Life Extension Magazine®
Research Update – June 2022
Subsequent to the 2017 publication of the encouraging results regarding “triple therapy” of intravenous vitamin C, thiamine, and hydrocortisone for sepsis (referenced below), numerous research teams and institutions attempted to confirm those findings. However, in the years since, findings from multiple high-quality trials have been mixed, largely finding no benefit to this treatment.26-32
In June 2022, a paper published in the New England Journal of Medicine reported results of the LOVIT randomized, placebo-controlled trial of intravenous vitamin C, with or without thiamine and hydrocortisone, for sepsis.33 Conducted in 872 patients in Canada, New Zealand, and France, this trial found that after four weeks those who had been treated with vitamin C had a 21% higher risk of a composite endpoint of persistent organ dysfunction and death compared to those who received placebo.
A systematic literature review found that blinded trials at low risk of bias did not report a benefit from intravenous vitamin C. Trials that extended the assessment of mortality out to 90 days tended to show harm from the treatment.34 Current evidence strongly suggests that intravenous vitamin C or “triple therapy” for sepsis likely has no benefit and may increase the risk of poor outcomes.
This article has a lot of personal meaning because it reveals information that could have saved the lives of some of my family members…if only I had known about this sooner.
Here is what the Centers for Disease Control and Prevention reports on the impact of sepsis:1
- About 250,000 Americans die from sepsis each year.
- More than 1.5 million Americans get sepsis each year.
- One in three patients who die in a hospital have sepsis.
Despite these staggering numbers, most people have never heard of sepsis.
Sepsis is a complex syndrome characterized by oxidative damage, hyper-inflammation, immune dysfunction, poor tissue oxygenation, and hyper-coagulation, usually brought on by an infectious agent.2,3
When susceptible persons are exposed to a pathogen, there can be an uncontrolled inflammatory response that disrupts organ function and blood flow.
Instead of targeting the offending bacteria or virus, the immune system mounts inflammatory reactions that can result in circulatory collapse, multi-organ failure, and eventual death.
What you need to know
There is an urgent need to find better treatments for sepsis, as it causes approximately 250,000 American deaths each year. A recent clinical study has revealed that a combination therapy with vitamin C was able to significantly reduce mortality from septic shock compared to conventional treatment. Unfortunately, mainstream media did not give this study the attention it needs.
In a study published in 2017, a group of 47 hospitalized sepsis patients were treated with intravenous vitamin C, hydrocortisone, and vitamin B1.
Compared to sepsis patients treated with conventional therapy, those receiving the intravenous vitamins and hydrocortisone had a striking 87% reduced mortality.4
These impressive small-scale studies have ignited eight new clinical trials in 2018 that will use this three-prong approach, i.e., intravenous vitamin C, vitamin B1, and hydrocortisone.
As you're about to learn, this kind of approach to sepsis treatment was demonstrated decades ago. Millions may have needlessly succumbed because this therapy was overlooked by the medical establishment.
I recently came across a set of Power Point slides that one of our scientists presented in 1999.
It described the staggering costs of hospitalized sepsis patients, along with better ways to treat sepsis that had been published in the 1990s.
Move forward 20 years and virtually none of those published methods to save sepsis patients have been adopted into hospital practice.
Sepsis is a frustrating condition to offer suggestions for from the outside. That's because the septic patient is confined to a hospital, where the treating physician exerts dictatorial authority.
Over the past decades, we at Life Extension® have tried to assist sepsis patients' family members who request intravenous vitamin C, thiamine, and glutathione. The ICU physician's response is consistently "no" and the result too often is agonizing death of the patient.
There has been fierce hostility by many physicians against the use of intravenous vitamins in the hospital setting, despite persuasive evidence of efficacy. This prejudice may soon change.
How Sepsis Kills
Sepsis can strike at any age, but elderly people with compromised immunity are the most vulnerable.
Sepsis often arises from a bacterial infection that results in widespread blood clotting, abnormal immune and inflammatory responses, oxidative stress, and mitochondrial dysfunction.2,3
As inflammatory cytokines destroy endothelial linings, blood abnormally coagulates and organs (lungs, kidneys, brain) lose circulation.
