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Confusion
Anxiety
Difficulty breathing
Fatigue, malaise
Head and neck infections Severe headache, neck stiffness, altered mental status,
earache, sore throat, sinus pain/tenderness, cervical/submandibular lymphadenopathy
Pelvic and genitourinary (GU) infections Pelvic or flank pain, adnexal tenderness or
masses, vaginal or urethral discharge, dysuria, frequency, urgency
Bone and soft-tissue infections Localized limb pain or tenderness, focal erythema,
edema, swollen joint, crepitus in necrotizing infections, joint effusions
Diagnosis
Patients with sepsis may present in a myriad of ways, and a high index of clinical suspicion is
necessary to identify subtle presentations. The hallmarks of severe sepsis and septic shock are
changes that occur at the microvascular and cellular level and may not be clearly manifested
in the vital signs or clinical examination. This process includes diffuse activation of
inflammatory and coagulation cascades, vasodilation and vascular maldistribution, capillary
endothelial leakage, and dysfunctional utilization of oxygen and nutrients at the cellular level.
Cardiac monitoring, noninvasive blood pressure monitoring, and pulse oximetry are indicated
in patients with septic shock.
Laboratory tests
The following are investigative studies to detect a clinically suspected focal infection, the
presence of a clinically occult focal infection, and complications of sepsis and septic shock:
Coagulation studies (eg, prothrombin time [PT], activated partial thromboplastin time
[aPTT], fibrinogen levels)
Renal and hepatic function tests (eg, creatinine, blood urea nitrogen, bilirubin,
alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, albumin,
lipase)
Blood cultures
Imaging studies
The following radiologic studies, as indicated, may be used to evaluate patients with
suspected severe sepsis and septic shock:
Abdominal ultrasonography
Management
Patients with sepsis, severe sepsis, and septic shock require admission to the hospital. Initial
treatment includes support of respiratory and circulatory function, supplemental oxygen,
mechanical ventilation, and volume infusion.
Treatment of patients with septic shock has the following major goals:
Resuscitate the patient from septic shock by using supportive measures to correct
hypoxia, hypotension, and impaired tissue oxygenation (hypoperfusion)
Identify the source of infection and treat with antimicrobial therapy, surgery, or both
(source control)
Early recognition
Source control
Proper ventilator management with low tidal volume in patients with acute respiratory
distress syndrome (ARDS)
Pharmacotherapy
The following medications are used in the management of septic shock:
Surgery
Patients with focal infections should be sent for definitive surgical treatment after initial
resuscitation and administration of antibiotics.[2] However, although urgent management is
indicated for hemodynamically stable patients without evidence of acute organ failure, delay
of invasive procedures for as long as 24 hours may be possible if the patient receives very
close clinical monitoring and appropriate antimicrobial therapy.[2]
Certain conditions will not respond to standard treatment for septic shock until the source of
infection is surgically removed (eg, intra-abdominal sepsis [perforation, abscesses],
empyema, mediastinitis, cholangitis, pancreatic abscesses, pyelonephritis or renal abscess
from ureteric obstruction, infective endocarditis, septic arthritis, infected prosthetic devices,
deep cutaneous or perirectal abscess, and necrotizing fasciitis).
When possible, percutaneous drainage of abscesses and other well-localized fluid collections
is preferred to surgical drainage.[2] However, any deep abscess or suspected necrotizing
fasciitis should undergo drainage in the surgical suite.
See Treatment and Medication for more detail.
Background
Over many years, the terms sepsis and septicemia have referred to several ill-defined clinical
conditions present in a patient with bacteremia. Definitions have not changed greatly since
1914, when Schottmueller wrote, Septicemia is a state of microbial invasion from a portal of
entry into the blood stream which causes sign of illness.
In practice, these 2 terms have often been used interchangeably; however, only about half of
patients with signs and symptoms of sepsis have positive results on blood culture.[3, 4, 5]
Furthermore, not all patients with bacteremia have signs of sepsis. It follows, therefore, that
sepsis and septicemia are not in fact identical.
In the past few decades, the discovery of endogenous mediators of the host response has led
to the recognition that the clinical syndrome of sepsis is the result of excessive activation of
host defense mechanisms rather than the direct effect of microorganisms. Sepsis and its
sequelae represent a continuum of clinical and pathophysiologic severity.
Serious bacterial infections at any site in the body (see the image below), with or without
bacteremia, are usually associated with important changes in the function of every organ
system in the body. These changes are mediated mostly by elements of the host immune
system against infection. Shock is deemed present when volume replacement fails to increase
blood pressure to acceptable levels and when associated clinical evidence indicates
inadequate perfusion of major organ systems, with progressive failure of organ system
functions.
This article does not cover sepsis of the neonate or infant. Special consideration must be
given to neonates, infants, and small children with regard to fluid resuscitation, appropriate
antibiotic coverage, intravenous (IV) access, and vasopressor therapy. (See Neonatal Sepsis,
Pediatric Sepsis, Treatment of Sepsis and Septic Shock in Children, Shock in Pediatrics, and
Shock and Hypotension in the Newborn.)
Hypovolemic shock
Obstructive shock
Distributive shock
Cardiogenic shock
in diagnosis comes in knowing when a localized infection has become systemic and requires
more aggressive hemodynamic support. No criterion standard exists for the diagnosis of
endothelial dysfunction, and patients with sepsis may not initially present with frank
hypotension and overt shock.
Clinicians often use the terms sepsis, severe sepsis, and septic shock without following
commonly understood definitions. In 1991, the American College of Chest Physicians
(ACCP) and the Society of Critical Care Medicine (SCCM) convened a consensus conference
to establish definitions of these and related terms.[6, 7]
Systemic inflammatory response syndrome
The term systemic inflammatory response syndrome (SIRS) was developed in an attempt to
describe the clinical manifestations that result from the systemic response to infection (fever
or hypothermia, tachycardia, tachypnea, and hyperleukocytosis or leukopenia). Criteria for
SIRS are considered to be met if at least 2 of the following 4 clinical findings are present:
Respiratory rate (RR) higher than 20 breaths/min or arterial carbon dioxide tension
(PaCO 2) lower than 32 mm Hg
White blood cell (WBC) count higher than 12,000/L or lower than 4000/L or with
10% immature (band) forms
Note that a patient can have a severe infection without meeting SIRS criteria; conversely,
SIRS criteria may be present in the setting of many other illnesses not caused by an infectious
process (see the image below).
