ADVANCES IN SEPSIS
Research for diagnosis, treatment, and management of sepsis has become a continuing challenge for the medical profession. New and effective protocols may promote better care for critically ill septic patients.
This section of the website offers a window into the forward thinking about improving sepsis outcomes, by providing brief summaries of more current approaches, and internet links for further reading and investigation. It is not all-inclusive, and it will continually evolve as new theories, clinical trials, strategies, and innovative solutions are presented.
VAGUS NERVE/SEPSIS
The vagus nerve is the tenth of twelve paired cranial nerves that wanders from the brain stem through the organs in the neck, thorax, and abdomen. It has a number of branching nerves that come into contact with the heart, lungs, voice box, stomach and ears. The vagus nerve carries incoming information from the nervous system to the brain, providing information about what the body is doing, and also transmits outgoing information which governs a range of reflex responses. It helps to regulate the heartbeat, control muscle movement, keep a person breathing, and transmit a variety of chemicals through the body.
Dr. Kevin Tracey, director and chief executive head of the Center for Biomedical Sciences at the Feinstein Institute, and his associates, are working to solve the sepsis puzzle by studying the immune system and the vagus nerve which controls the body's inflammatory response. Their goals are to prevent sepsis, or reverse the process before sepsis, an overwhelming, out of control inflammatory response to an infection or trauma turns deadly.
They are testing the effects of vagus nerve stimulation in blocking the inflammatory response that leads to sepsis. Stimulating the vagus nerve reduces the production of cytokines, or immune system mediators, and blocks inflammation. The nerve "circuitry" called the "inflammatory reflex" is controlled by a neurochemical called acetylcholine. As they discover the role of the vagus nerve in the modulation of inflammatory reactions, new ways to treat sepsis may evolve.
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LEAKING BLOOD VESSELS/SEPSIS
Dr. Warren Lee of St. Michael's Hospital in Toronto states that leaking blood vessels- previously thought to be merely a symptom of the illness, may actually be a cause of sepsis. Widespread leakage from small blood vessels leading to swelling in tissues and organs (edema) is a key feature of sepsis. There have been no clinical trials of drugs designed to prevent or treat leaky blood vessels, and evidence suggests that the breakdown in endothelial barrier function plays a crucial role in the pathogenesis of sepsis. The endothelium is the thin layer of cells that lines the interior surface of blood vessels. New theories may change our thinking about sepsis, and lead to novel treatments that could reduce mortality.
"DEATH SWITCH" PROTEIN/SEPSIS BIOLOGICAL MECHANISMS
Researchers from Rhode Island Hospital have identified a protein that plays a dual role in the liver during sepsis. The protein, known as Receptor Interacting Protein 1 or RIP1, acts as a "death switch", and as a pro-survival mechanism. It is believed that it plays a key role in cell function during sepsis, and if the pro-survival trigger can be identified, it could have major implications on how sepsis is treated in the future, helping to possibly develop new therapeutic targets that can mitigate the effects of cellular/organ damage, and reduce mortality.
1. http://www.sciencedaily.com/releases/2011/02/110202102746.htm
2. The Dual Functions of Rip1 in Fas-Induced Hepatocyte Death During Sepsis. Shock,
2011; : 1 DOI : 1097/SHK.ObO13e31820b2db1 (journal)
THE "SEPSIS BELT"
New research reveals that residents living in a region of the southeastern United States known as the "Stroke Belt" which spans 11 states from Louisiana to Virginia, are also at greater risk for sepsis.
"In 2010, we examined the death rates from sepsis across the United States," said Dr. Henry Wang, associate professor and vice chair for research in the University of Alabama at Birmingham (UAB) department of medicine. "Laying it out on a map, we saw that the states with the highest mortality formed a cluster in the Southeast United States, closely mirroring the appearance of the Stroke Belt."