This can lead to a dangerous drop in blood pressure (septic shock) that results in patients dying from multisystem organ failure.5
Sepsis is the most expensive cause of hospitalization in the United States and contributes to 35%-56% of all in-hospital deaths.6,7
It's the primary reason that older people are admitted to intensive care units (ICU).
New Definitions of Sepsis
Recognizing that cases of sepsis are being underreported and undertreated, an article published by the American Medical Association proposed new definitions as follows:17
• Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.
• Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone.
These new definitions may assist physicians in recognizing sepsis signs and symptoms before irreversible inflammatory/oxidative damage occurs, along with loss of organ function and needless deaths.
But for too many people, progressive treatments (such as high-dose intravenous antioxidants) for sepsis are delayed or not even instituted before the patient "expires."
Lingering Effects of Sepsis
It used to be thought that if a patient could survive the acute inflammatory response and make it out of the hospital, they would slowly return to normal.
But that is not how it works. It turns out that more than 40% of sepsis patients are readmitted to the hospital within 3 months after going home.8
This creates a chronic problem that becomes costlier and more dangerous as patients get weaker with each new septic-related attack.
Sepsis survivors are at increased risk of dying for months to years after the acute infection is cured.
Better initial and follow-up treatments are urgently needed.
Low Vitamin C in Sepsis Patients
A study published in 2017 looked at vitamin C plasma levels in sepsis patients.9
This study found overall that critically ill sepsis patients had low vitamin C levels with one-third having frank vitamin C deficiency.
Nearly 40% of septic shock patients in this study were deficient in vitamin C compared to 25% of non-septic patients.9 (Septic shock is severe sepsis that often precedes death.)
The doctors who conducted this study noted these low levels of vitamin C despite sepsis patients being given, on average, 125 mg a day of vitamin C by mouth or IV.9
Readers of this magazine know a daily vitamin C dose of 125 mg is trivial. Yet much of conventional medicine still views this as adequate.
This misconception is startling when considering hospitalized patients rapidly use up their vitamin C to suppress acute oxidative reactions brought on by sepsis-induced inflammation.
This is not the first study that identified low vitamin C levels in septic patients. This finding was uncovered more than 20 years earlier.10,11
A 2018 published report titled "Vitamin C: The next step in sepsis management?" describes mechanisms through which vitamin C functions to suppress inflammation and oxidation while improving blood flow to organs.12
Despite making robust arguments for patients presenting with sepsis symptoms to be treated with vitamin C, the conclusions from this 2018 review paper were that "further evidence is needed to support this in practice."12
When initially reading this, I wondered who the author thinks is going to fund future studies of a non-patentable therapy like intravenous vitamin C?
I was gratified to learn there are eight new clinical trials initiating this year (2018) that will study the effects of intravenous vitamin C, thiamine, and hydrocortisone in sepsis patients. Funding is coming largely from philanthropic donors.13
Hydrocortisone + Vitamin C = Synergy
The introduction to this editorial described a 2017 published study whereby sepsis patients were given intravenous vitamin C, vitamin B1, and the anti-inflammatory drug hydrocortisone.
This study showed only four of 47 (8.5%) septic patients treated with these vitamins (+ hydrocortisone) died compared to 19 of 47 (40.4%) of historic controls. This represents a remarkable 87% reduction in mortality.4
In this 2017 study, the Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group (vitamins + hydrocortisone). None of these treated patients developed progressive organ failure.4
Patients in the treatment group were weaned off a class of drug used to support blood pressure (vasopressors) 18 hours after starting the vitamins + hydrocortisone protocol.
Control patients, on the other hand, needed these blood pressure-boosting drugs for about 54 hours…three times longer than the group treated with intravenous vitamins + hydrocortisone.4
(Vasopressors constrict blood vessels and thereby boost dangerously low blood pressure.)
Why Hydrocortisone + Vitamins Are Effective
The same researchers who showed remarkable survival improvements (87% better) in human sepsis patients sought to clarify why vitamin C + hydrocortisone was so effective in their study.
