Sepsis

Sepsis (, 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 ulcers 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).

Signs and symptoms
In addition to symptoms related to the provoking infection, sepsis is characterized by presence of acute inflammation 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 or over 38 C. 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. 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.

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 syndrome (SIRS). Defined by the presence of two or more of the following findings:
 * Body temperature < 36 °C or > 38 °C (hypothermia or fever).
 * Heart rate > 90 beats per minute.
 * Respiratory rate > 20 breaths per minute or, on blood gas, a PaCO2 less than 32 mm Hg (4.3 kPa) (tachypnea or hypocapnia due to hyperventilation).
 * White blood cell count < 4,000 cells/mm3 or > 12,000 cells/mm3 (< 4 × 109 or > 12 × 109 cells/L), or greater than 10% band forms (immature white blood cells). (leukopenia, leukocytosis, or bandemia).
 * Sepsis. Defined as SIRS in response to a confirmed infectious process. 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.
 * Severe sepsis. Defined as sepsis with organ dysfunction, hypoperfusion, or hypotension.
 * Septic shock. Defined as sepsis with refractory arterial hypotension 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 oliguria and altered mental status. Patients are defined as having septic shock 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 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 (indirect bilirubin)
 * 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.
 * 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 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 > 3°C
 * Respiratory dysfunction (in the absence of cyanotic heart disease or known chronic lung disease)
 * 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
 * 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%
 * 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 retardation
 * Hematologic dysfunction
 * platelet count < 80,000/mm3 or 50% drop from maximum in chronically thrombocytopenic patients, OR
 * international normalized ratio (INR) > 2
 * Disseminated intravascular coagulation
 * Renal dysfunction
 * 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)
 * total serum bilirubin ≥ 4 mg/dl, OR
 * 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.

Neonatal sepsis
In common clinical usage, 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 clinically because these symptoms often do not arise in neonates until death is imminent and unpreventable.

Pathophysiology
Systemic inflammatory response syndrome 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 viruses 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 burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis.

Management
The therapy of sepsis rests on antibiotics, 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.

Early goal directed therapy
Early goal directed therapy (EGDT), developed at Henry Ford Hospital by Emaneul 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 greater 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. 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 insufficiency 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
Recombinant activated protein C (drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality 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 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 States 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.

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 Science 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 Medicine, 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.