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With a grant from the National Institute of Nursing Research, Dr. Wang intends to examine the risk factors for sepsis and potential reasons for the cluster. Possible causes could include pre-existing medical conditions, health behaviors, diet, genetics, environment and air pollution.
The regional distribution of a disease may provide important insights regarding its pathophysiology, risk factors and clinical care. This research may provide new ways to prevent sepsis, and can help identify the characteristics of persons most likely to be hospitalized for sepsis, as well as lead to strategies to prevent onset.
SIMULATION TRAINING FOR SEPSIS
Simulation training is used to identify and treat early signs of sepsis, with a goal aimed at reducing the rate of reported sepsis-associated mortality. Recognizing the early signs and symptoms of sepsis is of upmost importance.
Samuel Merritt University, located in Oakland, California, and the Health Science Simulation Center (HSSC) use human-like mannequins, managed by sophisticated computer software to enable healthcare providers to learn, practice, repeat procedures, and watch themselves on video as often as necessary in order to correct mistakes, fine-tune their skills, and develop patient practice that can optimize clinical outcomes. Simulation exercises provide a real life scenario, and the mannequins provide a safe learning environment, without putting patients at risk.
SimSuite Medical Simulation Corporation in Denver, Colorado has produced the SimSuite Sepsis Program which is the only simulation-based training solution that focuses on early identification, as well as implementation of therapies using hands-on education. Training is accomplished using the Laerdal SimMan, SimMan 3G, or the SimMan Essential Simulator.
On their website they offer a web course in two formats: Sepsis Concise, and Sepsis Comprehensive.
Sepsis Concise focuses on early identification of sepsis and the Surviving Sepsis Campaign Resuscitation Bundle, while Sepsis Comprehensive includes Sepsis Concise content and additional content on the pathophysiology of sepsis. The goal of this program is to increase and reinforce the competence and confidence of any healthcare team member associated with the care of individuals who present or develop sepsis.
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The SimSuite Mobile Simulation Lab based in Denver has visited Stockton, California where staff members from St. Joseph's Medical Center and San Joaquin General Hospital had the opportunity to get hands-on training with a lifelike mannequin programmed to go into septic shock. Doctors had to react in real time during their three-hour training sessions or they could lose the patient. Simulation provides consistent, standardized training that will reinforce guidelines and improve patient outcomes.
RAPID SEPSIS DIAGNOSIS/MINOLAB
Researchers at the Fraunhofer Institute for Cell Therapy and Immunology hope to improve survival rates with a product called MinoLab, a new testing platform which they claim will be able to provide results in under an hour. Current sepsis tests can take up to two days, which can delay treatment until it is too late. One of their scientists, Dr. Dirk Kuhlmeier, explains that: "After taking a sample of blood, magnetic nanoparticles bind themselves to the target cell in the blood sample through specific catcher molecules. We then use a simple magnet to transfer the particles onto the plastic card along with the pathogens and move them through various miniaturized reaction chambers which is where the polymerase chain reaction takes place. This is a method for copying even the smallest DNA sequences of pathogens millions of times. After it is copied, the nanoparticles transport the pathogen DNA into the detection chamber where a new type of magnetoresisitive biochip can identify pathogens and antibiotics resistances. "
ANTI-SEPSIS PRODUCTS
Here are a few products that represent extensive efforts to improve survival and reduce mortality in sepsis. Some are in different stages of development with different phases of clinical trials used to evaluate safety and efficacy. The challenge of treating sepsis is huge, and the battle continues.
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CYTOFAB
CytoFab, or AZD9773, developed by AstraZeneca, is an ovine polyclonal anti-TNF-alpha antibody fragment for the treatment of sepsis. CytoFab goes right to the heart of the matter, and blocks the inflammatory cascade at its start, no matter what the cause.
