Background

Distributive shock results from excessive vasodilation and the impaired distribution of blood
flow. Septic shock is the most common form of distributive shock and is characterized by
considerable mortality (treated, around 30%; untreated, probably >80%). In the United States, this
is the leading cause of noncardiac death in intensive care units (ICUs). (See Pathophysiology,
Etiology, Epidemiology, and Prognosis.)
Other causes of distributive shock include systemic inflammatory response syndrome (SIRS) due
to noninfectious inflammatory conditions such as burns and pancreatitis; toxic shock
syndrome (TSS); anaphylaxis; reactions to drugs or toxins, including insect bites, transfusion
reaction, and heavy metal poisoning; addisonian crisis; hepatic insufficiency; and neurogenic
shock due to brain or spinal cord injury. (See Pathophysiology and Etiology.)

Types of shock
Shock is a clinical syndrome characterized by inadequate tissue perfusion that results in endorgan dysfunction. It can be divided into the following 4 categories:

Distributive shock (vasodilation), which is a hyperdynamic process

Cardiogenic shock (pump failure)
Hypovolemic shock (intravascular volume loss)
Obstructive shock (physical obstruction of blood circulation and inadequate blood
oxygenation)

Systemic inflammatory response syndrome

The American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM)
Consensus Conference Committee defined SIRS as the presence of at least 2 of the following 4
criteria (see Presentation)[1] :

Core temperature of higher than 38C (100.0F) or lower than 36C (96.8F)
Heart rate of more than 90 beats per minute
Respiratory rate of more than 20 breaths per minute or arterial carbon dioxide tension
(PaCO 2) less than 32mm Hg

White blood cell (WBC) count of more than 12,000/L, less than 4,000/L, or more than
10% immature (band) forms
The clinical suspicion of systemic inflammatory response syndrome by an experienced clinician is
of utmost importance.

Patient education
For patient education information, see Shock and Cardiopulmonary Resuscitation (CPR).

Pathophysiology
In distributive shock, the inadequate tissue perfusion is caused by loss of the normal responses of
vascular smooth muscle to vasoconstrictive agents coupled with a direct vasodilating effect. The
net result in a fluid-resuscitated patient is a hyperdynamic, hypotensive state associated with
increased mixed venous O2saturation; however, evidence of tissue ischemia as manifest by an
increased serum lactate, presumably due to intraorgan functional shunts.
Early septic shock (warm or hyperdynamic) causes reduced diastolic blood pressure; widened
pulse pressure; flushed, warm extremities; and brisk capillary refill from peripheral vasodilation,
with a compensatory increase in cardiac output. In late septic shock (cold or hypodynamic),
myocardial contractility combines with peripheral vascular paralysis to induce a pressure-

dependent reduction in organ perfusion. The result is hypoperfusion of critical organs such as the
heart, brain, and liver.
The hemodynamic derangements observed in septic shock and SIRS are due to a complicated
cascade of inflammatory mediators. Inflammatory mediators are released in response to any of a
number of factors, such as infection, inflammation, or tissue injury. For example, bacterial products
such as endotoxin activate the host inflammatory response, leading to increased pro-inflammatory
cytokines (eg, tumor necrosis factor (TNF), interleukin (IL) 1, and IL-6. Toll-like receptors are
thought to play a critical role in responding to pathogens as well as in the excessive inflammatory
response that characterizes distributive shock; these receptors are considered possible drug
targets.
Cytokines and phospholipid-derived mediators act synergistically to produce the complex
alterations in vasculature (eg, increased microvascular permeability, impaired microvascular
response to endogenous vasoconstrictors such as norepinephrine) and myocardial function (direct
inhibition of myocyte function), which leads to maldistribution of blood flow and hypoxia. Hypoxia
also induces the upregulation of enzymes that create nitric oxide, a potent vasodilator, thereby
further exacerbating hypoperfusion.
The coagulation cascade is also affected in septic shock. Activated monocytes and endothelial
cells are sources of tissue factors that activate the coagulation cascade; cytokines, such as IL-6,
also play a role. The coagulation response is broadly disrupted, including impairment of
antithrombin and fibrinolysis. Thrombin generated as part of the inflammatory response can
trigger disseminated intravascular coagulation (DIC). DIC is found in 25-50% of patients
with sepsis and is a significant risk factor for mortality.[2, 3]
During distributive shock, patients are at risk for diverse organ system dysfunction that may
progress to multiple organ failure (MOF). Mortality from severe sepsis increases markedly with the
duration of sepsis and the number of organs failing.
In distributive shock due to anaphylaxis, decreased SVR is due primarily to massive histamine
release from mast cells after activation by antigen-bound immunoglobulin E (IgE), as well as
increased synthesis and release of prostaglandins.
Neurogenic shock is due to loss of sympathetic vascular tone from severe injury to the nervous
system.

Etiology
The most common etiology of distributive shock is sepsis. Other causes include the following:

SIRS due to noninfectious conditions such as pancreatitis, burns, or trauma

TSS
Anaphylaxis
Adrenal insufficiency
Reactions to drugs or toxins
Heavy metal poisoning
Hepatic insufficiency
Neurogenic shock
All of these conditions share the common characteristic of hypotension due to decreased SVR and
low effective circulating plasma volume.

Septic shock

The most common sites of infection, in decreasing order of frequency, include the chest,
abdomen, and genitourinary tract.
Septic shock is commonly caused by bacteria, although viruses, fungi, and parasites are also
implicated. Gram-positive bacteria are being isolated more, with their numbers almost similar to
those of gram-negative bacteria, which in the past were considered to be the predominant
organisms. Multidrug-resistant organisms are increasingly common. [4]

Systemic inflammatory response syndrome

Causes of SIRS include the following:

Infection
Burns
Surgery
Trauma
Pancreatitis
Fulminant hepatic failure

Toxic shock syndrome

TSS can result from infection with Streptococcus pyogenes (group AStreptococcus)
or Staphylococcus aureus.

