Sepsis
Encyclopedia
Sepsis (ˈsɛpsɨs, from Gr. : the state of putrefaction or decay) is a potentially deadly medical
condition that is characterized by a whole-body inflammatory
state (called a systemic inflammatory response syndrome
or SIRS) and the presence of a known or suspected infection
. The body may develop this inflammatory response by the immune system
to microbes in the blood
, urine
, lungs, skin
, or other tissues. A lay term for sepsis is blood poisoning, also used to describe septicaemia. Severe sepsis is the systemic inflammatory response, plus infection, plus the presence of organ dysfunction.
Septicemia (also septicaemia or septicæmia [ˌsɛp.tə.ˈsi.miə],) is a related medical term referring to the presence of pathogenic organisms in the bloodstream, leading to sepsis. The term has not been sharply defined. It has been inconsistently used in the past by medical professionals, for example as a synonym of bacteremia
, causing some confusion.
Severe sepsis is usually treated in the intensive care unit
with intravenous fluids and antibiotics. If fluid replacement isn't sufficient to maintain blood pressure
, specific vasopressor medications can be used. Mechanical ventilation
and dialysis
may be needed to support the function of the lungs and kidneys, respectively. To guide therapy, a central venous catheter
and an arterial catheter may be placed; measurement of other hemodynamic variables (such as cardiac output
, or mixed venous oxygen saturation) may also be used. Sepsis patients require preventive measures for deep vein thrombosis
, stress ulcer
s and pressure ulcers, unless other conditions prevent this. Some patients might benefit from tight control of blood sugar levels
with insulin
(targeting stress hyperglycemia
), low-dose corticosteroids or activated drotrecogin alfa (recombinant
protein C
).
present throughout the entire body, and is, therefore, frequently associated with fever
and elevated white blood cell
count (leukocytosis
) or low white blood cell count and lower-than-average temperature, and vomiting
. The modern concept of sepsis is that the host's immune response to the infection causes most of the symptoms of sepsis, resulting in hemodynamic consequences and damage to organs. This host response has been termed systemic inflammatory response syndrome
(SIRS) and is characterized by an elevated heart rate
(above 90 beats per minute), high respiratory rate (above 20 breaths per minute or a partial pressure
of carbon dioxide in the blood of less than 32), abnormal white blood cell count (above 12,000, lower than 4,000, or greater than 10% band forms) and elevated or lowered body temperature, i.e. under 36 °C (96.8 °F) or over 38 °C (100.4 °F). Sepsis is differentiated from SIRS by the presence of a known or suspected pathogen
. For example SIRS and a positive blood culture for a pathogen indicates the presence of sepsis. Sometimes you can suspect having a sepsis by noticing a red line following a vein. However, in many cases of sepsis no specific pathogen is identified.
This immunological response causes widespread activation of acute-phase proteins, affecting the complement system
and the coagulation
pathways, which then cause damage to the vasculature as well as to the organs. Various neuroendocrine counter-regulatory systems are then activated as well, often compounding the problem. Even with immediate and aggressive treatment, this may progress to multiple organ dysfunction syndrome
and eventually death
.
Examples of end-organ dysfunction include the following:
More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.
Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.
(BSI), such as meningitis
, pneumonia
, pyelonephritis
, or gastroenteritis
. in the setting of fever. Criteria with regards to hemodynamic compromise or respiratory failure are not useful clinically because these symptoms often do not arise in neonates until death is imminent and unpreventable.
or SIRS is evidence of the body's ongoing inflammatory response. When SIRS is suspected or known to be caused by an infection, this is sepsis. Severe sepsis occurs when sepsis leads to organ dysfunction, such as trouble breathing
, coagulation or other blood abnormalities, decreased urine production
, or altered mental status. If the organ dysfunction of severe sepsis is low blood pressure (hypotension
), or insufficient blood flow (hypoperfusion) to one or more organs (causing, for example, lactic acidosis
), this is septic shock.
Sepsis can lead to multiple organ dysfunction syndrome
(MODS) (formerly known as multiple organ failure), and death. Organ dysfunction results from local changes in blood flow, from sepsis-induced hypotension
(< 90 mmHg or a reduction of ≥ 40 mmHg from baseline) and from diffuse intravascular coagulation, among other things.
Sepsis can be defined as the body's response to an infection. An infection is caused by microorganisms or bacteria
invading the body and can be limited to a particular body region or can be widespread in the bloodstream. Sepsis
is acquired quickest with infections developed in surgery
and physical contact with someone with sepsis.
Bacteremia
is the presence of viable bacteria
in the bloodstream. Likewise, the terms viremia
and fungemia
simply refer to virus
es and fungi
in the bloodstream. These terms say nothing about the consequences this has on the body. For example, bacteria can be introduced into the bloodstream during toothbrushing. This form of bacteremia almost never causes problems in normal individuals. However, bacteremia associated with certain dental procedures can cause bacterial infection of the heart valves (known as endocarditis
) in high-risk patients. Conversely, a systemic inflammatory response syndrome can occur in patients without the presence of infection, for example in those with burn
s, polytrauma, or the initial state in pancreatitis
and chemical pneumonitis
.
s, surgical drainage of infected fluid collections, fluid replacement and appropriate support for organ dysfunction. This may include hemodialysis
in kidney failure, mechanical ventilation
in pulmonary
dysfunction, transfusion of blood products
, and drug and fluid therapy for circulatory failure. Ensuring adequate nutrition—preferably by enteral feeding, but if necessary by parenteral nutrition—is important during prolonged illness.
