients with this cocktail, with the same reproducible response. Our therapeutic cocktail has now been used in hundreds of patients across the globe with strikingly similar results; see typical example below:

Josh from OHIO: “Elderly man with ischemic cardiomyopathy, EF 15% pacer/AICD at baseline presented to outside hospital with shock and BP 60/30.  Given 2-3 liters fluid (as per SEP-1 guidelines) and immediately went into respiratory failure requiring intubation.  Shipped to us intubated on four vasopressors with AKI     (Cr 3).   Eventually he ended up growing Group B Strep from his blood with procalcitonin of 43.  Started on cocktail and within a day his pressor requirements melted away and he was extubated. His kidneys have improved and he is walking around the ICU.  Tomorrow he will probably leave the ICU with no residual organ dysfunction, no volume overload, and No ICU complications.  A screenshot of his vitals is below to prove that I’m not making this up (screenshot not included to protect the privacy of patient, according to HIPPA rules).”

Curro from Spain: “In my intensive care unit I have integrated the vitamin C protocol into SEPSIS with spectacular results. We still only have 6 patients but all have gone very well. Thank You so much for your great work.”

Q. After the publication of your work, how has your protocol been extended? What experience have you gathered from the other centers?

A.  In excess of 30 medical centers across the US and the World are now using this protocol in daily practice. As already indicated, the results are reproducible time and time again and hundreds of lives have been saved.

Q. Do you think adopting your treatment is a matter of patents and money?

A. The wonderful thing about our novel intervention is that nobody will become rich from this therapy (including me); it is cheap and readily available. It is not possible to patent these drugs or the combination (as far as I understand). This is important as the burden of sepsis is in “resource poor” countries which cannot afford expensive designer pharmaceutical drugs.

Q. What do you think about the opinion of those who have criticized your protocol?

A. Criticism and skepticism is an essential part of scientific discourse; however it must be professional, scientific and not personal.  Our protocol was not “sucked out of thin air”…. there is an enormous body of scientific research to support using all three components; all we did was put them together.

Q. From your critical care experience, do you think it is currently the best treatment in cases of sepsis or septic shock?

A. We believe this treatment is an important component for the treatment of sepsis and septic shock; but cannot be applied in isolation; the important components are:

• Early identification of sepsis.
• Early prescription of the right antibiotic (s), in the right dose.
• Adequate source control (very important).
• A physiologic, restrictive fluid strategy with the early use of norepinephrine (VERY IMPORTANT).
• The “metabolic resuscitation protocol”; steroids,  vitamin C and thiamine
• State of the art supportive care… based on the best scientific evidence
• A multidisciplinary, team approach to patient care

Q. Do you think it is important to know to what degree each protocol components work?

A. As indicated previously, each component has some benefit but together the sum is more than the parts. This is no different to the approach oncologists use to treat cancer; almost every oncology protocol uses multiple drugs that target different pathways.

Q. What about the safety of IV vitamin C, particularly in patients with renal impairment.

Vitamin C (in the doses we recommend) is extremely safe, even in patients with renal impairment. We have checked serum oxalate levels in patients with chronic renal failure (not receiving hemodialysis) at the end of treatment with the cocktail and these are all in the safe range. Vitamin C is a small molecule that is freely dialyzable and is safe (in the doses we recommend) in patients receiving renal replacement therapy (CRRT or conventional HD). We have closely followed the serum creatinine in our patients with acute kidney injury treated with the cocktail; the creatinine has fallen in ALL treated patients (see Graph below).

Dosages of 150g (100 times the dose we use) have been safely given to patients with cancer. The only precaution with such high doses is chronic renal impairment which increases the risk of hyper-oxalosis and worsening renal function. Hyper-oxalosis and acute kidney injury has not been reported in patients receiving less than10 g/day. These facts have been well documented in the literature. The only other potential complication with these pharmacologic doses of vitamin C, is hemolysis in patients with G6PD deficiency (see below).

