A generalized inflammatory and procoagulant response to infection that results in acute organ dysfunction and, in 30-50% of cases, death.
Estimated to be responsible for 20% of the world’s deaths.
Approximately 20 to 30% of patients admitted to an ICU have sepsis.
A life-threatening organ dysfunction due to dysregulated host response to infection.
The leading cause of morbidity and mortality in hospitalized patients:contributes to between a third and half of deaths in hospitals.
Pulmonary infections account for nearly 70% of patients admitted for sepsis in the ICU.
Sepsis remains the leading cause of death and disability, present in 53% of hospitalizations leading to death or discharge to hospice.
It remains the most common cause of both in-hospital deaths and unplanned readmission in the United States.
When sepsis manifests clinically, the disease process may be so advanced or severe that the chances of survival are reduced even with rapid therapy.
Incidence increasing.
Affects an an estimated 55 million people worldwide each year.
Syndrome accompanies severe infection and characterized by systemic inflammation and widespread tissue injury.
Sepsis is triggered by a dysregulated immune response to infection with and organ damage as a result.
Sepsis is characterized by a dysregululated host response to infection, manifesting as both hyperinflammatory and hypo inflammatory, with macrocirculatory and microcirculatory dysfunction, leading to organ injury.
Initial organ injury potentiates further system deterioration.
Severe sepsis described in instances in which sepsis is complicated by acute organ dysfunction.
Most episodes of sepsis begin outside the hospital setting.
This is defined as a known or suspected infection plus systemic manifestations of infections which includes traditional systemic inflammatory response syndrome criteria such as tachycardia, tachypnea, leukocytosis, fever, hypothermia as well as other metabolic perturbations or organ dysfunction.
Involves early activation of pro and anti-inflammatory responses along with modifications in nonimmunologic pathways such as cardiovascular, neuronal, autonomic , hormonal, bioenergetic, metabolic, and coagulation, all of which have prognostic significance.
Severe sepsis defined is sepsis plus infection induced organ dysfunction or infection induced acute tissue hypoperfusion.
The incidence of sepsis as a result of gram-positive bacteria and fungi have increased over time in the US.
Organ dysfunction associated with severe sepsis include acute lung injury, acute kidney injury, coagulopathies, liver dysfunction, and cardiovascular abnormalities.
Tissue hypoperfusion abnormalities in severe sepsis include: hypotension, elevated lactate levels, oliguria, and altered mental status.
Overlap exist between tissue hypoperfusion and abnormalities in organ dysfunction associated with the cardiovascular system.
May be associated with a state of immune suppression due to decreased
responsiveness, exhaustion, and apoptotic depletion of immune cells and an increase In T regulatory and myeloid derived suppressor cells.
Associated with significant biological and clinicals heterogeneity in affected patients with age,
concurrent injuries, medications and the source of infection and further complexity
This immune suppression that accompanies sepsis can contribute to late
sepsis mortality in the ICU caused by an increased occurrence of secondary infections.
In a large majority of patients surviving sepsis multiple mechanisms of protracted immunosuppression occur after the initial inflammatory phase.
After intensive care unit admission, sepsis survivors experience mental and physical impairments and increased mortality even up to 24 months.
Sepsis rates doubled between 2000 and 2008.
Septicemia is the most expensive condition treated in US hospitals, counting for $24 billion in healthcare cost annually.
Sepsis affects more than 1.7 million Americans a year.
Sepsis accounts for more than 270,000 deaths per year.
Sepsis ranks as the third leading cause of death in the US.
Over 62% of people hospitalized with primary diagnosis of sepsis have to be readmitted within 30 days.
Sepsis is the most expensive in-hospital condition costing more than $20 billion per year
Severe sepsis is the leading cause of hospital death.
In 2011 severe sepsis was the most expensive reason for hospitalization in the US.
High mortality rate attributed to multiple mechanisms including abnormal myocardial performance.
Reductions in preload and afterload may be responsible for cardiovascular events.
Hemodynamic instability may occur due to microvascular dysfunction, hypoxemia, capillary leak, or interstitial edema.
Severe sepsis occurs in 2% of hospital admissions.In 2011 severe sepsis was the most expensive reason for hospitalization in the US.
Severe sepsis represents 10% of ICU admissions.
Sepsis can present in 3 different stages:uncomplicated sepsis, severe sepsis, and septic shock.
Uncomplicated sepsis is the most common form and may not require hospitalization.
Severe sepsis refers to sepsis plus sepsis-induced organ dysfunction with tissue hypoperfusion.
Septic shock is referred to as a complication of sepsis manifested by either hypotension refractory to fluid resuscitation or by hyperlactatemia.