A problem in the adequate management of septic patients has been the delay in administering therapy after sepsis has been recognized. Published studies have demonstrated that for every hour delay in the administration of appropriate antibiotic therapy there is an associated 7% rise in mortality. A large international collaboration was established to educate people about sepsis and to improve patient outcomes with sepsis, entitled the "Surviving Sepsis Campaign
". The Campaign has published an evidence-based review of management strategies for severe sepsis, with the aim to publish a complete set of guidelines in subsequent years.
by Emanuel Rivers
, MD, is a systematic approach to resuscitation that has been validated in the treatment of severe sepsis and septic shock
. It is meant to be started in the Emergency Department. The theory is that a step-wise approach should be used, having the patient meet physiologic goals, to optimize cardiac preload, afterload, and contractility, thus optimizing oxygen delivery to the tissues. A recent meta-analysis
showed that EGDT provides a benefit on mortality in patients with sepsis. some controversy around its uses remained, and a number of trials were in progress in an attempt to resolve this.
In EGDT, fluids are administered until the central venous pressure
(CVP), as measured by a central venous catheter
, reaches 8–12 cm of water (or 10–15 cm of water in mechanically ventilated patients). Rapid administration of several liters of isotonic crystalloid solution is usually required to achieve this. If the mean arterial pressure
is less than 65 mmHg or the systolic blood pressure is less than 90 mmHg, vasopressors or vasodilators are given as needed to reach the goal. Once these goals are met, the mixed venous oxygen saturation (SvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the SvO2 is less than 70%, blood is given to reach a hemoglobin of 10 g/dl and then inotropes are added until the SvO2 is optimized. Elective intubation may be performed to reduce oxygen demand if the SvO2 remains low despite optimization of hemodynamics. Urine output is also monitored, with a minimum goal of 0.5 ml/kg/h. In the original trial, mortality was cut from 46.5% in the control group to 30.5% in the intervention group. An appropriate decrease in serum lactate
however may be equivalent to Sv02 and either to obtain. The Surviving Sepsis Campaign guidelines recommend EGDT for the initial resuscitation of the septic patient with a level B strength of evidence (single randomized control trial).
and tissue resistance (the word 'relative' resistance should be avoided) to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency. Treatment with corticosteroids might be most beneficial in those with septic shock
and early severe acute respiratory distress syndrome
(ARDS), whereas its role in other patients such as those with pancreatitis
or severe pneumonia
is unclear. These recommendations stem from studies showing benefits from low dose hydrocortisone treatment for septic shock patients and methylprednisolone
in ARDS patients. However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. ACTH stimulation testing is not recommended to confirm the diagnosis. The method of cessation of glucocorticoid drugs is variable, and it is unclear whether they should be weaned or simply stopped abruptly.
activated protein C
(drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality just increase adverse events and thus was not recommended for use. Other reviews however comment that it may be effective in those with very severe disease.
Approximately 20–35% of patients with severe sepsis and 40–60% of patients with septic shock die within 30 days. Others die within the ensuing 6 months. Late deaths often result from poorly controlled infection, immunosuppression, complications of intensive care, failure of multiple organs, or the patient's underlying disease.
Prognostic stratification systems such as APACHE II
indicate that factoring in the patient's age, underlying condition, and various physiologic variables can yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of underlying disease most strongly influences the risk of death. Septic shock is also a strong predictor of short- and long-term mortality. Case-fatality rates are similar for culture-positive and culture-negative severe sepsis.
Some patients may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most sepsis patients makes the incidence of this difficult to quantify or to study. A preliminary study of nine patients with septic shock showed abnormalities in seven patients by MRI.
sepsis is the second-leading cause of death in non-coronary Intensive Care Unit
(ICU) patients, and the tenth-most-common cause of death overall according to data from the Centers for Disease Control and Prevention
(the first being heart disease). Sepsis is common and also more dangerous in elderly, immunocompromised, and critically ill patients. It occurs in 1–2% of all hospitalizations and accounts for as much as 25% of ICU bed utilization. It is a major cause of death in intensive-care units worldwide, with mortality rates that range from 20% for sepsis, through 40% for severe sepsis, to over 60% for septic shock
.
coined the term endotoxin
at the beginning of the 20th century to denote the pyrogenic principle associated with Vibrio cholerae
. It was soon realised that endotoxins were expressed by most and perhaps all Gram negative organisms. The lipopolysaccharide character of enteric endotoxins was elucidated in the 1944 by Shear. The molecular character of this material was determined by Luderitz et al in 1973.
It was discovered in 1965 that a strain of C3H/HeJ mice
were immune to the endotoxin induced shock. The genetic locus for this effect was dubbed Lps. These mice were also found to be hypersusceptible to infection by Gram negative bacteria. These observations were finally linked in 1998 by the discovery of the Toll-like receptor
gene 4 (TLR 4)Genetic mapping work, performed over a period of 5 years showed that TLR4 was the sole candidate locus within the Lps critical region strongly implying that a mutation within TLR4 must account for the lipopolysaccharide resistance phenotype. The defect in the TLR4 gene that lead to the endotoxin resistant phenotype was discovered to be due to a mutation in the cytoplasmic domain.
