Sepsis

Sepsis is a serious medical condition characterized by a whole-body inflammatory state (called a systemic inflammatory response syndrome or SIRS) caused by infection.^[1][2] The body may develop this inflammatory response to microbes in the blood. The related layman's term is blood poisoning.

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 drugs can be used. Artificial 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).^[3]

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.^[4] 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.^[5] 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] Septicemia is an ill-defined term referring to the presence of bacteria or their toxins in the blood.^[6] The term improperly mixes components of bacteremia and sepsis, and has been abandoned as a concept.^[2]

Signs and symptoms

In addition to symptoms related to the provoking infection, sepsis is characterized by evidence of acute inflammation present throughout the entire body, and is therefore frequently associated with fever and elevated white blood cell count (leukocytosis). 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.

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.

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 multiple organ failure).^[7] 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 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.

Definition of sepsis

Sepsis is considered present if infection is highly suspected or proven and two or more of the following systemic inflammatory response syndrome (SIRS) criteria are met:^[2]

• Heart rate > 90 beats per minute (tachycardia)
• Body temperature < 36 °C (96.8 °F) or > 38 °C (100.4 °F) (hypothermia or fever)
• 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 < 4000 cells/mm³ or > 12000 cells/mm³ (< 4 x 10⁹ or > 12 x 10⁹ cells/L), or greater than 10% band forms (immature white blood cells). (leukopenia, leukocytosis, or bandemia)

Fever and leukocytosis are features of the acute phase reaction, while tachycardia is often the initial sign of hemodynamic compromise. Tachypnea may be related to the increased metabolic stress due to infection and inflammation, but may also be an ominous sign of inadequate perfusion resulting in the onset of anaerobic cellular metabolism.

In children, the SIRS criteria are modified in the following fashion:^[8]

• Heart rate > 2 standard deviations above normal for age in the absence of stimuli such as pain and drug administration, OR unexplained persistent elevation for greater than 30 minutes to 4 hours. In infants, also includes Heart rate < 10th percentile for age in the absence of vagal stimuli, beta-blockers, or congenital heart disease OR unexplained persistent depression for greater than 30 minutes.
• Body temperature obtained orally, rectally, from Foley catheter probe, or from central venous catheter probe > 38.5°C or < 36°C. Temperature must be abnormal to qualify as SIRS in pediatric patients.
• Respiratory rate > 2 standard deviations above normal for age OR the requirement for mechanical ventilation not related to neuromuscular disease or the administration of anesthesia.
• White blood cell count elevated or depressed for age not related to chemotherapy, or greater than 10% bands + other immature forms.

Note that SIRS criteria are very non-specific,^[9] and must be interpreted carefully within the clinical context. These criteria exist primarily for the purpose of more objectively classifying critically-ill patients so that future clinical studies may be more rigorous and more easily reproducible.

Consensus definitions however continue to evolve with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.^[9]

To qualify as sepsis, there must be an infection 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

The more critical subsets of sepsis are severe sepsis (sepsis with acute organ dysfunction) and septic shock (sepsis with refractory arterial hypotension). Alternatively, when two or more of the systemic inflammatory response syndrome criteria are met without evidence of infection, patients may be diagnosed simply with "SIRS." Patients with SIRS and acute organ dysfunction may be termed "severe SIRS."

Patients are defined as having "severe sepsis" if they have sepsis plus signs of systemic hypoperfusion: either end organ dysfunction or a 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:^[10]

• 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.^[8]

• 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
• 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

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.

It is difficult to clinically exclude sepsis in newborns less than 90 days old who have fever (defined as a temperature > 38°C (100.4°F). Except in the case of obvious acute viral bronchiolitis, the current practice in newborns less than 30 days old is to perform a complete workup including complete blood count with differential, blood culture, urinalysis, urine culture, and cerebrospinal fluid(CSF) studies and CSF culture, admit the newborn to the hospital, and treat empirically for serious bacterial infection for at least 48 hours until cultures are demonstrated to show no growth. Attempts have been made to see if it is possible to risk stratify newborns in order to decide if a newborn can be safely monitored at home without treatment despite having a fever. One such attempt is the Rochester criteria.

