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Practice Essentials

Sepsis or septic shock is systemic inflammatory response syndrome (SIRS) secondary to a


documented infection. This response is a state of acute circulatory failure characterized by
persistent arterial hypotension despite adequate fluid resuscitation or by tissue hypoperfusion
(manifested by a lactate concentration >4 mg/dL) unexplained by other causes. See the image
below.

Venn diagram showing the overlap of infection, bacteremia,


sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

Essential update: Study suggests lower hemoglobin transfusion threshold


yields similar outcomes in septic shock
In a randomized clinical trial, adults with septic shock (N=998) in 32 intensive care units
(ICUs) were randomized to a transfusion hemoglobin threshold of 7 g/dL or 9 g/dL.[1]
Outcomes among patients receiving blood transfusion at the higher hemoglobin threshold
were similar to those among patients receiving blood transfusion at the lower threshold but
with fewer transfusions.
At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold
group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died
(relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P =0.44).[1] The numbers of
patients who had ischemic events, patients who had severe adverse reactions, and patients
who required life support were similar in the two intervention groups.

Signs and symptoms


Detrimental host responses to infection occupy a continuum that ranges from sepsis to severe
sepsis to septic shock and multiple organ dysfunction syndrome (MODS). The specific
clinical features depend on where the patient falls on that continuum.
Signs and symptoms of sepsis are often nonspecific and include the following:

Fever, chills, or rigors

Confusion

Anxiety

Difficulty breathing

Fatigue, malaise

Nausea and vomiting

Alternatively, typical symptoms of systemic inflammation may be absent in severe sepsis,


especially in elderly individuals.
It is important to identify any potential source of infection. Localizing signs and symptoms
referable to organ systems may provide useful clues to the etiology of sepsis and are as
follows:

Head and neck infections Severe headache, neck stiffness, altered mental status,
earache, sore throat, sinus pain/tenderness, cervical/submandibular lymphadenopathy

Chest and pulmonary infections Cough (especially if productive), pleuritic chest


pain, dyspnea, dullness on percussion, bronchial breath sounds, localized rales, any
evidence of consolidation

Cardiac infections Any new murmur, especially in patients with a history of


injection or IV drug use

Abdominal and gastrointestinal (GI) infections Diarrhea, abdominal pain,


abdominal distention, guarding or rebound tenderness, rectal tenderness or swelling

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

Skin infections Petechiae, purpura, erythema, ulceration, bullous formation,


fluctuance

See Clinical Presentation for more detail.

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:

Complete blood count with differential

Coagulation studies (eg, prothrombin time [PT], activated partial thromboplastin time
[aPTT], fibrinogen levels)

Blood chemistry (eg, sodium, chloride, magnesium, calcium, phosphate, glucose,


lactate)

Renal and hepatic function tests (eg, creatinine, blood urea nitrogen, bilirubin,
alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, albumin,
lipase)

Blood cultures

Urinalysis and urine cultures

Gram stain and culture of secretions and tissue

Imaging studies
The following radiologic studies, as indicated, may be used to evaluate patients with
suspected severe sepsis and septic shock:

Chest, abdominal, or extremity radiography

Abdominal ultrasonography

Computed tomography of the abdomen or head

See Workup for more detail.

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:

Start adequate antibiotics (proper spectrum and dose) as early as possible

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)

Maintain adequate organ system function, guided by cardiovascular monitoring, and


interrupt the progression of MODS

Management principles for septic shock include the following:

Early recognition

Early and adequate antibiotic therapy

Source control

Early hemodynamic resuscitation and continued support

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:

Alpha-/beta-adrenergic agonists (eg, norepinephrine, dopamine, dobutamine,


epinephrine, vasopressin, phenylephrine)

Isotonic crystalloids (eg, normal saline, lactated Ringer solution)

Volume expanders (eg, albumin)

Antibiotics (eg, cefotaxime, ticarcillin-clavulanate, piperacillin-tazobactam,


imipenem-cilastatin, meropenem, clindamycin, metronidazole, ceftriaxone,
ciprofloxacin, cefepime, levofloxacin, vancomycin)

Corticosteroids (eg, hydrocortisone, dexamethasone)

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.