It had previously been shown that cells of hematopoietic origin are required for the lethal effect of lipopolysaccharide. Endotoxin sensitive mice may be rendered resistant to endotoxin if their bone marrow is ablated with radiation and it is then reconstituted with hematopoietic precursors derived from endotoxin resistant mice. Conversely, lipopolysaccharide sensitivity may be restored to resistant mice mice if they are colonized by hematopoietic precursors from endotoxin sensitive animals. These experiments showed that endotoxin was interacting with receptors on cells derived from the hematopoietic system to produce its effects.
In 1990 it was shown that CD14
acts to concentrate plasma lipopolysaccharide and that this effect evokes a strong response by mononuclear phagocytic cells. Because CD14 lacks a cytoplasmic domain it was clear that at least one other protein was required for the endotoxin response. The Lps locus was considered to be the most likely candidate and so it proved.
Although it now known that endotoxin binds to CD14 and that CD14 then interacts with TLR4, the molecular details concerning precisely this contributes to the generation of the septic syndrome are currently the subject of active research.
It was shown in 1999 that mutations in TLR 2 could significantly reduce the systemic response to Gram positive infections. Although less likely than Gram negative organisms to cause septic shock, infection with Gram positive organisms remains a problem in intensive care and in neonates. Like TLR 4 much work is currently being done to elucidate the mechanism of the response to these organisms.
showed that SphK1 is highly elevated in inflammatory cells from patients with sepsis and inhibition of the molecular pathway reduced the proinflammatory response triggered by bacterial products in the human cells. Moreover, the study also showed the mortality rate of mice with experimental sepsis was reduced when treated with a SphK1 blocker. Similarly, inhibition of the p38 MAPK signaling transduction pathway may help to block enhanced procoagulatory activities during septicemia.
, nitrite treatment, in sharp contrast with the worsening effect of inhibiting NO-synthesis, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in mice.
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
condition that is characterized by a whole-body inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
state (called a systemic inflammatory response syndrome
Systemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
or SIRS) and the presence of a known or suspected infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
. The body may develop this inflammatory response by the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
to microbes in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, lungs, skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, or other tissues. A lay term for sepsis is blood poisoning, also used to describe septicaemia. Severe sepsis is the systemic inflammatory response, plus infection, plus the presence of organ dysfunction.
Septicemia (also septicaemia or septicæmia [ˌsɛp.tə.ˈsi.miə],) is a related medical term referring to the presence of pathogenic organisms in the bloodstream, leading to sepsis. The term has not been sharply defined. It has been inconsistently used in the past by medical professionals, for example as a synonym of bacteremia
Bacteremia
Bacteremia is the presence of bacteria in the blood. The blood is normally a sterile environment, so the detection of bacteria in the blood is always abnormal....
, causing some confusion.
Severe sepsis is usually treated in the intensive care unit
Intensive Care Unit
thumb|220px|ICU roomAn intensive-care unit , critical-care unit , intensive-therapy unit/intensive-treatment unit is a specialized department in a hospital that provides intensive-care medicine...
with intravenous fluids and antibiotics. If fluid replacement isn't sufficient to maintain blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
, specific vasopressor medications can be used. Mechanical ventilation
Mechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
and dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
may be needed to support the function of the lungs and kidneys, respectively. To guide therapy, a central venous catheter
Central venous catheter
In medicine, a central venous catheter is a catheter placed into a large vein in the neck , chest or groin...
and an arterial catheter may be placed; measurement of other hemodynamic variables (such as cardiac output
Cardiac output
Cardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
, or mixed venous oxygen saturation) may also be used. Sepsis patients require preventive measures for deep vein thrombosis
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
, stress ulcer
Stress ulcer
Stress ulcers are single or multiple mucosal defects which can become complicated by upper gastrointestinal bleeding during the physiologic stress of serious illness...
s and pressure ulcers, unless other conditions prevent this. Some patients might benefit from tight control of blood sugar levels
Glycemia
Glycemia means the presence, or the level, of glucose in one's blood. Related words include:* Hyperglycemia, an unusually high concentration of sugar in the blood* Hypoglycemia, an unusually low concentration of sugar in the blood...
with insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
(targeting stress hyperglycemia
Stress hyperglycemia
Stress hyperglycemia is a medical term referring to transient elevation of the blood glucose due to the stress of illness...
), low-dose corticosteroids or activated drotrecogin alfa (recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
).
Signs and symptoms
In addition to symptoms related to the provoking infection, sepsis is characterized by presence of acute inflammationInflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
present throughout the entire body, and is, therefore, frequently associated with fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
and elevated white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
count (leukocytosis
Leukocytosis
Leukocytosis is a raised white blood cell count above the normal range in the blood. It is frequently a sign of an inflammatory response, most commonly the result of infection, and is observed in certain parasitic infections...
) or low white blood cell count and lower-than-average temperature, and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
. The modern concept of sepsis is that the host's immune response to the infection causes most of the symptoms of sepsis, resulting in hemodynamic consequences and damage to organs. This host response has been termed systemic inflammatory response syndrome
Systemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
(SIRS) and is characterized by an elevated heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
(above 90 beats per minute), high respiratory rate (above 20 breaths per minute or a partial pressure
Partial pressure
In a mixture of ideal gases, each gas has a partial pressure which is the pressure which the gas would have if it alone occupied the volume. The total pressure of a gas mixture is the sum of the partial pressures of each individual gas in the mixture....
of carbon dioxide in the blood of less than 32), abnormal white blood cell count (above 12,000, lower than 4,000, or greater than 10% band forms) and elevated or lowered body temperature, i.e. under 36 °C (96.8 °F) or over 38 °C (100.4 °F). Sepsis is differentiated from SIRS by the presence of a known or suspected pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
. For example SIRS and a positive blood culture for a pathogen indicates the presence of sepsis. Sometimes you can suspect having a sepsis by noticing a red line following a vein. However, in many cases of sepsis no specific pathogen is identified.
