Sepsis, also called septicemia, is a life-threatening clinical syndrome that is caused by an overwhelming immune system response to bacterial infection. Commonly called “blood poisoning”, sepsis is a global healthcare issue that occurs more frequently than heart attacks and claims more than 250,000 lives every year in the United States alone.
Sepsis is extremely common throughout the world, and is the leading cause of death in developing countries, responsible for 60-80% of their overall mortality rates.Sepsis is also one of the most expensive causes of hospitalization.
Table of Contents
Data released from the CDC shows that the US spends roughly 20 billion dollars annually on the treatment of septicemia, which translates to a daily cost of over 55 million dollars. This is partly due to the lengthy treatment time frame required to treat the condition- sepsis patients remain in hospital roughly 75% longer than other patients.
Defined as a presence of pathogenic organisms or their toxins in the blood and tissues, sepsis is a serious condition that causes a wide range of life-threatening symptoms such as fever, rapid heart rate, extreme sweating, dizziness, respiratory difficulty, loss of consciousness and even organ failure. Sepsis can develop from any form of infection if the correct conditions arise, with individuals that suffer from low immune system function at higher risk.
Fortunately, sepsis is a systemic health condition that can be easily avoided by practicing preventative measures, adhering to healthy lifestyle practices and maintaining a balanced, nutritional diet. There are a number of natural health supplements and foods that provide a great deal of protection from sepsis, as well as homeopathic treatment techniques that can significantly minimize the risk of contracting this dangerous condition.
In this article, we’ll present a detailed explanation of what sepsis is and how it occurs in the body, as well as information on the key indicators and treatment methods of the syndrome. We’ll also take a look at the six most effective natural techniques and remedies you can use to protect your body from sepsis.
Sepsis Explained
The medical definition of sepsis has changed multiple times throughout history, as the complex nature of the condition makes it difficult to delineate a clear and concise summary of the syndrome. The most recent revision of the definition occurred in 2016, when the Third International Consensus Task Force defined sepsis as a life threatening organ dysfunction caused by the immune system response to infection.
Sepsis can be generally defined as a condition in which an infection reaches the bloodstream, triggering a massive immune system response. This large scale immune system response damages the organs and tissue of the body, resulting in three primary criteria that are used to define the condition:
- Altered mental state
- Respiratory function faster than 22 breaths per minute
- Low blood pressure
Sepsis is not a contagious condition- it occurs inside of the body in response to external pathogens or bacteria. The external factors that cause sepsis can be infectious, with bacterial agents such as Streptococcus pyogenes, Staphylococcus aureus, and Enterococcus the most common causes. These pathogens commonly colonize the body either through skin and soft tissue infections, or via urinary tract infections.
Hospitals, especially in the developing world, are actually one of the most common places in which sepsis occurs, due to the prevalence of pathogens in medical conditions. The medical practices in the developing countries in which sepsis occurs commonly overlook basic hygienic practices such as the sterilization of medical equipment, which can transfer pathogens between patients and induce septicemia.
All instances of sepsis, or septic shock, an advanced and severe form of the condition, develop from smaller, less dangerous infections. Sepsis develops when the infection becomes severe enough to reach the bloodstream, which causes Systemic Inflammatory Response Syndrome. Left untreated, sepsis progresses into septic shock, which causes dangerously low blood pressure, resulting in organ failure, respiratory failure, loss of consciousness and death.
Sepsis fast facts:
- Sepsis is caused by a severe infection reaching the bloodstream
- Sepsis progresses into severe sepsis, which, in turn, progresses into septic shock
- Sepsis is one of the most dangerous medical conditions in the world
Sepsis Key Indicators & Symptoms
The symptoms that may indicate the presence of sepsis in the body can be subtle, difficult to identify, and are commonly mistaken for the symptoms of other serious diseases. The primary identifying factor in any sepsis diagnosis in an existing severe infection. The most common symptoms of sepsis include:
- Low blood pressure
- Dizziness or fatigue
- Chills or hot flushes
- Shivering, fever, or low body temperature
- Altered consciousness or confusion
- Fast breathing or shortness of breath
- Fast heart rate
- Low urine production
- Skin discoloration
- High blood sugar levels
The above symptoms are generally present in the earlier stages of sepsis, and worsen as the condition proceeds into severe sepsis and septic shock. More serious symptoms caused by sepsis include extremely high white blood cell count, low blood oxygen levels, and organ failure. Severe sepsis can also present as slurred speech, a feeling of impending doom or anxiety, or diarrhea and vomiting.