Q. Is there a risk of oxalate accumulation in patients with chronic renal failure (CRF) on dialysis? Is there a level of renal failure beyond which you would advise dose-reducing the Vitamin C?

A. This is the one area that did concern us and we have explored in much detail (also see response above). In patients with CRF on HD there is no issue with oxalate. AKI is common in patients with sepsis; we have found that the Cr comes down in all cases (see graph above).  What is trickier is the situation in patients who have CRF and AKI… together with septic shock.  We had one such patient at the very beginning in whom we tried a dosage adjustment (lower dose based on CrCl) ; he failed to respond to the cocktail.  We have subsequently used the standard dose (1.5 g IV q 6) in all patients with CRF and the Cr has fallen in all. We monitored oxalate levels in the first half-dozen or so of these patients; the levels were in the safe range. In patients at highest risk of kidney injury, I would suggest that the Cr be closely monitored and should the Cr increase it is not unreasonable to stop the vitamin C on day 3 (and measure a serum oxalate level) until further safety data is available on these patients; however we believe it is safe to continue treatment with vitamin C in patients receiving CRRT.

Q. In the dosage used can Vitamin C have pro-oxidant affects?

No. Although ascorbate is widely considered an antioxidant, its reduction of transition metals such as Fe3 + and Cu2 + is well known to generate reactive oxygen species, including the hydroxyl radical. . These reactions are potentially important for interpretation of in vitro, cell culture, or tissue incubation experiments, where free metal ions might exist. In patients iron is tightly bound to proteins, free iron atoms don't exist. An extensive review of in vivo studies by Carr and Frei found little evidence for a pro-oxidant effect of ascorbate on markers of DNA, protein, and lipid oxidation. In the very high doses used as adjunctive treatment of cancer (100-150g), production of H2O2 occurs in the cancer but not healthy tissue. Similarly, depletion of intracellular anti-oxidants has been described in tumor cells but not normal cells.

Q. In vitro studies indicate that high dose vitamin C may activate platelets and promote clotting, what about the dosage you recommend.

So here is the answer. It’s all in the dose. Low dose (the dose we use) prevents platelet aggregation, clotting, and endothelial activation and restores microcirculatory flow. High dose vitamin C may activate platelets and clotting. We were very, very, very careful in the dose we chose… we believe this is the lowest dose that has a major biological effect in sepsis (in synergy with steroids);

With our dose plasma levels are in the range of about 0.2mmol/L.  This level is 10x less than that in the Fowler study looking at platelet aggregation (W. J Crit Care 2017;4 37)…. and we only administer vitamin C for 4 days and not 8 days as in the study.

Q. What about the risk of hemolysis in patients with G6PD deficiency

A. Low dose Vitamin C is protective against hemolysis in patients with G6-PD deficiency. It only causes hemolysis in very high doses. We have not had any issue with hemolysis…. or any other complication.

Q. Was the duration (of Vitamin C) for 4 days or until discharge, whichever came first?  It would also be interesting to know the mean duration of vitamin C therapy as this was not contained in the article.

 A. Yes that is a bit confusing. The max duration of Rx was 4 days (16 doses). If the patient was discharged prior to the 4^th day we stopped the treatment at that point. The average duration of Rx was 3.6 +/- 0.6 days.

Q, ‘’Twenty-eight (59.6%) patients in the control group were treated with hydrocortisone.’’ From these 28/47 patients in the control group, was there an analysis done on the mortality outcome for these patients specifically?

A. During the control period hydrocortisone was used at the discretion of the treating physician. While the sample size is very small the use of hydrocortisone (as opposed to no hydrocortisone) did not appear to have an effect on any of the outcome measures.

Q. It would have been interesting to have a prospective study comparing the effect of vitamin C + Thiamine to a hydrocortisone group alone. I do believe this might be the variable that may have created such a gap between the primary outcome results.