Strawberry tongue in a child with staphylococcal toxic shock


syndrome. Reproduced with permission from Drage, LE. Life-threatening rashes:
dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.
Multiple organ dysfunctions, the extreme end of the continuum, are incremental degrees of
physiologic derangements in individual organs (ie, processes rather than events). Alteration in
organ function can vary widely, ranging from a mild degree of organ dysfunction to frank
organ failure. (See Multiple Organ Failure of Sepsis, Systemic Inflammatory Response
Syndrome (SIRS), Toxic Shock Syndrome, and Septic Thrombophlebitis .)

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.)

Shock Classification, Terminology, and Staging


Shock is identified in most patients by hypotension and inadequate organ perfusion, which
may be caused by either low cardiac output or low systemic vascular resistance. Circulatory
shock can be subdivided into 4 distinct classes on the basis of underlying mechanism and
characteristic hemodynamics, as follows:

Hypovolemic shock

Obstructive shock

Distributive shock

Cardiogenic shock

These classes of shock should be considered and systematically differentiated before a


definitive diagnosis of septic shock is established.
Hypovolemic shock results from the loss of blood volume caused by such conditions as
gastrointestinal (GI) bleeding, extravasation of plasma, major surgery, trauma, and severe
burns. Patients suffering from hypovolemic shock demonstrate tachycardia, cool clammy
extremities, hypotension, dry skin and mucous membranes, and poor turgor.
Obstructive shock results from an intrinsic or extrinsic obstruction of circulation. Pulmonary
embolism and pericardial tamponade both result in obstructive shock.
Distributive shock is caused by excessive vasodilation and impaired distribution of blood
flow (eg, direct arteriovenous shunting), and it is characterized by decreased resistance or
increased venous capacity from the vasomotor dysfunction. Patients with this type of shock
have high cardiac output, hypotension, a large pulse pressure, a low diastolic pressure, and
warm extremities with good capillary refill. These findings on physical examination strongly
suggest a working diagnosis of septic shock.
Cardiogenic shock is characterized by primary myocardial dysfunction, which renders the
heart unable to maintain adequate cardiac output. Affected patients demonstrate clinical signs
of low cardiac output while showing evidence of adequate intravascular volume. The patients
have cool clammy extremities, poor capillary refill, tachycardia, a narrow pulse pressure, and
low urine output.

Definitions of key terms


The basis of sepsis is the presence of infection associated with a systemic inflammatory
response that results in physiologic alterations at the capillary endothelial level. The difficulty

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:

Temperature higher than 38C (100.4F) or lower than 36C (96.8F)

Heart rate (HR) higher than 90 beats/min

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).

Venn diagram showing the overlap of infection, bacteremia,


sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.
In 2001, as a follow-up to the original ACCP/SCCM conference, an International Sepsis
Definitions Conference was convened, with representation not only from the ACCP and the
SCCM but also from the European Society of Intensive Care Medicine (ESICM), the
American Thoracic Society (ATS), and the Surgical Infection Society (SIS). The following
definitions of sepsis syndromes were published to clarify the terminology used to describe the
spectrum of disease that results from severe infection.[8]
Sepsis

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:

Alteration in mental state

Hypoxemia (arterial oxygen tension [PaO 2] < 72 mm Hg at a fraction of inspired


oxygen [FIO 2] of 0.21, with overt pulmonary disease not being the direct cause of
hypoxemia)

Elevated plasma lactate level (4 mmol/L)

Oliguria (urine output < 30 mL or 0.5 mL/kg for at least 1 hour)

Severe sepsis and septic shock


Severe sepsis is defined as sepsis that is complicated by end-organ dysfunction, as signaled
by altered mental status, an episode of hypotension, elevated creatinine concentration, or
evidence of disseminated intravascular coagulopathy (DIC).
Septic shock is defined as a state of acute circulatory failure characterized by persistent
arterial hypotension despite adequate fluid resuscitation or by tissue hypoperfusion
(manifested by a lactate concentration >4 mg/dL) that is unexplained by other causes.
Patients receiving inotropic or vasopressor agents may not be hypotensive by the time that
they manifest hypoperfusion abnormalities or organ dysfunction.