An easy way of remembering the key signs of sepsis can can be summarized in this mnemonic acronym:
- Shivering, cold body temperature, or fever
- Extreme pain or discomfort
- Pale or discolored skin
- Sleepy behaviour or inability to stay awake
- I feel like I may die
- Shortness of breath
Identifying the key indicators and symptoms of sepsis as soon as they occur is critical in ensuring effective treatment. If you believe you may have any of the symptoms of sepsis and are suffering from a serious infection, it’s important to seek the advice of a medical professional as soon as possible.
The Causes and Potential Risk Factors of Sepsis
Sepsis can be caused by any kind of infection in the body, but most commonly arises from infections in the abdomen, pelvis, urinary tract, and lungs. Sepsis is also frequently contracted during extended hospital stays due to poor sanitary conditions. Some of the most common medical procedures that cause sepsis are any kind of invasive surgery or the fitting of urinary catheters.
Following are some of the most common sources of infection that can lead to sepsis:
- Skin infections, including fungal infections. Cellulitis, which is frequently caused by the insertion of a contaminated intravenous catheter, is a leading cause of medical infection.
- Lung infections and respiratory diseases such as pneumonia
- Bladder, urethra or kidney infections, especially UTIs
- Post-surgery infections
- More severe forms of the flu
- Brain and nervous system infections such as encephalitis or meningitis
- Peritonitis, which is caused by an inflammation of the membrane that lines the abdominal wall
- Infections of the gallbladder or bile ducts
- Appendicitis
- Bone or heart infections
- Untreated tissue infections caused by cuts or scrapes
Sepsis can occur in even small playground scrapes if the infection is left untreated for an extended period of time. Pregnancy and childbirth are also leading causes of sepsis. Sepsis that occurs during pregnancy is referred to as maternal sepsis, while post-childbirth sepsis is called postpartum sepsis. A study published in 2013 reported that sepsis is the leading cause of maternal death in the UK, and accounts for roughly 7.6% of maternal deaths in the United States.
The biological mechanism that induces sepsis in the body is linked to the immune system. The immune system usually deals with infection in just one location, and generates white blood cells that are sent to the site of the infection to destroy the pathogens responsible. As part of this process, the tissue in the infected area becomes inflamed to prevent the pathogen from spreading throughout the body. When a pathogen is able to infect the bloodstream of the body, this localized immune system response begins to affect the entire body.
The extreme inflammation caused by sepsis is called Systemic Inflammatory Response Syndrome and damages tissue throughout the body, interfering with the ability of the circulatory system to pump blood to muscles, tissue, and organs. Virtually everybody has the capacity to contract sepsis, although there are several risk factors that increase the chance of developing blood poisoning.
People who meet the following criteria are more at risk of developing sepsis:
- Individuals with immune system disorders such as HIV, leukaemia, or crohn’s disease. In these individuals, the immune system is weaker and less efficient in removing infection from the body, which can allow pathogens to colonize the bloodstream.
- Individuals taking medication that can interfere with immune system function such as steroid treatments or chemotherapy
- Elderly individuals or young children
- Pregnant women
- Individuals suffering from long term health conditions, such as diabetes.
- Individuals that possess a genetic proclivity to infection
- Individuals in hospital or those undergoing surgery
- Individuals that require mechanical ventilation to breathe
- Individuals with untreated infected wounds or injuries
There are several strains of antibiotic resistant bacteria that are extremely prone to causing sepsis. These pathogens possess the ability to shrug off the effects of antibiotics due evolution and natural selection.
Many forms of bacteria that are antimicrobial resistant, such as MRSA, are extremely endemic, causing 20,000 deaths annually in the US alone. Worryingly, these “superbugs” are mostly contracted in hospital environments, where they contribute greatly to the development of sepsis in sick individuals.
Diagnosis Methods Used to Identify Sepsis
The systemic nature of sepsis makes it difficult to diagnose unless the symptoms are severe. There is no conclusive test to determine whether an individual has sepsis- diagnosis generally consists of a battery of tests that analyze the blood, urine and saliva of a patient.