Adrenal insufficiency
Adrenal insufficiency can result from the following:

Destruction of adrenal glands due to autoimmune disease, infection (tuberculosis, fungal

infection, acquired immunodeficiency syndrome [AIDS]), hemorrhage, cancer, or surgical
removal
Suppression of hypothalamic-pituitary-adrenal axis by exogenous steroid, usually with
doses at 20 mg daily or higher
Hypopituitarism
Metabolic failure in hormone production due to congenital conditions or drug-induced
inhibition of synthetic enzymes (eg, metyrapone, ketoconazole)

Anaphylaxis
Anaphylaxis can develop as a result of the following:

Drugs such as penicillins and cephalosporins

Heterologous proteins such as Hymenoptera venom, foods, pollen, and blood serum
products

Epidemiology
Occurrence in the United States
Sepsis develops in more than 750,000 patients per year in the United States. Angus and
colleagues estimated that, by 2010, 1 million people per year would be diagnosed with sepsis.
[5]
From 1979-2000, the incidence of sepsis increased by 9% per year.

International occurrence
Sepsis is a common cause of death throughout the world and kills approximately 1,400 people
worldwide every day.[6, 7]

Age-related demographics

Increased age correlates with increased risk of death from sepsis.

Prognosis
The mortality rate after development of septic shock is 20-80%. [8] Data suggest that mortality due
to septic shock has decreased slightly because of new therapeutic interventions. [9] Early
recognition and appropriate therapy are central to maximizing good outcomes. Identifying patients
with septic shock in the emergency department, as opposed to identifying them outside of it,
results in significantly improved mortality. In one study, the mortality rate for emergency
department-identified patients was 27.7%, compared with 41.1% for patients identified outside of
the emergency department.[10]
Higher mortality rates have also been associated with the following:

Advanced age
The finding of positive blood cultures
Infection with antibiotic-resistant organisms such as Pseudomonas aeruginosa
Elevated serum lactate levels
Impaired immune function
Alcohol use
Poor functional status prior to the onset of sepsis.
Mortality rates associated with other forms of distributive shock are not well documented.

Complications
Duration of delirium is an independent predictor of long-term cognitive impairment. At 3-month and
12-month follow-up, as many as 79% and 71% of patients have cognitive impairment. About one
third remain severely impaired.[11, 12, 13]

History
Patients with shock frequently present with tachycardia, tachypnea, hypotension, altered mental
status changes, and oliguria.
Patients with septic shock or systemic inflammatory response syndrome (SIRS) may have prior
symptoms that suggest infection or inflammation of the respiratory tract, urinary tract, or
abdominal cavity.
Septic shock occurs frequently in hospitalized patients with risk factors such as indwelling
catheters or venous access devices, recent surgery, or immunosuppressive therapy.
Patients with anaphylaxis commonly have recent iatrogenic (drug) or accidental (bee sting)
exposure to an allergen and coexisting respiratory symptoms, such as wheezing and dyspnea,
pruritus, or urticaria.
Staphylococcal toxic shock syndrome (TSS) is still observed most commonly in women who are
menstruating, but it is also associated with recent soft-tissue injury, cutaneous infections,
postpartum and cesarean delivery, wound infections, pharyngitis, and focal staphylococcal
infections, such as abscess, empyema, pneumonia, and osteomyelitis. Patients often have a
history of influenzalike illness (fever, arthralgias, myalgias) and a desquamating rash.

Pancreatitis may be another cause of distributive shock; expect symptoms of abdominal pain that
radiate to the back, as well as nausea and vomiting. Burns also have been described as a cause
of distributive shock.

Adrenal insufficiency
Adrenal insufficiency as a cause of shock should be considered in any patient with hypotension
who lacks signs of infection, cardiovascular disease, or hypovolemia.
Long-term treatment with corticosteroids may result in inadequate response of the adrenal axis to
stress, such as infection, surgery, or trauma, and subsequent onset or worsening of shock.
If the clinical picture is consistent with adrenal insufficiency in a person without this diagnosis,
consider that this could be the first presentation of this disorder.
There is a high incidence of adrenal insufficiency in critically ill patients infected with the human
immunodeficiency virus (HIV), although this incidence varies with the criteria used to diagnose
adrenal insufficiency.[14]

Physical Examination
Cardinal features of distributive shock include the following:

Change in mental status

Heart rate - Greater than 90 beats per minute (note that heart rate elevation is not evident
if the patient is on a beta blocker)
Hypotension - Systolic blood pressure less than 90 mm Hg or a reduction of 40 mm Hg
from baseline
Respiratory rate - Greater than 20 breaths per minute
Extremities - Frequently warm, with bounding pulses and increased pulse pressure
(systolic minus diastolic blood pressure) in early shock; late shock may present as critical organ
dysfunction
Hyperthermia - Core body temperature greater than 38.3C (101F)
Hypothermia - Core body temperate less than 36C (96.8F)
Pulse oximetry - Relative hypoxemia
Decreased urine output
Clinical symptoms of the underlying infections found in distributive shock include the following:

Pneumonia - Dullness to percussion, rhonchi, crackles, bronchial breath sounds

Urinary tract infection - Costovertebral angle tenderness, suprapubic tenderness, dysuria
and polyuria