This immunological response causes widespread activation of acute-phase proteins, affecting the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
and the coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
pathways, which then cause damage to the vasculature as well as to the organs. Various neuroendocrine counter-regulatory systems are then activated as well, often compounding the problem. Even with immediate and aggressive treatment, this may progress to multiple organ dysfunction syndrome
Multiple organ dysfunction syndrome
Multiple organ dysfunction syndrome ', previously known as multiple organ failure or multisystem organ failure , is altered organ function in an acutely ill patient requiring medical intervention to achieve homeostasis...
and eventually death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
.
Diagnosis
According to the American College of Chest Physicians and the Society of Critical Care Medicine, there are different levels of sepsis:- Systemic inflammatory response syndromeSystemic inflammatory response syndromeSystemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
(SIRS). Defined by the presence of two or more of the following findings:- Body temperature < 36 °C (96.8 °F) or > 38 °C (100.4 °F) (hypothermiaHypothermiaHypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
or feverFeverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
). - Heart rateHeart rateHeart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
> 90 beats per minute. - Respiratory rateRespiratory rateRespiratory rate is also known by respiration rate, pulmonary ventilation rate, ventilation rate, or breathing frequency is the number of breaths taken within a set amount of time, typically 60 seconds....
> 20 breaths per minute or, on blood gasBlood gasBlood gas is a term used to describe a laboratory test of blood where the purpose is primarily to measure ventilation and oxygenation. The source is generally noted by an added word to the beginning; arterial blood gases come from arteries, venous blood gases come from veins and capillary blood...
, a PaCO2 less than 32 mm Hg (4.3 kPaKPAKPA may refer to:* Kenya Ports Authority* Kiln phosphoric acid, a dry process to produce phosphoric acid at high temperature in a kiln* Kilopascal , a unit of pressure* Known-plaintext attack, a method of cryptanalysis* Korean People's Army...
) (tachypneaTachypneaTachypnea means rapid breathing. Any rate between 12-20 breaths per minute is normal. Tachypnea is a respiration rate greater than 20 breaths per minute. - Distinction from other breathing terms :...
or hypocapniaHypocapniaHypocapnia or hypocapnea also known as hypocarbia, sometimes incorrectly called acapnia, is a state of reduced carbon dioxide in the blood. Hypocapnia usually results from deep or rapid breathing, known as hyperventilation....
due to hyperventilationHyperventilationHyperventilation or overbreathing is the state of breathing faster or deeper than normal, causing excessive expulsion of circulating carbon dioxide. It can result from a psychological state such as a panic attack, from a physiological condition such as metabolic acidosis, can be brought about by...
). - White blood cellWhite blood cellWhite blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
count < 4,000 cells/mm3 or > 12,000 cells/mm3 (< 4 × 109 or > 12 × 109 cells/LLitrepic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre...
), or greater than 10% band forms (immature white blood cells). (leukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, leukocytosisLeukocytosisLeukocytosis is a raised white blood cell count above the normal range in the blood. It is frequently a sign of an inflammatory response, most commonly the result of infection, and is observed in certain parasitic infections...
, or bandemiaBandemiaBandemia refers to an excess of band cells released by the bone marrow into the blood. The ICD diagnosis code for bandemia is 288.66.It is a signifier of infection or inflammation....
).
- Body temperature < 36 °C (96.8 °F) or > 38 °C (100.4 °F) (hypothermia
- Sepsis. Defined as SIRS in response to a confirmed infectious process. Infection can be suspected or proven (by culture, stain, or polymerase chain reactionPolymerase chain reactionThe polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
(PCR)), or a clinical syndrome pathognomonic for infection. Specific evidence for infection includes WBCs in normally sterile fluid (such as urine or cerebrospinal fluidCerebrospinal fluidCerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
(CSF)); evidence of a perforated viscusViscusIn anatomy, a viscus is an internal organ, and viscera is the plural form. The viscera, when removed from a butchered animal, are known collectively as offal...
(free air on abdominal x-ray or CT scan; signs of acute peritonitis); abnormal chest x-ray (CXR) consistent with pneumoniaPneumoniaPneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
(with focal opacification); or petechiae, purpuraPurpuraPurpura is the appearance of red or purple discolorations on the skin that do not blanch on applying pressure. They are caused by bleeding underneath the skin...
, or purpura fulminansPurpura fulminansPurpura fulminans is a haemorrhagic condition usually associated with sepsis or previous infection. It occurs mainly in babies and small children.It was first described by Guelliot in 1884.- Presentation :...
. - Severe sepsis. Defined as sepsis with organ dysfunction, hypoperfusion, or hypotension.
- Septic shockSeptic shockSeptic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...