If a doctor believes a patient may exhibit the key indicators of sepsis, the first step taken is to assess the recent medical history of the patient to check for any infections, review family medical history, and note any recent medical procedures that may have been performed, such as catheter insertion or surgery. The second step is usually a blood test, which will test for various conditions such as:
- The presence of pathogens in the blood
- Blood clotting inhibition
- Low oxygen levels
- Abnormal organ function in the kidneys or liver
- Low electrolyte levels
Other tests that may be conducted after a blood analysis include a urine test to check for the presence of bacterial in excreta, swap tests of the mouth or open wounds, and a mucus secretion test.
Further testing beyond these methods is rare, but can include x-ray analysis of the lungs, CT scans of the internal organs, ultrasound assessment of the reproductive organs or gallbladder, and MRI assessment of soft tissue.
Sepsis Treatment
A sepsis diagnosis results in immediate medical treatment to slow the progression of the infection in the body. Haste is critical in the treatment of sepsis, as it advances quickly through the body and develops into shock rapidly.
There are a number of medications that are commonly used to treat sepsis, which typically come in the form of powerful intravenous antibiotics. Other medications used to treat sepsis include:
- Blood pressure boosting medications called vasoactive medication
- Intravenous insulin, used to balance blood sugar levels
- Inflammation-reducing corticosteroids
- Pain medication
Along with these medications, treatment of sepsis also includes the intravenous application of large amounts of fluids to keep the body hydrated. In advanced cases of sepsis, kidney failure may require a patient to be placed on a dialysis machine to assist in removing toxins, waste, and salt from the blood.
Advanced sepsis may also require surgery to remove abscesses from inside the body that are caused by extensive infection.
Modern medicine has greatly improved the survivability rates of individuals that have developed sepsis. A six-year study of sepsis episodes observed in an ICU that was published in the Croatian Medical Journal in 2006 reports the mortality rates of sepsis, severe sepsis, and septic shock as 17%, 33.7% and 72%, respectively.
Patients that are treated during the early stages of sepsis, when the primary symptom is systemic inflammatory-response syndrome, possess a much higher survival rate, at 93%.
Early identification and treatment is key in treating sepsis, and provides a far greater chance of recovery. There are, however, a number of long-term consequences of developing sepsis. Post-Sepsis syndrome, or PSS, affects up to 50% of individuals that have recovered from sepsis. The symptoms of this condition include:
- Anxiety, hallucinations, and panic attacks
- Insomnia
- Chronic fatigue
- Poor cognitive function and an inability to concentrate
- Chronic muscle and joint pain
These symptoms can be caused by some of the drastic medical procedures that are used to treat severe forms of sepsis, such as the surgical amputation of the extremities that is necessitated by sepsis-induced gangrene.
The systemic infection caused by sepsis can also damage the respiratory system, causing respiratory difficulty and an increased risk of developing lung infections. The psychological symptoms of PSS are linked to post traumatic stress disorder, which is common in patients that have survived life-threatening illnesses.
As with any disease or systemic clinical condition, the best method of treatment is prevention. Let’s take a look at some of the most effective natural ways you can protect your body from sepsis:
6 Natural Ways to Protect Your Body From Sepsis
As there is no definitive cure for sepsis, only treatment methods, it’s important to practice a preventative lifestyle to ensure you never develop the signs of this dangerous condition. Sepsis is caused by a variety of factors that always ensue from untreated infection and inflammation.
Minimizing your chances of developing an infection and reducing the total amount of inflammation in the body protects the body from these two primary causes, significantly improving your long term health.
1. Use Antibiotics Sparingly
The high prevalence of antimicrobial resistant pathogens in the hospital environment contribute a great deal to the endemic nature of sepsis. These pathogens are resistant to antibiotics, and cannot be treated by many medical treatments, meaning they are able to infect the body and rapidly cause sepsis.
A global report on the surveillance of antimicrobial resistant pathogens released by the World Health Organization in 2014 observes that antibiotic-resistant diseases and bacteria are now at an all-time high, with a post-antibiotic medical world a very real possibility by the end of the 21st century[1]. Referred to as the “Antibiotic Resistance Crisis”, the sudden increase in the phenomena of the rapid emergence of resistant bacteria is caused by the overuse and misuse of antibiotic medications[2].
The increase in drug-resistant bacteria has been demonstrated to contribute to both increased rates of sepsis diagnosis in individuals with lung infections, and an increase in the associated mortality rates[3]. A 2016 study that assessed the pathogenic source of sepsis in over 13,000 newborn babies found that sepsis rates have increased at an alarming speed due to the rapid rate at which these pathogens invade the body and the ineffectiveness of modern medicine in treating them[4].