Intra-abdominal infection or acute abdomen - Focal or diffuse tenderness to palpation,

diminished or absent bowel sounds, rebound tenderness

Gangrene or soft-tissue infection - Pain out of proportion to lesion, skin discoloration and
ulceration, desquamating rash, areas of subcutaneous necrosis
Anaphylaxis is characterized by the following clinical symptoms:

Respiratory distress
Wheezing
Urticarial rash
Angioedema
TSS is characterized by the following clinical symptoms:
High fever

Diffuse rash with desquamation on the palms and soles over a subsequent 1-2 weeks
Hypotension (may be orthostatic) and evidence of involvement of 3 other organ systems
Streptococcal TSS more frequently presents with focal soft-tissue inflammation and is less
commonly associated with diffuse rash. Occasionally, it can progress explosively within hours.
Adrenal insufficiency is characterized by the following clinical symptoms:

Hyperpigmentation of skin, oral, vaginal, and anal mucosal membranes may be present in
chronic adrenal insufficiency.
In acute or acute-on-chronic adrenal insufficiency brought on by physiologic stress,
hypotension may be the only physical sign.

Diagnostic Considerations
Conditions to consider in the differential diagnosis of distributive shock include the following:

Anaphylaxis
Burns
Carbon monoxide poisoning
Drug reaction
Heavy metal poisoning
Insect bite
Major surgery
Neurogenic shock
Thyrotoxicosis
Toxic shock syndrome (TSS)
Cyanide toxicity
Thrombotic thrombocytopenic purpura (TTP)

Differential Diagnoses

Acute Pancreatitis

Adrenal Crisis

Cardiac Tamponade

Cardiogenic Shock

Hemorrhagic Shock

Myocardial Infarction

Myxedema Coma or Crisis

Pulmonary Embolism

Septic Shock

Systemic Inflammatory Response Syndrome

All patients with evidence of distributive shock should undergo the following studies:

Complete blood count (CBC) with differential

Urinalysis
Electrolytes
Blood urea nitrogen (BUN)
Creatinine
Glucose
Urine cultures
Blood cultures
Possibly arterial blood gas or at least venous blood gas
Serum lactate - Especially with metabolic acidosis or if an elevated anion gap is present
If pneumonia is suspected, sputum Gram stain and culture should be performed.
All patients with a suspected intra-abdominal pathologic condition or hepatic insufficiency should
undergo the following studies:

Serum bilirubin
Alkaline phosphatase
Aspartate aminotransferase (AST), alanine aminotransferase (ALT)
Prothrombin time (PT)/activated partial thromboplastin time (aPTT)/INR (international
normalized ratio)

Amylase, lipase
All patients with suspected disseminated intravascular coagulation (DIC) should undergo the
following studies:

Obtain PT, aPTT, fibrin split products, D-dimer assay, fibrinogen level, and platelet count.
Examine peripheral blood smear for signs of erythrocyte microangiopathic changes, such
as schistocytes.

Electrocardiography
Electrocardiography should be performed to examine the patient for evidence of underlying
pathologic cardiac conditions (left ventricular hypertrophy, cor pulmonale, low voltage, bundle
branch block) or acute changes of ischemia or pericarditis.

Imaging Studies
Imaging studies may be integral to defining the source of infection and identifying areas in need of
drainage. All patients should undergo chest radiography. However, radiographic studies may not
be sensitive enough to reveal intra-abdominal pathologic conditions. Consequently, computed
tomography (CT) scanning has become the diagnostic test of choice for suspected intraabdominal causes of sepsis. Consider abdominal and pelvic CT scans with oral contrast and
intravenous contrast if these sites are found to be clinically suspicious for infection.
In suspected cases of cholecystitis or pancreatitis, abdominal ultrasonography is most useful to
assess for cholelithiasis, biliary dilatation, and fluid collections around the gallbladder or the head
of the pancreas.
Point-of-care ultrasonography/echocardiography may be performed at the bedside in critically ill
patients to evaluate cardiac function, fluid status, and response to hemodynamic intervention and
to exclude tamponade.

Procedures

Lumbar puncture
Lumbar puncture (LP) is indicated in patients with nuchal rigidity, headache, or unexplained
neurologic findings or in patients with sepsis and altered level of consciousness without another
apparent source of infection. A CT scan of the head should be performed prior to LP whenever
feasible.

Arterial catheters
The use of pulmonary artery catheters (PACs) was the standard of care for decades (see Table 1,
below). However, data now suggest an increase in mortality with the use of PAC monitoring,
calling this practice into question. Additionally, current parameters for PAC-guided resuscitation
may not be appropriate. A randomized trial of the use of PACs in elderly, high-risk surgical patients
found no benefit to therapy directed by PACs compared with treatment per the standard of care. [15,
16]

Table 1. Pulmonary Artery Catheter Findings in Common Shock States (Open Table in a new
window)
Diagnosis

Pulmonary Capillary Wedge Pressure

Cardiac Output

Cardiogenic shock*

Increased

Decreased

Increased

Decreased

Normal or decreased

Decreased

Decreased

Decreased

Normal or decreased

Increased or normal

Normal or decreased

Increased or normal

Extracardiac obstructive shock

1. Pericardial tamponade

2. Pulmonary embolism

Hypovolemic shock
Distributive shock

1. Septic shock

2. Anaphylactic shock

*In cardiogenic shock due to a mechanical defect, such as mitral regurgitation, forward cardiac output is reduced, although the measured cardiac
output may be unreliable. Large V waves are commonly observed in the pulmonary capillary wedge tracing in mitral regurgitation.