A.  As already indicated, and as supported by our bench research [7] we believe that vitamin C and hydrocortisone act synergistically on multiple metabolic pathways to limit and reverses the multiple derangement in cellular and organ dysfunction that occurs in sepsis. The added benefit of IV thiamine requires further study. Additional basic science and clinical studies are required to confirm our preliminary findings.

Q. Our surgeons will not let us use this cocktail as they believe it impairs wound healing and increases the risks of secondary infections.

A. This is a common and absurd myth. There are multiple mechanistic reasons why the cocktail may actually promote wound healing and prevent secondary infections. Septic patients have critically low vitamin C levels. It is well known that vitamin C is essential for collagen formation and wound healing. In addition, vitamin C improves microcirculatory flow, macrophage and T cell function and prevents the development of post-sepsis immunosuppression. [8]

The prolonged (greater than 10 days) use of moderate- to high-dose corticosteroids (> 400mg hydrocortisone equ./day) is well known to impair wound healing and increase the risk of opportunistic infections. However, it is likely that a short course of low dose corticosteroid has the opposite effect. A short course of preoperative glucocorticoid has been shown to attenuate the post-operative inflammatory response which leads to decreased morbidity and shorter length of stay.[9-11]  It is important to emphasize that the “metabolic resuscitation protocol” uses stress doses of hydrocortisone (200 mg/day), with these doses being equivalent to that produced by a maximally stressed normally functioning adrenal gland; this dose of hydrocortisone is likely to promote resolution of tissue inflammation and promote wound healing. By attenuating and reducing the highly catabolic inflammatory response, the anti-inflammatory cocktail with reduce the degree of protein breakdown and therefore promote wound healing. It should be further noted that as part of our evidence based supportive approach to patient care we advocate the use of a nutritional formula high in omega-3 fatty acids and whey protein; such a nutritional formula promotes wound healing. [12,13]

In a landmark randomized cross-over study, Keh and colleagues evaluated the clinical and immunological response of “low” dose corticosteroids (240 mg/day hydrocortisone for 3 days) in patients with septic shock.[14] In this study hydrocortisone simultaneously decreased circulating levels of both pro- and anti-inflammatory cytokines whilst at the same time preserving competence of adaptive immunity.  Importantly, in vitro granulocyte function (respiratory burst and phagocytosis) remained intact, indicating that low-dose hydrocortisone did not suppress innate defense mechanisms. The results of the study by Keh and colleagues are supported by the HYPOLYTE study where 150 patients with severe trauma were randomly assigned to a continuous intravenous infusion of either hydrocortisone (200 mg/d for 5 days) or placebo.[15] By intention to treat analysis 35.6% of hydrocortisone patients developed hospital acquired pneumonia (the primary end-point) as compared to 51.3% of placebo patients (hazard ratio, 0.51; 95% confidence interval 0.30-0.83; P=.007). Macrophage dysfunction plays an important role in mediating the immunosuppression which characterizes critical illness.[16] It should be noted that glucocorticoids cause a phenotypic switch of macrophages (M1 to M2) with the differentiation of a specific anti-inflammatory phenotype which is actively involved in resolution of inflammation.[17]  M2 cells show efficient phagocytic activity, high expression of scavenger receptors and have different chemokine expression profiles compared with M1 macrophages.[18,19]

Schulze et al performed a randomized, double-blind, placebo-controlled trial that investigated the effects of acute, preoperative corticosteroid administration on cutaneous wound healing.[8] In this study of 24 patients, a single dose of 30 mg/kg methylprednisolone (equivalent to 10 000 mg of hydrocortisone; 100 times the dose used in our protocol) or placebo was administered intravenously 90 minutes prior to colon resection. There was not difference in wound healing between the two groups. Proline levels in the collagen and the amount of collagen accumulation within the wounds was evaluated over a 10 day postoperative period, with no difference being reported between the groups. This results of this study suggested that acute, high-dose steroid administration does not significantly affect wound healing, as measured by both clinical and biochemical parameters.  Wang and colleagues reviewed the literature on the use of corticosteroids in the perioperative period and wound healing. [20] These authors concluded that “the preponderance of human literature found that high-dose corticosteroid administration for < 10 days has no clinically important effect on wound healing.”

