Background:
In 1914, Schottmueller wrote, "Septicemia is a state of microbial
invasion from a portal of entry into the blood stream which causes sign of
illness." The definition did not change significantly over the years because
sepsis and septicemia were considered to refer to a number of ill-defined
clinical conditions in addition to bacteriemia. In practice, the terms often
were used interchangeably; however, less than one half of the patients who have
signs and symptoms of sepsis have positive blood cultures.
In the late 1960s, several reports appeared describing remote organ failure
(eg, pulmonary failure, liver failure) as a complication of severe sepsis. In
1975, a classic editorial by Baue was entitled "Multiple, progressive or
sequential systems failure, a syndrome of the 1970s." This concept was
formulated as the basis of a new clinical syndrome. Several terms were cloned
thereafter, such as multiple organ failure, multiple system organ failure, and
multiple organ system failure, to describe this evolving clinical syndrome of
otherwise unexplained progressive physiological failure of several
interdependent organ systems. More recently, the term multiple organ dysfunction
syndrome (MODS) has been proposed as a more appropriate description.
Multiorgan failure from sepsis
Sepsis is a clinical syndrome that complicates severe infection and is
characterized by systemic inflammation and widespread tissue injury. In this
syndrome, tissue is removed from the original insult that displayed the signs of
inflammation, such as vasodilatation, increased microvascular permeability, and
leukocyte accumulation. Multiple organ dysfunction is a continuum, with
incremental degrees of physiological derangements in individual organs; it is a
process rather than an event. Alteration in organ function can vary widely from
a mild degree of organ dysfunction to frank organ failure. The degree of organ
dysfunction has a major clinical impact. The term MODS is defined as a clinical
syndrome in which the development of progressive and potentially reversible
physiological dysfunction in 2 or more organs or organ systems induced by a
variety of acute insults, including sepsis, is characteristic.
In 1991, the American College of Chest Physicians/Society of Critical Care
Medicine Consensus Panel developed definitions of the various stages of sepsis,
which are as follows:
- Infection is a microbial phenomenon in which an inflammatory response to
the presence of microorganisms or the invasion of normally sterile host tissue
by these organisms is characteristic.
- Bacteremia is the presence of viable bacteria in the blood.
- Systemic inflammatory response syndrome (SIRS) may follow a variety of
clinical insults, including infection, pancreatitis, ischemia, multiple
trauma, tissue injury, hemorrhagic shock, or immune-mediated organ injury.
- Sepsis is a systemic response to infection. This is identical to SIRS,
except that it must result from infection.
- Septic shock is sepsis with hypotension (systolic BP <90 mm Hg or a
reduction of 40 mm Hg from baseline) despite adequate fluid resuscitation.
Concomitant organ dysfunction or perfusion abnormalities (eg, lactic acidosis,
oliguria, obtundation) are present in the absence of other known causes.
- MODS is the presence of altered organ function in a patient who is acutely
ill such that homeostasis cannot be maintained without intervention. Primary
MODS is the direct result of a well-defined insult in which organ dysfunction
occurs early and can be directly attributable to the insult itself. Secondary
MODS develops as a consequence of a host response and is identified within the
context of SIRS. The inflammatory response of the body to toxins and other
components of microorganisms causes the clinical manifestations of sepsis.
The sepsis syndrome is recognized clinically by the presence of 2 or more of
the following:
- Temperature greater than 38°C or less than 36°C
- Heart rate greater than 90 beats per minute
- Respiratory rate greater than 20 breaths per minute or a PaCO2 in arterial
gas less than 32 mm Hg
- WBC count greater than 12,000 cells/mm3, less than 4,000
cells/mm3, or greater than 10% band forms
Pathophysiology:
Pathogenesis
Sepsis has been referred to as a process of malignant intravascular
inflammation. Normally, a potent, complex, immunologic cascade ensures a prompt
protective response to microorganism invasion in humans. A deficient immunologic
defense may allow infection to become established; however, an excessive or
poorly regulated response may harm the host through maladaptive release of
indigenously generated inflammatory compounds.
Lipid A and other bacterial products release cytokines and other immune
modulators that mediate the clinical manifestations of sepsis. Interleukins,
tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and other
colony-stimulating factors are produced rapidly within minutes or hours after
interactions of monocytes and macrophages with lipid A. TNF release becomes a
self-stimulating process (an autocrine), and release of other inflammatory
mediators, including interleukin-1 (IL-1), platelet activating factor, IL-2,
IL-6, IL-8, IL-10, INF, and eicosanoids, further increases cytokine levels. This
leads to continued activation of polymorphonuclear leukocytes (PMNs),
macrophages, and lymphocytes; proinflammatory mediators recruit more of these
cells (a paracrine process). All of these processes create a state of
destructive immunologic dissonance.
