Sepsis Is a Top Cause of Death in Hospitals

Sepsis is a medical emergency that may become fatal or leave an individual with a significant disability. Data from the CDC1 show that every year at least 1.7 million adults in the U.S. develop sepsis and 1 of every 3 who die in the hospital has sepsis.

While these numbers are shocking, a review of the literature2 shows the incidence of sepsis has grown over the last three decades at a rate quicker than population growth.

The percentage of severe sepsis cases has also increased from 25% in 1993 to 44% in 2003, indicating that not only is the incidence of sepsis rising, but also the number of severe cases.3 Sepsis develops as an overwhelming immune response to an infection.4

The Sepsis Alliance calls this one of the most common misconceptions about the condition, as sepsis is not an infection but rather the body’s response to an infection.5 The second most common misconception is sepsis starts in the hospital. But, sepsis is more likely to start in the community from an infection caused by bacteria or a virus, parasite or fungus.

The immune response triggered by an infection may lead to leaky blood vessels, blood clots, poor blood flow, and in severe cases organ failure.6 When blood pressure drops in combination with a weakened heart it leads to septic shock.

The underlying trigger, an infection, often starts in the community. This may clarify why it is often misdiagnosed in the beginning, which increases the potential risk for disability and death.7

Missed diagnosis leads to death and disability

A missed diagnosis may sometimes mean the difference between life and death. Researchers from Johns Hopkins University School of Medicine found that 74.1% of all serious harms from mistaken diagnoses occurred due to a vascular event, infection or cancer.8

The findings came from an analysis of 11,592 claims of missed diagnosis from 55,377 cases. They were pulled from an extensive medical malpractice claims database. The researchers identified diseases accounting for the majority of morbidity and mortality using the Controlled Risk Insurance Company (CRICO)’s Comparative Benchmarking System, which represents 28.7% of all U.S. malpractice claims.9

They pulled data from events that happened between 2006 and 2015 and found that the average age of individuals who had a missed diagnosis was 49 years. More than half (51.7%) were female, including 53% who died. The most frequent conditions found in the categories were stroke, sepsis and lung cancer.

The financial cost of the severe cases was $1.8 billion in malpractice awards over 10 years.10 Data from malpractice cases showed that missed and delayed diagnoses that cause death or disability are most often associated with cancer, vascular issues and infections.11 Dr. David Newman-Toker, director of the Armstrong Institute Center for Diagnostic Excellence at Johns Hopkins University, commented on the results:12

“We know that diagnostic errors happen across all areas of medicine. There are over 10 thousand diseases, each of which can manifest with a variety of symptoms, so it can be daunting to reckon about how to even start tackling diagnostic problems.

Our findings suggest that the most serious harms can be attributed to a surprisingly small number of conditions. It still won’t be an simple or quick fix, but that gives us both a place to start and real hope that the problem is fixable.”

According to the press release, the researchers believe their data confirm13 “inaccurate or delayed diagnosis remains the most common, most catastrophic and most costly of medical errors.” The authors noted it will take a systemwide effort, including research and quality improvement, to focus on interventions to reduce errors.14


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Recognize the symptoms of sepsis

Sepsis affects both genders across all age groups and socioeconomic categories. If you have an infection that progresses to sepsis, this may increase your risk of death. Researchers have found the death rate of those with sepsis is 10% compared to the 1% of hospitalized patients who don’t develop sepsis.15

In this study,16 researchers found most of the patients in two groups already had sepsis when they were admitted to the hospital; the Sepsis Alliance reports this is common.17 Those who had less severe symptoms when they showed up were in the majority of those who died. This may be related to a delay in diagnosis in those who present with less severe symptoms.

It’s vital to recognize the signs and symptoms of sepsis so you can see your doctor straight away and question about it. One of the reasons sepsis may be misdiagnosed is it often looks like something else. Many of the symptoms may be confused with a terrible cold or the flu.

But, the symptoms tend to develop more quickly than you would expect. The Sepsis Alliance recommends using the acronym TIME to remember some of the more common symptoms:18

T — Temperature higher or lower than normal?

I — Have you now or recently had any signs of an infection?

M — Are there any changes in mental status? For example, do you feel confused or are you extra sleepy?

E — Are you experiencing any extreme pain or illness; do you have the feeling that you may die?