The target profile includes: indication as a first-line treatment of adult patients with severe sepsis, a mechanism of action as an anti-inflammatory agent that interrupts the cytokine cascade, reduction in ventilator days, reduction in mortality, and minimal side effects. Phase IIb clinical trials data show that CytoFab has potential to become a routine addition to first-line care in severe sepsis. Studies continue to compare efficacy and safety of CytoFab dosing regimens in adult patients with severe sepsis.
TALACTOFERRIN ALPHA
Talactoferrin, a novel dendritic cell recruiter and activator (DCRA), is a unique recombinant form of human lactoferrin, an important immunomodulatory protein. It was produced by scientists at Baylor College of Medicine, Houston, Texas, in 1998, which paved the way for testing its potential.
Lactoferrin, found in the highest concentration in milk, is expressed throughout the body in immune cells and on all body surfaces exposed to the external environment. Lactoferrin plays an important role in helping to establish the immune system, including the GALT, in infants.
Agennix, a private biotechnology company has developed and tested talactoferrin and retains worldwide rights to it. Their company focuses on development of novel therapies that have the potential to substantially improve the length and quality of life of critically ill patients in areas of major unmet medical need. Talactoferrin has shown potential for reduction in mortality in patients with severe sepsis. A Phase 3 trial is being planned and is scheduled to start in the early Fall of 2011.
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TORAYMYXIN
Spectral Diagnostics Inc. of Canada, has developed a product called a Toraymyxin cartridge, a blood purification device that absorbs endotoxin from the bloodstream, when added to conventional therapy, significantly improved hemodynamics and organ dysfunction, and reduced 28-day mortality in patients with severe sepsis and septic shock.
The technical name for Toraymyxin is a Polymyxin B extracorporeal direct hemoperfusion adsorption column. Hemoperfusion is a medical process to remove a toxic substance (in this case endotoxin) from a patient's blood by pumping blood over an absorbent surface. By passing an endotoxemic patient's blood through the device, endotoxin, a major cause of sepsis, is removed from the bloodstream.
The cartridge or column is packed with the antibiotic Polymyxin B, which has a high affinity for endotoxin, absorbing it as blood passes through. Spectral holds the rights for Toraymyxin in the United States and Canada, and continues clinical trials for severe sepsis and septic shock.
SEPSIS RESEARCH
Sepsis as a research problem can have many specific targets where scientists test theories and refine treatments. Innovative research is an ongoing process that studies sepsis mechanisms, therapies and interventions, develops new technology, and provides clinical trials. Clinical trials are conducted in phases from initial studies, to controlled studies, to expanded studies, determining safety, efficacy, and evaluating overall benefits and risks.
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6. Clinical Laboratory News- is a monthly publication that is an authoritative source for timely analysis
of issues and trends affecting clinical laboratories, clinical laboratorians, and the practice of clinical
laboratory science.
The State of Sepsis Care, Clinical Laboratory News, March 2011: volume 37, Number 3
7. The National Institutes of Health (NIH) Clinical Center in Bethesda, MD is the nation's largest hospital
devoted to clinical research, with a vision to lead the global effort in training today's investigators
and discovering tomorrow's cures. Dr. Peter Eichacker in the Critical Care Medicine Department is one
example of their doctors who has a research interest in sepsis.
8. Fraunhofer-Gesellschaft. Fraunhofer is Europe's largest application-oriented research organization.
Their research efforts are geared entirely to people's needs: health, security, communication, energy,
and environment. The Fraunhofer Institute for Cell Therapy and Immunology develops, optimizes, and
validates methods and products for the Business Units,Agents, Cell Therapy, Diagnostics and Biobanks.
SEPSIS VACCINE/COWS
A specialized anti-sepsis vaccine, called J-5, has been developed by Dr. Alan Cross, a professor at the University of Maryland, School of Medicine. The concept is to vaccinate dairy cows with an anti-sepsis vaccine and harvest colostrum (immune milk) that is enriched with highly specific yet broadly cross-reactive antibodies against endotoxin. The vaccine has already proven safe in human trials, and showed protective efficacy in various animal models. Thus, it has potential for use in both prevention and treatment of sepsis.