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

Moderate ARDS A PaO 2/FIO 2 ratio of 100-200 and a PEEP 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)

Occurrence within 1 week of a known clinical insult or worsening respiratory


symptoms

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

Severe Sepsis Criteria


Arterial hypoxemia: PaO2/FIO2 < 250
in absence of pneumonia and < 200 in
presence of pneumonia
Hyperbilirubinemia: Plasma total Hyperbilirubinemia: Plasma total
bilirubin >4 mg/dL or 70 mol/L bilirubin >2 mg/dL or 34.2 mol/L
Creatinine increase >0.5 mg/dL or Creatinine >2 mg/dL or 176.8 mol/L
44.2 mol/L

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

Ileus: Absent bowel sounds


INR >1.5, aPTT >60 s, or platelets INR >1.5 or platelets < 100,000/L
< 100,000/L
Hyperlactatemia >1 mmol/L;
Hyperlactatemia: Above upper limits

decreased capillary refill or


mottling

of laboratory normal

Hemodynamic status: SBP < 90 mm


Hemodynamic status: SBP < 90
Hg, MAP < 70 mm Hg, or SBP
mm Hg, MAP < 70 mm Hg, or SBP decrease >40 mm Hg
decrease >40 mm Hg

Central nervous
system

Confusion, lethargy, coma

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.

Diagram depicting the pathogenesis of sepsis and multiorgan


failure. DIC = disseminated intravascular coagulation; IL = interleukin.

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.

Mediator-induced cellular injury


The evidence that sepsis results from an exaggerated systemic inflammatory response
induced by infecting organisms is compelling. Inflammatory mediators are the key players in
the pathogenesis of sepsis (see Table 2 below).
Table 2. Mediators of Sepsis (Open Table in a new window)
Type
Mediator
Cellular
LPS
mediators Lipoteichoic acid
Peptidoglycan
Superantigens
Endotoxin
Humoral Cytokines
mediators
TNF- and IL-1

Activity
Activation of macrophages, neutrophils, platelets, and
endothelium releases various cytokines and other
mediators

Activate inflammatory pathways


Potent proinflammatory effect

Acts as pyrogen, stimulates B- and T-cell proliferation

IL-6

IL-8

Neutrophil chemotactic factor, activation and


degranulation of neutrophils

IL-10

Inhibits cytokine production, induces


immunosuppression
Activates macrophages and T cells

MIF

G-CSF

Complement
Nitric oxide
Lipid mediators

Promotes neutrophil and macrophage, platelet


activation
Promotes neutrophil and macrophage, platelet
activation and chemotaxis, other proinflammatory
effects
Involved in hemodynamic alterations of septic shock;
cytotoxic, augments vascular permeability,
contributes to shock
Enhance vascular permeability and contribute to lung
injury

Phospholipase A2

PAF

Eicosanoids

Arachidonic acid
metabolites
Adhesion molecules

Selectins

Leukocyte
integrins

High mobility
box1

Augment vascular permeability


Enhance neutrophil-endothelial cell interaction,
regulate leukocyte migration and adhesion, and play
a role in pathogenesis of sepsis; increased levels of
VAP-1 activity and anchor protein SDC-1 content
have been found in critically ill patients with septic
shock[14]

Late mediator of endotoxin-induced lethality and


tissue repair

G-CSF = granulocyte colony-stimulating factor; IL = interleukin; LPS = lipopolysaccharide;


MIF = macrophage inhibitory factor; PAF = platelet-activating factor; SDC-1 = syndecan-1;
TNF = tumor necrosis factor; VAP-1 = vascular adhesion protein1.

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:

Toll-like receptors (TLRs)

Nucleotide-oligomerization domain leucine-rich repeat proteins

Cytoplasmic caspase activation and recruiting domain helicases

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

Macrophage migration inhibition factor (MIF or MMIF)

Granulocyte colony-stimulating factor (G-CSF)

Granulocyte macrophage colony-stimulating factor (GM-CSF)

In addition, cytokines activate the coagulation pathway, resulting in capillary microthrombi


and end-organ ischemia.[16, 17, 18] (See Abnormalities of coagulation and fibrinolysis.)
Gram-positive and gram-negative bacteria induce a variety of proinflammatory mediators,
including the cytokines mentioned above, which play a pivotal role in initiating sepsis and
shock. Various bacterial cell-wall components are known to release the cytokines, including
lipopolysaccharide (LPS; gram-negative bacteria), peptidoglycan (gram-positive and gramnegative bacteria), and lipoteichoic acid (gram-positive bacteria).
Several of the harmful effects of bacteria are mediated by proinflammatory cytokines induced
in host cells (macrophages/monocytes and neutrophils) by the bacterial cell-wall component.
The most toxic component of gram-negative bacteria is the lipid A moiety of LPS, which
leads to cytokine induction via lipoteichoic acid. Additionally, gram-positive bacteria may
secrete superantigen cytotoxins that bind directly to the major histocompatibility complex
(MHC) molecules and T-cell receptors, leading to massive cytokine production.

