Sepsis and Septic Shock

Definitions

Systemic inflammatory response syndrome (SIRS)—Two or more of the following,

due to either an infectious or a noninfectious etiology:

• Temperature _38_C or _36_C

• Respiratory rate _24 breaths/ min

• Heart rate _90 beats/ min

• WBC count _12,000/_L or _4000/_L, or _10% bands

Sepsis—SIRS witha proven or suspected microbial etiology

Severe sepsis—Sepsis withone or more signs of organ dysfunction

Septic shock—Sepsis witharterial blood pressure _90 mmHg or 40 mmHg

below pt’s normal blood pressure for at least 1 hdespite fluid resuscitation

Etiology

• Blood cultures are positive in 20–40% of sepsis cases and in 40–70% of

septic shock cases. Of cases with positive blood cultures, _40% are due to

gram-positive bacteria, 35% to gram-negative bacteria, and 7% to fungi.

• Any class of microorganism can cause severe sepsis.

• A significant proportion of cases have negative microbiologic data.

Epidemiology and Risk Factors

The incidence of severe sepsis and septic shock is increasing in the United

States, with _300,000 cases each year. Two-thirds of cases occur in pts hospitalized

for other reasons. Sepsis is a contributing factor in _200,000 deaths

eachyear in the United States.

The higher incidence of sepsis is due to the aging of the population, longer

survival of pts withch ronic diseases, medical treatments (e.g., with steroids or

antibiotics), and invasive procedures (e.g., catheter placement). Gram-negative

sepsis is associated withunderlying diabetes mellitus, lymphoproliferative disorders, cirrhosis of the liver, burns, neutropenia, and indwelling urinary catheters. Gram-positive sepsis is associated withindwelling mechanical devices and intravascular catheters, IV drug use, and burns. Fungal sepsis is associated with neutropenia and broad-spectrum antimicrobial therapy.

Pathogenesis and Pathology

Local and Systemic Host Responses

• Recognition of microbial molecules by tissue phagocytes triggers production

and release of cytokines and other mediators that increase blood flow to the

infected site, enhance the permeability of local blood vessels, attract neutrophils

to the infected site, and elicit pain.

• Through intravascular thrombosis (the hallmark of the local immune response),

the body attempts to wall off invading microbes and prevent the spread

of infection and inflammation. Key features of the systemic immune response

include intravascular fibrin deposition, thrombosis, and DIC; the underlying

mechanisms are the activation of intrinsic and extrinsic clotting pathways, impaired function of the protein C–protein S inhibitory pathway, depletion of

antithrombin and protein C, and prevention of fibrinolysis by increased plasma

levels of plasminogen activator inhibitor 1.

Organ Dysfunction and Shock

• Endothelial injury: Widespread endothelial injury is believed to be the major

mechanism for multiorgan dysfunction.

• Septic shock: The hallmark is a decrease in peripheral vascular resistance

despite increased levels of vasopressor catecholamines. Cardiac output and

blood flow to peripheral tissues increase, and oxygen utilization by these tissues

is greatly impaired.

Clinical Features

• Hyperventilation

• Encephalopathy (disorientation, confusion)

• Hypotension

• DIC, acrocyanosis, ischemic necrosis of peripheral tissues (e.g., digits)

• Skin: hemorrhagic lesions, bullae, cellulitis. Skin lesions may suggest specific

pathogens—e.g., petechiae and purpura with Neisseria meningitidis, ecthyma

gangrenosum in neutropenic pts with Pseudomonas aeruginosa.

• Gastrointestinal: nausea, vomiting, diarrhea, ileus, cholestatic jaundice

• Hypoxemia: ventilation-perfusion mismatchand increased alveolar capillary

permeability withincreased pulmonary water content

Major Complications

• Cardiopulmonary manifestations:

Acute respiratory distress syndrome (progressive diffuse pulmonary infiltrates

and arterial hypoxemia) develops in _50% of pts withsevere

sepsis or septic shock.

Hypotension: Normal or increased cardiac output and decreased systemic

vascular resistance distinguish septic shock from cardiogenic or hypovolemic

shock.

Myocardial function is depressed withdecreased ejection fraction.

• Renal manifestations: oliguria, azotemia, proteinuria, renal failure due to

acute tubular necrosis

• Coagulation: thrombocytopenia in 10–30% of pts. With DIC, platelet counts

usually fall below 50,000/_L.

• Neurologic manifestations: polyneuropathy with distal motor weakness in

prolonged sepsis

Laboratory Findings

• Leukocytosis with a left shift, thrombocytopenia

• Prolonged thrombin time, decreased fibrinogen, presence of D-dimers, suggestive

of DIC

• Hyperbilirubinemia, increase in hepatic aminotransferases, azotemia, proteinuria

• Metabolic acidosis, elevated anion gap, elevated lactate levels, hypoxemia

Diagnosis

Definitive diagnosis requires isolation of the microorganism from blood or a

local site of infection. Culture of infected cutaneous lesions may help establish

the diagnosis. Lacking a microbiologic diagnosis, the diagnosis is made on

clinical grounds.

TREATMENT

1. Antibiotic treatment: See Table 15-1.

2. Removal or drainage of a focal source of infection

a. Remove indwelling intravascular catheters and send tips for quantitative

culture; replace Foley and other drainage catheters.

b. Rule out sinusitis in pts withnasal intubation.

c. Perform CT or MRI to rule out occult disease or abscess.

3. Hemodynamic, respiratory, and metabolic support

a. