MATH+ Protocol for COVID-19 and Dr Paul Marik

The MATH+ Protocol Story

January, 2020. Dr. Paul E. Marik, Professor of Medicine and Chief of the Division of Pulmonary and Critical Care Medicine at the Eastern Virginia Medical School in Norfolk, Virginia, creates a COVID-19 hospital treatment protocol for the medical school. Called the EVMS protocol, it is based on Dr. Marik’s safe, effective treatment protocol for sepsis — the famous “Marik Cocktail” of intravenous Hydrocortisone, Ascorbic Acid, and Thiamine (HAT).

• CITRIS-ALI, a large double-blind placebo controlled trial of high dose ascorbic acid (AA) in Acute Respiratory Distress Syndrome (ARDS) found that mortality decreased and ICU length-of-stay were markedly reduced in the treatment group.
• The reasons for the lack of immediate adoption of this therapy in ARDS can only be explained by the fact that the original primary outcome analysis failed to account for all the early excess deaths in the control group, where no Sequential Organ Failure Assessment (SOFA) score was assigned to the patients who died. A subsequent letter to the editor demanded an analysis accounting for the early deaths. The study authors complied, and reported the primary outcome of SOFA score to be statistically significantly decreased at 96 hours. Thus CITRIS-ALI, although inexplicably initially portrayed as a negative trial, was later found to be profoundly positive in terms of achieving its primary outcome and important secondary outcomes.

Update: Vitamin C and Sepsis: Surprising results from the LOVIT trial (June 2022, NEJM)

January/February, 2020. Dr. Marik discusses the EVMS protocol with Dr. Pierre Kory, then Associate Professor of Medicine and Chief of Pulmonary and Critical Care at the University of Wisconsin School of Medicine & Public Health in Madison, Wisconsin. Dr. Kory shares his interest in the research and treatment of intravenous AA (ascorbic acid) in septic shock and ARDS with the hopes of finding a reduced need for fluids, vasopressor support, and intubation in COVID patients. Their discussions lead to a decision on a more aggressive dosing strategy for both AA and anticoagulation, to optimally counteract the hyper-inflammation and hyper-coagulability they and others have seen at the bedside and from the COVID outbreaks in China and Italy. The decision on anti-coagulation type and dosing is also heavily influenced by early investigations done using sophisticated clotting assays by Dr. Kory and his group of seasoned critical care doctors and expert hematologists.

March 13, 2020. The United States declares a national emergency in response to the pandemic. New York City becomes the first major “hot spot” in the country, where 20% of hospitalized cases develop acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represents a viral pneumonia and no anti-coronaviral therapy exists, nearly all national and international health care societies advocate a primary focus on supportive care, avoiding therapies outside of randomized controlled trials, with specific recommendations to avoid the use of corticosteroids. This recommendation stands in opposition to the EVMS protocol which includes hydrocortisone. Inexplicably high mortality rates are reported, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in supportive care strategies.

March 16–21, 2020. New York City internist Keith Berkowitz searches for a way to treat his patients who contract COVID. He finds the EVMS protocol and calls Dr. Marik, who suggests he also talk to Dr. Kory. Convinced of the benefits of intravenous AA, Dr. Berkowitz wants to get word of the new treatment protocol to government officials and the media. He calls his longtime patient, former CBS News Correspondent Betsy Ashton, for advice. Newly locked down in New York City, Betsy is eager to help him reach out to major media in an effort to potentially save thousands of lives. Dr. Berkowitz urges Drs. Marik and Kory to recruit more critical-care experts to the cause.

March 22–28, 2020. Dr. Howard Kornfeld, a board-certified emergency medicine specialist best known for his Recovery Without Walls pain control clinic in Mill Valley, California, also independently researches and finds the EVMS protocol. He contacts Dr. Marik. Dr. Kornfeld is certain that the protocol, with its enormous potential for saving lives, needs to reach governors and the media. He contacts writer Joyce Kamen, who heads the Kamen Creative Public Relations firm in Cincinnati, Ohio. Kamen’s husband, Dr. Fred Wagshul, is a Pulmonologist and Medical Director of the Lung Center of America, and is also a clinical instructor at the Wright State University School of Medicine in Dayton, Ohio. Both Joyce Kamen and Dr. Wagshul join to help spread the word of the highly promising protocol. Dr. Marik invites Dr. G. Umberto Meduri, Professor of Medicine, Div. of Pulmonary, Critical Care and Sleep Medicine, at the University of Tennessee Health Science Center in Memphis, Tennessee; Dr. Joseph Varon, Chief of Staff & Chief of Critical Care at United Memorial Medical Center in Houston, Texas; and Dr. José Iglesias, Associate Professor of Medicine, Hackensack Meridien School of Medicine at Seton Hall, Department of Nephrology & Critical Care, Community Medical Center, Department of Nephrology, Jersey Shore University Medical Center, Neptune, New Jersey, to join the group. All three, like himself, are leading ascorbic acid experts and are eager to help Dr. Marik create an effective treatment for the challenging new disease that threatens millions around the globe.

