AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Shock is defined as a clinical syndrome due to inadequate tissue perfusion that results in end-organ dysfunction. Shock is categorized according to etiology, including cardiogenic, hypovolemic, compressive/obstructive shock (eg, cardiac tamponade and pulmonary embolism), distributive shock (eg, severe sepsis, pancreatitis, anaphylaxis), endocrine (eg, adrenal insufficiency, hyper or hypothyroid), neurogenic, and shock due to other miscellaneous causes (eg, carbon monoxide).

Distributive shock is characterized by decreased systemic vasomotor tone, usually qualified as a decreased systemic vascular resistance (SVR). With fluid resuscitation, effective circulating volume increases and often creates a hyperdynamic pattern and increased cardiac output associated with a low-to-normal blood pressure. This form of shock is referred to as distributive; in this setting, autoregulation and the pattern of peripheral blood flow distribution are disrupted. If hypotension also develops, then blood flow to pressure-dependent organs, such as the kidney, gut, and liver decreases despite an increase in baseline total blood flow. This gives rise to the paradoxical increase in mixed venous O₂ saturation (SvO₂) associated with signs of organ ischemia (metabolic acidosis and hyperlactatemia).

Septic shock, which is due to a complex systemic inflammatory response to infection, is the most commonly encountered form of distributive shock. In the United States, this is the most common cause of noncardiac death in intensive care units (ICUs). Other causes of distributive shock include systemic inflammatory response syndrome (SIRS) due to noninfectious inflammatory conditions; toxic shock syndrome (TSS); anaphylaxis; drug or toxin reactions, including insect bites, transfusion reaction, and heavy metal poisoning; Addisonian crisis; hepatic insufficiency; and neurogenic shock due to brain or spinal cord injury.

Pathophysiology

The decreased tissue perfusion in distributive shock is due to several factors that reduce peripheral vasomotor tone and vasoresponsiveness. Acute septic shock presents as a hypodynamic hypotensive state as the circulating inflammatory response targets the vascular endothelium–vascular smooth muscle interface. The main factor that induces this initial shock state is an increase in the unstressed volume of the peripheral capacitance vessels (eg, splanchnic circulation), as more blood is sent to otherwise underperfused low metabolic activity vascular beds. This results in a decrease in effective circulatory volume.

Additionally, since the inflammatory response is initially spread through the blood stream, the vascular endothelium is specifically targeted. Impaired vascular endothelial integrity results in increased capillary permeability with extravascular loss of protein-rich intravascular volume into the interstitium. Myocardial dysfunction and complete cardiovascular collapse, probably related tointracellular energy failure and apoptosis, represent the final stages of fatal septic shock. Since impaired myocardial contractility, if present, develops in the setting of reduced afterload and fluid resuscitation, load-dependent measures of cardiac performance, such as left ventricular ejection fraction, stroke volume, and cardiac output, are often maintained. Controversy exists as to whether left ventricular dilation, if present, is an adaptive process or an epiphenomenon of fluid resuscitation, but it has little prognostic significance.

The hemodynamic changes of distributive shock may be subdivided into early or late; these are primarily characterized by the evolution of changes in contractility and dilation of peripheral small vessels and the impact of resuscitation efforts. Early septic shock (warm or hyperdynamic) is characterized by peripheral vasodilation that causes flushed warm extremities with a compensatory increase in cardiac output due to the combined effects of fluid resuscitation and peripheral vasodilation. 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 released in response to infection, inflammation, or tissue injury and the neurohumoral response to those stimuli, including activation of the contact system and coagulation through the extrinsic pathway. This cascade occurs in response to bacterial products such as endotoxin, with activation of host inflammatory factors such as tumor necrosis factor (TNF), interleukin (IL)-1b, and IL-6.