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.

Abnormalities of coagulation and fibrinolysis


An imbalance of homeostatic mechanisms leads to disseminated intravascular coagulopathy
(DIC) and microvascular thrombosis, causing organ dysfunction and death.[23] Inflammatory
mediators instigate direct injury to the vascular endothelium; the endothelial cells release
tissue factor (TF), triggering the extrinsic coagulation cascade and accelerating thrombin
production. Plasma levels of endothelial activation biomarkers are higher in patients with
sepsis-induced hypotension than in patients with hypotension from other causes.[24]
The coagulation factors are activated as a result of endothelial damage. The process is
initiated through binding of factor XII to the subendothelial surface, which activates factor
XII. Subsequently, factor XI and, eventually, factor X are activated by a complex of factor
IX, factor VIII, calcium, and phospholipid. The final product of the coagulation pathway is

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.

When intravascular volume is augmented, the cardiac output usually is elevated


(hyperdynamic phase of sepsis and shock).
Although cardiac output is elevated, the performance of the heart, reflected by stroke work as
calculated from stroke volume and blood pressure, is usually depressed. Factors responsible
for myocardial depression of sepsis include myocardial depressant substances, coronary
blood flow abnormalities, pulmonary hypertension, various cytokines, NO, and beta-receptor
downregulation.
Although cardiac output is elevated, the arterialmixed venous oxygen difference is usually
narrow, and the blood lactate level is elevated. This implies that low global tissue oxygen
extraction is the mechanism that may limit total body oxygen uptake in septic shock. The
basic pathophysiologic problem seems to be a disparity between oxygen uptake and oxygen
demand in the tissues, which may be more pronounced in some areas than in others.
This disparity is termed maldistribution of blood flow, either between or within organs, with a
resultant defect in the capacity for local extraction of oxygen. During a fall in the oxygen
supply, cardiac output becomes distributed so that the most vital organs, such as the heart and
brain, remain relatively better perfused than nonvital organs are. However, sepsis leads to
regional changes in oxygen demand and regional alteration in the blood flow of various
organs.
The peripheral blood flow abnormalities result from the balance between local regulation of
arterial tone and the activity of central mechanisms (eg, the autonomic nervous system).
Regional regulation and the release of vasodilating substances (eg, NO and prostacyclin) and
vasoconstricting substances (eg, endothelin) affect regional blood flow. Increased systemic
microvascular permeability also develops, remote from the infectious focus, and contributes
to edema of various organs (eg, the lung microcirculation) and to the development of ARDS.
In patients experiencing septic shock, oxygen delivery is relatively high, but the global
oxygen extraction ratio is relatively low. Oxygen uptake increases with rising body
temperature despite a fall in oxygen extraction.
In patients with sepsis who have low oxygen extraction and elevated arterial lactate levels,
oxygen uptake depends on oxygen supply over a much wider range than normal. Therefore,
oxygen extraction may be too low for tissue needs at a given oxygen supply, and oxygen
uptake may increase with a boost in oxygen supplya phenomenon termed oxygen uptake
supply dependence or pathologic supply dependence. This concept is controversial, however;
some investigators argue that supply dependence is an artifact rather than a real phenomenon.
Maldistribution of blood flow, disturbances in the microcirculation, and, consequently,
peripheral shunting of oxygen are responsible for diminished oxygen extraction and uptake,
pathologic supply dependency of oxygen, and lactate acidemia in patients experiencing septic
shock.

Mechanisms of organ dysfunction


Sepsis is described as an autodestructive process that permits the extension of the normal
pathophysiologic response to infection (involving otherwise normal tissues), resulting in

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

Direct cytotoxicity Endotoxin, TNF-, and NO may cause damage to mitochondrial


electron transport, leading to disordered energy metabolism; this is called cytopathic
or histotoxic anoxia (ie, inability to use oxygen even when it is present)

Apoptosis (programmed cell death) This is the principal mechanism by which


dysfunctional cells are normally eliminated; 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 in patients with sepsis

Immunosuppression Interaction between proinflammatory and anti-inflammatory


mediators may lead to an imbalance and an inflammatory reaction, immunodeficiency
may predominate, or both may occur

Coagulopathy Subclinical coagulopathy signified by mild elevation of the thrombin


time or activated partial thromboplastin time (aPTT) or by a moderate reduction in
platelet count is extremely common, but overt DIC is rare; coagulopathy is caused by
deficiencies of coagulation system proteins, including protein C, antithrombin III, and
TF inhibitors

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] :

Exudative phase (edema and hemorrhage)

Proliferative phase (organization and repair)

Fibrotic phase (end-stage fibrosis)

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.

