Paul Marik's Critical Care Research and Textbooks

Table of Contents

1. 1. Three Editions of an Evidence-Based Critical Care Textbook
2. 2. Early Research in Johannesburg and London, Ontario
3. 3. Central Venous Pressure and the Tale of Seven Mares
4. 4. Dynamic Tests of Fluid Responsiveness
5. 5. Fluid Overload and Fluids in Sepsis
6. 6. Corticosteroid Insufficiency in Critical Illness
7. 7. Stress Hyperglycemia as a Survival Response
8. 8. Feeding the Critically Ill Patient
9. 9. Aspiration Pneumonitis and Aspiration Pneumonia
10. 10. A 2012 Review of Dietary Supplements
11. 11. Publication Record and the Bridge to His Later Work
12. Key Research Papers
13. Connections
14. Featured Videos

1. Three Editions of an Evidence-Based Critical Care Textbook

Marik is the sole author of a critical-care textbook that went through three editions with the scientific publisher Springer. The publisher’s records list the author as “Paul Ellis Marik”.

• First edition, 2001: Handbook of Evidence-Based Critical Care, published under Springer’s Berlin and Heidelberg imprint. It appeared while he was working in critical care medicine in Pittsburgh.
• Second edition, 2010: Handbook of Evidence-Based Critical Care, second edition, Springer New York. This edition is organised by organ system. A library catalogue describes its aim as helping clinicians find the evidence for or against an intervention.
• Third edition, 2015: Evidence-Based Critical Care, third edition, with the title shortened, from Springer International Publishing. It carries a 2015 copyright, was released in December 2014, and runs to about 835 pages.

The title of every edition carries the same idea: that the care of the critically ill patient is to be measured against the published evidence rather than habit. The research described in the sections below — on fluids, on steroids, on blood sugar and on feeding — is the kind of material the books gather and organise by organ system.

His later book, Cancer Care: The Role of Repurposed Drugs and Metabolic Interventions in Treating Cancer (first edition 2023, second edition 2024), belongs to a different field and is covered on its own page: Cancer Care: Paul Marik’s Book on Repurposed Drugs.

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2. Early Research in Johannesburg and London, Ontario

Two papers from 1993 show the themes that would run through Marik’s career: how to judge a patient’s circulation at the bedside, and whether a standard treatment really delivers what it promises.

Reading the arterial pressure tracing (1993)

In a single-author paper in Anaesthesia and Intensive Care, Marik studied patients on breathing machines in an intensive care unit. When a machine pushes air into the lungs, the systolic blood pressure rises and falls slightly with each breath; animal data had suggested that the size of this swing may signal a low blood volume. Marik collected 300 sets of measurements from 226 patients and compared the swing with the pulmonary capillary wedge pressure, a pressure measured through a catheter in the lung artery. The correlation was strong (−0.86 across all 300 observations), and he concluded that analysis of the arterial pressure tracing may be useful in estimating the wedge pressure in ventilated patients. The idea that the breath-by-breath swing in a pressure tracing carries information about the circulation returns in his later work on fluid responsiveness.

Old stored blood and the gut (1993)

Working at the Victoria Hospital Research Institute in London, Ontario, with William J. Sibbald, Marik studied 23 critically ill patients with sepsis on breathing machines who received 3 units of packed red blood cells. Transfusion was then commonly used to push oxygen delivery to very high levels in sepsis. The study, published in JAMA, found no increase in the body’s measured oxygen uptake for up to 6 hours after the transfusion. It also found an inverse link between the age of the stored blood and the acidity inside the stomach wall (a sign of oxygen supply to the gut): in patients who received blood stored for more than 15 days, the stomach-wall pH consistently fell after transfusion. The authors concluded that patients given old red cells developed evidence of reduced blood flow to the gut, and proposed that stiff stored red cells may block small blood vessels in some organs.