All of these act synergistically with other cytokines and phospholipid-derived mediators 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 American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference Committee defined the following 4 clinical subcategories of systemic inflammatory response:

• Systemic inflammatory response with 2 or more of the following - a core temperature of higher than 38°C or lower than 36°C; a heart rate of more than 90 beats per minute; respiratory rate of more than 20 breaths per minute; WBC count of more than 12,000 10³/µL, less than 4,000 10³/µL, or more than 10% bands.
• Systemic inflammatory response with sepsis - meets criteria for SIRS, source of infection is established
• Systemic inflammatory response with severe sepsis - sepsis plus hypoperfusion and dysfunction or organs, as evidenced by hypotension (systolic blood pressure of more than 90 mm Hg or a decrease of more than 40 mm Hg from baseline), lactic acidosis, oliguria, a change in mental status
• Systemic inflammatory response with septic shock - severe sepsis in a patient who does not respond to intravenous fluid resuscitation and vasopressors

The inflammatory response to endotoxin and other microbial products in septic shock and the effects of cytokines such as IL-6 also activate the coagulation system through common stimuli. 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.

During distributive shock, patients are at risk for diverse and remote 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 occurs as peripheral vascular tone decreases.

Frequency

United States

Sepsis develops in more than 500,000 patients per year. Angus and colleagues have estimated that, by 2010, 1 million people per year will be diagnosed with sepsis.

Mortality/Morbidity

• The overall death rate after development of septic shock is 35-50%. Recent data suggest that mortality due to septic shock has decreased slightly over the past decade.
• Higher mortality rates have been associated with 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 and poor functional status prior to the onset of sepsis.
• Mortality rates associated with other forms of distributive shock are not well documented.

Age

Increased age correlates with increased risk of death from sepsis.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Patients with shock frequently present with dyspnea or respiratory distress, mental status changes, and obtundation.
• 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.
• 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.
  • Adrenal insufficiency also occurs in as many as 20% of patients with acquired immunodeficiency syndrome (AIDS).
• Streptococcal TSS is associated with recent soft tissue injury, surgery, pharyngitis. Patients often have a history of influenzalike illness (fever, arthralgias, myalgias) and a desquamating rash.
• Staphylococcal toxic shock syndrome (TSS) is still observed most commonly in women who are menstruating, but it is also associated with cutaneous infections, postpartum and cesarean delivery, wound infections, and focal staphylococcal infections, such as abscess, empyema, pneumonia, and osteomyelitis.
• Pancreatitis may also be a cause of distributive shock; expect symptoms of abdominal pain that radiate to the back and nausea and vomiting.
• Burns have been described as a cause of distributive shock.

Physical

• Cardinal features of distributive shock include the following:
• • Hypotension - With systolic blood pressure less than 90 mm Hg or a reduction of 40 mm Hg from baseline
  • Heart rate - Greater than 90 beats per minute (Note that heart rate elevation is not evident if the patient is on a beta-blocker.)
  • 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 (In late shock, hypoperfusion may be present.)
  • Hyperthermia - Core body temperature greater than 38.3°C or 101.0°F
  • Hypothermia - Core body temperate less than 36°C or 96.8°F
  • Pulse oximetry - Relative hypoxemia
  • Decreased urine output
  • Change in mental status
• Underlying infection
• • Pneumonia
    • Dullness to percussion
    • Rhonchi
    • Crackles
    • Bronchial breath sounds
  • Urinary tract infection
    • Costovertebral angle tenderness
    • Suprapubic tenderness
    • Dysuria
  • 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 ulceration
    • Skin discoloration
    • Desquamating rash
    • Areas of subcutaneous necrosis
• Anaphylaxis
  • Respiratory distress
  • Wheezing
  • Urticarial rash
  • Angioedema
• Toxic shock syndrome
  • 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.
• Adrenal insufficiency
  • 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.