A study performed at Strong Memorial Hospital in Rochester, New York, showed that infants ≤ 60 days old meeting the following criteria were at low-risk for having a serious bacterial illness^[11]:

• generally well appearing
• previously healthy
  • full term (at ≥37 weeks gestation)
  • no antibiotics perinatally
  • no unexplained hyperbilirubinemia that required treatment
  • no antibiotics since discharge
  • no hospitalizations
  • no chronic illness
  • discharged at the same time or before the mother
• no evidence of skin, soft tissue, bone, joint, or ear infection
• WBC count 5,000-15,000/mm³
• absolute band count ≤ 1,500/mm³
• urine WBC count ≤ 10 per high power field (hpf)
• stool WBC count ≤ 5 per high power field (hpf) only in infants with diarrhea

Those meeting these criteria likely do not require a lumbar puncture, and are felt to be safe for discharge home without antibiotic treatment, or with a single dose of intramuscular antibiotics, but will still require close outpatient follow-up.

Diagnosis

The medical history and clinical examination can provide important elements regarding the cause and severity of sepsis.

The identification of the causative microbe in sepsis can provide useful information. Imaging (such as chest X-rays or CT scans) and laboratory techniques (such as urine microscopy or lumbar puncture) are often necessary to find the source of the infection. The exact causative organism is confirmed by microbiological culturing in the laboratory (blood cultures and cultures from suspected sites of infections such as urine cultures, sputum cultures, and so on). However, this is a slow process as it takes a few days to grow up the cultures and correctly identify the pathogens. New molecular diagnostic tests are now available that uses genetic material from the pathogen to quickly (within hours) provide results. However, current practice is to directly prescribe broad spectrum antibiotics to the patient.

The effects of the condition on the function of the organs should be documented to guide therapy. This can involve measurement of blood levels of lactate, blood gas sampling, and other blood tests. Because patients on the intensive care unit are predisposed to hospital-acquired infections (especially related to the presence of catheters), they may require surveillance cultures.

Treatment

Sepsis in 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,^[3] 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.^[12] A recent meta-analysis showed that EGDT provides a benefit on mortality in patients with sepsis.^[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). This may require around 6 liters of isotonic crystalloid solution, rapidly administered. 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.^[12] The Surviving Sepsis Campaign guidelines recommends EGDT for the initial resuscitation of the septic patient with a level B strength of evidence (single randomized control trial).^[3]

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]

During critical illness, a state of adrenal insufficiency and tissue resistance (the word 'relative' resistance should be avoided^[15]) to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency.^[15] 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.^[15] These recommendations stem from studies showing benefits from low dose hydrocortisone treatment for septic shock patients and methylprednisolone in ARDS patients.^{[16][17][18][19][20][21]} 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.^[15] Glucocorticoid drugs should be weaned and not stopped abruptly.

Sepsis and suspected sepsis in 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. In addition to fluid resuscitation and supportive care, a common antibiotic regimen in infants with suspected sepsis is a beta-lactam antibiotic (usually ampicillin) in combination with an aminoglycoside (usually gentamicin) or a third-generation cephalosporin (usually cefotaxime—ceftriaxone is generally avoided in neonates due to the theoretical risk of causing biliary stasis.) The organisms which are targeted are species that predominate in the female genitourinary tract and to which neonates are especially vulnerable to, specifically Group B Streptococcus, Escherichia coli, and Listeria monocytogenes (This is the main rationale for using ampicillin versus other beta-lactams.) Of course, neonates are also vulnerable to other common pathogens that can cause meningitis and bacteremia such as Streptococcus pneumoniae and Neisseria meningitidis. Although uncommon, if anaerobic species are suspected (such as in cases where necrotizing enterocolitis or intestinal perforation is a concern, clindamycin is often added.

Experimental

Infusion of the short chain fatty acid sodium butyrate inhibits high-mobility group box 1 protein (HMGB1) preventing the lethality of severe sepsis in rats.^[22]

Prognosis

Prognosis can be estimated with the MEDS score.^[23]

References

See also

• Meningococcemia
• Septic shock
• Systemic inflammatory response syndrome

External links

• Surviving Sepsis Campaign
• International Sepsis Forum