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3. Central Venous Pressure and the Tale of Seven Mares

For decades, doctors in intensive care units and operating rooms used the central venous pressure — the pressure in the large vein that returns blood to the heart, measured through a central line — to decide whether a patient needed more intravenous fluid. Marik’s best-known critical-care paper challenged that practice.

The 2008 systematic review

In 2008, while at Thomas Jefferson University, Marik, Baram and Vahid published a systematic review in Chest with the subtitle “the tale of seven mares”. They screened 213 articles and pooled 24 studies with 803 patients. Their abstract reports:

• The pooled correlation between central venous pressure and measured blood volume was only 0.16.
• Overall, 56% of patients responded to a fluid challenge (their heart pumped more after fluid was given).
• The pooled area under the curve — a measure of how well a test sorts patients, where 0.5 is no better than chance — was 0.56 for central venous pressure in predicting that response.
• Baseline central venous pressure was 8.7 mm Hg in patients who responded to fluid and 9.7 mm Hg in those who did not, a difference that was not significant.

The authors concluded that the review showed a very poor relationship between central venous pressure and blood volume, that neither the pressure nor its change could predict the response to a fluid challenge, and that central venous pressure should not be used to make clinical decisions about fluid management.

The 2013 update: “a plea for some common sense”

Five years later Marik and Cavallazzi, now at Eastern Virginia Medical School, noted that central venous pressure was still being recommended for this purpose despite the earlier review. Their updated meta-analysis in Critical Care Medicine pooled 43 studies (22 in intensive care units, 20 in operating rooms, one in healthy volunteers). On average 57% of patients responded to fluid, and the summary area under the curve was again 0.56, the same in intensive care units and operating rooms. Their conclusion: there are no data to support the widespread practice of using central venous pressure to guide fluid therapy, and this approach to fluid resuscitation should be abandoned.

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4. Dynamic Tests of Fluid Responsiveness

If a single pressure reading cannot tell who needs fluid, what can? Marik’s answer, developed with others, was to watch how the heart’s output changes when the amount of blood returning to it is briefly changed.

The 2009 systematic review of waveform variation

Marik, Cavallazzi, Vasu and Hirani reviewed 29 studies with 685 patients on breathing machines. They measured how well three “dynamic” signals in the arterial pressure tracing — the variation in pulse pressure, in stroke volume (the blood pumped per beat) and in systolic pressure with each breath — predicted the response to fluid. The areas under the curve were 0.94, 0.84 and 0.86, compared with 0.55 for central venous pressure. For pulse pressure variation the mean threshold was 12.5%, with a sensitivity of 0.89 and a specificity of 0.88. The authors concluded that these dynamic signals are highly accurate in critically ill patients, but noted a limit: the technique works only in patients on controlled ventilation who are not breathing on their own.

Work with Monnet and Teboul

Marik wrote two reviews in Annals of Intensive Care with the French intensive-care physicians Xavier Monnet and Jean-Louis Teboul. The 2011 review states that only about half of unstable patients in intensive care units and operating rooms respond to a fluid challenge, that under-resuscitation starves organs of blood while over-resuscitation raises illness and death, and that filling pressures such as central venous pressure cannot predict the response. It describes dynamic tests that use the change in stroke volume during mechanical ventilation or after a passive leg raise (lifting the legs to send blood from the legs back to the heart), measured continuously by Doppler methods, pulse contour analysis or bioreactance.

The 2016 update states that the risk of overzealous fluid administration has been clearly established and that the traditional use of central venous pressure and other “static” markers should be abandoned. It reports that pulse pressure and stroke volume variation are reliable only under strict conditions, that the passive leg-raising test is now supported by solid evidence, and that a newer end-expiratory occlusion test is easy to perform in ventilated patients. Unlike the traditional fluid challenge, the authors write, these dynamic tests do not lead to fluid overload.