Causes

The most common etiology of distributive shock is sepsis due to infection. Other causes include SIRS due to noninfectious conditions such as pancreatitis or trauma, TSS, anaphylaxis, adrenal insufficiency, drug or toxin reactions, heavy metal poisoning, hepatic insufficiency, and neurogenic shock. All of these conditions share the common characteristic of hypotension due to decreased systemic vascular resistance 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.
  • Twenty-five percent of sepsis is caused by gram-positive bacteria, 25% by gram-negative bacteria, 15% by a mix of gram-positive and gram-negative bacteria, and 5-10% by fungal pathogens. Multidrug-resistant organisms are increasingly common.
• SIRS (see ACCP/SCCM definition)
• • Infection
  • Surgery
  • Trauma
  • Pancreatitis
  • Fulminant hepatic failure
• Toxic shock syndrome
• • Streptococcus pyogenes (group A Streptococcus)
  • Staphylococcus aureus
• Adrenal insufficiency
• • Destruction of adrenal glands due to autoimmune disease, infection (tuberculosis, fungal infection, AIDS), hemorrhage, cancer, or surgical removal
  • Suppression of hypothalamic-pituitary-adrenal axis by exogenous steroid
  • Hypopituitarism
  • Metabolic failure in hormone production due to congenital conditions or drug-induced inhibition of synthetic enzymes (eg, metyrapone, ketoconazole)
• Anaphylaxis
• • Drugs such as penicillins and cephalosporins
  • Heterologous proteins such as Hymenoptera venom, foods, pollen, and blood serum products

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Drug reaction
Heavy metal poisoning
Carbon monoxide poisoning
Cyanide poisoning
Insect bite
Major surgery
Neurogenic shock
Thyrotoxicosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• All patients with evidence of distributive shock should undergo the following studies:
• • Blood cultures
  • Urine cultures
  • CBC count with differential
  • Arterial blood gas
  • Serum lactate if metabolic acidosis or elevated anion gap is present
  • Electrolytes
  • BUN
  • Creatinine
  • Glucose
  • Urinalysis
• If pneumonia is suspected, sputum Gram stain and culture should be performed.
• All patients with a suspected intraabdominal 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)
  • Amylase, lipase
• All patients with suspected adrenal insufficiency should undergo the following studies:
  • Cosyntropin stimulation test
  • Random serum cortisol: Level greater than 20 essentially rules out adrenal insufficiency.
• 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.

Imaging Studies

• All patients should undergo chest radiography.
• With the advent of CT scanning, the use of abdominal radiography has become less common in the diagnostic workup of shock. These studies may not be sensitive enough to reveal intra-abdominal pathologic conditions.
• In suspected cases of cholecystitis or pancreatitis, abdominal ultrasound is most useful to assess for cholelithiasis, biliary dilatation, and fluid collections around the gallbladder or the head of the pancreas.
• CT scan is the diagnostic test of choice for suspected intra-abdominal cause of sepsis. Consider abdominal and pelvic CT scans with oral contrast, intravenous contrast, or both if these sites are found to be clinically suspicious for infection.

Other Tests

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

Procedures

• 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.
• The use of pulmonary artery catheters (PACs) was the standard of care for decades; however, recent data 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 recent 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. See Table 1.

  Table 1. Pulmonary Artery Catheter Findings in Common Shock States

  Diagnosis	Pulmonary Capillary Wedge Pressure	Cardiac Output
  Cardiogenic shock*	Increased	Decreased
  Extracardiac obstructive shock 1. Pericardial tamponade† 2. Pulmonary embolism	Increased Normal or decreased	Decreased Decreased
  Hypovolemic shock	Decreased	Decreased
  Distributive shock 1. Septic shock 2. Anaphylactic shock	Normal or decreased Normal or decreased	Increased or normal Increased or normal

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

  †The hallmark finding is equalization of right atrial mean, right ventricular end-diastolic, PA end-diastolic, and pulmonary capillary wedge pressure.