The hallmark finding is equalization of right atrial mean, right ventricular end-diastolic, pulmonary artery (PA) end-diastolic, and pulmonary
capillary wedge pressures.

Arterial catheter placement should be considered in hemodynamically unstable patients who are
receiving continuous infusions of vasoactive drugs or in patients requiring frequent arterial blood
gas measurements (eg, patients on mechanical ventilation). The arterial catheter can be placed

radially, femorally, axillary, but never brachially. Some patients can be managed with the pulse
oximetry wave graphic only.

Transthoracic and transesophageal echocardiography

Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) may be
used to estimate right atrial filling and right ventricular volumes in patients with undetermined fluid
status. TTE is a noninvasive method for the assessment of left ventricular function. This technique
has several limitations, being time consuming, operator dependent, and limited by preexisting
pulmonary disease or chest wall injuries.
TEE is a somewhat more invasive test that provides excellent structural information in the critically
ill patient. This technique allows the assessment of preload, ventricular wall motion abnormalities,
and the pericardium.

Other minimally invasive techniques

Thoracic bioelectrical impedance (TBI)
This technique relies on formulas to estimate stroke volume and cardiac output based on the
measured bioimpedance of blood velocity and volume of blood flow through the aorta.
Pulse-induced CO (PiCO), lithium dilution CO (LiCO), and FloTrac
Via an arterial catheter, cardiac output (CO) can be continuously monitored. FloTrac does not
require calibration. Stroke volume and continuous systemic vascular resistance (SVR) can be
measured and calculated using basic patient information.
Total circulating blood volume (TCBV)
This is measured using indocyanine green infusion and is quantified using spectrophotometry.
Microcirculatory imaging
Microcirculatory imaging techniques, such as orthogonal polarization spectral and side-stream
dark-field imaging, have allowed direct observation of the microcirculation at the bedside. They
have demonstrated different types of heterogenous flow patterns of microcirculatory abnormalities
in different types of distributive shock and may complement early goal-directed therapy in shock

Approach Considerations
The primary goals of treatment are to reverse the underlying cause of shock (eg, treat the infection
by draining abscesses and debridement) and hemodynamic stabilization of the patient.
The management of patients with shock is multifactorial and guidelines are evolving. [19, 20, 21, 22, 23] Of
note, the Surviving Sepsis Campaign (SSC), composed of international experts, assessed the
available evidence and published consensus guidelines. [24]

Monitoring
All patients with distributive shock should be admitted to an intensive care unit (ICU). Vital signs
and fluid intake and output should be measured and charted on an hourly basis. Daily weights
should be obtained, and adequate intravascular access should be secured. A central venous
access device should be considered if vasoactive drug support is required. Placement of

pulmonary artery (PA) and arterial catheters should be considered. Most patients should have an
indwelling urinary catheter.
Oxygen should be administered immediately by mask. In patients with altered mental status,
respiratory distress, or severe hypotension, elective endotracheal intubation and mechanical
ventilation should be considered; these avoid emergent intubation in the event of subsequent
respiratory arrest. Mechanical ventilation can also aid in hemodynamic stabilization, by decreasing
the demands posed by the respiratory muscles on the circulation (as much as 40% of the cardiac
output during respiratory distress).

Prophylaxis
All patients should be treated prophylactically against thromboembolic disease, gastric stress
ulceration, and pressure ulcers.

Resuscitation
Early, efficient resuscitation is the key. The duration of hypotension before antibiotic treatment has
been found to be a critical factor in determining mortality.[25] Rivers et al found a significant
decrease in in-hospital mortality when patients were treated with early, goal-directed therapy.
[26]
This protocol-driven resuscitation strategy focused on optimizing hemodynamic parameters and
reversing hypoperfusion beginning in the emergency department; these protocols have been
successfully implemented not only in research centers, but also in community-based settings. [27, 28,
29, 30]
.
As soon as hypoperfusion is detected, continue fluid over the first 6 hours using protocol-defined
goals for central venous pressure, mean arterial pressure, urine output, and/or mixed venous
oxygen saturation. If central venous oxygen saturation of more than 70% is not achieved in the
first 6 hours, SSC recommendations suggest (based on clinical assessment) transfusing packed
red blood cells, targeting a hematocrit at greater than or equal to 30% or treatment with
dobutamine.[31, 32, 33] However, two major studies (ARISE,[34] ProCESS[35] ) have not shown improved
survival with protocol-based therapy, as compared with nonprotocol "usual" therapy. Furthermore,
a major study on a perioperative, cardiac outputguided hemodynamic therapy algorithm, with the
use of inotropic medication for patients with major gastrointestinal surgery, also did not show
increased survival.[36] The impact of these three studies on protocol-based therapy is currently
controversial.
The choice of fluid for resuscitation has been a matter of ongoing debate. The SSC recommends
the use of either colloids or crystalloids, finding inadequate evidence to recommend one over the
other. The Saline Versus Albumin Fluid Evaluation (SAFE) trial found crystalloid and colloid to be
equally safe and effective for ICU patients. In contrast to prior studies, it also found no difference
or increased mortality among patients receiving albumin. [37, 38, 39, 40, 41]
A meta-analysis revealed that passive leg raising-induced changes in cardiac output (PLR-cCO)
can reliably predict fluid responsiveness, regardless of ventilation mode and cardiac rhythm.
[42]
PLR-cCO has a significantly higher predictive value than arterial pulse pressure.
A retrospective cohort study of trauma patients who received allogeneic packed red blood cells
sought to determine the association between infection or death and blood storage duration.
Results showed that patients who received 7 units or more of older blood had a higher risk of
complicated sepsis compared with patients who received 1 or fewer units. The effects of
allogeneic blood is best reduced by avoiding unnecessary transfusions, but it may also be
important to avoid transfusions of multiple units of older blood.[43]
In the Multicenter Randomized Efficacy of Volume Substitution and Insulin Therapy in Severe
Sepsis (VISEP) study, comparing hydroxyethyl starch (HES) to Ringer's lactate, the HES group

had higher rates of renal failure and more days on renal replacement therapy. Additional
investigation is required to fully appreciate the risks versus benefits of this intervention. [44, 45]