Q. We believe that the finding from your study are spurious, that the results are biased and the conclusion overstated. There is no high-quality evidence that any of the three interventions individually improves survival in patients with sepsis. The substantial methodological flaws of the study question its external validity and veracity. We highly recommend meticulous assessment of all patient-important benefits and harms of vitamin C, hydrocortisone and thiamine prior to adopting this unproven strategy in clinical ICU practice (synopsis of letter to the Editor of Chest by Moller et al).[21]

A, First and foremost it is important to state that we do not refute, nor did we attempt to mask, the characteristics of our study:  retrospective, single center, non-randomized, and un-blinded.  We initiated this therapy after our review of small trials in similar populations.[22,23] We agree that the supporting data on efficacy was not robust, but felt that the available safety data on these particular interventions justified their introduction as salvage therapy in patients that were unlikely to survive. Our anecdotal experience was impressive and led to our use of this treatment in a number of consecutive patients.  Our decision to describe and publish our experience occurred afterwards, thus the methodological characteristics were unmodifiable.  As a consequence of this study design, we understand why the results of our study have been met with some skepticism by the scientific community. We are in agreement with Dr. Moller et al that additional trials should be performed to support or refute the findings of our study. As stated in our conclusion, “…additional studies are required to confirm our preliminary findings.”  However, given our experience, we felt that publication of these results were necessary, and indeed our ethical responsibility.

Sepsis is common, debilitating, and often lethal.  Despite exhaustive attempts at therapies to interrupt the mechanism of a dysregulated immune response and subsequent organ damage, we are currently limited to antibiotics and supportive care as our only consensus therapeutic measures.  We recognize that the decision to use three readily available pharmacologic agents each with limited supporting clinical data can be viewed as “unconventional”. However, therapeutic interventions in the absence of high quality randomized controlled trials (RCTs) are commonplace in the ICU. When using such interventions the clinician must balance the potential consequences of the disease with the safety of the proposed therapy.  It is our opinion that the safety profile of vitamin C, thiamine, and hydrocortisone, [22-26]  in the setting of a disease without alternative treatments and an exceedingly high mortality, allows clinicians to use this therapeutic intervention with the goal of preventing death and limiting the complications and long-term sequela of this devastating disease; However, we continue to support the effort to investigate this therapy further in  studies across the world.

The mortality reductions described in retrospective studies are often not reproduced in large, multi-center, RCTs. However, a therapy that effectively targets pivotal pathways in patients’ with sepsis could plausibly result in a large reduction in mortality. The associated reduction in the dose of vasopressors, SOFA score and procalcitonin clearance in our treated patients, all independent markers of the successful treatment of sepsis[1], suggest a true biologic effect.  In addition, we have independent validation that the sepsis mortality in our hospital has been dramatically impacted since the introduction of this novel therapeutic intervention.  It has previously been suggested  that “…the best hope for therapeutic advances [in sepsis] will depend on broad-base targeting, in which multiple components are targeted at the same time.”[27] Such combination “chemo-therapy” targeting multiple biological pathways is the standard approach in the treatment of malignant disease. While the benefits of vitamin C, hydrocortisone, and thiamine alone are likely limited,[22,23,26,28] we believe that these medications act synergistically to effect the desired outcomes. Laboratory evidence of a synergistic interaction between hydrocortisone and vitamin C in preserving endothelial integrity supports this claim.[7]

