Sepsis

Sepsis (/spss/; Greek , putrefaction and decay) is a potentially fatal whole-body inflammation (a systemic inflammatory response syndrome or SIRS) caused by severe infection.[1][2] Sepsis can continue even after the infection that caused it is gone. Severe sepsis is sepsis complicated by organ dysfunction. Septic shock is sepsis complicated by a high lactate level or by shock that does not improve after fluid resuscitation.[3] Bacteremia is the presence of viable bacteria in the blood. The term septicemia, the presence of microorganisms or their toxins in the blood, is no longer used by the consensus committee.[2] Sepsis causes millions of deaths globally each year.[4] Sepsis is caused by the immune system's response to a serious infection, most commonly bacteria, but also fungi, viruses, and parasites in the blood, urinary tract, lungs, skin, or other tissues. Sepsis can be thought of as falling within a continuum from infection to multiple organ dysfunction syndrome.[5] Common symptoms of sepsis include those related to a specific infection, but usually accompanied by high fevers, hot, flushed skin, elevated heart rate, hyperventilation, altered mental status, swelling, and low blood pressure. In the very young and elderly, or in people with weakened immune systems, the pattern of symptoms may be atypical, with hypothermia and without an easily localizable infection.[6][7] Sepsis is usually treated with intravenous fluids and antibiotics. If fluid replacement is not sufficient to maintain blood pressure, vasopressors 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, mixed venous oxygen saturation or stroke volume variation) may also be used. Sepsis patients require preventive measures for deep vein thrombosis, stress ulcers and pressure ulcers, unless other conditions prevent this. Some might benefit from tight control of blood sugar levels with insulin (targeting stress hyperglycemia).[4] The use of corticosteroids is controversial.[8] Activated drotrecogin alfa (recombinant activated protein C), originally marketed for severe sepsis, has not been found to be helpful, and has recently been withdrawn from sale.[9]

Signs and symptoms

Charlotte Cleverley-Bisman, with sepsis due to meningococcemia.

In addition to symptoms related to the provoking infection, sepsis is frequently associated with either fever or hypothermia, rapid breathing, elevated heart rate, confusion, and edema.[10] Early signs are elevated heart rate, decreased urination, and elevated blood sugar, while signs of established sepsis are confusion, metabolic acidosis with compensatory respiratory alkalosis (which can manifest as faster breathing), low blood pressure, decreased systemic vascular resistance, higher cardiac output, and dysfunctions of blood coagulation.[11] Sepsis may also lead to a drop in blood pressure, resulting in shock. This may result in lightheadedness. Bruising or intense bleeding may also occur.

Cause
The most common primary sources of infection resulting in sepsis are the lungs, the abdomen, and the urinary tract.[12] Typically, 50% of all sepsis cases start as an infection in the lungs. No source is found in one third of cases.[12] The infectious agents are usually bacteria but can also be fungi and viruses.[12] While gramnegative bacteria were previously the most common cause of sepsis, in the last decade, grampositive bacteria, most commonly staphylococci, are thought to cause more than 50% of cases of sepsis.[13]

Diagnosis
Systemic inflammatory response syndrome[14] Finding Value Temperature <36 C (96.8 F) or >38 C (100.4 F) Heart rate >90/min Respiratory rate >20/min or PaCO2<32 mmHg (4.3 kPa) 9 WBC <4x10 /L (<4000/mm), >12x109/L (>12,000/mm), or 10% bands Prompt diagnosis is crucial to the management of sepsis, as initiation of early-goal-directed therapy is key to reducing mortality from severe sepsis.[15] Within the first three hours of suspected sepsis, diagnostic studies should include measurement of serum lactate, obtaining appropriate cultures before initiation of antimicrobial treatment, so long as this does not delay antimicrobial treatment by more than 45 minutes.[15] To identify the causative organism(s), at least two sets of blood cultures (aerobic and anaerobic bottles) should be obtained, with at least one drawn percutaneously and one drawn through each vascular access device (such as an IV catheter) in place more than 48 hours.[15] If other sources are suspected, cultures of these sources, such as urine, cerebrospinal fluid, wounds, or respiratory secretions, should be obtained as well, so long as this does not delay antimicrobial treatment.[15]

Within six hours, if there is persistent hypotension despite initial fluid resuscitation of 30ml/kg,

or if initial lactate is 4 mmol/L (36 mg/dL), central venous pressure and central venous oxygen saturation should be measured.[15] Lactate should be re-measured if the initial lactate was elevated.[15] Within twelve hours, it is essential to diagnose or exclude any source of infection that would require emergent source control, such as necrotizing soft tissue infection, peritonitis, cholangitis, intestinal infarction.[15]

Definitions
According to the American College of Chest Physicians and the Society of Critical Care Medicine, there are different levels of sepsis:[2]

Systemic inflammatory response syndrome (SIRS) is the presence of two or more of the following: abnormal body temperature, heart rate, respiratory rate or blood gas, and white blood cell count. Sepsis is defined as SIRS in response to an infectious process.[16] Severe sepsis is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (manifesting as hypotension, elevated lactate, or decreased urine output).[17] Septic shock is severe sepsis plus persistently low blood pressure following the administration of intravenous fluids.[4]

Infection
Infection can be suspected or proven (by culture, stain, or polymerase chain reaction (PCR)), or a clinical syndrome pathognomonic for infection. Specific evidence for infection includes WBCs in normally sterile fluid (such as urine or cerebrospinal fluid (CSF)); evidence of a perforated viscus (free air on abdominal x-ray or CT scan; signs of acute peritonitis); abnormal chest x-ray (CXR) consistent with pneumonia (with focal opacification); or petechiae, purpura, or purpura fulminans.