Dr. Cross has recently completed a license agreement with Bali BioSciences LLC to produce the sepsis antibody colostrums, and is seeking an organization for distribution. This innovative research may be a major breakthrough in finding solutions for sepsis, since currently there is only one other licensed drug on the market to treat sepsis, called xygris.
ACTIVE IMMUNIZATION
A group of researchers from The Scripps Research Institute (TSRI) have designed a vaccine that might be used against the pernicious consequences of severe sepsis. Their strategy is to develop a new immunomodulatory treatment for septic shock by using active immunization to protect patients against sepsis.
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Active immunization involves exposing patients to a substance that resembles the pathogen that one is immunizing against. This is fundamentally different than passive immunization that infuses antibodies into a patient to target poisonous endotoxins. If the vaccine works, the body responds with an effective immune response both to the vaccine and to the pathogens that are later encountered.
Preclinical studies (2002) have shown that the vaccine provided outstanding protection, and clinical models are planned with the hope that future formulations may be administered well in advance of major surgery for protection to hospital patients.
1. http://www.scripps.edu/news/press/111302.html
2. Angew. Chem. Int. Ed. Engl. 2002 Nov 15; 41 (22): 4242-4 (international journal,
Angewandte Chemie)
SEPSIS ORGANIZATIONS/RESOURCES
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SEPSIS/ANTIBIOTICS NOW
Early and aggressive treatment increases your chances of surviving sepsis. Antibiotics are an important part of treatment, and need to begin immediately, even though an infectious agent may not yet be identified.
The Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock recommend that appropriate antibiotic therapy includes: beginning intravenous antibiotics as early as possible, and always within the first hour of recognizing severe sepsis and septic shock, and using broad spectrum antibiotics, which are effective against a wide range of bacteria.
The challenge for advances in sepsis is to implement reliable, timely delivery of basic care tasks, such as antibiotic delivery, which is interconnected with early recognition and immediate basic management, and requiring completion in a narrow time frame.
Antibiotic therapy is just one of the six tasks of the "Sepsis Six" developed by the Survive Sepsis organization. Their program director, Dr. Ron Daniels, intensely explores and evaluates current challenges of diagnostic and therapeutic interventions for reliable and timely implementation of basic tasks in clinical practice that will improve sepsis outcomes and save more lives. He vividly presents the case for a pragmatic, operational view of sepsis basic care, and reminds us that a majority of published work linking quality and antimicrobial administration has been advanced by collaborative efforts of intensivists and microbiologists over recent years.
A peek back into antibiotic history would remind us that combined efforts produce significant results. Sir Alexander Fleming, a Scottish biologist stretched the antibiotic horizon with his discovery of penicillin in 1928, (explored and previously noted in the thesis work of Ernest Duchesne back in 1896). Over the next eleven years, British biochemists Ernst Chain and Sir Howard Florey isolated and purified penicillin. In 1939 they carried out clinical trials. Penicillin was first used on humans in the early 1940's, and soon made its way into mass production. For their extraordinary achievements which revolutionized medical science, Fleming, Chain, and Florey received the Nobel Prize for Medicine.
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UPDATE/ THE EXODUS OF XIGRIS
Xigris (drotrecogin alfa, activated) emerged on the market for treatment of severe sepsis after The Recombinant Human Activated Protein C Worldwide Evaluation (PROWESS) trial that evaluated its safety and efficacy, which helped it gain approval by the FDA in November, 2001, and licensing in the European Union in 2002. Activated Protein C helped keep coagulation in check and enhanced fibrinolysis, with associated risks of increased bleeding, while specific mechanisms for its clinical effect were not known.