There are no alternatives to antibiotic medications in treating many of these pathogens, meaning without controlled, responsible use of antibiotics, the current Antibiotic Resistance Crisis could become far worse. You can help to fight the superbug crisis by minimizing your use of antibiotics, relying on the immune system of your own body to heal yourself from less dangerous illnesses such as the common cold instead of seeking an antibiotic prescription.
While minimizing your use of antibiotics doesn’t have an immediate effect on the ability of your own body to prevent sepsis, reducing the frequency at which you use them helps to control the spread of antibiotic resistance for everybody on the planet, minimizing the overall diagnosis rate of sepsis and lowering the statistical chance that you may develop it.
Antibiotics and sepsis quick facts:
- Irresponsible antibiotic use leads to the spread of medicine-resistant pathogens
- Antibiotic resistant bacteria significantly increase the mortality rate and prevalence of sepsis
- Minimizing antibiotic use helps to prevent the spread of antibiotic resistant pathogens
2. Probiotic Foods & Supplements
The human digestive system contains billions upon billions of tiny microorganisms that work in synergy with the human body. Called gut flora, these organisms are collectively referred to as the microbiome, and play a significant role in the health of the body, often referred to as the “forgotten organ”[5]. The microbiome of the body has a mutualistic relationship- the body provides them with food, and, in turn, they provide the body with key vitamins, fatty acids, and protect it from pathogens.
Gut flora have been conclusively scientifically proven to contribute significantly to the efficiency and effectiveness of the immune system, preventing pathogens from colonizing the body[6]. A 2008 meta-analysis of 26 different clinical investigations into the role of the microbiome found that up to 70% of the immune system of the body is located in the gut[7].
Probiotics are microorganisms in the form of yeasts and bacteria that have a positive effect on the balance of gut flora, considered to be “good” bacteria. The health benefits of probiotics have been known to medical science for over 100 years, and recent clinical investigations show that they have a powerful ability to prevent bacterial infection[8]. Improving the health of your microbiome is a highly effective method of reducing the risk of developing sepsis.
The link between probiotics and sepsis has been demonstrated in multiple clinical trials. A 2013 clinical trial performed by the University of Colorado School of Medicine found that administration of probiotic supplements in the early stages of sepsis can significantly lower mortality rates and improve recovery speed[9]. An earlier investigation conducted by the University of Alberta in 2008 demonstrated that probiotics are able to significantly improve immune system function in individuals with sepsis by minimizing infection[10].
There are many ways to increase your probiotic intake. Foods such as yogurt, dark chocolate, pickles, fermented milk products, and sauerkraut are all rich in probiotics. Probiotic supplements are also highly effective ways to improve gut health, with strains such as L. acidophilus and Lactobacillus commonly available in capsule form.
Probiotics and sepsis quick facts:
- The gut contains microorganisms that promote immune system function
- Healthy gut flora can help to prevent sepsis
- Probiotic supplements and foods improve immune system function
3. Practice Proper Wound Care
Untreated infections are one of the primary causes of sepsis. If left untreated or cared for improperly, even a relatively minor wound can present a serious risk of causing sepsis in the body. Maintaining proper wound care has been clinically proven to significantly reduce the risk of developing sepsis[11].
Proper wound care involves five essential steps to ensure infection does not take hold in the body. If you suffer a minor wound that does not require immediate hospitalization, always follow these steps to ensure you’re practicing proper wound care:
- Clean the wound. Gently cleaning a wound with clean water and mild, natural soap will remove foreign materials and pathogens that can cause infection.
- Prevent infection with a natural antibiotic agent. Avoid antibiotic creams for this purpose, as they contribute to the spread of antibiotic resistant pathogens. Honey is a surprisingly effective treatment for this purpose- it has been clinically proven in 15 separate clinical trials to speed up wound healing and prevent infection when used as a topical wound treatment[12].
- Cover the wound. Light, clean medical gauze is the best wound covering, and should be applied in 3-4 layers to ensure the wound does not become dirty.
- Practice hygienic wound maintenance. Once the initial gauze has been removed, wounds should be cleaned, natural antibacterial agents reapplied and gauze changed 1-4 times daily, depending on wound drainage.