• Arterial catheter placement should be considered in patients who are hemodynamically unstable, who are receiving continuous infusions of vasoactive drugs, or who require frequent arterial blood gas or venous blood draws (eg, patients on mechanical ventilation).
• Both transthoracic (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: it is time consuming, operator dependent, and limited by pre-existing 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 include the following:
• • 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.
  • PiCCO, LiCO, and FloTrac: Via an arterial catheter, cardiac output 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.
  • Measurement of total circulating blood volume (TCBV) is measured using indocyanine green infusion and quantified using spectrophotometry.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The 2 primary goals of distributive shock treatment are to reverse the underlying cause of shock (eg, treat the infection by draining abscesses and debridement) and to hemodynamically stabilize the patient.

All patients with distributive shock should be admitted to an ICU. Vital signs and fluid intake and output should be measured and charted on an hourly basis. Daily weights should be obtained. Adequate intravenous 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, as discussed under Procedures. Most patients should have an indwelling urinary catheter placed. All patients should be treated prophylactically against thromboembolic disease, gastric stress ulceration, and pressure ulcers. Blood glucose levels should be maintained at less than 110 mg/dL, and adequate hematocrit (depending on comorbid conditions) should also be maintained.

Patients with shock should be initially resuscitated as efficiently as possible. Rivers et al found a significant decrease in in-hospital mortality when patients were treated with early goal-directed therapy, beginning in the emergency department. Specific therapies discussed below are directed toward this goal.

• 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 strongly considered. This avoids emergent intubation in the event of subsequent respiratory arrest. Mechanical ventilation also can 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).
• Hemodynamic support should begin with fluid resuscitation. Crystalloid fluids, such as 0.9% NaCl or lactated Ringer solution, should be infused rapidly in 250- to 500-mL boluses, with frequent reassessment of blood pressure, extremities, skin turgor, and urine output to determine response to therapy. A mean arterial pressure of 60 mm Hg or systolic blood pressure of 90-100 mm Hg should be the usual hemodynamic goal. If a PA catheter is present, a pulmonary capillary occlusion pressure of less than 18 mm Hg is a reasonable goal of fluid therapy, as fluid resuscitation to higher vascular pressures may produce pulmonary edema. No evidence shows that fluid resuscitation to a defined central venous pressure (CVP) or pulmonary arterial occlusion pressure improves outcome. Little evidence supports use of colloids, such as albumin, in most instances. If anemia is present, packed red blood cells can be administered to achieve a hemoglobin concentration of 7-9 g/dL.
  • In patients with hypotension due to sustained septic shock in whom fluid resuscitation is unable to reverse hypotension, the use of a systemic vasopressor agent is indicated to restore blood flow to pressure-dependent vascular beds (eg, the heart and brain). Several vasopressor agents are available, and no clear advantage of one over the others is apparent.
  • As a second-line treatment, vasopressin may be helpful to increase mean arterial pressure and systemic vascular resistance and may be considered in patients refractory to inotropic agents in whom cardiac output is already more than 3.5 L/min/m². Endogenous vasopressin is released as part of the physiologic response to shock. As shock continues, endogenous vasopressin levels may be depressed, perhaps due to depletion of stores or through impaired hypophyseal function in the setting of infection; this contributes to refractory hypotension. Vasopressin causes vasoconstriction by acting on the V1 receptors of vascular smooth muscle. 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.
• If the blood pressure fails to improve after 2-3 L of rapid crystalloid infusion or after reaching the target pulmonary artery occlusion pressure, vasoactive drug therapy with either dopamine or norepinephrine should be initiated. An adequate hemodynamic response is not achieved with dopamine infusion rates of 15-20 mg/kg/min in upwards of 40% in all patients with severe sepsis. If dopamine is tried first and fails to increase mean arterial pressure to more than 60 mm Hg or if excessive tachycardia or tachyarrhythmias develop, norepinephrine (Levophed) should be used. Similar to vasopressin, 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, since 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 inotrophy 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.