Vasoactive drugs
In patients with hypotension due to sustained septic shock in whom fluid resuscitation does not
reverse hypotension, the use of systemic vasopressors is indicated to restore blood flow to
pressure-dependent vascular beds (eg, the heart and brain). Either norepinephrine or dopamine
should be used as first-line treatment; no evidence suggests the use of one over the other.
Several vasopressor agents are available. (See Table 2, below.)
If dopamine is tried first and fails to increase mean arterial pressure to more than 60mm Hg or if
excessive tachycardia or tachyarrhythmias develop, norepinephrine (Levophed) should be used.
As a second-line treatment, phenylephrine (Neo-Synephrine) may be added to or substituted for
dopamine. Dobutamine may be added to the therapeutic regimen when cardiac output is low,
recognizing that this drug acts primarily as a positive inotropic agent and may further decrease
systemic vascular resistance (SVR).
Importantly, because severe sepsis is usually associated with some degree of myocardial
depression, the use of an unopposed alpha stimulant to increase vasomotor tone without a
concomitant increase in inotropy decreases cardiac output. This was the universal finding when
nitric oxide synthase inhibitors were used to treat the hypotension of septic shock in a large
prospective, clinical trial. The doses and cardiovascular characteristics of commonly used
vasoactive drugs for shock are summarized in Table 2, below.
Vasopressin
As a second-line treatment, vasopressin may be helpful to increase mean arterial pressure and
SVR and may be considered in patients who are refractory to inotropic agents and have a cardiac
output that is already more than 3.5 L/min/m2. Endogenous vasopressin is released from the
pituitary gland as part of the physiologic response to shock, acting on V1 receptors of vascular
smooth muscle to induce vasoconstriction. As shock continues, endogenous vasopressin levels
may be depressed, perhaps due to depletion of the stores or impaired hypophyseal function in the
setting of infection. This contributes to refractory hypotension. [46, 47, 48, 49]
In this setting of hypotension, treatment with exogenous vasopressin has a role. Vasopressin
treatment carries the risk of acidosis by causing splanchnic vasodilation and resultant ischemia.
Myocardial ischemia is also possible, given increased afterload and coronary vasoconstriction.
Although current treatment guidelines support vasopressins use, a randomized trial in which
vasopressin was added to ongoing norepinephrine treatment did not find a benefit to the use of
vasopressin over norepinephrine, suggesting that additional investigation will be required to define
vasopressins role.[49] In a 2012 meta-analysis, Serpa et al found that vasopressin treatment in
patients with vasodilatory shock was safe and was associated with reduced mortality.[50]
Table 2. Vasoactive Drugs in Sepsis and the Usual Hemodynamic Responses(Open Table in a
new window)
Dose

Principal Mechanism

Cardiac
Output

Blood
Pressure

SV
R

Dobutamine

2-20 mcg/kg/min

Beta 1

++

Dopamine

5-10 mcg/kg/min

Beta 1, dopamine

++

Drug
Inotropic agents

(low dose)

Epinephrine (low
dose)

0.06-0.20 mcg/kg/min

Beta 1, beta 2 >alpha

++

>10 mcg/kg/min

Alpha, beta 1, dopamine

++

++

(high dose)

0.21-0.42 mcg/kg/min

Alpha >beta 1, beta 2

++

++

Norepinephrine

0.02-0.25 mcg/kg/min

Alpha >beta 1, beta 2

++

++

Phenylephrine

0.2-2.5 mcg/kg/min

Alpha

++

++

Vasopressin

0.10-0.40 U/min

V1 receptor

++

(very low dose)

1-4 mcg/kg/min

Dopamine

+/-

+/-

Milrinone

0.4-0.6 mcg/kg/min after loading dose; 50 mcg/kg

bolus over 5 min

Phosphodiesterase
inhibitor

+/-

Inotropic agents and vasoconstrictors

Dopamine (high
dose)
Epinephrine

Vasoconstrictors

Vasodilators
Dopamine

Alpha and beta refer to agonist activity at these adrenergic receptor sites.

Beta 1-adrenergic effects are inotropic and increase contractility.

Beta 2-adrenergic effects are chronotropic.[51]

Antimicrobial Treatment
In all patients with suspected sepsis, blood and urine cultures should be collected prior to empiric
antibiotic therapy, provided that this does not cause a significant delay in treatment. At least 2
blood cultures should be collected and should be drawn percutaneously, as well as from any
vascular access site. Cultures such as respiratory tract secretions and cerebrospinal fluid should
be collected if infection at these sites is suspected clinically.
Patients who receive prompt effective antimicrobial therapy are more likely to survive than are
patients whose antibiotic therapy is delayed; measurable increases in mortality occur for each

hours delay in antibiotic treatment. Because initial therapy must be empiric, antimicrobial
coverage should be broad and should have good penetration to all suspected sites of infection.
The choice of agent should be guided by history, suspected site of infection, comorbid diseases,
and pathogen susceptibility patterns in the hospital and community. Avoid antibiotics recently
received by the patient. Treatment of fungal infection should be considered and selection of an
antifungal agent should be guided by the local prevalence of Candida species. Recommended
empiric antibiotic regimens based on the suspected site are outlined in Table 3, below.
Antimicrobial regimens should be tailored once the causative pathogen and its susceptibility are
identified because narrow-spectrum treatment decreases the risk of superinfection with resistant
organisms. The duration of therapy varies based on clinical context, but the SSC guidelines
suggest that the typical duration will be 7-10 days, with adjustments made for factors such as
underlying immune status and undrainable foci of infection.
Consider the removal of any devices, such as intravenous or urinary catheters and prostheses.
Surgical drainage or debridement should be performed promptly, when appropriate (eg, intraabdominal abscess, necrotizing fasciitis).
Table 3. Empiric Antimicrobial Therapy in Septic Shock Based on Suspected Site of
Infection (Open Table in a new window)
Suspected Source