These researchers pursued answers by identifying lethal pathologies of sepsis including endothelial dysfunction and capillary leakage.14
Using endothelial cells from human lungs, the researchers were able to identify how vitamin C and hydrocortisone together enable robust protective effects against inflammatory damage to vascular cells.
This finding showed that vitamin C or hydrocortisone alone was not satisfactory. But when combined before or after inflammation was induced, vitamin C + hydrocortisone demonstrated a dramatic reversal of loss of vascular barrier function, i.e., capillary permeability.
The ability of vitamin C to protect against capillary leakage should not be surprising since that is a critical role this nutrient plays in a healthy body.
Death by scurvy (severe vitamin C deficiency) often comes from massive internal bleeding as the scurvy victim's vasculature can no longer contain blood volume.15
A paper published in 2017 describes prior studies in animal and experimental models of sepsis, which demonstrate the ability of vitamin C to protect against microvascular dysfunction caused by the kind of systemic inflammation that occurs in sepsis.16
Pioneering ICU Doctor Defies the Critics
If you happen to reside anywhere near Norfolk, Virginia, and require hospitalization, you may want to enroll as a patient of Dr. Paul Marik at Sentara Norfolk General Hospital.
Dr. Marik has incorporated intravenous vitamins + hydrocortisone therapy into routine treatment of sepsis. Patients threatened with death are instead leaving the hospital alive within days.
Local media are reporting on Dr. Marik's "miracle juice," quoting an ICU nurse:18
"We started having patient after patient have these remarkable results…They'd be at death's door and, 24 to 48 hours later, they had turned around. We have seen patients walk out of here we didn't think would leave."
Critics state that full blown clinical trials involving large numbers of septic patients are required to prove this therapy is really working.
Dr. Marik agrees, but initially noted it may be difficult to fund large studies because it uses a drug (hydrocortisone) and vitamins that have been on the market for decades. Dr. Marik was quoted earlier this year:18
"We are curing (sepsis) for $60. No one will make any money off it."
The good news is that new studies using this protocol are being launched this year, despite there being no blockbuster new drug involved.
Our Correspondence with Dr. Marik
In response to these incredible findings, we reached out to Dr. Marik to see how his protocol was working in large numbers of hospitalized sepsis patients.
He replied that over 700 American patients have now been treated with consistent response. He stated there was no evidence of side effects in thousands of patients treated around the world using his protocol of intravenous vitamin C, thiamine and hydrocortisone.
When asked if additional nutrients or drugs might provide greater benefits, Dr. Marik replied:
"I believe that our current combo is safe, cheap and very effective...so it's difficult to beat this."
He went on to state that there are three new clinical trials using his protocol underway or about to begin in the United States and another five around the world are beginning.
With 250,000 Americans perishing each year from sepsis, I am gratified to learn that this protocol of intravenous vitamins + hydrocortisone is being studied and may soon be incorporated into standard medical practice.
Example of Cynicism in Year 2018
In response to successful case histories published in 2017, a review of the science behind intravenous vitamin C in sepsis treatment was published in 2018.12
While acknowledging the beneficial mechanisms and findings of efficacy of intravenous vitamin C, the concluding remarks of this 2018 review were:
"Further research is required to prove its value in treatment."12
This conclusion did not surprise me, because it is similar to virtually every other study showing remarkable benefits against sepsis, but insisting that "more" research is needed.
With hundreds of thousands of Americans likely to die from sepsis this year,23 and robust data indicating that large numbers can be saved, it is beyond cruel to deny a septic patient the option of intravenous vitamin C, thiamine plus hydrocortisone.
Economics of Sepsis Treatment
The annual cost of treating sepsis in the United States is $23 billion.24 Sepsis treatment is a huge revenue driver for hospitals.
Patients who present or contract sepsis are confined to the ICU for days, weeks or months, often on ventilators and receiving multiple IVs.
Hospitals can bill Medicare and insurance companies hundreds of thousands of dollars for each septic patient.
There is now a way for people with symptoms that indicate sepsis to potentially prevent it, possibly utilizing intravenous vitamin C and thiamine in outpatient infusion centers.