While sepsis may be triggered by a virus, parasite or fungus, most cases are triggered by bacteria, and your doctor may not be able to pinpoint the source of the infection.19 Sepsis often produces:20,21,22

A high fever with chills and shivering

Rapid breathing (tachypnea)

Rapid heartbeat (tachycardia)

Unusual level of sweating (diaphoresis)


Confusion or disorientation

Slurred speech

Diarrhea, nausea or vomiting

Difficulty breathing, shortness of breath

Severe muscle pain

Low urine output

Cold and clammy skin

Skin rash

New York regulated care slightly reduces number of deaths

Your physicians and health care staff are humans, capable of making mistakes and misdiagnosis. After the study was published, Newman-Toker commented:23

“For many patients, misdiagnosis causes severe harm and expense, and in the worst cases, death. This study shows us where to focus to start making a difference for patients. It tells us that tackling diagnosis in these three specific disease areas could have a major impact on reducing misdiagnosis-related harms.”

Researchers from the second study call for more standardization of treatment to reduce hospital mortality, writing:24

“Performance improvement efforts in the treatment of sepsis have primarily focused on standardizing care for the most severely ill patients, whereas interventions for treating other patients with sepsis are less well defined. Given their prevalence, improving standardized care for patients with less severe sepsis could drive future reductions in hospital mortality.”

New York state was the first to start a sepsis regulation program, mandating implementation of specific protocols if sepsis was suspected.25,26 Lead author Dr. Jeremy Kahn of the University of Pittsburgh’s School of Medicine commented on the thought of standardizing care:27

“Rarely in the U.S. do we force hospitals to implement specific clinical protocols. Typically, quality improvement is achieved through financial incentives and public reporting. For the first time, state officials are enshrining in regulations that hospitals must follow certain evidence-based protocols when it comes to sepsis. And our study finds that, at least in New York, it seemed to work.”

After evaluation of more than 1 million sepsis admissions in 509 hospitals in New York and comparing those against four control states that were not using standardized sepsis regulations, the team found the number who died in hospital in New York was slightly lower.28

After accounting for confounding factors, New York state’s death rate from sepsis was 3.2% lower than would have been expected, compared to results the control states experienced over the same years.

What you need to know before you go to the hospital

While any reduction in deaths from sepsis is a step in the right direction, the standardized care enacted in New York in 2013 included only lactate measurements and antibiotic and vasopressor treatments done within the first three and six hours of admission, including:29

Within the first three hours Within the first six hours

blood cultures before antibiotics

30 mL/kg fluid bolus for patients with hypotension or lactate>4 meq/L

lactate measurements

vasopressors for hypotension refractory to fluids

broad-spectrum antibiotics

re-measurement of lactate

This treatment protocol completely overlooks the rising number of antibiotic-resistant infections and the sepsis protocol developed by Dr. Paul Marik, chief of pulmonary and critical care medicine at Sentara Norfolk General Hospital in East Virginia.30

Although Marik’s protocol was published after New York enacted the standardized treatment protocol, it doesn’t appear it will be integrated straight away. Marik’s protocol relies on the synergistic effect of hydrocortisone, ascorbic acid (vitamin C) and thiamine (HAT) for the treatment of severe sepsis and septic shock.31

In his initial retrospective study of patients treated in his hospital, they found that those treated with the protocol suffered an 8.5% mortality rate as compared to 40.4% in the control group.32 The overall reduction in numbers of individuals who succumbed to sepsis is vastly different than those reported in the New York study where hospitals experienced a 3.2% overall reduction.33

Researchers evaluating the same protocol in patients presenting with septic shock after cardiac surgery found the combination reduced the need for vasopressors in adult surgical patients.34 A review of clinical studies found patients who were treated with the protocol demonstrated beneficial effects without safety concerns.35

In a follow-up paper,36 Marik recommended daily measurements of procalcitonin (PCT) as an essential component of the strategy. During the pilot study his team noted an 86% decrease in procalcitonin compared to a 34% decrease in controls. He believes with the HAT protocol, people were more likely to survive because of reduced inflammatory responses and fewer instances of organ failure.

He also found the decline in PCT37 was not found with single use of vitamin C. Marik reported treating more than 1,200 patients with the protocol and noted PCT decline was reproducible with just a few exceptions. If PCT baseline levels failed to fall by 50% in the first 24 hours they realized the incorrect antibiotic was given or there was inadequate source control.

Marik wrote that this finding may improve patient outcomes by allowing for an early change in antibiotics or a more aggressive source control,38 or actions that are taken to control the infection.39

Partial protocol not effective

Administering one or two of the three factors in the protocol and expecting positive results is like giving half a dose of antibiotics and expecting it to work. It is vital to note that Marik uses the protocol as an adjunct, or addition to, antibiotic therapy and not as the only treatment.40

The protocol was designed so that all three work together. But, some critics argue that the treatment has41 “yet to be proven safe and effective in randomized clinical trials,” which they believe42 “exemplifies the phenomenon some called ‘science by press release.'”