March 31, 2020. Betsy Ashton writes the first press release about the new treatment entitled “Hospitals use IV’s of Vitamin C and other low-cost, readily available drugs to cut the death rate for COVID-19 and the need for ventilators.” She reports that Dr. Paul Marik has treated four seriously ill COVID patients, including an 86-year old man suffering heart disease, who was admitted to the hospital on 100% oxygen — a patient not likely to survive. All four survived. Dr. Joe Varon’s sixteen COVID patients had gotten off ventilators in 24 hours instead of 10–21 days. Joyce Kamen pens and publishes a similar article on medium.com the next day.

April 5, 2020. Dr. Kornfeld hosts the first Zoom meeting, allowing all eight doctors, plus the two media experts, to meet each other and plot the best way to get word of the safe, inexpensive, readily available, and seemingly effective treatment out to the world. The five critical care experts begin sharing many papers a day on a multitude of pathophysiologic and therapeutic topics, while also regularly discussing clinical insights and experiences with their wide network of intensivist colleagues from New York, Italy, and even China. Many deliberations over drugs and dosages follow, deciding whether to use all or limit some of the components in the EVMS protocol, and particularly focus on which corticosteroid to use. Dr. Meduri’s expertise in and rationale for the use of methylprednisolone wins the steroid argument. Needing a name for their group, they decide to call themselves the Front Line Covid-19 Critical Care Consortium.

April 6, 2020. Betsy Ashton writes, and Joyce Kamen designs, the first press releases of the newly formed FLCCC group. The releases urge immediate adoption of the early intervention protocol to reduce the need for ventilators and prevent mortality from COVID-19 disease. They report that Dr. Paul Marik has treated seven seriously ill COVID patients in his Norfolk, Virginia, hospital, and Dr. Joe Varon has treated twenty-four at United Memorial Medical Center in Houston, Texas. Both doctors used the new formula and all patients survived. Joyce Kamen then sets up Facebook and Twitter accounts for the group and posts the releases online. Dr. Keith Berkowitz, through one of a large circle of high-profile contacts, sends the protocol to the White House COVID-19 response team headed at the time by Jared Kushner. This would be the first of four instances where high profile members of the medical, political, and media community would send the protocol to the White House for consideration.

Mid-April, 2020. Throughout April, the doctors read and share studies, modify the dosages, and care for more patients. Dr. Kornfeld sets up the covid19criticalcare.com website for the group hosted by Malik Soomar of webconsuls.com. Joyce Kamen interviews and edits videos of the doctors talking about the new protocol for the website, and for social media platforms. During the group’s second Zoom meeting, Joyce talks about the benefits of naming the protocol with an easy to remember acronym. During that meeting, Fred Wagshul scribbles out the names of the key medicines and MATH+ is born — the letters standing for components Methylprednisolone, Ascorbic acid, Thiamin, and Heparin, with the “+” indicating a few other medicines, such as melatonin, zinc, and vitamin D3 to be added based on the high safety, low cost, and emerging scientific data suggesting efficacy.

MATH+ Protocol

The MATH+ Hospital Treatment Protocol for COVID-19 is designed for hospitalized patients, to be initiated as soon as possible after they develop respiratory difficulty and require oxygen supplementation. The three core pathophysiologic processes that have been identified are severe hypoxemia, hyperinflammation, and hypercoagulability. This combination medication protocol is designed to counteract these processes either through the use of single agents or in synergistic actions. A unique insight into this disease made by members of our group is that the majority of patients initially present with an inflammatory reaction in the lungs called “organizing pneumonia,” which is the body’s reaction to injury and is profoundly responsive to corticosteroid therapy. If the organizing pneumonia response is left untreated or presents as a rapidly progressive sub-type, a condition called Acute Respiratory Distress Syndrome (ARDS) follows.

The two main therapies that can reverse and/or mitigate the extreme inflammation causing ARDS are the combination of the corticosteroid Methylprednisolone and the antioxidant Ascorbic acid, which is given intravenously and in high doses. Both of these medicines have multiple synergistic physiologic effects and have been shown in multiple randomized controlled trials to improve survival in ARDS, particularly when given early in the disease. Thiamine is given to optimize cellular oxygen utilization and energy consumption, protecting the heart, brain, and immune system. Given the numerous clinical and scientific investigations that have demonstrated consistent, reproducible, and excessive levels of hyper-coagulation, particularly in the severely ill, the anticoagulant Heparin is used to both prevent and help in dissolving blood clots that appear with a very high frequency. The “+” sign indicates several important co-interventions that have a combination of strong physiologic rationale with existing or emerging pre-clinical and clinical data to support their use in similar conditions or in COVID-19 itself, and all with a well-established safety profile. Such adjunctive therapies are continuously being evaluated and amended as the published medical evidence evolves.