Sepsis is described as an autodestructive process that permits extension of
the normal pathophysiologic response to infection to involve otherwise normal
tissues and results in MODS.
Specific organ involvement
Organ dysfunction or organ failure may be the first clinical sign of sepsis,
and no organ system is immune from the consequences of the inflammatory excesses
of sepsis.
Circulation
Significant derangement in autoregulation of circulation is typical of
sepsis. Vasoactive mediators cause vasodilatation and increase the microvascular
permeability at the site of infection. Nitric oxide plays a central role in the
vasodilatation of septic shock. Also, impaired secretion of vasopressin may
occur, which may permit persistence of vasodilatation.
Central circulation: Changes in both systolic and diastolic ventricular
performance occur in sepsis. Through the use of the Frank Starling mechanism,
cardiac output often is increased to maintain the BP in the presence of systemic
vasodilatation. Patients with preexisting cardiac disease are unable to increase
their cardiac output appropriately.
Regional circulation: Sepsis interferes with the normal distribution of
systemic blood flow to organ systems; therefore, core organs may not receive
appropriate oxygen delivery.
Microcirculation is the key target organ for injury in sepsis syndrome. A
decrease in the number of functional capillaries causes an inability to extract
oxygen maximally, which is caused by intrinsic and extrinsic compression of
capillaries and plugging of the capillary lumen by blood cells. Increased
endothelial permeability leads to widespread tissue edema of protein-rich fluid.
Redistribution of intravascular fluid volume resulting from reduced arterial
vascular tone, diminished venous return from venous dilation, and release of
myocardial depressant substances causes hypotension.
Pulmonary dysfunction
Endothelial injury in the pulmonary vasculature leads to disturbed capillary
blood flow and enhanced microvascular permeability, resulting in interstitial
and alveolar edema. Neutrophil entrapment within the pulmonary microcirculation
initiates and amplifies the injury to alveolar capillary membranes. Acute
respiratory distress syndrome (ARDS) is a frequent manifestation of these
effects.
Gastrointestinal dysfunction and nutrition
The GI tract may help propagate the injury of sepsis. Overgrowth of bacteria
in the upper GI tract may be aspirated into the lungs, producing nosocomial
pneumonia. The normal barrier function of the gut may be affected, allowing
translocation of bacteria and endotoxins into the systemic circulation and
extending the septic response. Septic shock usually causes ileus, and the use of
narcotics and sedatives delays institution of enteral feeding. The optimal level
of nutritional intake is interfered with in the face of high protein and calorie
requirements.
Liver
By virtue of the role of the liver in host defense, the abnormal synthetic
functions caused by liver dysfunction can contribute to both the initiation and
progression of sepsis. The reticuloendothelial system of the liver acts as a
first line of defense in clearing bacteria and their products; liver dysfunction
leads to a spillover of these products into systemic circulation.
Renal dysfunction
Acute renal failure often accompanies sepsis due to acute tubular necrosis.
The mechanism is by systemic hypotension, direct renal vasoconstriction, release
of cytokines (eg, TNF), and activation of neutrophils by endotoxins and other
peptides, which contribute to renal injury.
Central nervous system dysfunction
Involvement of the CNS in sepsis produces encephalopathy and peripheral
neuropathy. The pathogeneses is poorly defined.
Mechanisms of organ dysfunction and injury
The precise mechanisms of cell injury and resulting organ dysfunction in
sepsis are not understood fully. Multiorgan dysfunction syndrome is associated
with widespread endothelial and parenchymal cell injury because of the following
proposed mechanisms:
- Hypoxic hypoxia: The septic circulatory lesion disrupts tissue
oxygenation, alters the metabolic regulation of tissue oxygen delivery, and
contributes to organ dysfunction. Microvascular and endothelial abnormalities
contribute to the septic microcirculatory defect in sepsis. The reactive
oxygen sepsis, lytic enzymes, and vasoactive substances (nitric oxide,
endothelial growth factors) lead to microcirculatory injury, which is
compounded by the inability of the erythrocytes to navigate the septic
microcirculation.