Sepsis is defined as the presence of infection in association with SIRS, that is, a systemic
immune response caused by an infection. The presence of SIRS is, of course, not limited to
sepsis, but in the presence of infection, an increase in the number of SIRS criteria observed
should alert the clinician to the possibility of endothelial dysfunction, developing organ
dysfunction, and the need for aggressive therapy.
Certain biomarkers have been associated with the endothelial dysfunction of sepsis. However,
although levels of biomarkers such as procalcitonin may be useful in differentiating between
sepsis (generally >10 ng/mL) and SIRS (generally < 2 ng/mL),[9] the use of sepsis-specific
biomarkers has not yet translated to establishing a clinical diagnosis of sepsis, particularly in
the emergency department (ED) setting.
Two markers that may have potential roles in guiding the management of sepsis are the
circulating apoptosis markers full-length and caspase-cleaved cytokeratin 18 (CK18) and
nucleosomal DNA (nDNA), as suggested by the results of a small, noninterventional,
multicenter study that made use of enzyme-linked immunosorbent assays (ELISAs).[10]
In septic patients who survived, levels of full-length and caspase-cleaved CK18 were
decreased within 48 hours after treatment initiation; during the same period, levels were
increased in septic patients who died within 28 days of admission.[10] Furthermore, when the
investigators compared patients who required renal support with those who did not,
significantly higher baseline levels of nDNA and total soluble CK18 levels were found in the
group requiring renal support.[10] More data are needed to evaluate these findings.
At least 1 of the following manifestations of inadequate organ function or perfusion is
typically included in sepsis:
Bacteremia
Bacteremia is defined as the presence of viable bacteria within the liquid component of
blood. It may be primary (without an identifiable focus of infection) or, more often,
secondary (with an intravascular or extravascular focus of infection). Although sepsis is
associated with bacterial infection, bacteremia is not a necessary ingredient in the activation
of the inflammatory response that results in severe sepsis. In fact, septic shock is associated
with culture-positive bacteremia in only 30-50% of cases.[3, 4, 5]
Multiple organ dysfunction syndrome
Multiple organ dysfunction syndrome (MODS) is defined as the presence of altered organ
function in a patient who is acutely ill and in whom homeostasis cannot be maintained
without intervention. MODS may eventually lead to multiple organ failure syndrome
(MOFS) and death. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
are common manifestations of MODS or MOFS. However, other conditions besides sepsis
can cause MODS, including trauma, burns, and severe hemorrhagic shock.
Acute lung injury and acute respiratory distress syndrome
In 1994, the American-European Consensus Conference on ARDS agreed on standard
definitions of ALI and ARDS.[11] However, these definitions were subsequently replaced by
the following consensus, referred to as the Berlin Definition of ARDS, which essentially does
away with the classification of ALI in favor of classifying ARDS as mild, moderate, or
severe[12] :
Mild ARDS An oxygenation abnormality with a PaO 2/FIO 2 ratio of 200-300 and a
positive end-expiratory pressure (PEEP) or continuous positive airway pressure
(CPAP) of 5 cm H 2 O or higher
Severe ARDS A PaO 2/FIO 2 ratio of 100 or less and a PEEP of 5 cm H 2 O or higher
Bilateral opacities on chest radiographs that are not fully explained by effusions,
lobar/lung collapse, or nodules
Edema not of cardiac origin or caused by fluid overload In the absence of risk
factors for ARDS, this requires objective assessment (eg, via echocardiography)
MODS staging
Two well-defined forms of MODS exist. In either, the development of ALI or ARDS is of key
importance to the natural history, though ARDS is the earliest manifestation in all cases.
In the more common form of MODS, the lungs are the predominant, and often the only, organ
system affected until very late in the disease. Patients with this form of MODS most often
present with a primary pulmonary disorder (eg, pneumonia, aspiration, lung contusion, neardrowning, chronic obstructive pulmonary disease [COPD] exacerbation, hemorrhage, or
pulmonary embolism [PE]).
Progression of lung disease occurs to meet the ARDS criteria. Pulmonary dysfunction may be
accompanied by encephalopathy or mild coagulopathy and persists for 2-3 weeks. At this
time, the patient either begins to recover or progresses to develop fulminant dysfunction in
other organ systems. Patients who develop another major organ dysfunction often do not
survive.
In the second, less common, form of MODS, the presentation is quite different. Patients
affected by this form often have an inciting source of sepsis in organs other than the lung; the
most common sources are intra-abdominal sepsis, extensive blood loss, pancreatitis, and
vascular catastrophes.
Not only does ALI or ARDS develop early, but dysfunction also develops in other organ
systems, including the hepatic, hematologic, cardiovascular, and renal systems and central
nervous system (CNS). Patients remain in a pattern of compensated dysfunction for several
weeks, then either recover or deteriorate further.
Criteria for mild and severe organ dysfunction have been established by the 2012 Surviving
Sepsis Guidelines (see Table 1, below).
Table 1. Surviving Sepsis Guidelines Criteria for Organ Dysfunction (Open Table in a new
window)
Organ System
Sepsis Criteria
Pulmonary
Arterial hypoxemia: PaO2/FIO2 <
300
Hepatic
Renal
Acute oliguria: Urine output < 0.5 Acute oliguria: Urine output <
mL/kg/hr for 2 hr despite
0.5mL/kg/hr for 2 hr despite
adequate fluid resuscitation
adequate fluid resuscitation
Gastrointestinal
Hematologic
Cardiovascular
of laboratory normal
Central nervous
system
aPTT = activated partial thromboplastin time; FIO2 = fraction of inspired oxygen; INR =
international normalized ratio; MAP = mean arterial pressure; PaO2 = partial pressure of
oxygen; PEEP = positive end-expiratory pressure; PT = prothrombin time; SBP = systolic
blood pressure.