Recommended Antibiotic Therapy

Alternative Therapy

No source evident in a healthy host

Third-generation cephalosporin, eg, ceftriaxone 2 g IV

q12h, ceftizoxime, ceftazidime

Nafcillin and aminoglycoside,

imipenem, piperacillin/tazobactam

No source evident in an
immunocompromised host

Ceftazidime 2 g IV q8h plus aminoglycoside

Imipenem or piperacillin/tazobactam
plus aminoglycoside

No source evident in a user of intravenous

drugs

Nafcillin 2 g IV q4h plus aminoglycoside

Vancomycin plus aminoglycoside,

ceftazidime, imipenem, or
piperacillin/tazobactam

Bacterial pneumonia, community acquired

Ceftriaxone 2 g IV q12-24 h plus macrolide

Levofloxacin 750mg IV q24h,

cotrimoxazole or imipenem plus
macrolide

Bacterial pneumonia, hospital acquired

Piperacillin/tazobactam 4.5 g IV q6h plus

aminoglycoside, plus levofloxacin 750 mg IV q24h

Imipenem plus aminoglycoside, plus

macrolide

Urinary tract infection

Ampicillin 2 g IV q4h plus aminoglycoside

Fluoroquinolone or third-generation
cephalosporin plus aminoglycoside

Mixed aerobic and anaerobic abdominal

sepsis, aspiration pneumonia, pelvic
infection, and necrotizing cellulitis

Third-generation cephalosporin or ampicillin 2 g IV

q4h plus aminoglycoside plus clindamycin 600 mg IV
q8h or metronidazole 500 mg IV q6h

Fluoroquinolone plus clindamycin,

imipenem, piperacillin/tazobactam

Meningitis

Ceftriaxone 2 g IV q12h plus vancomycin

Meropenem plus vancomycin,

chloramphenicol plus cotrimoxazole
plus vancomycin

Cellulitis/erysipelas

Nafcillin 2 g IV q4h

Cefazolin, vancomycin, clindamycin

Toxic shock syndrome (TSS) or

streptococcal necrotizing fasciitis

Clindamycin 600 mg IV q8h

Cephalosporin, vancomycin, nafcillin

Preventing Microvascular Thrombosis

This has become a strategy for preventing sepsis-related organ failure. Disseminated
intravascular coagulation (DIC) is a critical factor in driving the progression of sepsis. Activated
protein C (APC), an endogenous protein that decreases thrombosis and inflammation, has been
used for septic shock but was withdrawn by the company for lack of significant efficiency.[9, 52, 53, 54, 55,
56, 57, 58]

Corticosteroids

The role of corticosteroids as an adjunct treatment for septic shock has been an area of debate.
The role of corticosteroids in sepsis is a matter of debate, with positive and negative studies in the
literature. Low-dose hydrocortisone and fludrocortisone have been used for patients with severe
sepsis and adrenal insufficiency who remain hypotensive after fluid resuscitation and pressors and
were traditionally thought to reduce mortality in this subgroup. [59, 60, 61, 62]
In contrast to prior studies, however, a multi-site, double-blind, placebo-controlled trial found that
low-dose hydrocortisone did not affect mortality at 28 days, although patients receiving
hydrocortisone had an earlier reversal of shock. Also in contrast to prior work, this study did not
find that a corticotropin stimulation test predicted response to hydrocortisone. Additional studies
are required to address these discrepancies.
The SSC recommendations acknowledge this controversy and support giving hydrocortisone only
to hypotensive patients poorly responsive to fluid resuscitation and vasopressors. Given findings
that suggest the adrenocorticotropic hormone (ACTH) stimulation test does not predict response
to steroids, this test is no longer recommended. Hydrocortisone, rather than dexamethasone or
fludrocortisone, is the steroid of choice; it is not yet clear if adding fludrocortisone to
hydrocortisone provides added benefit. [63]

Glucose
Protocol-driven management of glucose (target < 150-180 mg/dL) is recommended, with
monitoring every 1-2 hours until glucose levels are stable and then every 4 hours thereafter. This
SSC recommendation is based on studies that found decreased mortality, length of stay, and
complications such as renal impairment. Of note, intensive glucose management has been
associated with higher rates of severe hypoglycemic events and, in some studies, has not been
associated with improved mortality.

NO Scavenger
Pyridoxalated hemoglobin polyoxyethylene (PHP) is a hemoglobin-based nitric oxide (NO)
scavenger that has been shown to increase systemic blood pressure and reduce vasopressor and
ventilation needs in patients with NO-induced shock without adversely affecting cardiac output,
organ function, or survival. The results of its use in distributive shock in a multicenter, randomized,
placebo-controlled, phase II study were promising, but further studies are needed to provide a
definitive answer.[64]

Treatment of Anaphylaxis
If anaphylaxis is suspected, 0.2-0.5 mL subcutaneous of 1:1000 epinephrine should be
administered immediately, with repeated doses every 20 minutes as needed. Epinephrine can be
administered by continuous infusion of 30-60 mL/h of 1:10,000 dilution in severe reactions.
Diphenhydramine 50-80 mg intramuscular or intravenous may be administered for urticaria or
angioedema. Inhaled bronchodilators or intravenous steroids can be administered for
bronchospasm.