Mortality for severe sepsis is 30-50% and as high as 50-60% for septic shock.
Bloodstream infections are common in patients with vascular access devices, and those on chemotherapy, more frequent in those who have compromised immunity, including cancer patients, transplant patients or patients receiving immunosuppressive agents.
Risk factors include corticosteroid therapy, multiple sites of trauma, aides, recent surgery, gunshot wounds, diabetes, acute and chronic renal insufficiency and cirrhosis.
Associated abnormalities include endothelial dysfunction, apoptosis, activation and increased production of cytokines, activation and extra vascular transmigration of white blood cells, activation of platelets, activation of the coagulation and activation of the complement system.
Infectious pathogens, possess molecular patterns, including lipopolysaccharide in gram-negative bacteria and peptidoglycan in gram-positive bacteria, and such molecules bind to host cell receptors, or pattern-recognition receptors, including cell-surface toll-like receptors and several types of cytoplasmic receptors(Adib-Conquy M).
When pathogen associated molecules bind to cellular receptors, intracellular signaling pathways are activated increasing transcription of inflammatory cytokines, up regulation of adhesion molecule expression, stimulation of humeral responses, stimulation of cell mediated immunity, and activation of vascular endothelial cells.
Cytokines activate the coagulation cascade and inhibit fibrinolysis, resulting in pro-inflammatory effects and dysregulation of coagulation.
Disseminated intravascular coagulation is a manifestation of coagulation dysregulation.
Definition is a systemic inflammatory syndrome with 2 or more of the of the following: fever, increased heart rate, increased respiratory rate and elevated white blood cell count, with a concomitant pathological infection.
Data suggests that there is a worse prognosis for patients with severe sepsis who have an elevated cardiac troponin levels.
Syndrome suspected with fever, tachycardia with a rate greater than90 beats per minute, respiratory rate more than 20 breaths per minute, PaCo2 on arterial gas analysis of less than 32 mm Hg, white blood cell count greater than 12,000 cells/microL, or greater than 10% band forms.
Nearly 900,000 cases per year in the U.S. with 55%-65% survivorship.
Approximately 500,000 patients with severe sepsis in the U.S. annually present to emergency departments.
Incidence approximately 3 per 1000 persons.
Incidence ranges from 50-300 cases per 100,000 population, with a short term mortality of 20-25% and increases to 50% when shock is present.
The prevalence of sepsis organ dysfunction, severe sepsis, is 11% and nearly half of the patients with severe sepsis and septic shock (Bone RC).
Incidence of severe sepsis estmated to be 76 to 110 cases per year per 100,000 population (Engel C).
As many deaths annually as those from myocardial infarction.
Leading cause of death in hospitalized adult patients.
A positive correlation exists between the frequency of sepsis and mortality rates in the ICU.
Higher incidence of severe sepsis among blacks than whites (Barnato AE).
Racial differences in severe sepsis due to higher infection rate and to higher risk of acute organ dysfunction in blacks than whites based on analysis of infection related hospitalizations from 2005 hospital discharge data of 7 US states and infection related emergency department visits from the 2003-2007 National Ambulatory Survey (Mayr FB).
Mortality rates range from 38-59%.
After discharge from the hospital for sepsis there is a 10% risk of readmission and almost a 20% risk of death, usually within the first six months.
Severe sepsis may be community and healthcare associated infections.
Inappropriate antimicrobacterial therapy is associated with increased mortality and morbidity in patients with neutropenic fever, and severe sepsis.
There is a lack of benefit of early antibiotics in patients who have a systemic inflammatory response syndrome criteria with end organ damage that is identified through electronic alerts (Seetharaman S).
Patients who survive severe sepsis have an impaired quality of life compared to age and sex adjusted general population, as long as one half years following recovery (Karlsson S).
Statins may modulate innate, and adaptive immune system and anti-inflammatory effects and counteract deleterious effects of sepsis on the coagulation system by inhibiting tissue factor expression and reducing prothrombin fragment levels and by increasing the expression of thrombomodulin.
Infection source most commonly lung, abdomen and urinary tract.
Pneumonia accounts for about half of all cases.
Source of infection not determined in 20% of patients.
Increasingly common among hospitalized patients.
Increasing incidence because of an increased aging population, increased use of immunosuppressive drugs , HIV, increasing antibiotic resistance and increased invasive health care interventions.
Leading cause of death in noncoronary ICU’s.
The 10th leading cause of death overall in the U.S.
Incidence of severe sepsis is increasing over time, with rates of hospital station for severe sepsis increase from 66.8 per 100,000 population to 132 per 100,000 population between 1993 and 2003 (Dombrovsky).