Q. The study lacked blinding, randomization, concurrent controls, case-control propensity-matching, and had a small sample size, thus substantially increasing the risk of false benefits due to confounding combined with selection and ascertainment biases. Acute renal failure associated with vitamin C is a known safety issue; the sample size lacked statistical power to detect this side-effect. Considering the poor evidence on the safety and efficacy of vitamin C, and how swiftly an adaptive RCT can be done, we believe there is no ethical or scientific justification to use vitamin C outside of a clinical trial at this time. (Edited letter from Kalil et al).[29]

A.  With regards to the methodological issues, we have acknowledged that this was not a prospective, randomized and blinded study.[30]  However, our findings were so compelling that we believed we had the ethical obligation to report our results.  Furthermore, we clearly stated in the paper that “this inexpensive and readily available intervention has the potential to reduce the global mortality from sepsis. Additional studies are required to confirm our preliminary findings”

The statement by Kalil et al asserting that there is “poor evidence on the safety and efficacy of Vitamin C”, is not supported by the scientific literature. Intravenous Vitamin C has been evaluated in unselected surgical ICU patients,[24] patients with burns [31] those with pancreatitis [32] and in two pilot studies of patients with severe sepsis and septic shock.[22,25] All these studies demonstrated improved outcomes with no safety concerns. In addition, vitamin C has shown benefit in patients those undergoing general anesthesia with etomidate[33,34] and in patients receiving contrast agents,[35,36] again with no safety concerns. Furthermore, our experience with having treated over 300 patients, together with the experience of dozens of practitioners across the world and a comprehensive review of the literature clearly establishes that in the dosage used in our study, there are no safety issues with the use of vitamin C.  Dosages of 150g (100 times the dose used in our protocol) have been safely given to patients with cancer.[37-39] The only precaution with such high doses is in patients with chronic renal impairment, with the risk of hyper-oxalosis and worsening renal function. Hyper-oxalosis and acute kidney injury has not been reported in patients receiving less than 10 g/day. In addition, high dose vitamin C is contraindicated in patients with glucose-6 phosphate deficiency. Contrary to Kalil’s assertion, many practitioners believe that it is unethical not to offer a patient who is at a high risk of dying a therapeutic intervention that is completely safe and inexpensive with the potential to save their life!

Q. So whats next!

A.  We believe that this is just the beginning of this interesting journey. Additional basic science studies are required to explore the pathways responsible for the synergistic effect of corticosteroids and vitamin C. Furthermore, the role of thiamine needs to be evaluated. Pharmacodynamic studies need to be performed to evaluate the optimal dosage strategy, the need for a loading dose and to compare bolus versus a continuous infusion of vitamin C. Randomized controlled clinical trials (RCT) are now being planned in the USA and across the world.

Disclosure:

We did not invent vitamin C, hydrocortisone or thiamine. We hold no patents or intellectual property on these drugs nor the combination of drugs. The use of Vitamin C as part of our resuscitation protocol was built on the work of many investigators who preceded us, namely Dr. James Lind (1749) [40],  Dr. Albert Szent-Gyorgyi (1928) [41], Dr. Fred Klenner (1949) [42] Professor Linus Pauling (1971-1986) [43-46],     Dr. Arthur Kalokerinos (1960-1982) [47,48] Dr. Sebastian Padayatty (2004) [49], Dr John Wilson (2009-2013) [50,51] and Professor Alpha (Berry) Fowler [22,52,53], to name but a few. While we fortuitously come up with this combination of agents in an attempt to save the life of a patient, we do not claim “ownership” of this protocol. Furthermore, It is important to strongly emphasize the “metabolic resuscitation protocol” was not “sucked out of thin air” but rather is supported by a considerable body of basic- and clinical science.

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Paul Marik

Intensivist, Researcher, Myth-Buster, Status Quo Destabilizer

Latest posts by Paul Marik (see all)

• iSepsis- SEP-1: Conspiracy Theories and Fake News! - March 3, 2018
• iSepsis – Sepsis 3.0- Flogging a dead horse! - February 23, 2018
• iSepsis – Patients with sepsis have SCURVY - February 4, 2018