Clinical trials (PROWESS) helped bring Xigris into the market for improving survival and reducing mortality in severe sepsis back in 2001, while the PROWESS SHOCK study initiated in 2008 (as a condition for continued market authorization in Europe) has helped to usher it back out, due to a lack of sufficient efficacy.
On October 25, 2011, Eli Lilly and Company has announced the withdrawal of Xigris in all markets, following the results of the PROWESS SHOCK study.
"While there were no new safety findings, the study failed to demonstrate that Xigris improved patient survival and thus calls into question the benefit-risk profile of Xigris and its continued use," said Timothy Garnett, M.D., Lilly’s Senior Vice president and Chief Medical Officer.
"Patients currently receiving treatment with Xigris should have treatment discontinued, and Xigris treatment should not be initiated for new patients." "We believe that original Xigris approval was appropriate and these recent results were quite unexpected," Garnett added. "A contributing factor to these study results could be advances in the standard care for treating severe sepsis over the past 10 years."
There are great financial expenses and time investments that have been used for development of products, and determining safety and efficacy. The search for treatment of merciless, destructive sepsis continues.
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SEPSIS/DELIRIUM
Delirium is a shocking and bewildering event that I have had first-hand and full-force experience with, and it is a massive challenge to endure and overcome.
One of the effects of sepsis on patient experience is sepsis-associated delirium, a common and poorly understood complication of sepsis. Sepsis-associated delirium is a syndrome with a constellation of symptoms which can include: fluctuating levels of consciousness, illusions, hallucinations, inattention, clouding of consciousness, disorientation, disturbing dreams/nightmares, Circadian rhythm disturbances, insomnia, and daytime drowsiness. All of the above can lead to emotional disturbances resulting in possible depression, anxiety, fear and irritability.
Delirium is an indication of brain dysfunction, and it is often invisible. It occurs in three forms: agitated or hyperactive, quiet or hypoactive, and mixed, such as daytime sedation and nocturnal agitation or behavioral problems. It is expressed by inattention, altered consciousness levels, and disorganized thinking.
Delirium is a confusion that comes on very fast, sometimes in just a few hours. When someone becomes delirious, it means that they cannot think clearly, have trouble paying attention, and are not aware of what is going on around them. Sometimes they may even see or hear things that are not really there, but seem very real to them.
The word delirium comes from Latin in the 1500's, loosely defined as going off the ploughed track or furrow, or simply said, "going off the track," which leads us to a reference to delirium as a state of acute mental confusion or disturbed consciousness, where a patient's cognitive function or perception is "off the track."
Delirium is defined as an acute change or fluctuation in mental status, inattention, and disorganized thinking, or an altered level of consciousness. The most common behavioral manifestation of acute brain dysfunction is delirium, which occurs in up to 60%-80% of mechanically ventilated medical and surgical ICU patients, and 50%-70% of non-ventilated medical ICU patients. The pathophysiology of delirium is elusive and has generated multiple levels of analysis such as : neuroimaging and neuroanatomic correlates of delirium, sedatives and analgesics,, sepsis, biomarkers and neurotransmitters, surgical factors and post-operative cognitive dysfunction (POCD), and future directions such as molecular genetics. Examining the mechanisms of ICU-related delirium is complex and requires extended research to develop a comprehensive view and improve outcomes.
In 27%-55% of sepsis cases, complications by a deterioration of mental status occur which are consistent with delirium, as consciousness, awareness, cognition and behavior are affected. Mortality is increased with the severity of delirium in septic patients, and a daily evaluation of patients should be implemented. There is no specific treatment for sepsis-associated delirium.
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Almost any medical illness, intoxication, or medication can cause delirium which is multifactorial in etiology (causation). It requires clinical investigation and observation to identify and treat delirium. There is a long list of causes that may include: infections, metabolic abnormalities, dementia, post-operative states, hypoxia, hepatic or renal failure, substance intoxication, septicemia, medication inducement, hypoperfusion states such as shock, and many other causes.