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 photomicrograph shows early stage (exudative stage)

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).

Photomicrograph showing delayed stage (proliferative or


organizing stage) of diffuse alveolar damage (DAD). Proliferation of type II pneumocytes has
occurred; hyaline membranes as well as collagen and fibroblasts are present.

Photomicrograph showing delayed stage (proliferative or


organizing stage) of diffuse alveolar damage (DAD). Fibrin stain depicts collagenous tissue,
which may develop into fibrotic stage of DAD.
The fibrotic phase occurs by the third or fourth week after the onset of ARDS, though it may
begin as early as the first week. The collagenous fibrosis completely remodels the lung, the
air spaces are irregularly enlarged, and alveolar duct fibrosis is apparent. Lung collagen
deposition increases, and microcystic honeycomb formation and traction bronchiectasis
follow.

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]

Hepatic and renal dysfunction


By virtue of the livers role in host defense, the abnormal synthetic functions caused by liver
dysfunction can contribute to both the initiation and the progression of sepsis. The hepatic
reticuloendothelial system acts as a first line of defense in clearing bacteria and their
products; liver dysfunction leads to a spillover of these products into the systemic circulation.
Acute kidney injury (AKI)previously termed acute renal failure (ARF)caused by acute
tubular necrosis often accompanies sepsis. The mechanism involves 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

Central nervous system (CNS) involvement in sepsis produces encephalopathy (septic


encephalitis) and peripheral neuropathy. The pathogenesis is poorly defined, but it may
involve systemic inflammation from either infectious or noninfectious causes,[31] as well as a
combination of the effects of hypoxemia, hypotension, hemorrhage, and medications such as
sedatives and analgesics.[31, 32]

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

Fungi (see the image below)


An 8-year-old boy developed
septic shock secondary to Blastomycosis pneumonia. Fungal infections are rare
causes of septic shock.

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).

Gram stain of blood showing the presence of Neisseria


meningitidis.

Risk factors
Risk factors for severe sepsis and septic shock include the following:

Extremes of age (< 10 years and >70 years)

Primary diseases (eg, liver cirrhosis, alcoholism, diabetes mellitus, cardiopulmonary


diseases, solid malignancy, and hematologic malignancy)

Immunosuppression (eg, from neutropenia, immunosuppressive therapy [eg, in organ


and bone marrow transplant recipients], corticosteroid therapy, injection or IV drug
use [see the image below], complement deficiencies, asplenia)

Major surgery, trauma, burns

Invasive procedures (eg, placement of catheters, intravascular devices, prosthetic


devices, hemodialysis and peritoneal dialysis catheters, or endotracheal tubes)

Previous antibiotic treatment

Prolonged hospitalization

Underlying genetic susceptibility

Other factors (eg, childbirth, abortion, and malnutrition)


A
28-year-old woman who was a former intravenous drug user (human
immunodeficiency virus [HIV] status: negative) developed septic shock secondary to
bilateral pneumococcal pneumonia.

Epidemiology
United States statistics
The incidence of sepsis has been growing in recent decades, for reasons that likely include
the following:

An increasingly elderly population

Increased recognition of the disease

Increased performance of invasive procedures and organ transplantation

Increased use of immunosuppressive agents and chemotherapy

Increased use of indwelling lines and devices

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.