. Defined as sepsis with refractory arterial hypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
or hypoperfusion abnormalities in spite of adequate fluid resuscitation. Signs of systemic hypoperfusion may be either end-organ dysfunction or serum lactate greater than 4 mmol/L. Other signs include oliguriaOliguriaOliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...
and altered mental status. Patients are defined as having septic shockSeptic shockSeptic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...
if they have sepsis plus hypotension after aggressive fluid resuscitation (typically upwards of 6 liters or 40 ml/kg of crystalloid solution).
Examples of end-organ dysfunction include the following:
- Lungs:acute lung injuryAcute lung injuryAcute lung injury is a diffuse heterogeneous lung injury characterized by hypoxemia, non cardiogenic pulmonary edema, low lung compliance and widespread capillary leakage...
(ALI) (PaO2/FiO2 < 300) or acute respiratory distress syndromeAcute respiratory distress syndromeAcute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
(ARDS) (PaO2/FiO2 < 200) - Brain: encephalopathyEncephalopathyEncephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
symptoms: agitation, confusion, coma; cause: ischemia, hemorrhage, microthrombi, microabscesses, multifocal necrotizing leukoencephalopathy - Liver: disruption of protein synthetic function: manifests acutely as progressive coagulopathyCoagulopathyCoagulopathy is a condition in which the blood’s ability to clot is impaired. This condition can cause prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.The normal clotting process depends on the interplay of various proteins in...
due to inability to synthesize clotting factors, disruption of metabolic functions: manifests as cessation of bilirubinBilirubinBilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
metabolism, resulting in elevated unconjugated serum bilirubin levels (indirect bilirubin) - Kidney: oliguriaOliguriaOliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...
and anuriaAnuriaAnuria means nonpassage of urine, in practice is defined as passage of less than 50 milliliters of urine in a day. Anuria is often caused by failure in the function of kidneys. It may also occur because of some severe obstruction like kidney stones or tumours. It may occur with end stage renal...
, electrolyte abnormalities, volume overload - Heart: systolic and diastolic heart failure, likely due to cytokines that depress myocyte function, cellular damage, manifest as a troponinTroponin400px|thumb|right|alt = Colored dice with checkered background|Ribbon representation of the human cardiac troponin core complex in the calcium-saturated form...
leak (although not necessarily ischemic in nature)
More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.
- Cardiovascular dysfunction (after fluid resuscitation with at least 40 ml/kg of crystalloid)
- hypotension with blood pressure < 5th percentile for age or systolic blood pressure < 2 standard deviations below normal for age, OR
- vasopressor requirement, OR
- two of the following criteria:
- unexplained metabolic acidosisMetabolic acidosisIn medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
with base deficit > 5 mEq/L - lactic acidosisLactic acidosisLactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
: serum lactate 2 times the upper limit of normal - oliguria (urine output < 0.5 ml/kg/hr)
- prolonged capillary refillCapillary refillCapillary refill is the rate at which blood refills empty capillaries. It can be measured by holding a hand higher than heart-level , pressing the soft pad of a finger or toe until it turns white, and taking note of the time needed for the color to return once pressure is released. Normal refill...
> 5 seconds - core to peripheral temperature difference > 3°C
- unexplained metabolic acidosis
- Respiratory dysfunction (in the absence of cyanotic heart disease or known chronic lung diseaseChronic lung diseaseChronic lung disease could refer to one of the following topics:* Asthma* Chronic bronchitis* Chronic obstructive pulmonary disease* EmphysemaOther related topics may include:* Arterial blood gas* Pulmonary function testing...
)- the ratio of the arterial partial-pressure of oxygen to the fraction of oxygen in the gases inspired (PaO2/FiO2) < 300 (the definition of acute lung injuryAcute lung injuryAcute lung injury is a diffuse heterogeneous lung injury characterized by hypoxemia, non cardiogenic pulmonary edema, low lung compliance and widespread capillary leakage...
), OR - arterial partial-pressure of carbon dioxide (PaCO2) > 65 torr (20 mmHg) over baseline PaCO2 (evidence of hypercapnic respiratory failure), OR
- supplemental oxygen requirement of greater than FiO2 0.5 to maintain oxygen saturation ≥ 92%
- the ratio of the arterial partial-pressure of oxygen to the fraction of oxygen in the gases inspired (PaO2/FiO2) < 300 (the definition of acute lung injury
- Neurologic dysfunction
- Glasgow Coma Score (GCS) ≤ 11, OR
- altered mental status with drop in GCS of 3 or more points in a patient with developmental delay/mental retardationMental retardationMental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
- Hematologic dysfunction
- plateletPlateletPlatelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count < 80,000/mm3 or 50% drop from maximum in chronically thrombocytopenic patients, OR - international normalized ratio (INR) > 2
- Disseminated intravascular coagulationDisseminated intravascular coagulationDisseminated intravascular coagulation , also known as disseminated intravascular coagulopathy or consumptive coagulopathy, is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases. DIC leads to the formation of small blood clots inside the blood...
- platelet
- Renal dysfunction
- serum creatinineCreatinineCreatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
≥ 2 times the upper limit of normal for age or 2-fold increase in baseline creatinineCreatinineCreatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
in patients with chronic kidney disease
- serum creatinine
- Hepatic dysfunction (only applicable to infants > 1 month)
- total serum bilirubinBilirubinBilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
≥ 4 mg/dl, OR - alanine aminotransferase (ALT) ≥ 2 times the upper limit of normal
- total serum bilirubin
Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.