End-organ dysfunction
Examples of end-organ dysfunction include the following:[18]

Lungs:acute lung injury (ALI) (PaO2/FiO2 < 300) or acute respiratory distress syndrome (ARDS) (PaO2/FiO2 < 200) Brain: encephalopathy symptoms: agitation, confusion, coma; cause: ischemia, hemorrhage, microthrombi, microabscesses, multifocal necrotizing leukoencephalopathy Liver: disruption of protein synthetic function: manifests acutely as progressive coagulopathy due to inability to synthesize clotting factors, disruption of metabolic functions: manifests as cessation of bilirubin metabolism, resulting in elevated unconjugated serum bilirubin levels Kidney: oliguria and anuria, electrolyte abnormalities, volume overload

Heart: systolic and diastolic heart failure, likely due to cytokines that depress myocyte function, cellular damage, manifest as a troponin leak (although not necessarily ischemic in nature)

More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.[19]

Cardiovascular dysfunction (after fluid resuscitation with at least 40 ml/kg of crystalloid) o hypotension with blood pressure < 5th percentile for age or systolic blood pressure < 2 standard deviations below normal for age, OR o vasopressor requirement, OR o two of the following criteria: unexplained metabolic acidosis with base deficit > 5 mEq/L lactic acidosis: serum lactate 2 times the upper limit of normal oliguria (urine output < 0.5 ml/kg/hr) prolonged capillary refill > 5 seconds core to peripheral temperature difference > 3C Respiratory dysfunction (in the absence of cyanotic heart disease or known chronic lung disease) o 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), OR o arterial partial-pressure of carbon dioxide (PaCO2) > 65 torr (20 mmHg) over baseline PaCO2 (evidence of hypercapnic respiratory failure), OR o supplemental oxygen requirement of greater than FiO2 0.5 to maintain oxygen saturation 92% Neurologic dysfunction o Glasgow Coma Score (GCS) 11, OR o altered mental status with drop in GCS of 3 or more points in a patient with developmental delay/intellectual disability Hematologic dysfunction 3 o platelet count < 80,000/mm or 50% drop from maximum in chronically thrombocytopenic patients, OR o international normalized ratio (INR) > 2 o Disseminated intravascular coagulation Renal dysfunction o serum creatinine 2 times the upper limit of normal for age or 2-fold increase in baseline creatinine in patients with chronic kidney disease Hepatic dysfunction (only applicable to infants > 1 month) o total serum bilirubin 4 mg/dl, OR o alanine aminotransferase (ALT) 2 times the upper limit of normal

Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.[1]

Differential diagnosis

The differential diagnosis for sepsis is broad and includes those conditions that can cause the systemic signs of SIRS: alcohol withdrawal, pulmonary embolus, thyrotoxicosis, anaphylaxis, adrenal insufficiency, and neurogenic shock.[11]

Neonatal sepsis
In common clinical usage, neonatal sepsis specifically refers to the presence of a bacterial blood stream infection (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 because these symptoms often do not arise in neonates until death is imminent and unpreventable.

Pathophysiology
Sepsis is caused by a combination of factors related to the invading organism(s) and the host (predisposing illnesses, genetics, and immune system).[20]

Microbial factors
A bacteria's capsule (for example, in certain strains of Streptococcus pneumoniae), can allow it to evade phagocytosis, while pili of some strains of E. Coli can allow this bacterium to adhere to the epithelium of the kidneys.[20] Sepsis caused by gram negative bacteria is thought to be largely due to the host's response to lipopolysaccharides, also called LPS or endotoxin, in the cell wall, while gram positive bacteria are more likely to cause sepsis by their release of exotoxins.[20] Some exotoxins can quickly lead to a rapid release of cytokines by acting as superantigens, which can simultaneously bind MHC and the T-cell receptor.[20] There are number of microbial factors which can cause the typical septic inflammatory cascade. An invading pathogen is recognised by its pathogen-associated molecular pattern (PAMP). Examples of PAMPs are lipopolysaccharides in Gram-negative bacteria, flagellin in Gramnegative bacteria, muramyl dipeptide in the peptidoglycan cell wall of a Gram-positive bacteria and CpG bacterial DNA. These PAMPs are recognised by the innate immune system's pattern recognition receptors (PRR). These receptors can be membrane-bound or cytosolic.[21] There are four families of PRRs: the toll-like receptors, the C-type lectin receptors, the nucleotide oligemerization domain-like receptors and the RigI-helicases. The association of a PAMP and a PRR will invariably cause a series of intracellular signalling cascades. Consequentially transcription factors like nuclear factor-kappa B and activating protein-1 will up regulate the expression of pro-inflammatory and anti-inflammatory cytokines.