Even if one is contracting the flu or other infections/trauma, these nutrients may help protect against short- and long-term tissue damage inflicted by inflammation-induced oxidative stress, while improving immune responses.
For those who develop sepsis, Dr. Marik's protocol of intravenous vitamin C, thiamine plus hydrocortisone may enable most to leave the hospital in days instead of lingering at death's door for agonizing periods.
With Medicare, Medicaid and private insurers so financially stressed, this represents a unique opportunity to significantly slash the healthcare cost burden.
How to Avoid Becoming a Sepsis Casualty
Anyone over age 60 is likely to suffer some degree of immune senescence leading to higher septic risk. Sepsis can strike people of any age, however, including neonates.
In reviewing Dr. Marik's sepsis protocol that is now being studied in several clinical trials, an intravenous dosage protocol administered in the hospital might consist of:
- Vitamin C: 1.5 grams (administered as an infusion over 30 to 60 minutes) every six hours for four days or until ICU discharge;
- Thiamine: 200 mg every 12 hours for four days or until ICU discharge;
- Hydrocortisone: 50 mg every six hours for seven days or until ICU discharge, followed by a taper over three days.
Vitamin C for Non-Bacterial Sepsis
While bacterial infection underlies most sepsis cases, it can also manifest from viral (influenza) infections and trauma (including wounds inflicted by surgery).
A case report published in 2017 described a 20-year-old girl with acute respiratory distress syndrome treated with high-dose intravenous vitamin C.19
The vitamin C was initiated because the girl appeared on the verge of death from septic shock.
The most common risk factor for acute respiratory distress syndrome is sepsis.20-22
When respiratory support with mechanical ventilation failed, extracorporeal membrane oxygenation (providing oxygen directly into blood circulated outside the body) was initiated in a desperate attempt to save this young girl.
After 12 hours on extracorporeal membrane oxygenation, her doctors went further by administering intravenous vitamin C.
The doctors report that infusing high-dose intravenous vitamin C into this young girl resulted in "rapid resolution of lung injury" with no evidence of any lung damage just one month later.19
Not all septic patients this far advanced are as fortunate.
Symptoms of Sepsis
The clinical presentation of sepsis is highly variable depending on a wide range of clinically relevant factors.3
Common sites of primary infection are respiratory, genital/urinary, gastrointestinal, skin, and soft tissue.
Fever is often the first manifestation of sepsis, with pneumonia being one of the most common presentations leading to sepsis.
Early initiation of therapy decreases in-hospital mortality. Some early indicators of sepsis include:25
- Fever
- Hypothermia (lower than normal body temperature)
- Heart rate >90 beats per minute
- Fast respiratory rate
- Altered mental status (confusion/coma)
- Edema (swelling)
- High blood glucose (without diabetes)
Since some of these symptoms might indicate a flu virus or other infection, it might make sense for people developing these symptoms to load up on oral antioxidant nutrients, or ideally, go to a local infusion center for intravenous administration of vitamin C, vitamin B1, and possibly glutathione.
The physician at the infusion center may also determine if a 50 mg dose of hydrocortisone is warranted.
Prompt treatment might enable one to avoid a hospital setting, assuming symptoms are mild.
If sepsis occurs while in a hospital, one's choices may be more limited.
My suggestion for Life Extension supporters is to call local hospitals and your doctor and inquire if progressive sepsis protocols (such as intravenous vitamin C, thiamine and hydrocortisone therapy) will be administered on request.
Hospitals (or physicians with hospital privileges) that agree to use this protocol might be the place to go if hospitalization is needed, or if sepsis symptoms occur.
With 250,000 Americans perishing each year from sepsis,1 we eagerly await results from clinical trials that will study the effects of intravenous vitamin C, thiamine and hydrocortisone on large numbers of sepsis patients.
My only regret is that these approaches were not implemented 20 years sooner, as data from the mid-1990s indicated a high degree of probable efficacy.
When winter approaches, one might want to bump up their oral vitamin C intake by a few thousand milligrams based on consistent data that sepsis patients often present with what we consider severe vitamin C deficiencies.