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5. Fluid Overload and Fluids in Sepsis

“Iatrogenic salt water drowning” (2014)

In a 2014 review with the striking title “Iatrogenic salt water drowning and the hazards of a high central venous pressure”, Marik argued against aggressive fluid resuscitation as the default first step for unstable patients. He traced that teaching to early goal-directed therapy and the Surviving Sepsis Campaign guidelines, and wrote that over the previous decade it had become clear that fluid overload is associated with more illness and more deaths in patients with severe sepsis, in surgical and trauma patients and in pancreatitis. In his account:

• Excess fluid builds up in vital organs and impairs kidney, liver and heart function.
• Extra water in the lungs is particularly lethal — the “salt water drowning” of the title.
• The guidelines targeted a central venous pressure above 8 mm Hg, and a pressure above that level has been shown to decrease blood flow in the smallest vessels and in the kidneys and is associated with a higher risk of kidney failure and death.
• Normal saline (0.9% salt solution), compared with balanced electrolyte solutions, is associated with a greater risk of acute kidney injury and death.

A national database of sepsis patients (2017)

In 2017 Marik and colleagues analysed a large United States hospital discharge database: 23,513 patients with severe sepsis and septic shock admitted from the emergency department to an intensive care unit in 2013. The abstract reports that patients received an average of 4.4 litres of fluid on their first intensive-care day, and that hospital mortality in the whole group was 25.8%. In the low range (1 to 4.99 litres) each extra litre was linked to a small fall in mortality (0.7% per litre). Above 5 litres, mortality rose by 2.3% for each additional litre, and total hospital cost rose by $999 per litre. The authors concluded that more than 5 litres of fluid on the first intensive-care day is associated with a significantly higher risk of death and higher costs.

His view of the sepsis guidelines

Marik also questioned the evidence base of the sepsis guidelines directly, in a 2011 editorial in the Journal of Intensive Care Medicine titled “Surviving sepsis guidelines and scientific evidence?”. His later vitamin C work in sepsis is covered on The HAT Protocol: Vitamin C, Thiamine and Hydrocortisone in Sepsis.

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6. Corticosteroid Insufficiency in Critical Illness

Steroid hormones are a thread through Marik’s work from the early 2000s onward, long before hydrocortisone became one of the three parts of his sepsis protocol.

“A new look at an old problem” (2002)

Writing from the Department of Critical Care Medicine at the University of Pittsburgh, Marik and Zaloga reviewed adrenal insufficiency in the critically ill. Their abstract explains that stress — from pain, fever or low blood pressure — switches on the hypothalamic-pituitary-adrenal axis, the hormone chain from the brain to the adrenal glands that produces cortisol. Increased cortisol action is an essential part of the stress response, they write, and even minor degrees of adrenal insufficiency can be fatal in the stressed patient. They describe dysfunction of this axis as common and underdiagnosed in the critically ill.

The 2008 international consensus statement

In 2008 Marik was first author of consensus statements from an international task force of the American College of Critical Care Medicine, drawn from the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, with invited endocrinologists. The task force coined the term critical illness-related corticosteroid insufficiency for the failure of the hormone axis during critical illness, caused by adrenal insufficiency together with tissue resistance to corticosteroids. Its abstract reports that:

• The condition should be suspected in patients with low blood pressure who respond poorly to fluids and drugs that raise blood pressure, particularly in sepsis.
• Adrenal insufficiency in critically ill patients is best diagnosed by a rise in total cortisol of less than 9 micrograms per decilitre after a 250-microgram dose of adrenocorticotrophic hormone, or a random total cortisol below 10 micrograms per decilitre.
• The benefit of glucocorticoid treatment at that time seemed limited to septic shock that depends on blood-pressure drugs and to early severe acute respiratory distress syndrome.
• The task force recommended hydrocortisone, 200 mg a day in four doses or 240 mg a day as a continuous infusion, for at least 7 days in septic shock, and methylprednisolone, 1 mg per kilogram a day for at least 14 days, in severe early acute respiratory distress syndrome.
• Glucocorticoids are to be weaned, not stopped abruptly, and dexamethasone was not recommended for this condition.