- Direct cytotoxicity: The endotoxin, TNF-alpha, and nitric oxide may cause
damage to mitochondrial electron transport, leading to disordered energy
metabolism. This is called cytopathic or histotoxic anoxia, an inability to
utilize oxygen even when it is present.
- Apoptosis: Apoptosis (programmed cell death) is the principal mechanism by
which dysfunctional cells are eliminated normally. The proinflammatory
cytokines may delay apoptosis in activated macrophages and neutrophils, but
other tissues, such as the gut epithelium, may undergo accelerated apoptosis.
Therefore, derangement of apoptosis plays a critical role in tissue injury of
sepsis.
- Immunosuppression: The interaction between proinflammatory and
anti-inflammatory mediators may lead to an imbalance. An inflammatory reaction
or immunodeficiency may predominate, or both may be present.
Coagulopathy
Subclinical coagulopathy signified by a mild elevation of the thrombin or
activated partial thromboplastin time (aPTT) or a moderate reduction in platelet
count is extremely common, but overt disseminated intravascular coagulation
(DIC) is rare. Deficiencies of coagulation system proteins, including protein C,
antithrombin 3, and tissue factor inhibitors, cause coagulopathy.
Characteristics of sepsis that influence outcomes
Clinical characteristics that relate to the severity of sepsis include an
abnormal host response to infection, the site and type of infection, the timing
and type of antimicrobial therapy, the offending organism, and the development
of shock, underlying disease, and the patients’ chronic health condition. The
location of patient at the time of septic shock also relates to the severity of
sepsis.
Frequency:
- In the US: Current estimates suggest that the incidence
of sepsis is greater than 500,000 cases per year. Approximately 40% of
patients who are septic may develop shock. Patients who are at risk include
those with positive blood cultures. Prevalence rates for SIRS of sepsis vary
from 20-60%.
- Internationally: A French study in 1996 found that severe
sepsis was present in 6.3% of all ICU admissions.
Mortality/Morbidity: Mortality from multiorgan dysfunction
syndrome remains high. Mortality from ARDS alone is 40-50%. Once additional
organ system dysfunction occurs, the mortality increases as much as 90%.
CLINICAL
History:
Symptoms of sepsis usually are nonspecific and include fever, chills,
and constitutional symptoms of fatigue, malaise, anxiety, or confusion. These
symptoms are not pathognomonic for infection and may be observed in a wide
variety of noninfectious inflammatory conditions. They may be absent in serious
infections, especially in elderly individuals.
- Sepsis, SIRS, septic shock, and multiorgan dysfunction syndrome represent
a clinical continuum. The specific features exhibited depend on where the
patient’s case falls on that continuum. SIRS is defined by the presence of 2
or more of the following:
- Temperature greater than 38.0°C or less than 36.0°C
- Heart rate greater than 90 beats per minute
- Respiratory rate greater than 20 breaths per minute
- WBC count greater than 12,000 cells/mm3, less than 4,000
cells/mm3, or more than 10% bands
- Fever is a common feature of sepsis. Fever from an infectious etiology
results from resetting the hypothalamus so that heat production and heat loss
are balanced to maintain a higher temperature. An abrupt onset of fever
usually is associated with a large infectious load.
- Chills are a secondary symptom associated with fever and result from
increased muscular activity in an attempt to produce heat in order to raise
the body temperature to the level required to reset the hypothalamus.
- Sweating occurs when the hypothalamus returns to its normal set point and
senses that the body temperature is above the desired level. Perspiration is
stimulated to evaporate and cool excess body heat.
- Alteration in mental function often is observed. Mild disorientation or
confusion especially is common in elderly individuals. More severe
manifestations include apprehension, anxiety, and agitation, and it may
eventually lead to coma. The mechanism of alteration in mental function is not
known, but altered amino acid metabolism has been proposed as one cause of
metabolic encephalopathy.
- Hyperventilation with respiratory alkalosis is a common feature of sepsis.
Stimulation of the medullary ventilatory center by endotoxins and other
inflammatory mediators has been proposed as the cause of
hyperventilation.