Timing is a critical factor in the efficacy of MATH+ and to achieving successful outcomes in patients ill with COVID-19. Patients must go to the hospital as soon as they experience difficulty breathing or have a low oxygen level. The MATH+ protocol should be administered soon after a patient meets criteria for oxygen supplementation (within the first hours after arrival in the hospital), in order to achieve maximal efficacy. Delayed therapy can lead to complications such as the need for mechanical ventilation. If administered early, the MATH+ formula of FDA-approved, safe, inexpensive, and readily available drugs may eliminate the need for ICU beds and mechanical ventilators and return patients to health.

Current MATH+ protocol: version 16, updated on Mar 5, 2022

A. CORE MEDICATION

Methylprednisolone

A. Upon oxygen requirement or abnormal chest X-ray

• Preferred: 80mg IV bolus, then 40mg IV twice daily 
• Alternate: 80mg / 240ml normal saline IV infusion at 10ml/hr 
• Follow COVID-19 Respiratory Failure protocol: www.flccc.net/respiratory-support-c19

A1. If no improvement in oxygenation in 1–3 days, double dose to 160mg/daily. 

A2. Upon need for FIO2 > 0.6 or ICU, escalate to “Pulse Dose” below (B) 

A3. Once off IMV, NPPV, or High flow O2, decrease to 20mg twice daily. Once off O2, then taper with 20mg/day × 5 days then 10mg/day × 5 days

B. Refractory Illness/ Cytokine Storm

• “Pulse” dose with 1 gram daily × 3 days
• Continue × 3 days then decrease to 160mg IV/ daily dose above, taper according to oxygen requirement (A). If no response or CRP/Ferritin high/rising, consider mega-dose IV ascorbic acid and/or “Therapeutic Plasma Exchange” below

Ascorbic Acid

O2 < 4L on hospital ward 

• 500–1000mg oral every 6 hours 
• Until discharge

O2 > 4 L or in ICU 

• 50mg/kg IV every 6 hours 
• Up to 7 days or until discharge from ICU, then switch to oral dose above

If in ICU and not improving 

• Consider mega-doses: 25 grams IV twice daily for 3 days 
• Completion of 3 days of therapy

Thiamine

ICU patients 

• 200mg IV twice daily 
• Up to 7 days or until discharge from ICU

Heparin (Low Molecular Weight Heparin)

If initiated on a hospital ward 

• 1mg/kg twice daily — monitor anti-Xa levels, target 0.6–1.1 IU/ml 
• Until discharge then start DOAC at half dose × 4 weeks

If initiated in the ICU 

• 0.5mg/kg twice daily — monitor anti-Xa levels, target 0.2–0.5 IU/ml
• Until discharge then start DOAC at half dose × 4 weeks

B. First Line Adjunctive Therapy (use in all hospitalized patients)

Ivermectin  

• Hospitalized patients 
• 0.6 mg/kg per dose — daily 2 (take with or after a meal) 
• For 5 days or until recovered

Nitazoxanide 

• Hospitalized patients 
• 500mg twice daily — (take with or after a meal) 
• For 5 days or until recovered

Dual Anti-Androgen Therapy 

• Hospitalized patients 
• 1. Spironolactone 100mg twice daily 
• 2. Dutasteride 2mg on day 1, followed by 1mg daily — or Finasteride 10mg daily 
• 14 days or until discharge from hospital

• ICU Patients 
• 1. Flutamide 250mg TID — or Bicalutamide 150mg daily 
• 2. Dutasteride 2mg on day 1, followed by 1mg daily — or Finasteride 10mg daily 
• 14 days or until discharge from hospital

Vitamin D 

• Hospitalized patients 
• Calcitriol: 0.5mcg on day 1, then 0.25mcg daily 
• 7 days

Melatonin 

• Hospitalized patients 
• 6–12mg PO at night 
• Until discharge

C. Second Line Adjunctive Therapy (use in addition to first line adjunctive therapies in all ICU patients)

Fluvoxamine 

• Hospitalized patients 
• 50mg PO twice daily — consider fluoxetine 30mg daily as an alternative (it is often better tolerated) 
• 10–14 days

Cyproheptadine 

• If any of: 1) on fluvoxamine, 2) hypoxemic, 3) tachypneic/respiratory distress, 4) oliguric/ kidney injury 
• 8mg — 3 x daily 
• until discharge, slow taper once sustained improvements noted

Zinc 

• Hospitalized patients 
• 75–100mg PO daily 
• Until discharge

Famotidine 

• Hospitalized Patients 
• 40–80mg PO twice daily 
• Until discharge

Atorvastatin 

• ICU Patients 
• 80mg PO daily 
• Until discharge

Therapeutic Plasma Exchange 

• Patients refractory to pulse dose steroids 
• 5 sessions, every other day 
• Completion of 5 exchanges

Please also review FLCCC I-MASK+ Prevention & Early Outpatient Treatment Protocol for COVID-19, which was developed for the prevention and early outpatient treatment of COVID-19. Both are physiologic-based combination treatment regimens developed by leaders in critical care medicine. All component medicines are FDA-approved, inexpensive, readily available and have been used for decades with well-established safety profiles.

For post-covid or long covid syndrome, check out Post-COVID Treatment Protocol.