Source: Dellinger RP, Levy MM, Rhodes A, et al, for the Surviving Sepsis Campaign
Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign:
international guidelines for management of severe sepsis and septic shock: 2012. Crit Care
Med. 2013 Feb;41(2):580-637.[13]
Pathophysiology
The pathophysiology of septic shock is not precisely understood but is considered to involve
a complex interaction between the pathogen and the hosts immune system (see the image
below). The normal physiologic response to localized infection includes activation of host
defense mechanisms that result in the influx of activated neutrophils and monocytes, release
of inflammatory mediators, local vasodilation, increased endothelial permeability, and
activation of coagulation pathways.
These response mechanisms occur during septic shock, but on a systemic scale, leading to
diffuse endothelial disruption, vascular permeability, vasodilation, and thrombosis of endorgan capillaries. Endothelial damage itself can further activate inflammatory and coagulation
cascades, creating, in effect, a positive feedback loop and leading to further endothelial and
end-organ damage.
Activity
Activation of macrophages, neutrophils, platelets, and
endothelium releases various cytokines and other
mediators
IL-6
IL-8
IL-10
MIF
G-CSF
Complement
Nitric oxide
Lipid mediators
Phospholipase A2
PAF
Eicosanoids
Arachidonic acid
metabolites
Adhesion molecules
Selectins
Leukocyte
integrins
High mobility
box1
Source: Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit
Care Med. 2009 Jan;37(1):291-304.[15]
Immunologic abnormalities
The following 3 families of pattern recognition receptors are involved in the initiation of the
sepsis response:
These receptors trigger the innate immune response and modulate the adaptive immune
response to infection.[15]
An initial step in the activation of innate immunity is the de novo synthesis of small
polypeptides (cytokines) that induce protean manifestations on most cell types, from immune
effector cells to vascular smooth muscle and parenchymal cells. Several cytokines are
induced, including tumor necrosis factor (TNF) and interleukins (ILs), especially IL-1. These
factors help keep infections localized; however, once the infection progresses, the effects can
also be detrimental.
Circulating levels of IL-6 correlate have a strong correlation with outcome. High levels of IL6 are associated with mortality, but the role of this cytokine in pathogenesis is not clear. IL-8
is an important regulator of neutrophil function, synthesized and released in significant
amounts during sepsis. IL-8 contributes to the lung injury and dysfunction of other organs.
Chemokines (eg, monocyte chemoattractant protein [MCP]-1) orchestrate the migration of
leukocytes during endotoxemia and sepsis. Other cytokines thought to play a role in sepsis
include the following:
IL-10
Interferon gamma
IL-12
The complement system is activated and contributes to the clearance of the infecting
microorganisms but probably also enhances the tissue damage. The contact systems become
activated; consequently, bradykinin is generated.
Hypotension, the cardinal manifestation of sepsis, occurs via induction of nitric oxide (NO).
NO plays a major role in the hemodynamic alterations of septic shock, which is a
hyperdynamic form of shock.
In a study that evaluated the role of active nitrogen molecules in the progression of septic
shock, investigators found not only that patients with sepsis and septic shock had elevated
mean levels of nitrite (NO2)/nitrate (NO3) (sepsis, 78.92 mol/L; septic shock, 97.20 mol/L)
as well as TNF- (sepsis, 213.50 pg/mL; septic shock, 227.38 pg/mL) but also that levels of
these 3 mediators increased with the severity of the sepsis.[19]
Another factor that contributes to the poor cellular oxygen utilization and tissue organ
dysfunction during sepsis is mitochondrial dysfunction.[20] This is associated with excessive
generation of peroxynitrates and reactive oxygen species (ROS) in combination with
glutathione depletion.
A dual role exists for neutrophils: They are necessary for defense against microorganisms, but
they may also become toxic inflammatory mediators, thereby contributing to tissue damage
and organ dysfunction. Lipid mediatorseicosanoids, platelet-activating factor (PAF), and
phospholipase A2are generated during sepsis, but their contributions to the sepsis
syndrome remain to be established.
Neutrophils are constitutively proapoptotic, a capacity that is essential for the resolution of
inflammation and cell turnover. Poor apoptosis is associated with poor cell clearance and a
proinflammatory state.
There is a growing body of evidence regarding sepsis-induced immunosuppression, which
may culminate in a worse prognosis and a greater predisposition to other nosocomial
infections.[21] In addition, there is evidence that patients with sepsis who have previously been
infected with cytomegalovirus may have worse outcomes than those who have not.[22] That
cytomegalovirus infection can also cause immunomodulation may be another factor
contributing to sepsis-induced immunosuppression.
the production of thrombin, which converts soluble fibrinogen to fibrin. The insoluble fibrin,
along with aggregated platelets, forms intravascular clots.
Inflammatory cytokines, such as IL-1, IL-1, and TNF-, initiate coagulation by activating
TF. TF interacts with factor VIIa to form factor VIIa-TF complex, which activates factors X
and IX. Activation of coagulation in sepsis has been confirmed by marked increases in
thrombin-antithrombin complexes and the presence of D-dimer in plasma, indicating
activation of the clotting system and fibrinolysis.[25, 26] Tissue plasminogen activator (t-PA)
facilitates conversion of plasminogen to plasmin, a natural fibrinolytic.
Endotoxins increase the activity of inhibitors of fibrinolysisnamely, plasminogen activator
inhibitor (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI). levels of protein C
and endogenous activated protein C (APC) are also decreased in sepsis. Endogenous APC is
an important inhibitor of coagulation cofactors Va and VIIa. Thrombin, via thrombomodulin,
activates protein C, which then acts as an antithrombotic in the microvasculature.
Endogenous APC also enhances fibrinolysis by neutralizing PAI-1 and accelerating t-PA
dependent clot lysis.