Delirium may be an early marker of sepsis rather than a predictor, and can be thought of as a prompt to investigate for sepsis. Delirium is strongly associated with sepsis and may even precede the development of sepsis, and is known as a common sign for end organ dysfunction in sepsis. One study of coronary artery bypass graft surgery (CABG) showed that delirium was the strongest independent predictor of sepsis, with 75% of the patients, delirium preceded sepsis. Delirium was defined as "a short-term mental disturbance marked by confusion, illusions, and cerebral excitement." Delirium may possibly be an independent factor for adverse outcomes.
Assessment Resources for ICU Delirium
The most important step in delirium management is early recognition, and once it is detected, efforts should focus on the causes, then treatment and management can address improving a patient's cognitive status and risk of adverse outcomes.
The Society of Critical Care Medicine (SCCM) clinical practice guidelines recommend that the emergence and/or persistence of delirium must be regularly monitored in critically ill patients. Two validated tools for assessing delirium in ICU patients are the CAM-ICU and the ICDSC.
The CAM-ICU (Confusion Assessment Method for the ICU) is designed for use by bedside clinicians, and takes less than two minutes to complete. Delirium assessment is done in two parts: Level of Consciousness, and Content of Consciousness.
Level of Consciousness uses the Richmond Agitation-Sedation Scale (RASS) to describe patient responses to voice and touch with plus or minus scoring ranging from unarouseable or deep sedation to very agitated or combative, with varied levels of sedation or alertness in between.
Content of Consciousness works at lighter levels of consciousness as patients display beginnings of meaningful responsiveness (i.e. response to voice). A four-feature worksheet is used to score patients.
Feature 1 measures acute change or fluctuating course of mental status (which is compared to pre-hospital baseline mental status).
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Feature 2 measures inattention through use of stimuli and tasks.
Feature 3 measures the altered level of consciousness (current RASS level).
Feature 4 measures disorganized thinking with questions and commands.
When I was asked questions over and over in the ICU, I became irritated and frustrated and wanted the nurses and doctors to go away and leave me alone. I was agitated, and my attention drifted in and out as the sepsis cascade escalated. I became disoriented.
The ICDSC is the Intensive Care Delirium Screening Checklist where 8 items are scored 1 (present) or 0 (absent) for a total of 8 points. A score of 4 or greater is a positive screen for delirium. Patients are evaluated for: altered level of consciousness, inattention, disorientation, hallucination-delusion-psychosis, psychomotor agitation or retardation, inappropriate speech or mood, sleep/wake cycle disturbance, and symptom fluctuation. The scale is completed based on information collected from each entire 8-hour shift or from the previous 24 hours.
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SEPSIS/BIOMARKERS
What is a biomarker? It is, "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention."
Biomarkers are key molecular or cellular events that link a specific environmental exposure to a health outcome. Biomarkers play an important role in understanding the relationships between exposure to environmental chemicals, the development of chronic human diseases, and the identification of subgroups that are at risk for disease. New technologies are seeking to develop sensitive biomarkers that can measure subtle changes in inflammation, oxidative damage, and other pathways that can lead to disease.
Biomarkers help to target and monitor therapy and are important for diagnostic (identification), prognostic (predicting outcomes), or physiologic (functional) status information. An example might be selecting appropriate therapy that would maximize efficacy, minimize toxicity, and assist in selecting dosage. A biomarker may be a substance measured in the blood or urine, or a measurement of a parameter such as blood pressure or brain activity.
Sepsis is a healthcare challenge, because sepsis can occur suddenly, progress swiftly, and patients can deteriorate rapidly. Time is the hidden enemy, because every hour of delayed treatment decreases survival by 7.6%.
The "gold standard " or reference standard for diagnosing sepsis has been blood culture. A serious disadvantage of this test is that it can take up to 2 days before the final result is available, and during this period, the condition of the patient can rapidly deteriorate. The gold standard lacks specificity or sensitivity, or both, and may not detect causative microorganisms. This can lead to diagnostic uncertainty.