- Eat healthy and rest well. The body can only heal when at rest. Be sure to provide your body with enough nutritional intake and water to promote fast wound healing.
By following these steps, it’s possible to lower the chance that your wound may become infected and therefore protect your body from sepsis. If your wound begins to exhibit the signs of infection, it’s important to seek medical attention from a trained professional immediately. The key indicators that a wound may be infected are:
- Cloudy discharge or pus draining from the wound
- Inflamed or red skin
- Red streaking around the wound
- Swelling, increased pain, or tenderness
- Fever
If you are in hospital, or recovering from surgery, it’s critically important to seek medical attention immediately if you notice any of the above symptoms.
Wound care and sepsis quick facts:
- Infected wounds are a major cause of sepsis
- Practicing proper wound care prevents wound infection
- Honey is an effective topical wound treatment that has been proven to prevent infection
4. Zinc and Selenium Supplements
Micronutrient intake has a powerful effect on the immune system. The link between the micronutrient intake of the body and immune system function has been conclusively proven in multiple clinical trials[13][14][15]. Failing to provide your body with the critical nutritional elements it needs has a wide range of deleterious effects, including anemia, fatigue, inflammation, and an increased risk of developing infections or disease.
While micronutrients perform a wide range of health-boosting functions in the body, two mineral micronutrients in particular have been observed to positively modulate immune system function dramatically and protect the body from sepsis. Both zinc and selenium are critical to preventing systemic infection- a 2015 clinical trial found that deficiency in these two essential elements can increase the risk of developing sepsis[16].
Supplementing the diet with these substances has been proven to both prevent sepsis and help to treat sepsis when it occurs. A 2016 clinical trial that assessed the efficacy of zinc in treating sepsis found that it is able to improve overall health in patients with sepsis[17]. Selenium supplementation has been demonstrated in multiple clinical trials to ameliorate the symptoms of sepsis, speed up the recovery process, and reduce sepsis mortality rates[18][19]
It’s easy to increase your selenium intake by adding foods such as grass-fed beef, brazil nuts, chicken, and fish to your diet. Zinc can be found in foods such as shrimp, kidney beans, flax, spinach, and pumpkin seeds. Both of these minerals are also commonly available in inexpensive daily supplement forms.
Zinc, selenium and sepsis quick facts:
- Zinc and selenium deficiency can increase the risk of developing sepsis
- Supplementing the diet with zinc and selenium improves immune system function
- Zinc and selenium are found in many common foods
5. Homeopathic Treatments
Homeopathy is a popular alternative medicine that involves using natural substances to treat illness and disease. Although the treatments used in homeopathy differ from those used in modern pharmaceutical medicine, they have been scientifically proven to deliver effective relief from a wide range of disorders and health conditions[20].
There have been a number of clinical trials that have investigated the efficacy of homeopathic solutions in treating sepsis in both the early stages and more severe forms. A randomized, double-blind, placebo-controlled clinical investigation performed by the Ludwig Boltzmann Institute for Homeopathy in 2005 found that homeopathic sepsis treatments have a 25% higher rate of effectiveness when compared to a placebo, concluding that homeopathic solutions are a useful therapeutic measure for the condition[21].
There are many other trials that conclude that homeopathy, while not able to completely cure sepsis, offer a great deal of therapeutic benefit[22][23]. A recent 2016 clinical trial also concluded that homeopathic solutions also have the ability to offer a degree of protection against respiratory infections, which are one of the primary causes of sepsis[24].
Homeopathy and sepsis fast facts:
- Homeopathy can help to alleviate the symptoms of sepsis and promote faster recovery
- Homeopathy increases sepsis survivability
- Homeopathy can prevent respiratory infections
6. Propolis
Propolis, like honey, is a substance made by bees that has a number of health benefits. Consisting of a resin-like mixture made from honey and tree sap, propolis is used by bees to construct beehives. This unique substance has been clinically proven to have a positive effect on the immune system, helping the body fight off infection[25].
Propolis is usually taken as a dietary supplement, but is also available in cream and lotion solutions for cosmetic health. The immunomodulatory effects of propolis are found through oral supplementation however, which is backed up by clinical evidence. A 2015 meta-study found that Brazilian red propolis is able to deliver anti-inflammatory and antimicrobial properties in patients suffering from sepsis, while another 2016 clinical trial found that it is able to prevent respiratory tract infections[26].