- The following localizing symptoms are some of the most useful clues to the
etiology of both fever and sepsis:
- Head and neck infections - Earache, sore throat, sinus pain, or swollen
lymph glands
- Chest and pulmonary infections - Cough, especially if productive;
pleuritic chest pain; and dyspnea
- Abdominal and GI infections - Abdominal pain, nausea, vomiting, and
diarrhea
- Pelvic and genitourinary infections - Pelvic or flank pain, vaginal or
urethral discharge, urea, frequency, urgency
- Bone and soft tissue infections - Focal pain or tenderness, focal
erythema, edema
Physical: Physical examination notes the general condition
of the patient first. Observe the overall hemodynamic condition to search for
signs of hyperperfusion. Look for signs suggestive of a focal infection. An
acutely ill, toxic appearance is a common feature in serious infections.
- The vital signs may suggest sepsis, even if fever is absent. As noted
above, tachypnea is common; tachycardia with an increased pulse pressure also
is common.
- Measure the body temperature accurately. Oral temperatures often are
unreliable; obtain rectal temperatures.
- Investigate signs of systemic tissue perfusion. In the early stages of
sepsis, cardiac output is well maintained or even increased. Along with
vasodilatory mediators, this may result in warm skin, warm extremities, and
normal capillary refill. As sepsis progresses, stroke volume and cardiac
output fall. Patients begin to manifest signs of poor distal perfusion,
including cool skin, cool extremities, and delayed capillary refill.
- The following physical signs suggest focal, usually bacterial,
infection:
- CNS infection - Profound depression in mental status and
meningismus
- Head and neck infections - Inflamed or swollen tympanic membranes, sinus
tenderness, pharyngeal exudates, stridor, cervical
lymphadenopathy
- Chest and pulmonary infections - Localized rales or evidence of
consolidation
- Cardiac infections - Regurgitant valvular murmur
- Abdominal and GI infections - Focal tenderness, guarding or rebound,
rectal tenderness, or swelling
- Pelvic and genitourinary infections - Costovertebral angle tenderness,
pelvic tenderness, cervical motion pain, and adnexal tenderness
- Bone and soft tissue infections - Focal erythema, edema, infusion, and
tenderness
- Skin infections - Petechiae and purpura
DIFFERENTIALS
Acute Renal Failure
Acute Respiratory Distress
Syndrome
Cardiogenic
Shock
Infective
Endocarditis
Pneumococcal Infections
Pneumonia,
Bacterial
Sepsis,
Bacterial
Septic
Shock
Shock,
Distributive
Shock,
Hemorrhagic
Streptococcus Group A
Infections
Systemic
Inflammatory Response Syndrome
Toxic Shock Syndrome
Urinary Tract
Infection, Females
Urinary Tract Infection, Males
Ventilation,
Mechanical
WORKUP
Lab Studies:
- Laboratory tests are useful in suspected sepsis or septic shock to assess
the general hematologic and metabolic condition of the patient. The
microbiologic studies provide results, which may indicate occult bacterial
infection or bacteremia, and indicate the specific microbial etiology.
- CBC with differential: An adequate hemoglobin concentration is necessary
to ensure oxygen delivery in shock. Maintain the hemoglobin at a level of 8
g/dL.
- Platelets: Acute phase reactants, platelets usually increase at the onset
of any serious stress. The platelet count will fall with persistent sepsis,
and DIC may develop.
- WBC count: The white cell differential and the WBC count may predict the
existence of a bacterial infection. In adults who are febrile, a WBC count
greater than 15,000 cells/mm3 or a neutrophil band count greater
than1500 cells/mm3 is associated with a high likelihood of
bacterial infection.
- Metabolic assessment: Perform metabolic assessment with serum
electrolytes, including magnesium, calcium, phosphate, and glucose, at regular
intervals.
- Renal and hepatic function: Assess renal and hepatic function with serum
creatinine, BUN, bilirubin, alkaline phosphate, and alanine aminotransferase
(ALT).
- Measurement of serum lactate provides an assessment of tissue
hypoperfusion.
- Elevated serum lactate indicates that significant tissue hypoperfusion
exists with the shift from aerobic to anaerobic metabolism.
- Serum lactate: Higher serum lactate indicates a worse degree of shock and
a higher mortality.
- Prothrombin time (PT) and activated partial thromboplastin time (aPTT):
Assess coagulation status with prothrombin time (PT) and activated partial
thromboplastin time (aPTT). Patients with clinical evidence of coagulopathy
require additional tests to detect the presence of DIC.
- Blood cultures: Indiscriminate use of blood cultures has low
utility.
- Blood culture is the primary modality for aiding in the diagnosis for
intravascular infections (eg, endocarditis) and infections of indwelling
intravascular devices.