In contrast, biomarker specificity and accuracy may play a major role in the sepsis puzzle by presenting a more rapid and accurate diagnosis, resulting in earlier intervention. However, the exact role of biomarkers in the management of septic patients remains undefined, because the septic response is an extremely complex chain of events involving inflammatory and anti-inflammatory processes, humoral and cellular reactions, and circulatory abnormalities. In one review, 34 biomarkers were identified that have been assessed for use specifically in the diagnosis of sepsis, and only 5 reported specificity and sensitivity values greater than 90%. Biomarkers may include: cytokines, cell markers, receptors, coagulation biomarkers, biomarkers related to vascular endothelial damage, vasodilation, organ dysfunction, or acute phase protein markers.
Considering the complexity of the sepsis response, it is unlikely that a single ideal biomarker will become the panacea for sepsis. Finding the right combination of several biomarkers for sepsis may be more effective.
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C-reactive protein (CRP), an acute phase protein, and Procalcitonin (PCT), an amino acid protein, have been most widely used, and Neutrophil CD64, a high infinity Fc receptor, in more recent years. Several other potentially clinically useful markers are being proposed and are currently being investigated. Applications and limitations comparing CRP and PCT implementation for sepsis diagnosis are also being investigated.
C-reactive protein (CRP) is an acute phase protein, the blood levels of which increase rapidly in response to infection, trauma, ischemia, burns, and other inflammatory conditions. Although used frequently in the ICU as a sepsis marker, the relation of CRP levels to organ damage is not well known. Daily measurement of CRP concentrations is useful in the detection of sepsis and is more sensitive than markers such as body temperature (BT) and white blood cell count (WBC), but some studies have shown it not to be a good marker of prognosis. PCT was found to be a better marker of sepsis than CRP. The course of PCT shows a closer correlation than that of CRP with the severity of infection and organ dysfunction.
Procalcitonin (PCT), an acute phase protein, is an innovative and highly specific marker for the diagnosis of clinically relevant bacterial infections and sepsis. It is a biomarker that reacts with high sensitivity and specificity and correlates better to the inflammatory activity of the immune system.
One major advantage of PCT compared to other parameters is its early and highly specific increase in response to bacterial infections and sepsis, and has been demonstrated to be the best marker for differentiating patients with sepsis from those with systemic inflammatory reaction not related to infectious cause. In septic conditions, increased PCT levels can be observed 3-6 hours after infectious challenge.
PCT has several advantages over inflammatory markers, including C-reactive protein (CRT). It shows an increase at an earlier stage in infection, and a more rapid decrease when the infection is controlled by the immune system supported by antibiotic therapy. PCT correlates with the extent and severity of infection, and has prognostic implications, namely predicting the course of disease and the risk for mortality in critically ill patients with infections, and in those with ventilator-associated pneumonia. PCT has been considered better than CRP for aiding sepsis diagnosis. Increasing levels of PCT are associated with lower survival rates.
Neutrophil CD64 seems to be a highly sensitive and reasonably specific biomarker for sepsis and other infections. Studies have shown that it could be taken into consideration as a sensitive and specific test for early diagnosis of sepsis, but it needs validation in large multicenter studies before it could be recommended as a sepsis biomarker for routine use in ICU patients. It may work best when combined with other biomarkers such as PCT in diagnosing sepsis in a critically ill patient.
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This discussion just barely touches the tip of the iceberg concerning biomarkers and sepsis. The research is vast, complicated, and appears to be a slow process of validation as it works its way toward bedside implementation. Biomarkers promise to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders. This transformation could aid therapeutic decision making, and hence improve the prognosis for patients with sepsis.
