Sepsis

Sepsis is a serious 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.^[1][2] 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, more aptly applied to septicemia (a deprecated term), below.

Septicemia (also septicaemia or septicæmia [sep⋅ti⋅cæ⋅mi⋅a],^[3] or erroneously septasemia and septisema) is a related but deprecated medical term referring to the presence of pathogenic organisms in the bloodstream, leading to sepsis.^[4] 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. The present medical consensus is therefore that the term "septicemia" is problematic and should be avoided.^[2]

Sepsis is usually treated in the intensive care unit with intravenous fluids and antibiotics. If fluid replacement is insufficient 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. 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).^[5]

Terminology

Severe sepsis occurs when sepsis leads to organ dysfunction, low blood pressure (hypotension), or insufficient blood flow (hypoperfusion) to one or more organs (causing, for example, lactic acidosis, decreased urine production, or altered mental status). Sepsis can lead to septic shock, multiple organ dysfunction syndrome (formerly known as multiple organ failure), and death. Organ dysfunction results from sepsis-induced hypotension (< 90 mmHg or a reduction of ≥ 40 mmHg from baseline) and diffuse intravascular coagulation, among other things.

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.^[6] 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.^[7] 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.^[2]

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 hemodynamic compromise and resultant metabolic derangement. Outward physical symptoms of this response frequently include a high heart rate (above 90 beats per minute), high respiratory rate (above 20 breaths per minute), elevated WBC count (above 12,000) and elevated or lowered body temperature (under 36 °C (97 °F) or over 38 °C (100 °F)). Sepsis is differentiated from SIRS by the presence of a known pathogen. For example SIRS and a positive blood culture for a pathogen indicates the presence of sepsis. Without a known infection, it's not possible to classify the above symptoms as sepsis, only SIRS.

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,^[2] 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 (97 °F) or > 38 °C (100 °F) (hypothermia or fever).
  • Heart rate > 90 beats per minute (tachycardia).
  • Respiratory rate > 20 breaths per minute or, on blood gas, a P_aCO₂ 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/dL. 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).

Examples of end-organ dysfunction include the following:^[8]

• Lungs
  • acute lung injury (ALI) (PaO₂/FiO₂ < 300) or acute respiratory distress syndrome (ARDS) (PaO₂/FiO₂ < 200)
• Brain
  • encephalopathy
    • symptoms:
      • agitation
      • confusion
      • coma
    • etiologies:
      • 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.^[9]

• 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.^[10]

Neonatal sepsis

In common clinical usage, sepsis specifically refers to the presence of a serious bacterial infection (SBI) (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.

Treatment

Adults and children

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,^[5] with the aim to publish a complete set of guidelines in subsequent years.

Early Goal Directed Therapy (EGDT), developed at Henry Ford Hospital by E. 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 one should use a step-wise approach, having the patient meet physiologic goals, to optimize cardiac preload, afterload, and contractility, thus optimizing oxygen delivery to the tissues.^[11] A recent meta-analysis showed that EGDT provides a benefit on mortality in patients with sepsis.^[12] As of December 2008 some controversy around its uses remains and a number of trials are ongoing in an attempt to resolve this.^[13]

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.^[11] 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).^[5]

Most therapies aimed at the inflammation process itself have failed to improve outcome, however drotrecogin alfa (activated protein C, one of the coagulation factors) has been shown to decrease mortality from about 31% to about 25% in severe sepsis. To qualify for drotrecogin alfa, a patient must have severe sepsis or septic shock with an APACHE II score of 25 or greater and a low risk of bleeding.^[14] However, since further trials have failed to replicate this result, the use of activated protein C is controversial and is currently the subject of a large trial that was demanded by the European Medicines Regulator.^[15]

During critical illness, a state of adrenal insufficiency and tissue resistance (the word 'relative' resistance should be avoided^[16]) to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency.^[16] 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.^[16] These recommendations stem from studies showing benefits from low dose hydrocortisone treatment for septic shock patients and methylprednisolone in ARDS patients.^{[17][18][19][20][21][22]} 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.^[16] Glucocorticoid drugs should be weaned and not stopped abruptly.

In some cases, sepsis may lead to inadequate tissue perfusion and necrosis. As this may affect the extremities, amputation may become necessary.

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 MEDS score.^[23] 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 dying. 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.^[24] A preliminary study of nine patients with septic shock showed abnormalities in seven patients by MRI.^[25]

Epidemiology

In the United States, sepsis is the second-leading cause of death in non-coronary 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).^[26] Sepsis is common and also more dangerous in elderly, immunocompromised, and critically ill patients.^[27] It occurs in 1–2% of all hospitalizations and accounts for as much as 25% of intensive-care unit (ICU) bed utilization. It is a major cause of death in intensive-care units worldwide, with mortality rates that range from 20% for sepsis to 40% for severe sepsis to >60% for septic shock.

Research

Inflammatory signal blocker

A study reported in Science (journal) 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.^[28]

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^[29]

See also

• Immune system
• Intensive care
• Meningococcemia
• Multiple organ dysfunction syndrome
• Pathogenic bacteria
• Septic shock
• Systemic inflammatory response syndrome

References

External links

• So More Survive - Sepsis Alliance
• Surviving Sepsis Campaign
• International Sepsis Forum
• Sepsis can strike, kill shockingly fast - CNN
• Sepsis Medline Plus
• Sepsis News Archive from insciences organisation