Age-adjusted, population-based mortality rates from 1993 to 2003 increased from 30.3 to 249.7 per hundred thousand population.
Survivors experience increase in morbidity and reduced quality of life.
Severe sepsis defined as the addition of acute organ dysfunction, hypoperfusion or hypotension.
Impaired cellular oxygenization important in the development of multiple organ failure.
Endotoxemia has multiple inflammatory, hematologic, procoagulant, anticoagulant and fibrinolytic disturbances.
During the process hypothalamic pituitary-adrenal axis affects inflammation via leukocytes, cytokines, and nitric oxide production.
Inflammatory cytokines may impair adrenocorticotropin stimulation of cortical release by the adrenal glands, or they may compete with intracellular glucocorticoid receptor function with the development of peripheral glucocorticoid resistance.
The three leading causes of nosocomial infections of the blood stream are coagulase-negative Staphylococci, Staphylococci aureus and enterococci.
30% have positive blood cultures.
Up to a third of patients have negative cultures from all sites.
Blood cultures that are positive represent true infections about half of the time (Weinstein MP).
Many blood cultures have coagulase negative staphylococci, which are the most common organisms grown from blood cultures, and 90% are contaminants.
When blood cultures with coagulation negative staphylococci do represent true infections it is usually associated with an intravenous catheter or other prosthetic material, such as a heart valve, a vascular graft or a stent.
IV catheters may account for as many as 23% of episodes of bacteremia and fungemia.
As many as 81% of bacteremias and fungemias are associated with a healthcare setting: Approximately 46% acquired in the hospital, 35% acquired in healthcare settings such as dialysis centers or intravenous infusion centers.
A significant number of people who develop sepsis have been hospitalized within the previous month.
The most common organisms causing true bacteremia are Staphylococcus aureus, E. coli is second, enterococci or third and Klebsiella a gram-negative organism is fourth.
Activation of clotting system with consumption of ATIII, protein S and protein C.
Efficacy of recombinant human activated protein C for severe sepsis and septic shock associated with a reduction of crude mortality from 30.8% in placebo group to 24.7% in group receiving human activated protein C, an absolute difference of 6.1%.
The development of neutropenia associated with a poor prognosis.
The risk of death associated with advancing age and hypotension.
Absence of fever is a risk factor for death, as is acquisition of infection during hospitalization, the presence of AIDS, malignancy and renal failure.
Protein C levels correlate with prognosis in patients with severe sepsis.
Reduced levels of protein C. correlate with increased risk of death.
Activated protein C in sepsis may inhibit systemic inflammation, and may inhibit nitric oxide induced vascular dysfunction.
Hospitalwide incidence of bacteremic sepsis is approximately .82 cases per 100 admissions.
Estimated sepsis rate 2.26 cases per hospital discharges.
An increase in gram-positive microorganisms in the respiratory tract as becoming the leading source of bacterial sepsis in ICU’s.
Rate of bacteremic sepsis 6.9 cases per 100 admissions to a critical care unit.
Mortality in women with hospital-acquired bloodstream infections is substantially greater than for men.
Patients with hematological dysfunction have increased mortality and morbidity.
Inverse relationship exits between the severity of sepsis and level of platelet count.
Primary cause of thrombocytopenia is nonimmune destruction of platelets.
Cardiovascular failure occurs in about 7% of patients, but reversible myocardial dysfunction described in 40-50% of these individuals.
Associated with biventricular dilation and reduced ejection fraction.
6-20% of patients with severe sepsis develop new onset atrial fibrillation.
New onset atrial fibrillation in severe sepsis is associated with higher mortality and prolonged hospitalization.
New onset atrial fibrillation in severe sepsis associated with an increased risk of and hospital stroke and death, compared with patients with no atrial fibrillation and patients with pre-existing atrial fibrillation (Walkey AJ et al).
Increased stroke associated with infections, and is particularly demonstrated by the fact that patients with severe sepsis have a six fold increase risk of in-hospital stroke compared with hospitalized patients without severe sepsis.
Myocardial impairment due to circulating myocardial depressant substances and not to hypoxia.
Cardiomyopathy associated with sepsis involves right and left side of the heart.
Children or more likely than adults to have cardiac dysfunction.
58% of children with low cardiac output and high systemic vascular resistance and 22% have both low cardiac output and low systemic vascular resistance in the presence of severe sepsis(Ceneviva G et al As you).
Lipopolysaccharide, IL-6,Il-1′, and TNF-α depress cardiac contractility.
May be associated with hypocalcemia which confers an adverse prognosis.
Goal directed therapy for patients with severe sepsis includes: Intravenous fluids, pressors,inotropic agents, and transfusions to correct physiologic derangements.