The 2017 guideline update

Marik was a co-author of the 2017 update, a guideline of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine written by 16 international experts. The task force was unable to agree on a single test that reliably diagnoses critical illness-related corticosteroid insufficiency. It suggested intravenous hydrocortisone below 400 mg a day for at least 3 days at full dose in septic shock that does not respond to fluids and moderate- to high-dose blood-pressure drugs (a conditional recommendation, low quality of evidence); suggested against corticosteroids in adults with sepsis without shock; suggested intravenous methylprednisolone 1 mg per kilogram a day in early moderate to severe acute respiratory distress syndrome; and did not suggest corticosteroids for major trauma.

“Dissecting facts from fiction” (2011)

In a 2011 commentary in Critical Care, Marik wrote that an intact hormone axis with effective glucocorticoid anti-inflammatory activity inside the cells is essential for survival after infection. Glucocorticoids, he explains, play a major role in regulating nuclear factor-kappa B, a switch that turns on inflammatory signalling genes; severe sepsis, however, may both reduce cortisol production and make the tissues resistant to it. The same reasoning — that critically ill patients can run short of a stress hormone — reappears in his later description of vitamin C as a stress hormone in sepsis.

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7. Stress Hyperglycemia as a Survival Response

In 2013 Marik and the Australian intensive-care physician Rinaldo Bellomo published a review with an exclamation mark in its title: “Stress hyperglycemia: an essential survival response!”

Their abstract notes that high blood sugar is common in critically ill patients and that both the admission and the average blood sugar during the stay are strongly associated with outcomes. Clinicians, researchers and policy makers, they write, assumed this link was causal and widely adopted protocols for tight blood-sugar control in hospital. A critical look at the literature, in their reading, showed that tight control in patients inside and outside intensive care units does not improve outcomes.

The authors propose instead that high blood sugar and insulin resistance during acute illness are an evolutionarily preserved adaptive response that increases the patient’s chances of survival, and that attempts to interfere with this complex response may be harmful. The paper reviews how stress hyperglycemia and insulin resistance arise and the protective role the authors assign to them during acute illness.

The idea is specific to acute illness. In his later cancer writing, Marik describes insulin resistance outside acute illness very differently, as a driver of disease; see Paul Marik’s Metabolic Approach to Cancer.

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8. Feeding the Critically Ill Patient

Much of Marik’s research with Gary Zaloga and later colleagues asked a practical question: when, how and how much should a critically ill patient be fed? Feeding through the gut with a tube is called enteral nutrition; feeding straight into a vein is called parenteral nutrition.

Early tube feeding (2001)

Marik and Zaloga’s systematic review in Critical Care Medicine analysed 15 randomised trials with 753 patients after surgery, trauma, head injury or burns, comparing early with delayed tube feeding. None of the trials included medical intensive-care patients. Early feeding was associated with significantly fewer infections (a relative risk reduction of 0.45) and a hospital stay 2.2 days shorter on average, with no significant difference in deaths or other complications. The authors wrote that the results support the benefit of starting tube feeding early but must be interpreted with some caution because the studies differed considerably.

Acute pancreatitis (2004)

In a meta-analysis in the BMJ, the same authors pooled six randomised trials with 263 patients with acute pancreatitis. Compared with feeding into a vein, tube feeding was associated with fewer infections (relative risk 0.45), fewer operations to control the pancreatitis and a hospital stay 2.9 days shorter on average. There was no significant difference in deaths or in non-infectious complications. The authors concluded that enteral nutrition should be the preferred route of nutritional support in acute pancreatitis.

How many calories (2016)

Guidelines at the time advised giving intensive-care patients 80 to 100% of their estimated energy needs. Marik and Hooper pooled six randomised trials with 2,517 patients that compared this “normocaloric” goal with deliberately lower feeding — either small “trophic” feeds or permissive underfeeding. They found no difference in acquired infections, hospital deaths, length of stay in the intensive care unit or days free of the breathing machine between the two approaches.