Age-, sex-, and race-related demographics


Sepsis and septic shock occur at all ages. However, a strong correlation exists between
advanced age and the incidence of septic shock, with a sharp increase in the number of cases
in patients older than 50 years.[42, 47] At present, most sepsis episodes are observed in patients
older than 60 years. Advanced age is a risk factor for acquiring nosocomial bloodstream
infection (BSI) in the development of severe forms of sepsis.
Overall, compared with younger patients, elderly patients are more susceptible to sepsis, have
less physiologic reserve to tolerate the insult from infection, and are more likely to have
underlying diseases; all of these factors adversely affect survival. In addition, elderly patients
are more likely to have atypical or nonspecific presentations with sepsis.
Epidemiologic data have shown that the age-adjusted incidence and mortality of septic shock
are consistently greater in men; the percentage of affected male patients ranges from 52% to
66%. However, it is not clear whether this difference can be attributed to an underlying
higher prevalence of comorbid conditions or to a higher incidence of lung infection in men,
or whether women are inherently protected against the inflammatory injury that occurs in
severe sepsis.[42, 43]
With regard to ethnicity, one large epidemiologic study showed that the risk of septicemia in
the nonwhite population is almost twice that in the white population, with the highest risk
accruing to black men.[43] Potential reasons for this difference include issues relating to
decreased access to health care and increased prevalence of underlying medical conditions.
Another large epidemiologic study tied the increased incidence of septic shock in the black
population to increased rates of infection necessitating hospitalization and increased

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:

Abnormal host response to infection

Site and type of infection

Timing and type of antimicrobial therapy

Offending organism

Development of shock

Any underlying disease

Patients long-term health condition

Location of the patient at the time of septic shock onset

Host immunogenetic variation

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

Infection with a resistant organism

Impaired host immune status

Poor prior functional status

Continued need for vasopressors past 24 hours

Development of sequential organ failure, despite adequate supportive measures and


antimicrobial therapy

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:

Higher severity of illness score

Acute failure of 2 or more organ systems at the time of sepsis

Shock

Low blood pH (< 7.3)

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.

Misalnya : reaksi tranfusi, sengatan serangga, gigitan ular berbisa


- Syok Neurogenik
Pada syok neurogenik terjadi gangguan perfusi jaringan yang disebabkan karena disfungsi
sistim saraf simpatis sehingga terjadi vasodilatasi.
Misalnya : trauma pada tulang belakang, spinal syok
4. Syok Obtruktif
Ketidakmampuan ventrikel untuk mengisi selama diastol sehingga secara nyata menurunkan
volume sekuncup dan endnya curah jantung
Misalnya : tamponade kordis, koarktasio aorta, emboli paru, hipertensi pulmoner primer.
C. Patofisiologi
Syok menunjukkan perfusi jaringan yang tidak adekuat. Hasil akhirnya berupa lemahnya
aliran darah yang merupakan petunjuk yang umum, walaupun ada bermacam-macam
penyebab. Syok dihasilkan oleh disfungsi empat sistem yang terpisah namun saling berkaitan
yaitu ; jantung, volume darah, resistensi arteriol (beban akhir), dan kapasitas vena. Jika salah
satu faktor ini kacau dan faktor lain tidak dapat melakukan kompensasi maka akan terjadi
syok. Awalnya tekanan darah arteri mungkin normal sebagai kompensasi peningkatan isi
sekuncup dan curah jantung. Jika syok berlanjut, curah jantung menurun dan vasokontriksi
perifer meningkat. 4, 6
Menurut patofisiologinya, syok terbagi atas 3 fase yaitu : 5,10
1. Fase Kompensasi
Penurunan curah jantung (cardiac output) terjadi sedemikian rupa sehingga timbul gangguan
perfusi jaringan tapi belum cukup untuk menimbulkan gangguan seluler. Mekanisme
kompensasi dilakukan melalui vasokonstriksi untuk menaikkan aliran darah ke jantung, otak
dan otot skelet dan penurunan aliran darah ke tempat yang kurang vital. Faktor humoral
dilepaskan untuk menimbulkan vasokonstriksi dan menaikkan volume darah dengan
konservasi air. Ventilasi meningkat untuk mengatasi adanya penurunan kadar oksigen di
daerah arteri. Jadi pada fase kompensasi ini terjadi peningkatan detak dan kontraktilitas otot
jantung untuk menaikkan curah jantung dan peningkatan respirasi untuk memperbaiki
ventilasi alveolar. Walau aliran darah ke ginjal menurun, tetapi karena ginjal mempunyai cara
regulasi sendiri untuk mempertahankan filtrasi glomeruler. Akan tetapi jika tekanan darah
menurun, maka filtrasi glomeruler juga menurun.
2. Fase Progresif
Terjadi jika tekanan darah arteri tidak lagi mampu mengkompensasi kebutuhan tubuh. Faktor
utama yang berperan adalah jantung. Curah jantung tidak lagi mencukupi sehingga terjadi
gangguan seluler di seluruh tubuh. Pada saat tekanan darah arteri menurun, aliran darah
menurun, hipoksia jaringan bertambah nyata, gangguan seluler, metabolisme terganggu,
produk metabolisme menumpuk, dan akhirnya terjadi kematian sel.