- Two populations, people who abuse IV drugs and patients with prosthetic
heart valves, are at high risk for endocarditis.
- Patients at risk for bacteremia include adults who are febrile with an
elevated WBC or neutrophil band counts, elderly patients who are febrile,
and patients who are febrile and neutropenic. These populations have a
20-30% incidence of bacteremia.
- The incidence of bacteremia is at least 50% in patients with sepsis and
evidence of end-organ dysfunction.
- Urinalysis and urine culture: Order a urinalysis and urine culture for
every patient who is septic. Urinary infection is a common source for sepsis,
especially in elderly individuals. Adults who are febrile without localizing
symptoms or signs have a 10-15% incidence of occult urinary tract infection
(UTI).
- Tissue staining and culture: Obtain secretions or tissue for Gram stain
and culture from sites of potential infection. Generally, the Gram stain is
the only available test to immediately document the presence of bacterial
infection and guide the choice of initial antibiotic therapy.
Imaging Studies:
- A variety of imaging modalities are employed to diagnose clinically
suspected focal infection, detect the presence of a clinically occult focal
infection, and detect complications of sepsis and septic shock.
- Obtain a chest radiograph in patients with severe sepsis because the
clinical examination is unreliable for pneumonia. Clinically occult
infiltrates have been detected by routine use of chest radiography in adults
who are febrile without localizing symptoms or signs and in patients who are
febrile and neutropenic without pulmonary symptoms.
- Supine and upright or lateral decubitus abdominal films may be useful
when an intraabdominal source is suspected.
- Ultrasound is the imaging modality of choice when a biliary tract source
is suspected to be the source of sepsis.
- CT scan is the imaging modality of choice for excluding intraabdominal
abscess or a retroperitoneal source of infection.
- Obtain a CT scan of the head in patients with evidence of increased
intracranial pressure (papilledema) or suggestion of focal mass lesions (eg,
focal defects, previous sinusitis or otitis, recent intracranial surgery) or
prior to lumbar puncture (LP) when meningitis is suspected.
- When there is clinical evidence of a deep, soft tissue infection, such
as, crepitus, bullae, hemorrhage, or foul smelling exudate, obtain a plain
radiograph. The presence of soft tissue gas and the spread of infection
beyond clinically detectable disease may require surgical
exploration.
Procedures:
- The LP needs to be performed urgently when meningitis or encephalitis is
suspected. In patients with an acute fulminant presentation, rapid onset of
septic shock, and severe impairment of mental status, rule out bacterial
meningitis by LP.
- Procedures, such as cardiac monitoring, noninvasive BP monitoring, and
pulse oximetry, are necessary because patients often require ICU admission
for invasive monitoring and support.
- Supplemental oxygen is provided during initial stabilization and
resuscitation.
- All patients in septic shock should have adequate venous access for volume
resuscitation. A central venous line also can be used to monitor central
venous pressure to assess intravascular volume status.
- An indwelling urinary catheter used to monitor urinary output is used as a
marker for adequate renal perfusion and cardiac output.
- Patients who have developed septic shock require right heart
catheterization with a pulmonary artery (Swan-Ganz) catheter. This catheter
provides an accurate assessment of the volume status of a patient who is
septic. The cardiac output measurement can be obtained. Furthermore,
determination of mixed venous oxygenation is helpful in determining the status
of tissue oxygenation.
- Most patients who are septic develop respiratory distress secondary to
severe sepsis or as a manifestation of septic shock. Pulmonary dysfunction of
sepsis (ARDS) also may occur. These patients need intubation and mechanical
ventilation for optimum respiratory support.
Staging:
Two well-defined forms of multiorgan dysfunction syndrome exist. In
both, the development of acute lung injury or ARDS is of key importance to the
natural history. ARDS is the earliest manifestation in all cases.
- In the more common form of multiorgan dysfunction syndrome, the lungs are
the predominant, and often the only, organ system affected until very late in
the disease. These patients most often present with primary pulmonary
disorder, such as pneumonia, aspiration, contusion, near drowning,
exacerbation of chronic obstructive pulmonary disease (COPD), hemorrhage, or
pulmonary embolism. Lung disease progresses to meet ARDS criteria.
Encephalopathy or mild coagulopathy may accompany pulmonary dysfunction, which
persists for 2-3 weeks. At this time, the patient either begins to recover or
progresses to develop fulminant dysfunction in another organ system. Once
another major organ dysfunction occurs, these patients frequently do not
survive.