The imbalance among inflammation, coagulation, and fibrinolysis results in widespread
coagulopathy and microvascular thrombosis and suppressed fibrinolysis, ultimately leading to
multiple organ dysfunction and death. The insidious nature of sepsis is such that
microcirculatory dysfunction can occur while global hemodynamic parameters such as blood
pressure may remain normal.[27]
Circulatory abnormalities
As noted (see Shock Classification, Terminology, and Staging), septic shock falls under the
category of distributive shock, which is characterized by pathologic vasodilation and shunting
of blood from vital organs to nonvital tissues (eg, skin, skeletal muscle, and fat). The
endothelial dysfunction and vascular maldistribution characteristic of distributive shock result
in global tissue hypoxia or inadequate delivery of oxygen to vital tissues. In addition,
mitochondria can become dysfunctional, thus compromising oxygen utilization at the cellular
level.
The predominant hemodynamic feature of septic shock is arterial vasodilation. The
mechanisms implicated in this pathologic vasodilation are multifactorial, but the primary
factors are thought to be (1) activation of adenosine triphosphate (ATP)-sensitive potassium
channels in vascular smooth muscle cells and (2) activation of NO synthase.
The potassium-ATP channels are directly activated by lactic acidosis. NO also activates
potassium channels. Potassium efflux from cells results in hyperpolarization, inhibition of
calcium influx, and vascular smooth muscle relaxation.[28] The resulting vasodilation can be
refractory to endogenous vasoactive hormones (eg, norepinephrine and epinephrine) that are
released during shock.
Diminished peripheral arterial vascular tone may cause blood pressure to be dependent on
cardiac output, so that vasodilation results in hypotension and shock if insufficiently
compensated by a rise in cardiac output. Early in septic shock, the rise in cardiac output is
often limited by hypovolemia and a fall in preload because of low cardiac filling pressures.
MODS. Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no
organ system is immune to the consequences of the inflammatory excesses of sepsis.
The precise mechanisms of cell injury and resulting organ dysfunction in patients with sepsis
are not fully understood. MODS is associated with widespread endothelial and parenchymal
cell injury occurring via 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; ROS, lytic enzymes, vasoactive substances (eg, NO), and endothelial
growth factors lead to microcirculatory injury, which is compounded by the inability
of the erythrocytes to navigate the septic microcirculation
Cardiovascular dysfunction
Significant derangement in the autoregulation of the circulatory system is typical in patients
with sepsis. Vasoactive mediators cause vasodilatation and increase the microvascular
permeability at the site of infection. NO plays a central role in the vasodilation of septic
shock. Impaired secretion of vasopressin may also occur, which may permit the persistence of
vasodilatation.
Changes in both systolic and diastolic ventricular performance occur in patients with sepsis.
Through the Frank-Starling mechanism, cardiac output is often increased to maintain blood
pressure in the presence of systemic vasodilatation. Patients with preexisting cardiac disease
are unable to increase their cardiac output appropriately.
Because sepsis interferes with the normal distribution of systemic blood flow to organ
systems, core organs may not receive appropriate oxygen delivery. The microcirculation is
the key target organ for injury in patients with sepsis. A decrease in the number of functional
capillaries leads to an inability to extract oxygen maximally; this inability 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 involving
protein-rich fluid.
Hypotension is caused by the redistribution of intravascular fluid volume that results from
reduced arterial vascular tone, diminished venous return from venous dilation, and release of
myocardial depressant substances.
Pulmonary dysfunction
The pathogenesis of sepsis-induced ARDS is a pulmonary manifestation of SIRS. A complex
interaction between humoral and cellular mediators, inflammatory cytokines and chemokines,
is involved in this process. A direct or indirect injury to the endothelial and epithelial cells of
the lung increases alveolar capillary permeability, causing ensuing alveolar edema. The
edema fluid is protein-rich; the ratio of alveolar fluid edema to plasma is 0.75-1.0, whereas in
patients with hydrostatic cardiogenic pulmonary edema, the ratio is less than 0.65.
Injury to type II pneumocytes decreases surfactant production; furthermore, the plasma
proteins in alveolar fluid inactivate the surfactant previously manufactured. These enhance
the surface tension at the air-fluid interfaces, producing diffuse microatelectasis.
Neutrophil entrapment within the pulmonary microcirculation initiates and amplifies the
injury to alveolar capillary membrane. ARDS is a frequent manifestation of these effects.
ALI (mild ARDS in the Berlin Definition) is a type of pulmonary dysfunction secondary to
parenchymal cellular damage that is characterized by endothelial cell injury and destruction,
deposition of platelet and leukocyte aggregates, destruction of type I alveolar pneumocytes,
an acute inflammatory response through all injury phases, and repair and hyperplasia of type
II pneumocytes. Migration of macrophages and neutrophils into the interstitium and alveoli
produces various mediators that contribute to the alveolar and epithelial cell damage.
If addressed at an early stage, ALI may be reversible, but in many cases, the host response is
uncontrolled, and ALI progresses to more severe ARDS. Continued infiltration occurs with
neutrophils and mononuclear cells, lymphocytes, and fibroblasts. An alveolar inflammatory
exudate persists, and type II pneumocyte proliferation is evident. If this process can be halted,
complete resolution may occur. In other patients, progressive respiratory failure and
pulmonary fibrosis develop.
The central pathologic finding in ARDS is severe injury to the alveolocapillary unit. After
initial extravasation of intravascular fluid, inflammation and fibrosis of pulmonary
parenchyma develop into a morphologic picture termed diffuse alveolar damage (DAD). The
clinical and pathologic evolution can be categorized into the following 3 overlapping
phases[29] :
The exudative phase of DAD occurs in the first week and is dominated by alveolar edema
and hemorrhage (see the images below). Other histologic features include dense eosinophilic
hyaline membranes and disruption of the capillary membranes. Necrosis of endothelial cells
and type I pneumocytes occur, along with leukoagglutination and deposition of platelet fibrin
thrombi.
DAD.
Acute respiratory distress syndrome (ARDS),
commonly observed in septic shock as a part of multiorgan failure syndrome, results in
pathologically diffuse alveolar damage (DAD). This is a high-powered photomicrograph of
early stage (exudative stage) DAD.