An international research agenda (2017)

Marik was also one of the co-authors of “The intensive care medicine research agenda in nutrition and metabolism”, published in Intensive Care Medicine in 2017, which set out open research questions in the field.

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9. Aspiration Pneumonitis and Aspiration Pneumonia

In 2001, while working in Pittsburgh, Marik wrote a single-author review for the New England Journal of Medicine titled “Aspiration pneumonitis and aspiration pneumonia”. The review is one of his most widely cited papers.

Its title states its central point: two different conditions follow when material from the mouth or stomach is breathed into the lungs, and they are distinct. Aspiration pneumonitis is the chemical injury caused by inhaled stomach contents; aspiration pneumonia is a lung infection caused by inhaling bacteria from the mouth and throat. The two are often grouped together under one label, and the review set out to separate them. PubMed lists no abstract for this paper, so this page does not report its detailed contents.

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10. A 2012 Review of Dietary Supplements

In 2012 Marik and Flemmer asked whether dietary supplements have beneficial health effects in industrialised nations. Their systematic review, in the Journal of Parenteral and Enteral Nutrition, included 63 randomised, placebo-controlled trials in non-pregnant adults in Western countries.

• No benefit was recorded in 45 studies; 10 of these showed a trend towards harm and 2 a trend towards benefit.
• Four studies reported harm: increased cancer deaths in two and increased fractures in two.
• A benefit was reported in 12 studies, 6 of them on vitamin D and 3 on omega-3 fatty acids. Single studies reporting a benefit for vitamin E, folic acid and ginkgo were not confirmed by larger trials.

The authors concluded that, with the possible exceptions of vitamin D and omega-3 fatty acids, there were no data to support the widespread use of dietary supplements in Western populations, and that many of them may be harmful. This sceptical review stands in contrast to his later work, in which vitamin C, thiamine, vitamin D, melatonin and other nutraceuticals play a central part in hospital and cancer protocols; those are covered on the sibling pages linked below.

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11. Publication Record and the Bridge to His Later Work

A PubMed author search for Marik’s name (using his initials, “Marik PE”) returned 424 records on 8 November 2026, and every affiliation checked belonged to him: Johannesburg, London (Ontario), Pittsburgh, Thomas Jefferson University and Eastern Virginia Medical School. From 2023 some of his papers are indexed under the shorter “Marik P”. The records span more than three decades, from a 1990 Johannesburg study of early death after heart attack to reviews published in 2025.

Several lines of his intensive-care research lead directly into the work he became known for later:

• Steroids: his work on corticosteroid insufficiency underlies the hydrocortisone in his 2017 sepsis protocol and the methylprednisolone in his COVID-19 hospital protocol.
• Stress hormones: the reasoning that critically ill patients can run short of a stress hormone carries over to his description of vitamin C as a stress hormone in sepsis.
• Questioning standard practice: the habit of testing a routine practice against the evidence — central venous pressure, large-volume fluid, tight blood-sugar control, the sepsis guidelines — runs through his later protocols.
• Metabolism: his work on stress hyperglycemia, feeding and nutrition in critical illness foreshadows his later interest in metabolism in cancer.

The later work is set out on the pages in the Connections list: the sepsis protocol, the COVID-19 protocols, his cancer book and his metabolic approach to cancer, together with his life and career.