Neonatal sepsis
In common clinical usage, sepsis specifically refers to the presence of a bacterial blood stream infectionBacteremia
Bacteremia is the presence of bacteria in the blood. The blood is normally a sterile environment, so the detection of bacteria in the blood is always abnormal....
(BSI), such as meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
, pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, pyelonephritis
Pyelonephritis
Pyelonephritis is an ascending urinary tract infection that has reached the pyelum or pelvis of the kidney. It is a form of nephritis that is also referred to as pyelitis...
, or gastroenteritis
Gastroenteritis
Gastroenteritis is marked by severe inflammation of the gastrointestinal tract involving both the stomach and small intestine resulting in acute diarrhea and vomiting. It can be transferred by contact with contaminated food and water...
. in the setting of fever. Criteria with regards to hemodynamic compromise or respiratory failure are not useful clinically because these symptoms often do not arise in neonates until death is imminent and unpreventable.
Pathophysiology
Systemic inflammatory response syndromeSystemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
or SIRS is evidence of the body's ongoing inflammatory response. When SIRS is suspected or known to be caused by an infection, this is sepsis. Severe sepsis occurs when sepsis leads to organ dysfunction, such as trouble breathing
Respiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
, coagulation or other blood abnormalities, decreased urine production
Oliguria
Oliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...
, or altered mental status. If the organ dysfunction of severe sepsis is low blood pressure (hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
), or insufficient blood flow (hypoperfusion) to one or more organs (causing, for example, lactic acidosis
Lactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
), this is septic shock.
Sepsis can lead to multiple organ dysfunction syndrome
Multiple organ dysfunction syndrome
Multiple organ dysfunction syndrome ', previously known as multiple organ failure or multisystem organ failure , is altered organ function in an acutely ill patient requiring medical intervention to achieve homeostasis...
(MODS) (formerly known as multiple organ failure), and death. Organ dysfunction results from local changes in blood flow, from sepsis-induced hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
(< 90 mmHg or a reduction of ≥ 40 mmHg from baseline) and from diffuse intravascular coagulation, among other things.
Sepsis can be defined as the body's response to an infection. An infection is caused by microorganisms or bacteria
invading the body and can be limited to a particular body region or can be widespread in the bloodstream. Sepsis
is acquired quickest with infections developed in surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
and physical contact with someone with sepsis.
Bacteremia
Bacteremia
Bacteremia is the presence of bacteria in the blood. The blood is normally a sterile environment, so the detection of bacteria in the blood is always abnormal....
is the presence of viable bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
in the bloodstream. Likewise, the terms viremia
Viremia
Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to bacteremia, a condition where bacteria enter the bloodstream.- Primary versus Secondary :...
and fungemia
Fungemia
-Pathogens:The most commonly known pathogen is Candida albicans, causing roughly 70% of fungemias, followed by Candida glabrata with 10%, Aspergillus with 1% and Saccharomyces as the fourth most common. However, the frequency of infection by C. glabrata, Saccharomyces boulardii, Candida tropicalis,...
simply refer to virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es and fungi
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
in the bloodstream. These terms say nothing about the consequences this has on the body. For example, bacteria can be introduced into the bloodstream during toothbrushing. This form of bacteremia almost never causes problems in normal individuals. However, bacteremia associated with certain dental procedures can cause bacterial infection of the heart valves (known as endocarditis
Endocarditis
Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves . Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices...
) in high-risk patients. Conversely, a systemic inflammatory response syndrome can occur in patients without the presence of infection, for example in those with burn
Burn
A burn is an injury to flesh caused by heat, electricity, chemicals, light, radiation, or friction.Burn may also refer to:*Combustion*Burn , type of watercourses so named in Scotland and north-eastern England...
s, polytrauma, or the initial state in pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
and chemical pneumonitis
Chemical pneumonitis
Aspiration pneumonitis or chemical pneumonitis is inflammation of the lung caused by aspirating or inhaling irritants. It is sometimes called a "chemical pneumonia", though it is not infectious...
.
Management
The therapy of sepsis rests on antibioticAntibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s, surgical drainage of infected fluid collections, fluid replacement and appropriate support for organ dysfunction. This may include hemodialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
in kidney failure, mechanical ventilation
Mechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
in pulmonary
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
dysfunction, transfusion of blood products
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
, and drug and fluid therapy for circulatory failure. Ensuring adequate nutrition—preferably by enteral feeding, but if necessary by parenteral nutrition—is important during prolonged illness.
A problem in the adequate management of septic patients has been the delay in administering therapy after sepsis has been recognized. Published studies have demonstrated that for every hour delay in the administration of appropriate antibiotic therapy there is an associated 7% rise in mortality. A large international collaboration was established to educate people about sepsis and to improve patient outcomes with sepsis, entitled the "Surviving Sepsis Campaign
Surviving Sepsis Campaign
The Surviving Sepsis Campaign is a global initiative to bring together professional organizations in reducing mortality from sepsis. The purpose of the SSC is to create an international collaborative effort to improve the treatment of sepsis and reduce the high mortality rate associated with the...
". The Campaign has published an evidence-based review of management strategies for severe sepsis, with the aim to publish a complete set of guidelines in subsequent years.
