“The Metabolic Resuscitation Protocol”.
A large body of experimental data has demonstrated that both corticosteroids and intravenous vitamin C reduce activation of nuclear factor kB (NF-kB) attenuating the release of pro-inflammatory mediators, reduce the endothelial injury characteristic of sepsis thereby reducing endothelial permeability and improving microcirculatory flow, augment the release of endogenous catecholamine’s and enhance vasopressor responsiveness.[1-8] In animal models these effects have resulted in reduced organ injury and increased survival. Corticosteroids have been evaluated in several clinical trials, with meta-analysis of these trials demonstrating somewhat conflicting outcomes. [9,10] Low-dose stress corticosteroids have proven to be safe with no increased risk of clinically important complications. While corticosteroids decrease vasopressor dependency the effect on the risk of developing organ failure and survival is less clear. Similarly intravenous Vitamin C has been evaluated in unselected surgical ICU patients,  patients with burns  those with pancreatitis  and in two pilot studies of patients with severe sepsis and septic shock. [14,15] In general these studies have demonstrated a reduction in the risk of multisystem organ failure (MSOF) although the effect on mortality is less clear. However, IV vitamin C was shown to be extremely safe with no recorded complications.
In vitro data has suggested that vitamin C and hydrocortisone may act synergistically (see also study below).[16-18] Barabutis et al have demonstrated that hydrocortisone together with vitamin C protects the vascular endothelium from damage by endotoxin while neither agent alone had this effect.  Based on these clinical and experimental data we initiated a treatment protocol for patients with severe sepsis and septic shock that included intravenous vitamin C, hydrocortisone and thiamine. We have demonstrated reproducibly and consistently that this therapeutic cocktail reverses the organ dysfunction of sepsis with a marked reduction in mortality. This protocol has now been adopted at multiple centers across the world with remarkably consist and reproducible results.
Ascorbate donates a single electron in all its redox reactions, generating the ascorbate radical. This radical is not very reactive with anything but itself. Dismutation of two ascorbate radicals forms a molecule each of ascorbate and dehydroascorbate. Hydrolysis of the lactone ring of dehydroascorbate irreversibly converts it to 2,3-diketo-1-gulonic acid which is then converted to oxalate. Oxalate is normally excreted by the kidney and serum levels will increase with renal impairment. In patients with renal impairment receiving mega-dose vitamin C ( > 50g), supersaturation of serum with oxalate may result in tissue deposition as well as crystallization in the kidney. [22,23] Glyoxylate, a byproduct of intermediary metabolism, is either reduced to oxalate or oxidized to CO2 by the enzyme glyoxylate aminotransferase; thiamine pyrophosphate is a co-enzyme required for this reaction.  Thiamine deficiency increases the conversion of glyoxylate to oxalate resulting in hyper-oxalosis. [25,26] In addition, thiamine is an essential co-enzyme for many of the reactions of the Krebs cycle and therefore play an essential role in intermediary metabolism and production of ATP. Thiamine deficiency is common in septic patients and is associated with an increased risk of death. For these reasons thiamine was added to the “metabolic resuscitation protocol”.
Several studies have administered vitamin C in doses exceeding 100g/day as adjuvant therapy in patients with cancer (excluding those with chronic renal failure) with no discernable side effects. [28-35] Vitamin C appears to be toxic to normal human cells (not cancer cells) at a concentration on greater than 25 mM.  A dose of 6g/day will achieve a steady state serum concentration of about 240uM [36-38] which is about 100 times less than the dose required to cause cellular toxicity. The package insert for vitamin C  lists no contraindications or adverse effects of the drug and states that as much as “6 grams has been administered without evidence of toxicity”. The package insert lists “acute Vitamin C deficiency” as the major indication for IV Vitamin C administration… it should noted noted that Vitamin C levels are undetectable or extremely low in critically ill patients. The only reported restriction to the use of high dose intravenous vitamin C is in patients with known glucose-6-phospahte deficiency (G6PD) in whom hemolysis has been reported, [40,41] and in patients with chronic renal failure who are at risk of hyper-oxalosis.
Patents with sepsis predictably have very low serum vitamin C levels, which can only be corrected with intravenous vitamin C in a dose of more than 3gm per day. [14,36,38] Based on published clinical data, vitamin C pharmacokinetic modeling as well as the package insert, we decided to administer 6 gm vitamin C per day divided in 4 equal doses as part of our “metabolic resuscitation protocol”. [11,14,15,36-39] This dosage is devoid of any reported complications or side effects. This dose of Vitamin C has proven anti-oxidant effects without any evidence of pro-oxidant activity. Hydrocortisone was dosed according to the consensus guidelines of the American College of Critical Care Medicine. Thiamine was included in the Vitamin C protocol at a dose of 200mg q 12 hourly.[27,43] This dosage strategy is listed below.