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UPDATE / ANTI-SEPSIS DRUG ERITORAN FAILS
No one wants to hear bad news, or defer hope concerning drugs specific to solving the sepsis puzzle. Unfortunately, the results of the clinical trials of the drug Eritoran, which doctors hoped would treat severe sepsis, were disappointing and failed to improve mortality in severe sepsis.
Eritoran joins a long list of experimental sepsis treatments that did not improve outcomes, such as the withdrawal of Xigris by Eli Lilly and Company in October, 2011, or Astrazeneca’s failed drug CytoFab.
Eritoran (eritoran tetrasodium), an endotoxin blocking agent, researched and developed by Japanese drug major Eisai, is a novel agent that blocks inflammatory reactions to the major endotoxin from gram-negative bacteria.
The Eritoran trials began in June, 2006, and finalized in 2013. By March, 2013, researchers reported that in phase III trials Eritoran did not significantly improve outcomes for patients with severe sepsis and septic shock. It was no better than a placebo in reducing mortality. This study is published in the March 20, 2013 issue of The Journal of The American Medical Association (JAMA).
However, bad news does remind us that; doctors, researchers and companies are still diligently confronting the challenges of the sepsis puzzle. May they never give up or get discouraged, considering the vast amount of time, effort and financing that is spent to conduct all of the phases of clinical trials.
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SEPSIS TRIGGERING
As a sepsis survivor, I intensely remember enduring a blurred, incomprehensible barrage of destructive medical events while I swirled in the mire of the uncontrolled systemic inflammatory response of the sepsis syndrome. I gasped for breath while I suffered acute liver and kidney failure, and many other symptoms and complications.
It was like an alarm system that had gone awry.
I felt disconnected mentally, physically and emotionally. Sepsis associated encephalopathy, delirium, and severe pain overcame me while confusion and disorientation overwhelmed me and spun me completely off balance. I felt scared and helpless in my altered state.
SEPSIS AND ENDOTOXIN
Endotoxin is a potent trigger of the sepsis cascade.
Sepsis is a life threatening condition caused by the body's response to bacterial products such as endotoxin. Endotoxin is an important pathogenic trigger of sepsis. Humans are extremely sensitive to endotoxin, and a significant invasion into the blood stream triggers a systemic inflammatory response of fever, tachycardia, and leukocytosis (elevated white blood cell count). Spectral Diagnostics Inc., has developed methods to measure endotoxin in 30 minutes, and innovative therapeutics to reduce blood endotoxin levels, and improve hemodynamics for patients with sepsis.
The human immune system identifies gram-negative bacteria by recognizing lipopolysaccharides (LPS), components of the microbial cell wall. This detection triggers massive inflammatory responses that help eradicate infections, but may also result in immunopathology if regulated improperly. Hence, LPS is also referred to as endotoxin.
LPS is the most prominent "alarm molecule" sensed by a host's early warning system, sensing invasion of gram-negative pathogens. In small doses LPS signaling is advantageous by orchestrating an appropriate microbial defense, and bacterial clearance mechanisms, but sudden releases of large quantities of LPS in the blood stream can be damaging to the host, initiating the release of dysregulated and potentially lethal army of inflammatory mediators and procoagulant factors in the systemic circulation. A massive response can generate diffuse endothelial injury, tissue perfusion, disseminated intravascular coagulation and refractory shock. The challenge remains to understand the precise molecular activity and possibly find ways to disrupt the LPS signaling.
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In a recent study, published in 2013, researchers at the University of North Carolina have identified a sensor pathway inside cells that acts like an alarm for the immune system.
Exterior and interior sensors work together to detect the molecule LPS. They are called TLR4 and caspace-11. TLR4 works on the outside and interconnects with caspace-11 inside a cell. This two-step defense mechanism may be the key to understanding how the immune system overreacts to a bacterial infection to such an extent that it does more harm than good, as in septic shock, which kills about half of its victims. The question is whether or not these same sensors go off in people with septic shock, and is there a means to block them with new innovative interventions and save lives.
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