Surgical Control of Shock Sources

In addition to prompt fluid resuscitation, hemodynamic support with vasoactive drugs, and prompt
establishment of broad-spectrum antibiotic coverage, source control is essential to effective
treatment of shock. Early efforts should be made to define sources in need of surgical intervention,
such as necrotizing fasciitis, cholangitis, abscess, intestinal ischemia, or an infected device. The
least-invasive means of intervention should be used. [65]
Multiple surgical modalities for source control are indicated, including the following:

Removal of infected catheters, infected prosthesis, and foreign bodies

Drainage (operative, endoscopic, percutaneous) of intra-abdominal abscess,
postoperative collections, soft-tissue abscess, and gallbladder sludge
Debridement of devitalized (traumatic or infected) tissue, pancreatic necrosis, and softtissue infections
Operative resection of inflamed, infarcted, ischemic, and perforated hollow viscus
Amputation of gangrenous extremities

Diet
Once the initial phase of resuscitation is complete, promptly institute nutritional support, usually
within 24 hours. This is especially important in malnourished patients (with temporal muscle
atrophy).
In patients who are intubated or obtunded, tube feedings should be initiated through a soft
nasogastric or orogastric feeding tube at a slow rate and increased over 12-24 hours to the target
rate.
If patients cannot be fed enterally, parenteral nutrition may be instituted until enteral feeding
becomes possible. Enteral feeding is preferred because it is less expensive and is associated with
lower rates of nosocomial infection than total parenteral nutrition.

Inpatient Care
Transfer of a patient admitted with distributive shock from the ICU to a stepdown or ward unit is
highly individualized. The patient's condition and prognosis must be assessed and matched to the
level of care in the receiving unit.
Generally, patients can be considered for transfer when they are hemodynamically stable without
vasoactive drugs, when ventilation and oxygenation is stable on supplemental oxygen delivered
by nasal cannula, when life-threatening metabolic derangements are absent, and when the
patients no longer require the high nursing and respiratory therapy ratios characteristic of ICU care
(ie, for frequent suctioning).

Transfer
Transferring a patient with distributive shock from one hospital to another exposes the patient to
risk and should be undertaken only when the receiving institution can offer the patient care that is
not available at the transferring hospital.
In general, institutions that care for critically ill patients need an appropriately staffed ICU that is
capable of delivering and monitoring mechanical ventilation and invasive monitoring devices such
as pulmonary artery (PA) catheters and arterial lines.
Modern surgical facilities, a radiology department equipped with ultrasonographic and CT
scanners, dialysis equipment, and medical specialists to deliver these specialized types of care
and procedures are also a minimum requirement. Lack of any one of these resources may
necessitate transfer.
Under certain circumstances, patients may also benefit from transfer to units that specialize in
care for trauma, burns, or cardiac or neurosurgical problems or to units where organ
transplantation is available.

Consultations
Intensivist

Consultation with or primary management by a board-certified medical or surgical intensivist is

indicated for all patients with distributive shock.
Experienced intensivists may be trained in pulmonary/critical care medicine, cardiology, surgery,
or anesthesiology. The choice of consultant may depend on patient characteristics and the
availability of local subspecialists.

Infectious disease specialist

Consultation with a subspecialist in infectious disease is appropriate whenever sepsis is
suspected as a cause of distributive shock.
This is particularly true when the locus of infection is unknown or unique patient characteristics
(such as travel history or occupation) raise the possibility of an unusual or rare infectious process.

Surgeon
Consultation with a surgeon should always be obtained when an abdominal source of sepsis is
suspected. Other indications for consultation with a surgeon include, but are not limited to,
necrotizing fasciitis, soft tissue abscess, empyema (thoracic surgeon), or brain abscess
(neurosurgeon).

Medication Summary
Because initial therapy must be empiric, antimicrobial coverage should be broad, with good
penetration to all suspected sites of infection. Other important factors in choosing an agent include
history, suspected site of infection, comorbid diseases, and pathogen susceptibility patterns in the
hospital and community. Avoid antibiotics recently received by the patient.
Antimicrobial regimens should be tailored once the causative pathogen and its susceptibility are
identified, because narrow-spectrum treatment decreases the risk of superinfection with resistant
organisms.
The role of corticosteroids as an adjunct treatment for septic shock has been an area of debate.
Recommendations from the Surviving Sepsis Campaign (SSC) support giving hydrocortisone only
to hypotensive patients who are poorly responsive to fluid resuscitation and vasopressors.
Hydrocortisone is the steroid of choice.[63]
The use of systemic vasopressors is indicated in patients with hypotension due to sustained septic
shock in whom fluid resuscitation does not reverse hypotension. Systemic vasopressors are used
to restore blood flow to pressure-dependent vascular beds (eg, the heart and brain). Either
norepinephrine or dopamine should be used as first-line treatment; no evidence suggests the use
of one over the other.