The proliferative phase is prominent in the second and third week after the onset of ARDS,
but it may begin as early as day 3. Organization of the intra-alveolar and interstitial exudate,
infiltration with chronic inflammatory cells, parenchymal necrosis, and interstitial
myofibroblast reaction occur. Proliferation of type II cells and fibroblasts, which convert the
exudate to cellular granulation tissue, is noted, as is excessive collagen deposition,
transforming into fibrous tissue (see the images below).
Gastrointestinal dysfunction
The gastrointestinal (GI) tract may help to propagate the injury of sepsis. Overgrowth of
bacteria in the upper GI tract may be aspirated into the lungs and produce nosocomial
pneumonia. The guts normal barrier function may be affected, thereby allowing translocation
of bacteria and endotoxin into the systemic circulation and extending the septic response.
Septic shock usually causes ileus, and the use of narcotics and sedatives delays the institution
of enteral feeding. This interferes with optimal nutritional intake, in the face of high protein
and energy requirements.
Glutamine is necessary for normal enterocyte functioning. Its absence in commercial
formulations of total parenteral nutrition (TPN) leads to breakdown of the intestinal barrier
and translocation of the gut flora into the circulation. This may be one of the factors driving
sepsis. In addition to inadequate glutamine levels, this may lessen the immune response by
decreasing leukocyte and natural killer (NK) cell counts, as well as total B-cell and T-cell
counts.[30]
Etiology
Most patients who develop sepsis and septic shock have underlying circumstances that
interfere with local or systemic host defense mechanisms. Sepsis is seen most frequently in
elderly persons and in those with comorbid conditions that predispose to infection, such as
diabetes or any immunocompromising disease. Patients may also have genetic susceptibility,
making them more prone to developing septic shock from infections that are well tolerated in
the general population.[33, 34, 35, 36, 37]
The most common disease states predisposing to sepsis are malignancies, diabetes mellitus,
chronic liver disease, and chronic kidney disease. The use of immunosuppressive agents is
also a common predisposing factor. In addition, sepsis is a common complication after major
surgery, trauma, and extensive burns. Patients with indwelling catheters or devices are also at
high risk.
In most patients with sepsis, a source of infection can be identified. The exceptions are
patients who are immunocompromised with neutropenia, in whom an obvious source often is
not found.
Causative microorganisms
Before the introduction of antibiotics, gram-positive bacteria were the principal organisms
that caused sepsis. Subsequently, gram-negative bacteria became the key pathogens causing
severe sepsis and septic shock. Currently, however, the rates of severe sepsis and septic shock
due to gram-positive organisms are rising again because of the more frequent use of invasive
procedures and lines in critically ill patients. As a result, gram-positive and gram-negative
microorganisms are now about equally likely to be causative pathogens in septic shock.[38, 39,
40, 41]
Respiratory tract and abdominal infections are the most frequent causes of sepsis, followed
by urinary tract and soft-tissue infections.[38, 39, 40, 41] Each organ system tends to be infected by
a particular set of pathogens (see below).
Lower respiratory tract infections cause septic shock in 35-50% of patients.[38, 39, 40, 41] The
following are the common pathogens:
Streptococcus pneumoniae
Klebsiella pneumoniae
Escherichia coli
Legionella spp
Haemophilus spp
Staphylococcus aureus
Pseudomonas spp
Anaerobes
Gram-negative bacteria
Abdominal and GI tract infections cause septic shock in 20-40% of patients.[38, 39, 40, 41] The
following are the common pathogens:
E coli
Enterococcus spp
Bacteroides fragilis
Acinetobacter spp
Pseudomonas spp
Enterobacter spp
Salmonella spp
Klebsiella spp
Anaerobes
Urinary tract infections cause septic shock in 10-30% of patients.[38, 39, 40, 41] The following are
the common pathogens:
E coli
Proteus spp
Klebsiella spp
Pseudomonas spp
Enterobacter spp
Serratia spp
Enterococcus spp
Candida spp
Infections of the male and female reproductive systems cause septic shock in 1-5% of
patients.[38, 39, 40, 41] The following are the common pathogens:
Neisseria gonorrhoeae
Gram-negative bacteria
Streptococci
Anaerobes
Soft-tissue infections cause septic shock in 5-10% of patients.[38, 39, 40, 41] The following are the
common pathogens:
S aureus
Staphylococcus epidermidis
Streptococci
Clostridium spp
Gram-negative bacteria
Anaerobes
Fungi
Infections due to foreign bodies cause septic shock in 1-5% of patients.[38, 39, 40, 41] S aureus, S
epidermidis, and fungi (eg, Candida species) are the common pathogens.
Miscellaneous infections, such as CNS infections, also cause septic shock in 1-5% of
patients.[38, 39, 40, 41] Neisseria meningitidis is a common cause of such infections (see the image
below).
Risk factors
Risk factors for severe sepsis and septic shock include the following:
Prolonged hospitalization
Epidemiology
United States statistics
The incidence of sepsis has been growing in recent decades, for reasons that likely include
the following:
A rise in chronic diseases such as end-stage renal disease (ESRD) and HIV infection
An analysis of a large sample from major US medical centers reported the incidence of severe
sepsis as 3 cases per 1000 population and 2.26 cases per 100 hospital discharges.[42] Of these
patients, 51.1% were admitted to an intensive care unit (ICU), and an additional 17.3% were
cared for in an intermediate care or coronary care unit. When analyzed in relation to age, the
incidence of severe sepsis ranged from 0.2 cases per 1000 admissions in children to 26.2 per
1000 in individuals older than 85 years.
In this analysis, mortality was 28.6% overall, ranging from 10% in children to 38.4% in
elderly people.[42] Hospital billing codes were used to identify patients with infection and
organ dysfunction consistent with the definition of severe sepsis. Severe sepsis resulted in an
average cost of $22,100 per case, with an annual total cost of $16.7 billion nationally.
In a large retrospective analysis, the National Center for Health Statistics used the National
Hospital Discharge Survey of 500 nonfederal US hospitals (which included more than 10
million cases of sepsis over a 22-year period) to report that septicemia accounted for 1.3% of
all hospitalizations.[43] The incidence of sepsis increased 3-fold between 1979 and 2000, from
83 cases per 100,000 population per year to 240 per 100,000.