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

1. Sistem pernafasan : nafas cepat dan dangkal


2. Sistem sirkulasi : ekstremitas pucat, dingin, dan berkeringat dingin, nadi cepat dan lemah, tekanan darah turun bila kehilangan darah mencapai 30%.
3. Sistem saraf pusat : keadaan mental atau kesadaran penderita bervariasi tergantung derajat
syok, dimulai dari gelisah, bingung sampai keadaan tidak sadar.
4. Sistem pencernaan : mual, muntah
5. Sistem ginjal : produksi urin menurun (Normalnya 1/2-1 cc/kgBB/jam)
6. Sistem kulit/otot : turgor menurun, mata cekung, mukosa lidah kering.
7. Individu dengan syok neurogenik akan memperlihatkan kecepatan denyut jantung yang
normal atau melambat, tetapi akan hangat dan kering apabila kulitnya diraba.

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

Kriteria diagnosis :13


1. Penurunan tekanan darah sistolik > 30 mmHg
2. Tanda perfusi jaringan kurang
3. Takikardi, pulsus lemah
H. Diagnosis Banding13
1. Semua jenis syok.
2. Sinkope (pingsan)
3. Histeria
I. Komplikasi6,10,11
1. Kegagalan multi organ akibat penurunan aliran darah dan hipoksia jaringan yang
berkepanjangan.
2. Sindrom distress pernapasan dewasa akibat destruksi pertemuan alveolus kapiler karena
hipoksia
3. DIC (Koagulasi intravascular diseminata) akibat hipoksia dan kematian jaringan yang luas
sehingga terjadi pengaktifan berlebihan jenjang koagulasi.
J. Penatalaksanaan2,12,13
Penanggulangan syok dimulai dengan tindakan umum yang bertujuan untuk memperbaiki
perfusi jaringan; memperbaiki oksigenasi tubuh; dan mempertahankan suhu tubuh. Tindakan
ini tidak bergantung pada penyebab syok. Diagnosis harus segera ditegakkan sehingga dapat
diberikan pengobatan kausal. Segera berikan pertolongan pertama sesuai dengan prinsip
resusitasi ABC. Jalan nafas (A = air way) harus bebas kalau perlu dengan pemasangan pipa
endotrakeal. Pernafasan (B = breathing) harus terjamin, kalau perlu dengan memberikan
ventilasi buatan dan pemberian oksigen 100%. Defisit volume peredaran darah (C =
circulation) pada syok hipovolemik sejati atau hipovolemia relatif (syok septik, syok
neurogenik, dan syok anafilaktik) harus diatasi dengan pemberian cairan intravena dan bila
perlu pemberian obat-obatan inotropik untuk mempertahankan fungsi jantung atau obat
vasokonstriktor untuk mengatasi vasodilatasi perifer. Segera menghentikan perdarahan yang
terlihat dan mengatasi nyeri yang hebat, yang juga bisa merupakan penyebab syok. Pada syok
septik, sumber sepsis harus dicari dan ditanggulangi.
Penanganannya meliputi:
1. Umum :
Memperbaiki sistim pernafasan :
- Bebaskan jalan nafas

- 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.