Vitamin C, Hydrocortisone and Thiamine dosing protocol
Vitamin C: Vitamin C is provided by the manufacturer 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 will then be 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 6 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 7 day shelf life after opening vial at a cost of $20 per vial.
Hydrocortisone: Patients are treated with hydrocortisone 50mg IV q 6 hourly for 4 days or until ICU discharge. Optional dosing strategy: Hydrocortisone 50 mg bolus, followed by a 24-hour continuous infusion of 200 mg for 4 days.
Thiamine: Patients will receive intravenous thiamine 200mg q 12 hourly for 4 days or until ICU discharge. 
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) , Dr. Albert Szent-Gyorgyi (1928) , Dr. Fred Klenner (1949)  Professor Linus Pauling (1971-1986) [47-50], Dr. Arthur Kalokerinos (1960-1982) [51,52] Dr. Sebastian Padayatty (2004) , Dr John Wilson (2009-2013) [6,7] and Professor Alpha (Berry) Fowler [1,2,14], 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. We believe that this exciting journey has just began and that there are still many questions to be answered.
Sepsis, Delirium and long-term Cognitive Dysfunction: Prevention Using Vitamin C??
Sepsis survivors are at an increased risk death, major adverse cardiovascular events, ischemic stroke, hemorrhagic stroke, myocardial infarction, recurrent sepsis and heart failure compared to population controls. [53,54] In addition, sepsis survivors incur long-term consequences, including developing new physical, psychiatric, and cognitive deficits. These deficits often limit their mobility and ability to perform day-to-day activities and impair quality of life.[54,55]
In addition to physical impairments, cognitive and neuropsychiatric complications are common following critical illness, particularly sepsis. The post sepsis-syndrome is similar in many respects to the post-traumatic stress disorder; patients suffer memory impairment, abnormalities of higher executive function, nightmares, anxiety disorders and depression. Semmler et al demonstrated that sepsis survivors showed cognitive deficits in verbal learning and memory and had a significant reduction of left hippocampal volume compared to healthy controls.
Delirium is very common in critically ill patients particularly those with sepsis. The risk of developing delirium is dependent on a complex interplay between predisposing and precipitating risk factors. Delirium is associated with negative outcomes including greater cognitive impairment after ICU discharge.[57,58] It is postulated that the neuro-psychiatric complications that occur in sepsis survivors may represent persistent neurological dysfunction initiated and or propagated by acute ICU delirium.
Vitamin C is concentrated almost 100-fold in neurons.[59-61] Vitamin C is an essential co-factor for the synthesis of dopamine, serotonin and norepinephrine. It is therefore not surprising that altered neuropsychiatric function has been reported in both the acute and chronic forms of scurvy.[62,63] Indeed, in the historical descriptions of scurvy, patients were described as having “gone insane”. Vitamin C levels are undetectable or very low in critically ill patients, particularly those with sepsis. Anecdotally, we have noted that none of our septic patients treated with our vitamin C protocol required treatment for delirium.
In an animal models, administration of ascorbic acid has been demonstrated to produce an antidepressant-like effect mediated by interaction with the monoaminergic and GABAa systems.[64,65] Gariballa evaluated the clinical significance of vitamin C deficiency among hospitalized acutely-ill older patients. In this study patients with vitamin C biochemical depletion had significantly increased symptoms of depression compared with those with higher concentrations at baseline and at 6 weeks. In a randomized controlled trial, Zhang et al demonstrated that 500 mg vitamin C PO BID improved the mood and decreased depression symptoms in a cohort of acutely hospitalized patients. In a randomized double-blind, placebo-controlled 14 day trial, Brody demonstrated that oral vitamin C resulted in a decrease in the Beck Depression scores with improved sexual intercourse frequency. A randomized, double-blind, placebo-controlled study in pediatric patients demonstrated that ascorbic acid was an effect adjunct to fluoxetine in the treatment of major depression.
We therefore propose/hypothesize that treatment with vitamin C during the acute phase of illness may limit the incidence and or severity/duration of delirium which may then limit or prevent the long-term neuro-psychiatric complications of sepsis. Furthermore, as treatment with the vitamin C cocktail reduces the duration of mechanical ventilation, duration of vasopressor support and duration of ICU stay we postulate that this intervention may promote early mobility and limit muscle loss thereby limiting critical illness myopathy (CIM) characteristic of critical illness and sepsis.
I will be posting my PowerPoint presentation on this topic as well as a Q/A post in response to all the questions received in a few days.
It should also be noted that “we” have received funding to do “large” RCT in the USA. Additional RCTs are being planned across the world.
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