Early use of goal directed therapy associated with a decrease in mortality from 46.5-30.5%(Rivers E).
Quantitative resuscitation, the use of protocol targeted physiological or laboratory goals to be achieved within the first several hours of presentation of septic patients, is associated with a survival benefit as indicated by a meta-analysis.(Jones AE).
Recommendations for adult severe sepsis:
Early resuscitation of the septic patient during the first six hours.
Sepsis: Diagnosis and Management.
Securing an airway, ensuring adequate oxygenation, obtaining IV access for fluid resuscitation, and antibiotic administration with prompt source control are the primary measures for treatment in patients with sepsis.
A metaanalysis of 70 studies revealed 46% of patients with sepsis were given inappropriate empiric therapy.
Fluid resuscitation is typically with crystalloid administration, empirical broad-spectrum antibiotics are administered within the first hour of presentation and directed to the most likely source of infection based on the history, physical examination and initial work up.
The initial work up includes CBC, coagulation studies, serum chemistries, liver function test, lactic level, arterial blood gas, blood cultures and imaging of suspected infectious source.
Anti-fungal agents are not empirically indicated in patients without neutropenia.
Definition of sepsis: life-threatening organ dysfunction caused by a dysregulated host response to infection.
Define septic shock as sepsis with circulatory, cellular, and metabolic dysfunction that is associated with a higher risk of mortality.
The measurement of serum lactate has been incorporated into the latest septic shock definition.
Respiratory, gastrointestinal, genitourinary, and skin and soft tissue infections are the most common sources of sepsis.
Pneumonia is the most common cause of sepsis.
Many with sepsis have fever, the clinical manifestation can be subtle, particularly in older patients and those who are immunocompromised.
Evaluation of patients with suspected sepsis include: basic laboratory tests, cultures, imaging studies as indicated, and sepsis biomarkers such as procalcitonin and lactate levels.
Fluid resuscitation is the priority in early management, including administering an intravenous crystalloid at 30 mL per kg within the first three hours.
Antimicrobial therapy should be initiated within three hours of presentation.
Vasopressor therapy is indicated if hypotension persists despite fluid administration.
Blood cultures to be taken before antibiotic therapy.
Administration of broad-spectrum antimicrobials within one hour of recognition of septic shock and severe sepsis without septic shock as the goal of therapy.
Empirical treatment for sepsis uses the beta lactams piperacillin and cefepime, which both provide broad in vitro activity against gram-positive and gram-negative organisms, including pseudomonas aeruginosa.
Guidelines recommend that adults with sepsis or septic shock should receive prolonged fusion of beta – lactams, after an initial bolus vs conventional intermittent infusion.
They are often used in combination with vancomycin to include activity against methicillin resistant staphylococcal aureus.
Delays in appropriate therapy are likely to occur in complex patients who are more likely to harbor resistant organisms and present in atypical ways.Patients should be managed with a bundle of interventions: measuring lactate level, obtaining blood cultures before administering antibiotics, administering broad-spectrum antibiotic‘s, administering 30 mL per kilogram of body weight if the patient has hypotension or a lactate level higher than 4 milli moles per liter, and administering vasopressors if the patient remains hypotensive despite fluid resuscitation.
The goal of the bundle is to be completed within three hours.
Imaging studies performed promptly to confirm potential source of infection.
Infection source control to be applied within 12 hours of diagnosis.
Initial fluid resuscitation with crystalloids and consideration of additional albumin in patients who continue to require substantial amounts of crystalloids to maintain adequate mean arterial pressure as well as avoidance of hetastarch formulations.
Initial fluid challenge with tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/ kilogram of crystalloids.(more rapid administration and greater amount of fluid may be needed in some patients).
Fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables.
Norepinephrine is the first choice vasopressor to maintain mean arterial pressure of 65 mmHg or greater.
Epinephrine or vasopressin when an additional agent is needed to maintain adequate blood-pressure.
Dopamine is not recommended except in highly selective circumstances.
Dobutamine infusion administered or added to vasopressor in the presence of a)myocardial dysfunction is suggested by elevated cardiac filling pressures and no cardiac output or b) ongoing signs of hypo perfusion despite achieving adequate intravascular volume and adequate mean arterial pressure.
Avoidance of intravenous hydrocortisone in the adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability.
High dose vitamin C with or without thiamine and steroids does not provide survivor benefits for patients with sepsis or septic shock.
Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator and vasopressor three days within 30 days (VICTAS Investigators).
In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C at a higher risk of death of persistent organ dysfunction at 28 days in those who received placebo (LOVIT investigators).