4. Trauma kepala (terdapat gangguan pada pusat otonom).


5. Suhu lingkungan yang panas, terkejut, takut.
C. Patofisiologi
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). Sebagai tambahan, penurunan dalam
efektifitas sirkulasi volume plasma sering terjadi dari penurunan venous tone, pengumpulan
darah di pembuluh darah vena, kehilangan volume intravaskuler dan intersisial karena
peningkatan permeabilitas kapiler. Akhirnya, terjadi disfungsi miokard primer yang
bermanifestasi sebagai dilatasi ventrikel, penurunan fraksi ejeksi, dan penurunan kurva fungsi
ventrikel.11,16
Pada keadaan ini akan terdapat peningkatan aliran vaskuler dengan akibat sekunder terjadi
berkurangnya cairan dalam sirkulasi. Syok neurogenik mengacu pada hilangnya tonus
simpatik (cedera spinal). Gambaran klasik pada syok neurogenik adalah hipotensi tanpa
takikardi atau vasokonstriksi kulit.15
Syok neurogenik terjadi karena reaksi vasovagal berlebihan yang mengakibatkan vasodilatasi
menyeluruh di regio splanknikus, sehingga perfusi ke otak berkurang. Reaksi vasovagal
umumnya disebabkan oleh suhu lingkungan yang panas, terkejut, takut atau nyeri. Syok
neurogenik bisa juga akibat rangsangan parasimpatis ke jantung yang memperlambat
kecepatan denyut jantung dan menurunkan rangsangan simpatis ke pembuluh darah.
Misalnya pingsan mendadak akibat gangguan emosional.5,10
Pada penggunaan anestesi spinal, obat anestesi melumpuhkan kendali neurogenik sfingter
prekapiler dan menekan tonus venomotor. Pasien dengan nyeri hebat, stress, emosi dan
ketakutan meningkatkan vasodilatasi karena mekanisme reflek yang tidak jelas yang
menimbulkan volume sirkulasi yang tidak efektif dan terjadi sinkop.9
D. Manifestasi Klinis
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 .
Sedangkan pada keadaan lanjut, sesudah pasien menjadi tidak sadar, barulah nadi bertambah
cepat. Karena terjadinya pengumpulan darah di dalam arteriol, kapiler dan vena, maka kulit
terasa agak hangat dan cepat berwarna kemerahan.3,4,14,15
E. Diagnosis
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
F. Diagnosis Banding

Diagnosis banding syok neurogenik adalah sinkop vasovagal. Keduanya sama-sama


menyebabkan hipotensi karena kegagalan pusat pengaturan vasomotor tetapi pada sinkop
vasovagal hal ini tidak sampai menyebabkan iskemia jaringan menyeluruh dan menimbulkan
gejala syok.1,9 Diagnosis banding yang lain adalah syok distributif yang lain seperti syok
septik, syok anafilaksi. Untuk syok yang lain biasanya sulit dibedakan tetapi anamnesis yang
cermat dapat membantu menegakkan diagnosis.2,4,7,8
G. Penatalaksanaan
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
1. Baringkan pasien dengan posisi kepala lebih rendah dari kaki (posisi Trendelenburg).
2. Pertahankan jalan nafas dengan memberikan oksigen, sebaiknya dengan menggunakan
masker. Pada pasien dengan distress respirasi dan hipotensi yang berat, penggunaan
endotracheal tube dan ventilator mekanik sangat dianjurkan. Langkah ini untuk menghindari
pemasangan endotracheal yang darurat jika terjadi distres respirasi yang berulang. Ventilator
mekanik juga dapat menolong menstabilkan hemodinamik dengan menurunkan penggunaan
oksigen dari otot-otot respirasi.13
3. Untuk keseimbangan hemodinamik, sebaiknya ditunjang dengan resusitasi cairan. Cairan
kristaloid seperti NaCl 0,9% atau Ringer Laktat sebaiknya diberikan per infus secara cepat
250-500 cc bolus dengan pengawasan yang cermat terhadap tekanan darah, akral, turgor kulit,
dan urin output untuk menilai respon terhadap terapi.
4. Bila tekanan darah dan perfusi perifer tidak segera pulih, berikan obat-obat vasoaktif
(adrenergik; agonis alfa yang indikasi kontra bila ada perdarahan seperti ruptur lien) :3,14,15
Dopamin
Merupakan obat pilihan pertama. Pada dosis > 10 mcg/kg/menit, berefek serupa dengan
norepinefrin. Jarang terjadi takikardi.
Norepinefrin
Efektif jika dopamin tidak adekuat dalam menaikkan tekanan darah. Monitor terjadinya
hipovolemi atau cardiac output yang rendah jika norepinefrin gagal dalam menaikkan
tekanan darah secara adekuat. Pada pemberian subkutan, diserap tidak sempurna jadi
sebaiknya diberikan per infus. Obat ini merupakan obat yang terbaik karena pengaruh
vasokonstriksi perifernya lebih besar dari pengaruh terhadap jantung (palpitasi). Pemberian
obat ini dihentikan bila tekanan darah sudah normal kembali. Awasi pemberian obat ini pada
wanita hamil, karena dapat menimbulkan kontraksi otot-otot uterus.
Epinefrin
Pada pemberian subkutan atau im, diserap dengan sempurna dan dimetabolisme cepat dalam
badan. Efek vasokonstriksi perifer sama kuat dengan pengaruhnya terhadap jantung Sebelum
pemberian obat ini harus diperhatikan dulu bahwa pasien tidak mengalami syok hipovolemik.

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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