Antibiotics
Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the
context of the clinical setting.
View full drug information

Nafcillin

Nafcillin is the initial therapy for suspected penicillin Gresistant streptococcal or staphylococcal
infections. Use parenteral therapy initially in severe infections, and change to oral therapy as the
condition warrants. Because of thrombophlebitis, particularly in elderly patients, administer nafcillin
parenterally for only a short period (1-2 d); change to the oral route as clinically indicated.
View full drug information

Ceftazidime (Fortaz, Tazicef)

Ceftazidime is a third-generation cephalosporin with broad-spectrum, gram-negative activity; lower

efficacy against gram-positive organisms; and higher efficacy against resistant organisms. It
arrests bacterial growth by binding to 1 or more penicillin-binding proteins.
View full drug information

Levofloxacin (Levaquin)

Levofloxacin is used for infections caused by multidrug-resistant, gram-negative organisms.

View full drug information

Ampicillin

Ampicillin has bactericidal activity against susceptible organisms. It serves as an alternative to

amoxicillin when the patient is unable to take medication orally. It is rarely used in septic shock.
View full drug information

Clindamycin (Cleocin)

Clindamycin is a lincosamide for the treatment of serious skin and soft-tissue staphylococcal
infections. It is also effective against aerobic and anaerobic streptococci (except enterococci).
Clindamycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl transfer
ribonucleic acid (tRNA) from ribosomes that cause RNA-dependent protein synthesis to arrest. It
also counteracts bacterial toxins.
View full drug information

Gentamicin

Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. It is used in combination

with an agent against gram-positive organisms and one that covers anaerobes.
Gentamicin is not the drug of choice (DOC). Consider using it if penicillins or other less-toxic drugs
are contraindicated, when it is clinically indicated, and in mixed infections caused by susceptible
staphylococci and gram-negative organisms.
Dosing regimens for gentamicin are numerous; adjust the dose based on creatinine clearance
(CrCl) and changes in the volume of distribution. It may be administered intravenously or
intramuscularly.
View full drug information

Tobramycin (TOBI)

Tobramycin is indicated in the treatment of staphylococcal infections when penicillin or potentially

less-toxic drugs are contraindicated and when bacterial susceptibility and clinical judgment
justifies its use.
View full drug information

Amikacin

Amikacin irreversibly binds to the 30S subunit of bacterial ribosomes. It blocks the recognition step
in protein synthesis, causing growth inhibition. Use the patient's ideal body weight (IBW) for the
dosage calculation.
View full drug information

Vancomycin

Vancomycin is a potent antibiotic that is directed against gram-positive organisms and is active
against Enterococcus species. It is useful in the treatment of septicemia and skin structure
infections. Vancomycin is indicated for patients who cannot receive or have failed to respond to
penicillins and cephalosporins or who have infections with resistant staphylococci. For abdominal
penetrating injuries, vancomycin is combined with an agent that is active against enteric flora and
anaerobes.
To avoid toxicity, the current recommendation is to assay vancomycin trough levels after the third
dose, drawn 0.5 hour prior to the next dosing. Use creatinine clearance to adjust the dose in
patients diagnosed with renal impairment.
Vancomycin is used in conjunction with gentamicin for prophylaxis in patients allergic to penicillin
who are undergoing gastrointestinal or genitourinary procedures.
View full drug information

Erythromycin (Erythrocin, E.E.S., Ery-Tab, EryPed)

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from
ribosomes that cause RNA-dependent protein synthesis to arrest. It is used for the treatment of
staphylococcal and streptococcal infections.
In children, age, weight, and the severity of infection determine proper dosage. When twice-daily
dosing is desired, the half-total daily dose may be taken every 12 hours. For more severe
infections, double the dose.
View full drug information

Azithromycin (Zithromax, Zmax)

Azithromycin is used to treat mild to moderate microbial infections.

View full drug information

Linezolid (Zyvox)

Linezolid provides gram-positive coverage, similar to vancomycin coverage.

View full drug information

Piperacillin/tazobactam (Zosyn)

This combination provides broad-spectrum coverage for gram-positive, gram-negative, and

anaerobic bacteria. It does not cover MRSA.

Corticosteroids
Class Summary
These agents have anti-inflammatory properties and cause profound and varied metabolic effects.
Corticosteroids modify the body's immune response to diverse stimuli.
View full drug information

Hydrocortisone (Solu-Cortef, Cortef)

Hydrocortisone is the corticosteroid of choice in shock because of its mineralocorticoid activity and
glucocorticoid effects. It may be given to hypotensive patients who are poorly responsive to fluid
resuscitation and vasopressors.

Vasopressors
Class Summary
These agents augment coronary and cerebral blood flow present during a state of low blood flow.
View full drug information

Vasopressin (ADH, Pitressin)

Vasopressin has vasopressor and antidiuretic hormone (ADH) activity. It increases water
resorption at the distal renal tubular epithelium (ADH effect). It promotes smooth muscle
contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects).
Vasoconstriction is also increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary,
and intrahepatic vessels.
View full drug information

Dopamine

Dopamine stimulates adrenergic and dopaminergic receptors. Its hemodynamic effect is dose
dependent. Lower doses predominantly stimulate dopaminergic receptors that, in turn, produce
renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation are produced by
higher doses.
After initiating therapy, increase the dose by 1-4mcg/kg/min every 10-30 minutes until the optimal
response is obtained. More than 50% of patients are maintained satisfactorily on doses of less
than 20mcg/kg/min.
View full drug information

Norepinephrine (Levarterenol, Levophed)

Norepinephrine is used in protracted hypotension following adequate fluid replacement. It

stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle
contractility and heart rate, as well as vasoconstriction. As a result, it increases systemic blood
pressure and cardiac output. Adjust and maintain infusion to stabilize blood pressure (eg, 80-100
mm Hg systolic) sufficiently to perfuse vital organs.
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