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Key Research Papers

1. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest. 2008;134(1):172-8. — PubMed PMID: 18628220
2. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit Care Med. 2013;41(7):1774-81. — PubMed PMID: 23774337
3. Marik PE, Cavallazzi R, Vasu T, Hirani A. Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically ventilated patients: a systematic review of the literature. Crit Care Med. 2009;37(9):2642-7. — PubMed PMID: 19602972
4. Marik PE, Monnet X, Teboul JL. Hemodynamic parameters to guide fluid therapy. Ann Intensive Care. 2011;1(1):1. — PubMed PMID: 21906322
5. Monnet X, Marik PE, Teboul JL. Prediction of fluid responsiveness: an update. Ann Intensive Care. 2016;6(1):111. — PubMed PMID: 27858374
6. Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care. 2014;4:21. — PubMed PMID: 25110606
7. Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med. 2017;43(5):625-632. — PubMed PMID: 28130687
8. Marik PE. Surviving sepsis guidelines and scientific evidence? J Intensive Care Med. 2011;26(3):201-2. — PubMed PMID: 21670091
9. Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest. 2002;122(5):1784-96. — PubMed PMID: 12426284
10. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937-49. — PubMed PMID: 18496365
11. Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. 2017;43(12):1751-1763. — PubMed PMID: 28940011
12. Marik PE. Glucocorticoids in sepsis: dissecting facts from fiction. Crit Care. 2011;15(3):158. — PubMed PMID: 21586102
13. Marik PE, Bellomo R. Stress hyperglycemia: an essential survival response! Crit Care. 2013;17(2):305. — PubMed PMID: 23470218
14. Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med. 2001;29(12):2264-70. — PubMed PMID: 11801821
15. Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus enteral nutrition in patients with acute pancreatitis. BMJ. 2004;328(7453):1407. — PubMed PMID: 15175229
16. Marik PE, Hooper MH. Normocaloric versus hypocaloric feeding on the outcomes of ICU patients: a systematic review and meta-analysis. Intensive Care Med. 2016;42(3):316-323. — PubMed PMID: 26556615
17. Arabi YM, Casaer MP, Chapman M, Heyland DK, Ichai C, Marik PE, et al. The intensive care medicine research agenda in nutrition and metabolism. Intensive Care Med. 2017;43(9):1239-1256. — PubMed PMID: 28374096
18. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665-71. — PubMed PMID: 11228282
19. Marik PE, Flemmer M. Do dietary supplements have beneficial health effects in industrialized nations: what is the evidence? JPEN J Parenter Enteral Nutr. 2012;36(2):159-68. — PubMed PMID: 22275325
20. Marik PE. The systolic blood pressure variation as an indicator of pulmonary capillary wedge pressure in ventilated patients. Anaesth Intensive Care. 1993;21(4):405-8. — PubMed PMID: 8214544
21. Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA. 1993;269(23):3024-9. — PubMed PMID: 8501845

PubMed Topic Searches

1. Marik: fluid responsiveness
2. Marik: corticosteroid insufficiency in critical illness
3. Marik: enteral nutrition in critical illness
4. Marik: stress hyperglycemia
5. Marik: aspiration pneumonitis and pneumonia

Further Reading

• Marik PE. Handbook of Evidence-Based Critical Care. Springer; 2001. — DOI: 10.1007/978-3-642-86943-3
• Marik PE. Handbook of Evidence-Based Critical Care. 2nd ed. Springer New York; 2010. — DOI: 10.1007/978-1-4419-5923-2
• Marik PE. Evidence-Based Critical Care. 3rd ed. Springer International Publishing; 2015. — DOI: 10.1007/978-3-319-11020-2
• Marik PE. Cancer Care: The Role of Repurposed Drugs and Metabolic Interventions in Treating Cancer. 2nd ed. 2024. — Publisher’s page

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Connections

• Dr. Paul Marik: Critical Care, Vitamin C and Repurposed Drugs
• Paul Marik: Life and Career
• The HAT Protocol: Vitamin C, Thiamine and Hydrocortisone in Sepsis
• MATH+ and Paul Marik’s COVID-19 Treatment Protocols
• Cancer Care: Paul Marik’s Book on Repurposed Drugs
• Paul Marik’s Metabolic Approach to Cancer
• Contemporary Practitioners
• Sepsis
• Adrenal Insufficiency
• Acute Respiratory Distress Syndrome
• Pancreatitis
• Vitamin C and Intensive Care Recovery

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