Early goal directed therapy
Early goal directed therapy (EGDT), developed at Henry Ford HospitalHenry Ford Hospital
Henry Ford Hospital, the flagship facility for , is an 805-bed tertiary care hospital, education and research complex located in Detroit ....
by Emanuel Rivers
Emanuel Rivers
Emanuel Rivers M.D. is a physician born and raised in River Rouge, Michigan which is a suburb of Detroit, MI. He is board certified in emergency medicine, internal medicine and critical care medicine...
, MD, is a systematic approach to resuscitation that has been validated in the treatment of severe sepsis and septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...
. It is meant to be started in the Emergency Department. The theory is that a step-wise approach should be used, having the patient meet physiologic goals, to optimize cardiac preload, afterload, and contractility, thus optimizing oxygen delivery to the tissues. A recent meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
showed that EGDT provides a benefit on mortality in patients with sepsis. some controversy around its uses remained, and a number of trials were in progress in an attempt to resolve this.
In EGDT, fluids are administered until the central venous pressure
Central venous pressure
Central venous pressure describes the pressure of blood in the thoracic vena cava, near the right atrium of the heart...
(CVP), as measured by a central venous catheter
Central venous catheter
In medicine, a central venous catheter is a catheter placed into a large vein in the neck , chest or groin...
, reaches 8–12 cm of water (or 10–15 cm of water in mechanically ventilated patients). Rapid administration of several liters of isotonic crystalloid solution is usually required to achieve this. If the mean arterial pressure
Mean arterial pressure
The mean arterial pressure is a term used in medicine to describe an average blood pressure in an individual. It is defined as the average arterial pressure during a single cardiac cycle.-Calculation:...
is less than 65 mmHg or the systolic blood pressure is less than 90 mmHg, vasopressors or vasodilators are given as needed to reach the goal. Once these goals are met, the mixed venous oxygen saturation (SvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the SvO2 is less than 70%, blood is given to reach a hemoglobin of 10 g/dl and then inotropes are added until the SvO2 is optimized. Elective intubation may be performed to reduce oxygen demand if the SvO2 remains low despite optimization of hemodynamics. Urine output is also monitored, with a minimum goal of 0.5 ml/kg/h. In the original trial, mortality was cut from 46.5% in the control group to 30.5% in the intervention group. An appropriate decrease in serum lactate
Lactate
Lactate may refer to:*The act of lactation*The conjugate base of lactic acid...
however may be equivalent to Sv02 and either to obtain. The Surviving Sepsis Campaign guidelines recommend EGDT for the initial resuscitation of the septic patient with a level B strength of evidence (single randomized control trial).
Steroids
During critical illness, a state of adrenal insufficiencyAdrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
and tissue resistance (the word 'relative' resistance should be avoided) to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency. Treatment with corticosteroids might be most beneficial in those with septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...
and early severe acute respiratory distress syndrome
Acute respiratory distress syndrome
Acute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
(ARDS), whereas its role in other patients such as those with pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
or severe pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
is unclear. These recommendations stem from studies showing benefits from low dose hydrocortisone treatment for septic shock patients and methylprednisolone
Methylprednisolone
Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug. It is marketed in the USA and Canada under the brand names Medrol and Solu-Medrol. It is also available as a generic drug....
in ARDS patients. However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. ACTH stimulation testing is not recommended to confirm the diagnosis. The method of cessation of glucocorticoid drugs is variable, and it is unclear whether they should be weaned or simply stopped abruptly.
Activated protein C
RecombinantRecombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
activated protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
(drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality just increase adverse events and thus was not recommended for use. Other reviews however comment that it may be effective in those with very severe disease.
Neonates
Note that, in neonates, sepsis is difficult to diagnose clinically. They may be relatively asymptomatic until hemodynamic and respiratory collapse is imminent, so, if there is even a remote suspicion of sepsis, they are frequently treated with antibiotics empirically until cultures are sufficiently proven to be negative.Prognosis
Prognosis can be estimated with the Mortality in Emergency Department Sepsis (MEDS) score.Approximately 20–35% of patients with severe sepsis and 40–60% of patients with septic shock die within 30 days. Others die within the ensuing 6 months. Late deaths often result from poorly controlled infection, immunosuppression, complications of intensive care, failure of multiple organs, or the patient's underlying disease.
Prognostic stratification systems such as APACHE II
APACHE II
APACHE II is a severity-of-disease classification system , one of several ICU scoring systems...
indicate that factoring in the patient's age, underlying condition, and various physiologic variables can yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of underlying disease most strongly influences the risk of death. Septic shock is also a strong predictor of short- and long-term mortality. Case-fatality rates are similar for culture-positive and culture-negative severe sepsis.
Some patients may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most sepsis patients makes the incidence of this difficult to quantify or to study. A preliminary study of nine patients with septic shock showed abnormalities in seven patients by MRI.
Epidemiology
In the United StatesUnited States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
sepsis is the second-leading cause of death in non-coronary Intensive Care Unit
Intensive Care Unit
thumb|220px|ICU roomAn intensive-care unit , critical-care unit , intensive-therapy unit/intensive-treatment unit is a specialized department in a hospital that provides intensive-care medicine...
(ICU) patients, and the tenth-most-common cause of death overall according to data from the Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
(the first being heart disease). Sepsis is common and also more dangerous in elderly, immunocompromised, and critically ill patients. It occurs in 1–2% of all hospitalizations and accounts for as much as 25% of ICU bed utilization. It is a major cause of death in intensive-care units worldwide, with mortality rates that range from 20% for sepsis, through 40% for severe sepsis, to over 60% for septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...