A subsequent large survey of emergency department (ED) visits showed that severe sepsis
accounted for more than 500,000 such visits annually (0.7% of total visits), that the majority
of patients presented to EDs without an academic affiliation, and that the mean length of stay
in the ED was approximately 5 hours.[44]
In a later report, the US Centers for Disease Control and Prevention (CDC) determined that
the inflation-adjusted aggregate cost for the treatment of hospital patients with sepsis
increased by 12% per year from 1997 to 2008.[45]
In a 2013 report, Gaieski et al showed that in a large population database, the use of different
epidemiologic methodologies affects the average annual incidence of severe sepsis, which
can vary as much as 3.5-fold, depending on the method utilized.[46] The investigators found
that when the codes for sepsis in the International Classification of Diseases, Ninth Revision
(ICD-9), were used, the incidence of severe sepsis doubled over a 6-year period (2004-2009).
It is possible that the higher incidence rates in this study, relative to those cited in previous
studies, may be attributable to the growing awareness of sepsis, the increased use of its code
classification, and the inclusion of both ICU and non-ICU patients.
development of organ dysfunction.[48] In this study, black patients with septic shock had a
higher incidence of underlying diabetes and renal disease, which may explain the higher rates
of infection. However, development of acute organ dysfunction was independent of
comorbidities.[48]
Prognosis
Mortality figures for severe sepsis and septic shock have commonly been quoted as ranging
from 20% to 50%. Clinical trials from the past decade have found the mortality associated
with septic shock to range from 24% to 41%.[38, 39, 40, 41] Although one report noted that crude
hospital mortality for severe sepsis was significantly lower in the United States (28%) than in
Europe (41%), the difference ceased to be significant when adjusted by disease severity.[40]
Mortality has been found to vary according to the degree of illness, which may range along a
spectrum extending from sepsis to severe sepsis to septic shock. The following clinical
characteristics are related to the severity of sepsis:
Offending organism
Development of shock
Factors consistently associated with increased mortality in sepsis include advanced age,
comorbid conditions, and clinical evidence of organ dysfunction.[42, 47] One study found that in
the setting of suspected infection, simply meeting SIRS criteria, without evidence of organ
dysfunction, did not predict increased mortality; this finding suggests that organ dysfunction
is a better predictor than SIRS criteria alone.[47] However, there is evidence that meeting
greater numbers of SIRS criteria is associated with increased mortality.[49]
Notably, tachypnea is the SIRS criterion that best predicts an adverse outcome. This is likely
because tachypnea is also an indicator of pulmonary organ dysfunction and a feature
commonly associated with pneumonia and ARDS, both of which are associated with
increased mortality in sepsis. Altered mental status is considered a sign of organ dysfunction
and is also associated with increased mortality.
In one epidemiologic study, reported mortality figures were 7% for SIRS, 16% for sepsis,
20% for severe sepsis, and 46% for septic shock.[50] Poor prognostic factors included the
following:
Advanced age
A link between impaired adrenal function and higher septic shock mortality has been
suggested. The adrenal gland is enlarged in patients with septic shock as compared with
control subjects. A study by Jung et al found that the absence of this enlargement, indicated
by total adrenal volume of less than 10 cm3, was associated with increased 28-day mortality
in patients with septic shock.[51]
A multicenter prospective study published by Brun-Buisson reported a mortality of 56%
during ICU stays and 59% during hospital stays,[3] with 27% of all deaths occurring within 2
days of the onset of severe sepsis and 77% occurring within the first 14 days. The risk factors
for early mortality in this study were as follows:
Shock
Studies have shown that appropriate selection and early administration of antibiotics (ie,
antibiotics that are effective against the organism that is ultimately identified) lead to a
significant reduction in mortality.[52] For this reason, it is important to initiate broad-spectrum
coverage until the specific organism is cultured and antibiotic sensitivities are determined.
Although mortality is known to be high, the effect of sepsis on survivors quality of life of
survivors has not been well characterized until comparatively recently. It is increasingly
evident that septic shock is often a major sentinel event that has lasting effects on the
patients independence, reliance on family support, and need for long-term nursing home or
institutionalized care.[53]
Prolonged tissue hypoperfusion can lead to long-term neurologic and cognitive sequelae.[16]
Newer evidence shows that septic shock in elderly persons leads to significant long-term
cognitive and functional disability in comparison with hospitalized individuals who have
nonsepsis conditions.