One such critic is Dr. Steven Simpson, chief medical officer at Sepsis Alliance.43 He points out the FDA has only approved one drug, Xigris, to treat sepsis that was passed largely on the basis of one phase-3 trial that stopped early when the researchers believed the results were positive.44

But, 10 years later the drug company pulled Xigris from the market as it failed to show any survival benefit in a placebo control trial involving 1,697 patients.45 Dr. H. Bryant Nguyen, director of the ICU at Loma Linda was involved in a retrospective study comparing the outcomes in patients who had and had not received the HAT protocol.46

The letter in JAMA reports this study showed no significant differences in the primary or secondary clinical outcomes, mortality or hospital length of stay. Nguyen commented to JAMA he was completely astonished some already considered HAT a standard of care despite what JAMA called a “dearth of evidence.”47

With Nguyen’s study, it is vital to note that patients were included in the HAT experimental group if they received at least one dose of the protocol.48 In other words, the researchers were evaluating results based on patients who may have received just one dose. That is like evaluating the effectiveness of an antibiotic after having received one dose.

In another recent study,49 scientists evaluated how well vitamin C and thiamine work to help people with sepsis. They found it did not improve survival, and this is most likely because the protocol is based on administration of all three compounds.

Synergistic effect of hydrocortisone and vitamins C and B1

Despite critiques of low-cost, easily accessible treatments for sepsis, there is ample evidence the treatment is safe and effective.50,51,52,53,54,55

While each part of the protocol is safe on an individual basis, they must be administered together to work effectively. Marik clarifies56 the combination targets multiple areas of the body’s response to an infection and helps restore the dysregulated immune response.

This then helps prevent organ failure and death. He goes on to discuss the excess production of reactive oxygen species underlies many of the damaging processes in sepsis.57 His team found the optimal dose of vitamin C was about 6 grams per day.

Corticosteroids help suppress the overactive immune responses in sepsis, but past studies Marik cited showed that while they have a biological effect when administered alone, the effect on patient outcomes is limited. The use of steroids is for the synergistic effect with vitamin C and thiamine.58

Thiamine deficiency has been found to be common among those suffering from sepsis,59,60,61 which leads to a reduction in activity of enzymes dependent on thiamine. This may trigger a sequence of metabolic events that compromises ATP production and energy. Marik finds:62

“Thiamine may act synergistically with glucocorticoids and vitamin C to limit mitochondrial oxidative injury and restore mitochondrial function and energy production. The anti-inflammatory properties of these agents likely restore the activity of the PDC, thereby improving ATP production. But, the interaction between thiamine and ascorbic acid is complex, and likely dependent on the clinical context and ascorbic acid dosing.”

Currently, a large ongoing trial is underway to test this treatment protocol. Researchers are using a prospective, double-blind, multicenter, placebo-controlled, randomized, adaptive sample size trial enrolling those with sepsis who have respiratory and/or circulatory compromise.63

Watch for post-sepsis syndrome

While some will recover fully from sepsis, for many the problems do not end at discharge from the hospital. Survivors may suffer physical, psychological and/or neurological consequences for the rest of their lives. The combination of symptoms is called post-sepsis syndrome and usually lasts between six and 18 months. Symptoms of post-sepsis syndrome may include:64,65

Lethargy (excessive tiredness)

Changes in peripheral sensation

Repeated infections at the original site or a new infection

Poor mobility

Muscle weakness

Shortness of breath

Chest pains

Swollen limbs

Joint and muscle pains


Hair loss

Dry flaking skin and nails

Taste changes

Poor appetite

Changes in vision

Difficulty swallowing

Reduced kidney function

Feeling cold

Excessive sweating




Post-traumatic stress disorder

Poor concentration

Small-term memory loss

Mood swings

Clouded thinking



Currently, there is no specific treatment for post-sepsis syndrome, but many get better over time. The U.K. Sepsis Trust66 recommends managing individual symptoms and supporting optimal health as you’re recovering. They encourage survivors to talk with friends and family and not to suffer with their symptoms in silence, as this helps to get through the hard time.

Not all medical professionals are aware of post-sepsis syndrome, so it may be helpful to talk about your symptoms and question for a referral to someone who may help manage your mental, physical and emotional challenges. Some survivors find their immune system is not as effective as long as a year following their recovery, resulting in one infection after another, including coughs and colds.

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