  Table 2. Vasoactive Drugs in Sepsis and the Usual Hemodynamic Responses

  Drug	Dose	PrincipalMechanism	Cardiac Output	Blood Pressure	SVR
  Inotropic agents
  Dobutamine	2-20 mcg/kg/min	Beta 1	++	+	+
  Dopamine (low dose)	5-10 mcg/kg/min	Beta 1, dopamine	++	+	+
  Epinephrine (low dose)	0.06-0.20 mcg/kg/min	Beta 1, beta 2 > alpha	++	+	+
  Inotropic agents and vasoconstrictors
  Dopamine (high dose)	>10 mcg/kg/min	Alpha, beta 1, dopamine	++	++	+
  Epinephrine (high dose)	0.21-0.42	Alpha > beta 1, beta 2	++	++	+
  Norepinephrine	0.02-0.25 mcg/kg/min	Alpha > beta 1, beta 2	+	++	++
  Vasoconstrictors
  Phenylephrine	0.2-2.5 mcg/kg/min	Alpha	+	++	++
  Vasopressin	0.4-0.10 U/min	V1 receptor	+	+	++
  Vasodilators
  Dopamine (very low dose)	1-4 mcg/kg/min	Dopamine	+/-	+/-	-
  Milrinone	0.4-0.6 mcg/kg/minafter loading dose; 50 mcg/kgbolus over 5 min	Phosphodiesterase inhibitor	+	+/-	-

  
  Alpha and beta refer to agonist activity at these adrenergic receptor sites. Beta 1-adrenergic effects are inotropic and increase contractility. Beta 2-adrinergic effects are chronotropic.
• In all patients with suspected sepsis, empiric antibiotic therapy should be initiated immediately following the collection of appropriate blood, urine, and other body fluid cultures when suggested based on the history and physical examination. Patients who receive prompt effective antimicrobial therapy are more likely to survive than those whose antibiotic therapy is delayed. Because initial therapy must be empiric, antimicrobial coverage should be broad, although tailoring the therapy based on the suspected site of infection is appropriate. Prophylactic treatment of fungal infection is not recommended. Recommended empiric antibiotic regimens based on suspected site are outlined in Table 3.

  Table 3. Empiric Antimicrobial Therapy in Septic Shock Based on Suspected Site of Infection

  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 q12-24h plus macrolide	Levofloxacin 500 mg IV q24h, cotrimoxazole or imipenem plus macrolide
  Bacterial pneumonia, hospital acquired	Ceftazidime 2 g IV q8h plus aminoglycoside, plus macrolide	Imipenem or piperacillin/tazobactam 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
  TSS or streptococcal necrotizing fasciitis	Clindamycin 600 mg IV q8h	Cephalosporin, vancomycin, nafcillin