http://emedicine.medscape.com/article/168402-overview#showall
Syok bukanlah merupakan suatu diagnosis. Syok merupakan sindrom klinis yang kompleks
yang mencakup sekelompok keadaan dengan manifestasi hemodinamik yang bervariasi tetapi
petunjuk yang umum adalah tidak memadainya perfusi jaringan.1
Setiap keadaan yang mengakibatkan tidak tercukupinya kebutuhan oksigen jaringan, baik
karena suplainya yang kurang atau kebutuhannya yang meningkat, menimbulkan tanda-tanda
syok.2
Diagnosa adanya syok harus didasarkan pada data-data baik klinis maupun laboratorium yang
jelas yang merupakan akibat dari berkurangnya perfusi jaringan. Syok mempengaruhi kerja
organ-organ vital dan penangannya memerlukan pemahanam tentang patofisiologi syok.3
Syok bersifat progresif dan terus memburuk. Lingkaran setan dari kemunduran yang
progresif akan mengakibatkan syok jika tidak ditangani segera mungkin.1
Syok neurogenik sebenarnya jarang terjadi. Pada syok neurogenik terdapat penurunan
tekanan darah sistemik sebagai akibat terjadinya vasodilatasi perifer dan penurunan curah
jantung. Vasodilatasi tersebut terjadi karena menurunnya resistensi perifer yang disebabkan
oleh gangguan saraf otonom sedangkan penurunan curah jantung disebabkan oleh
bertambahnya pengaruh nervus vagus pada jantung sehingga terjadi bradikardi. 4,5
A. Definisi
Syok (renjatan) adalah kumpulan gejala-gejala yang diakibatkan oleh karena gangguan
perfusi jaringan yaitu aliran darah ke organ tubuh tidak dapat mencukupi kebutuhannya.2
Syok sirkulasi dianggap sebagai rangsang paling hebat dari hipofisis adrenalis sehingga
menimbulkan akibat fisiologi dan metabolisme yang besar. Syok didefinisikan juga sebagai
volume darah sirkulasi tidak adekuat yang mengurangi perfusi, pertama pada jaringan non
vital (kulit, jaringan ikat, tulang, otot) dan kemudian ke organ vital (otak, jantung, paru-paru,
dan ginjal).1
Syok atau renjatan merupakan suatu keadaan patofisiologis dinamik yang mengakibatkan
hipoksia jaringan dan sel.5
Syok juga dapat diartikan sebagai suatu keadaan yang mengancam jiwa yang diakibatkan
karena tubuh tidak mendapatkan suplai darah yang adekuat yang mengakibatkan kerusakan
pada multiorgan jika tidak ditangani segera dan dapat memburuk dengan cepat.6
B. Klasifikasi
Syok secara umum dapat diklasifikasikan dalam 5 kategori etiologi yaitu : 1,2,4,7,8,9
1. Syok Hipovolemik
Syok yang disebabkan karena tubuh :
- Kehilangan darah/syok hemoragik
Hemoragik eksternal : trauma, perdarahan gastrointestinal
Hemoragik internal : hematoma, hematotoraks
- Kehilangan plasma : luka bakar
- Kehilangan cairan dan elektrolit
Eksternal : muntah, diare, keringat yang berlebih
Internal : asites, obstruksi usus
2. Syok Kardiogenik
Gangguan perfusi jaringan yang disebabkan karena disfungsi jantung misalnya : aritmia, AMI
(Infark Miokard Akut).
3. Syok Distributif
- Syok Septik
Syok yang terjadi karena penyebaran atau invasi kuman dan toksinnya didalam tubuh yang
berakibat vasodilatasi.
- Syok Anafilaktif
Gangguan perfusi jaringan akibat adanya reaksi antigen antibodi yang mengeluarkan
histamine dengan akibat peningkatan permeabilitas membran kapiler dan terjadi dilatasi
arteriola sehingga venous return menurun.
Dinding pembuluh darah menjadi lemah, tak mampu berkonstriksi sehingga terjadi
bendungan vena, vena balik (venous return) menurun. Relaksasi sfinkter prekapiler diikuti
dengan aliran darah ke jaringan tetapi tidak dapat kembali ke jantung. Peristiwa ini dapat
menyebabkan trombosis kecil-kecil sehingga dapat terjadi koagulopati intravasa yang luas
(DIC = Disseminated Intravascular Coagulation).
Menurunnya aliran darah ke otak menyebabkan kerusakan pusat vasomotor dan respirasi di
otak. Keadaan ini menambah hipoksia jaringan. Hipoksia dan anoksia menyebabkan
terlepasnya toksin dan bahan lainnya dari jaringan (histamin dan bradikinin) yang ikut
memperjelek syok (vasodilatasi dan memperlemah fungsi jantung). Iskemia dan anoksia usus
menimbulkan penurunan integritas mukosa usus, pelepasan toksin dan invasi bakteri usus ke
sirkulasi.
Invasi bakteri dan penurunan fungsi detoksikasi hepar memperjelek keadaan. Dapat timbul
sepsis, DIC bertambah nyata, integritas sistim retikuloendotelial rusak, integritas mikro
sirkulasi juga rusak. Hipoksia jaringan juga menyebabkan perubahan metabolisme dari
aerobik menjadi anaerobik. Akibatnya terjadi asidosis metabolik, terjadi peningkatan asam
laktat ekstraseluler dan timbunan asam karbonat di jaringan.
3. Fase Irrevesibel/Refrakter
Karena kerusakan seluler dan sirkulasi sedemikian luas sehingga tidak dapat diperbaiki.
Kekurangan oksigen mempercepat timbulnya ireversibilitas syok. Gagal sistem
kardiorespirasi, jantung tidak mampu lagi memompa darah yang cukup, paru menjadi kaku,
timbul edema interstisial, daya respirasi menurun, dan akhirnya anoksia dan hiperkapnea.
D. Manifestasi Klinis
Manifestasi klinis tergantung pada penyebab syok (kecuali syok neurogenik) yang meliputi : 2,
6,10,11
E. Derajat Syok
Menentukan derajat syok :4
1. Syok Ringan
Penurunan perfusi hanya pada jaringan dan organ non vital seperti kulit, lemak, otot rangka,
dan tulang. Jaringan ini relatif dapat hidup lebih lama dengan perfusi rendah, tanpa adanya
perubahan jaringan yang menetap (irreversible). Kesadaran tidak terganggu, produksi urin
normal atau hanya sedikit menurun, asidosis metabolik tidak ada atau ringan.
2. Syok Sedang
Perfusi ke organ vital selain jantung dan otak menurun (hati, usus, ginjal). Organ-organ ini
tidak dapat mentoleransi hipoperfusi lebih lama seperti pada lemak, kulit dan otot. Pada
keadaan ini terdapat oliguri (urin kurang dari 0,5 mg/kg/jam) dan asidosis metabolik. Akan
tetapi kesadaran relatif masih baik.
3. Syok Berat
Perfusi ke jantung dan otak tidak adekuat. Mekanisme kompensasi syok beraksi untuk
menyediakan aliran darah ke dua organ vital. Pada syok lanjut terjadi vasokontriksi di semua
pembuluh darah lain. Terjadi oliguri dan asidosis berat, gangguan kesadaran dan tanda-tanda
hipoksia jantung (EKG abnormal, curah jantung menurun).
F. Pemeriksaan1,6,9,11, 12
1. Anamnesis
Pada anamnesis, pasien mungkin tidak bisa diwawancara sehingga riwayat sakit mungkin
hanya didapatkan dari keluarga, teman dekat atau orang yang mengetahui kejadiannya, cari :
- Riwayat trauma (banyak perdarahan atau perdarahan dalam perut)
- Riwayat penyakit jantung (sesak nafas)
- Riwayat infeksi (suhu tinggi)
- Riwayat pemakaian obat ( kesadaran menurun setelah memakan obat).