Propolis has also been found to speed up burn healing, improve oral health, regulate blood sugar, and even protect the body from carcinogens. Tincture of propolis is a popular solution used by many natural health enthusiasts as it contains concentrated tree resins, which are the active health-boosting element of the substance.
Propolis and sepsis fast facts:
- Propolis is made by bees and is able to boost immune function
- Clinical trials prove the efficacy of propolis in treating sepsis
- Propolis can prevent infection from occurring in the body
Sepsis Health & Safety
Sepsis is a serious health condition that can progress rapidly from a simple infection to a life-threatening illness. If you believe you may be suffering from any of the symptoms associated with sepsis, it’s essential to consult a medical professional immediately, especially if you have an infection anywhere on or in your body. Always consult a doctor before using a natural treatment method to treat an illness, especially when considering using a natural alternative in lieu of a conventional medical solution.
Sepsis Summary
While sepsis is incredibly dangerous and life-threatening, it generally only occurs in individuals that already have a serious infection or are already ill. There is currently no cure for sepsis, but it can be effectively treated if identified early enough with a high success rate. Preventing sepsis through healthy lifestyle practices and protective techniques will stop infection from developing into sepsis.
Ensuring you’re getting the correct daily intake of micronutrients and maintaining proper hygiene not only protects your body from sepsis and infection, but also helps to keep your body healthy and full of energy. An overall healthy lifestyle will keep you active, out of hospital, and disease free, ensuring the long-term health of your body.
Sepsis Fast Facts
- Sepsis is a life-threatening infection of the blood
- Sepsis can be caused by untreated infections
- Antibiotic-resistant bacteria infections are a leading cause of sepsis
- Sepsis treatment is effective if the condition is identified early
- Prevention is the best form of treatment
- Probiotics, proper wound care, health supplements and homeopathy can all help prevent sepsis
- Sepsis requires immediate medical care- always consult a doctor if you believe you may exhibit signs of sepsis
- http://www.world-sepsis-day.org/?MET=SHOWCONTAINER&vCONTAINERID=11
- https://blogs.cdc.gov/safehealthcare/the-cost-of-sepsis/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968574/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684427/
- http://www.medicalnewstoday.com/articles/305782.php
- http://www.sepsis.org/sepsis/symptoms/
- http://journals.lww.com/anesthesia-analgesia/Fulltext/2013/10000/Maternal_Sepsis_Mortality_and_Morbidity_During.24.aspx
- http://www.nhs.uk/Conditions/Blood-poisoning/Pages/Causes.aspx
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937522/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840971/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2080418/
- https://www.ncbi.nlm.nih.gov/pubmed/9627170
- http://www.sepsis.org/sepsis/post-sepsis-syndrome/
- http://www.uofmhealth.org/news/archive/201210/sepsis-survivors-prone-respiratory-viral-infections
- http://www.hopkinsmedicine.org/news/media/releases/ptsd_symptoms_common_among_icu_survivors
- http://www.who.int/drugresistance/documents/surveillancereport/en/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/
- https://www.ncbi.nlm.nih.gov/pubmed/14620154
- https://www.ncbi.nlm.nih.gov/pubmed/27633433
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1500832/
- https://www.ncbi.nlm.nih.gov/pubmed/23426535
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515351/
- https://www.ncbi.nlm.nih.gov/pubmed/24285463
- https://www.ncbi.nlm.nih.gov/pubmed/23571641
- https://www.ncbi.nlm.nih.gov/pubmed/18806700
- https://www.ncbi.nlm.nih.gov/books/NBK6957/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495394/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC500310/
- https://www.ncbi.nlm.nih.gov/pubmed/17922955
- https://www.ncbi.nlm.nih.gov/pubmed/10944478
- https://www.ncbi.nlm.nih.gov/pubmed/25833826
- https://www.ncbi.nlm.nih.gov/pubmed/26616409
- https://www.ncbi.nlm.nih.gov/pubmed/23587641
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4095569/
- https://www.ncbi.nlm.nih.gov/pubmed/10853874
- https://www.ncbi.nlm.nih.gov/pubmed/15892486
- https://www.ncbi.nlm.nih.gov/pubmed/21459302
- https://www.ncbi.nlm.nih.gov/pubmed/19371570
- https://www.ncbi.nlm.nih.gov/pubmed/27004125
- https://www.ncbi.nlm.nih.gov/pubmed/17580109
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927136/