.
History
Severe systemic toxicity has been recognised since before the dawn of history but it was only in the 19th century that a spefic term - sepsis- was coined for this condition. By the end of the 19th century, it was widely believed that microbes produced substances that could injure the mammalian host and that soluble toxins released during infection caused the fever and shock that were commonplace during severe infections. PfeifferRichard Friedrich Johannes Pfeiffer
Richard Friedrich Johannes Pfeiffer was a German physician and bacteriologist.Pfeiffer was born in Zduny, Province of Posen, and died in Bad Landeck....
coined the term endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
at the beginning of the 20th century to denote the pyrogenic principle associated with Vibrio cholerae
Vibrio cholerae
Vibrio cholerae is a Gram-negative, comma-shaped bacterium. Some strains of V. cholerae cause the disease cholera. V. cholerae is facultatively anaerobic and has a flagella at one cell pole. V...
. It was soon realised that endotoxins were expressed by most and perhaps all Gram negative organisms. The lipopolysaccharide character of enteric endotoxins was elucidated in the 1944 by Shear. The molecular character of this material was determined by Luderitz et al in 1973.
It was discovered in 1965 that a strain of C3H/HeJ mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
were immune to the endotoxin induced shock. The genetic locus for this effect was dubbed Lps. These mice were also found to be hypersusceptible to infection by Gram negative bacteria. These observations were finally linked in 1998 by the discovery of the Toll-like receptor
Toll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...
gene 4 (TLR 4)Genetic mapping work, performed over a period of 5 years showed that TLR4 was the sole candidate locus within the Lps critical region strongly implying that a mutation within TLR4 must account for the lipopolysaccharide resistance phenotype. The defect in the TLR4 gene that lead to the endotoxin resistant phenotype was discovered to be due to a mutation in the cytoplasmic domain.
It had previously been shown that cells of hematopoietic origin are required for the lethal effect of lipopolysaccharide. Endotoxin sensitive mice may be rendered resistant to endotoxin if their bone marrow is ablated with radiation and it is then reconstituted with hematopoietic precursors derived from endotoxin resistant mice. Conversely, lipopolysaccharide sensitivity may be restored to resistant mice mice if they are colonized by hematopoietic precursors from endotoxin sensitive animals. These experiments showed that endotoxin was interacting with receptors on cells derived from the hematopoietic system to produce its effects.
In 1990 it was shown that CD14
CD14
Cluster of differentiation 14 also known as CD14 is a human gene.The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms. Either it is anchored into the membrane by a glycosylphosphatidylinositol tail or it appears in a soluble form...
acts to concentrate plasma lipopolysaccharide and that this effect evokes a strong response by mononuclear phagocytic cells. Because CD14 lacks a cytoplasmic domain it was clear that at least one other protein was required for the endotoxin response. The Lps locus was considered to be the most likely candidate and so it proved.
Although it now known that endotoxin binds to CD14 and that CD14 then interacts with TLR4, the molecular details concerning precisely this contributes to the generation of the septic syndrome are currently the subject of active research.
It was shown in 1999 that mutations in TLR 2 could significantly reduce the systemic response to Gram positive infections. Although less likely than Gram negative organisms to cause septic shock, infection with Gram positive organisms remains a problem in intensive care and in neonates. Like TLR 4 much work is currently being done to elucidate the mechanism of the response to these organisms.
PD-1 and monocytes/macrophages activation
PD-1 was found to be up-regulated on monocytes/macrophages during sepsis in human and mice. This up-regulation was related to the up-regulation of IL-10 levels in the blood. Interestingly, Said et al. showed that activated monocytes, which is the case in sepsis, express high levels of PD-1 and that triggering monocytes-expressed PD-1 by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.Inflammatory signal blocker
A study reported in the journal ScienceScience (journal)
Science is the academic journal of the American Association for the Advancement of Science and is one of the world's top scientific journals....
showed that SphK1 is highly elevated in inflammatory cells from patients with sepsis and inhibition of the molecular pathway reduced the proinflammatory response triggered by bacterial products in the human cells. Moreover, the study also showed the mortality rate of mice with experimental sepsis was reduced when treated with a SphK1 blocker. Similarly, inhibition of the p38 MAPK signaling transduction pathway may help to block enhanced procoagulatory activities during septicemia.
Nitric oxide
Medical research is focused on combating nitric oxide. Attempts to inhibit its production paradoxically led to a worsening of the organ damage and in an increased lethality, both in animal models and in a clinical trial in sepsis patients. In a study published in the Journal of Experimental MedicineJournal of Experimental Medicine
The Journal of Experimental Medicine is a peer-reviewed academic journal published by the Rockefeller University Press that publishes research papers and commentaries on the physiological, pathological, and molecular mechanisms that encompass the host response to disease...
, nitrite treatment, in sharp contrast with the worsening effect of inhibiting NO-synthesis, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in mice.
External links
- So More Survive – Sepsis Alliance
- Surviving Sepsis Campaign
- International Sepsis Forum
- Sepsis can strike, kill shockingly fast – CNNCNNCable News Network is a U.S. cable news channel founded in 1980 by Ted Turner. Upon its launch, CNN was the first channel to provide 24-hour television news coverage, and the first all-news television channel in the United States...
- Sepsis Medline Plus
- Sepsis News Archive from insciences organisation