• Consider removal of any devices such as intravenous or urinary catheters, prosthesis, or endotracheal tube. Surgical drainage or debridement should be performed promptly, when appropriate (eg, intra-abdominal abscess, necrotizing fasciitis). See Surgical Care.
• Preventing microvascular thrombosis has become a key strategy for preventing sepsis-related organ failure. Disseminated intravascular coagulation is a critical factor to drive the progression of sepsis. Activated protein C (APC), an endogenous protein that decreases thrombosis and inflammation, has become central to the treatment of severe sepsis.
  • Three large clinical trials have been completed using APC. In the patient in the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study, APC was shown to decrease the mortality from severe sepsis at 28 days from 31% to 25%. However, additional follow-up in these patients shows no benefit in long-term mortality. Serious bleeding risk increased from 2% in control patients to 3.5% in study patients. The greatest benefit was demonstrated in patients with severe sepsis (acute physiology and chronic health evaluation [APACHE] II > 25).
  • The Extended Evaluation of Recombinant Human Activated Protein C (ENHANCE) nonrandomized open-label trial also demonstrated a decreased 28-day mortality similar to that of the PROWESS study and also found that activated protein C carries an increased risk of bleeding. Risk of intracranial hemorrhage was increased (1.5% in those treated with APC vs 0.2% in the control patients) and fatal hemorrhage was 0.5% in the APC group compared with 0.2% in the non-APC group.
  • The Administration of Drotrecogin alfa (activated) Early Stage Severe Sepsis (ADDRESS) trial evaluated patients with APACHE II scores higher than 25 or single organ failure. The study was discontinued at the interim analysis; no mortality benefit was observed and bleeding risk was increased. Patients with recent surgery (subgroup analysis) had an increased mortality (21% vs 14%).
  • According to current literature, APC is not recommended for patients with an APACHE II score of more than 25 or with single organ failure. Additional studies are required to establish benefit of APC for those with higher APACHE scores and multiorgan failure. For patients with a history of recent surgery with any risk of bleeding, APC cannot be recommended. Still, currently, APC is indicated for the early treatment ( <12 hours from presentation) of severe sepsis with 2 or more organ failures and without contraindications.
• Recent studies in patients with severe sepsis found that corticosteroids may decrease vasopressor requirements and ameliorate organ dysfunction. For patients with severe sepsis and adrenal insufficiency, low-dose hydrocortisone and fludrocortisone decrease mortality.
• If anaphylaxis is suspected, 0.2-0.5 mL SC 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. If the agent was injected, a tourniquet may be applied to the extremity to slow absorption, and 0.2 mL of 1:1000 epinephrine can be injected at the site. Diphenhydramine 50-80 mg IM or IV may be administered for urticaria or angioedema. Inhaled bronchodilators or intravenous aminophylline can be administered for bronchospasm.
• If adrenal insufficiency is suspected, hydrocortisone should be administered at an initial dose of 125 mg IV every 6-8 hours after the performance of a cosyntropin stimulation test. If a delay in administration of steroid therapy for performance of the cosyntropin test might adversely affect the patient, dexamethasone may be administered immediately at 10 mg IV without interfering with subsequent measurements of serum cortisol levels.

Surgical Care

Effective treatment of shock includes a multidisciplinary approach. 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.

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
• Debridement of devitalized (traumatic or infected) tissue, pancreatic necrosis, and soft tissue infections
• Operative resection of inflamed, infarcted, ischemic, and perforated hollow viscus
• Amputation of gangrenous extremities

Consultations

• Consultation with a critical care specialist
• • 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.
• Consultation with an 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.
• Consultation with a 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).

Diet

• Once the initial phase of resuscitation is complete, promptly institute nutritional support, usually within 24 hours.
• 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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Initial drug therapy in distributive shock is discussed under Medical Care and summarized in Table 1 and Table 2.

Drug Category: Antibiotics

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

Drug Category: Corticosteroids

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

Drug Category: Vasopressors

These agents augment both coronary and cerebral blood flow present during a state of low blood flow.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further 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 they no longer require the high nursing and respiratory therapy ratios characteristic of ICU care (ie, for frequent suctioning).

Transfer

• Transfer of 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 capable of delivering and monitoring mechanical ventilation and invasive monitoring devices such as PA catheters and arterial lines.
• Modern surgical facilities, a radiology department equipped with ultrasound and CT scanner, 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, cardiac, or neurosurgical problems or units where organ transplantation is available.

Patient Education

• For excellent patient education resources, visit eMedicine's Shock Center and Public Health Center. Also, see eMedicine's patient education articles Shock and Cardiopulmonary Resuscitation (CPR).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to begin prompt antibiotic therapy
• Failure to electively intubate and mechanically ventilate, resulting in cardiopulmonary arrest
• Failure to localize site of infection, particularly when surgical drainage is indicated
• Failure to obtain appropriate consultation, such as infectious disease or surgical consults
• Failure to provide prophylaxis against venous thromboembolic disease, gastric bleeding, and pressure ulcers of the skin
• Failure to recognize and treat secondary infections, such as line infection, urinary catheter-associated infection, and nosocomial or ventilator-associated pneumonia
• Failure to provide nutritional support

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Oct 3, 2006