2. Pemeriksaan fisik
- Kulit
Suhu raba dingin (hangat pada syok septik hanya bersifat sementara, karena begitu syok
berlanjut terjadi hipovolemia)
Warna pucat (kemerahan pada syok septik, sianosis pada syok kardiogenik dan syok
hemoragi terminal)
Basah pada fase lanjut syok (sering kering pada syok septik).
- Tekanan darah
Hipotensi dengan tekanan sistolik < 80 mmHg (lebih tinggi pada penderita yang sebelumnya
mengidap hipertensi, normal atau meninggi pada awal syok septik)
- Status jantung
Takikardi, pulsus lemah dan sulit diraba.
- Status respirasi
Respirasi meningkat, dan dangkal (pada fase kompensasi) kemudian menjadi lambat (pada
syok septik, respirasi meningkat jika kondisi memburuk)
- Status Mental
Gelisah, cemas, agitasi, tampak ketakutan. Kesadaran dan orientasi menurun, sopor sampai
koma.
- Fungsi Ginjal
Oliguria, anuria (curah urin < 30 ml/jam, kritis)
- Fungsi Metabolik
Asidosis akibat timbunan asam laktat di jaringan (pada awal syok septik dijumpai alkalosis
metabolik, kausanya tidak diketahui). Alkalosis respirasi akibat takipnea
- Sirkulasi
Tekanan vena sentral menurun pada syok hipovolemik, meninggi pada syok kardiogenik
- Keseimbangan Asam Basa
Pada awal syok pO2 dan pCO2 menurun (penurunan pCO2 karena takipnea, penurunan pO2
karena adanya aliran pintas di paru).
3. Pemeriksaan Penunjang
- Darah (Hb, Hmt, leukosit, golongan darah), kadar elektrolit, kadar ureum, kreatinin, glukosa
darah.
- Analisa gas darah
- EKG
G. Diagnosis
- Terapi oksigen
- Bantuan nafas
Memperbaiki sistim sirkulasi:
- Pemberian cairan
- Hentikan perdarahan yang terjadi
- Monitor nadi, tekanan darah, perfusi perifer, produksi urin
Menghilangkan atau mengatasi penyebab syok.
2. Khusus :
Obat farmakologik :
- Tergantung penyebab syok
- Vasopresor (kontraindikasi syok hipovolemik)
- Vasodilator
SYOK NEUROGENIK
A. Definisi
Syok neurogenik merupakan kegagalan pusat vasomotor sehingga terjadi hipotensi dan
penimbunan darah pada pembuluh tampung (capacitance vessels).3
Syok neurogenik terjadi karena hilangnya tonus pembuluh darah secara mendadak di seluruh
tubuh.10
Syok neurogenik juga dikenal sebagai syok spinal. Bentuk dari syok distributif, hasil dari
perubahan resistensi pembuluh darah sistemik yang diakibatkan oleh cidera pada sistem saraf
(seperti: trauma kepala, cidera spinal, atau anestesi umum yang dalam).10,14
B. Etiologi
Penyebabnya antara lain : 3,4,5
1. Trauma medula spinalis dengan quadriplegia atau paraplegia (syok spinal).
2. Rangsangan hebat yang kurang menyenangkan seperti rasa nyeri hebat pada fraktur tulang.
3. Rangsangan pada medula spinalis seperti penggunaan obat anestesi spinal/lumbal.
Perlu diingat obat yang dapat menyebabkan vasodilatasi perifer tidak boleh diberikan pada
pasien syok neurogenik
Dobutamin
Berguna jika tekanan darah rendah yang diakibatkan oleh menurunnya cardiac output.
Dobutamin dapat menurunkan tekanan darah melalui vasodilatasi perifer.
Tekanan
Darah
Resistensi
Pembuluh
Darah
Sistemik
Obat
Dosis
Cardiac
Output
Dopamin
2,5-20
mcg/kg/menit
Norepinefri
n
0,05-2
mcg/kg/menit
++
++
Epinefrin
0,05-2
mcg/kg/menit
++
++
Fenilefrin
2-10
mcg/kg/menit
++
++
Dobutamin
2,5-10
mcg/kg/menit
+/-
KESIMPULAN
Syok bukanlah merupakan suatu diagnosis. Syok merupakan sindrom klinis yang kompleks
yang mencakup sekelompok keadaan dengan manifestasi hemodinamik yang bervariasi tetapi
petunjuk yang umum adalah tidak memadainya perfusi jaringan. Syok neurogenik merupakan
kegagalan pusat vasomotor sehingga terjadi hipotensi dan penimbunan darah pada pembuluh
tampung (capacitance vessels).1,3
Penyebab syok neurogenik antara lain: Trauma medula spinalis dengan quadriplegia atau
paraplegia (syok spinal), rangsangan hebat yang kurang menyenangkan seperti rasa nyeri
hebat pada fraktur tulang, rangsangan pada medula spinalis seperti penggunaan obat anestesi
spinal/lumbal, trauma kepala (terdapat gangguan pada pusat otonom), suhu lingkungan yang
panas, terkejut, takut.3,4,5
Syok neurogenik termasuk syok distributif dimana penurunan perfusi jaringan dalam syok
distributif merupakan hasil utama dari hipotensi arterial karena penurunan resistensi
pembuluh darah sistemik (systemic vascular resistance). 11,16
Diagnosis syok kardiogenik Hampir sama dengan syok pada umumnya tetapi pada syok
neurogenik terdapat tanda tekanan darah turun, nadi tidak bertambah cepat, bahkan dapat
lebih lambat (bradikardi) kadang disertai dengan adanya defisit neurologis berupa
quadriplegia atau paraplegia. 3,4,14,15
Konsep dasar untuk syok distributif adalah dengan pemberian vasoaktif seperti fenilefrin dan
efedrin, untuk mengurangi daerah vaskuler dengan penyempitan sfingter prekapiler dan vena
kapasitan untuk mendorong keluar darah yang berkumpul ditempat tersebut.4,9
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