For longer life,
William Faloon, Co-Founder
Life Extension Buyers Club
References
- Available at: https://www.cdc.gov/sepsis/datareports/index.html. Accessed June 22, 2018.
- Prescott HC, Angus DC. Enhancing Recovery From Sepsis: A Review. JAMA. 2018;319(1):62-75.
- Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-51.
- Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-38.
- Rossaint J, Zarbock A. Pathogenesis of Multiple Organ Failure in Sepsis. Crit Rev Immunol. 2015;35(4):277-91.
- Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA. 2014;312(1):90-2.
- Available at: https://www.sepsis.org/sepsis/definition. Accessed June 27, 2018.
- Prescott HC, Langa KM, Iwashyna TJ. Readmission diagnoses after hospitalization for severe sepsis and other acute medical conditions. JAMA. 2015;313(10):1055-7.
- Carr AC, Rosengrave PC, Bayer S, et al. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21(1):300.
- Galley HF, Howdle PD, Walker BE, et al. The effects of intravenous antioxidants in patients with septic shock. Free Radic Biol Med. 1997;23(5):768-74.
- Galley HF, Davies MJ, Webster NR. Ascorbyl radical formation in patients with sepsis: effect of ascorbate loading. Free Radic Biol Med. 1996;20(1):139-43.
- Teng J, Pourmand A, Mazer-Amirshahi M. Vitamin C: The next step in sepsis management? J Crit Care. 2018;43:230-4.
- Available at: https://tinyurl.com/yajzzbdq. Accessed June 27, 2018.
- Barabutis N, Khangoora V, Marik PE, et al. Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. Chest. 2017;152(5):954-62.
- Agarwal A, Shaharyar A, Kumar A, et al. Scurvy in pediatric age group - A disease often forgotten? J Clin Orthop Trauma. 2015;6(2):101-7.
- Tyml K. Vitamin C and Microvascular Dysfunction in Systemic Inflammation. Antioxidants (Basel). 2017;6(3).
- Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.
- Available at: http://pilotonline.com/news/local/health/article_7a3063e5-24cf-56c1-b25c-142731604196.html. Accessed June 22, 2018.
- Fowler Iii AA, Kim C, Lepler L, et al. Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J Crit Care Med. 2017;6(1):85-90.
- Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl J Med. 2017;377(6):562-72.
- Available at: https://emedicine.medscape.com/article/165139-overview#a4. Accessed June 27, 2018.
- Available at: https://www.thoracic.org/patients/patient-resources/breathing-in-america/resources/chapter-2-acute-respiratory-distress-syndrome.pdf. Accessed June 27, 2018.
- Available at: https://f1000research.com/articles/7-500/v1. Accessed June 27, 2018.
- Available at: https://www.hcup-us.ahrq.gov/reports/statbriefs/sb204-most-expensive-hospital-conditions.jsp?utm_source=ahrq&utm_medium=ahrqstat&utm_content=content&utm_term=hcup&utm_campaign=ahrq_sb_204_2016. Accessed June 22, 2018.
- Available at: https://www.sepsis.org/sepsis/symptoms. Accessed June 22, 2018.
- Chang P, Liao Y, Guan J, et al. Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial. CHEST. 2020;158(1):174-82.
- Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020;323(5):423-31.
- Hwang SY, Ryoo SM, Park JE, et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study. Intensive Care Medicine. 20202020/11/01;46(11):2015-25.
- Iglesias J, Vassallo AV, Patel VV, et al. Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. CHEST. 2020;158(1):164-73.
- Litwak JJ, Cho N, Nguyen HB, et al. Vitamin C, Hydrocortisone, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Analysis of Real-World Application. J Clin Med. 2019Apr 9;8(4).
- Moskowitz A, Huang DT, Hou PC, et al. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial. JAMA. 2020;324(7):642-50.
- Sevransky JE, Rothman RE, Hager DN, et al. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA. 2021;325(8):742-50.
- Lamontagne F, Masse MH, Menard J, et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med. 2022Jun 15.
- Agarwal A, Basmaji J, Fernando Shannon M, et al. Parenteral Vitamin C in Patients with Severe Infection: A Systematic Review. NEJM Evidence.0(0):EVIDoa2200105.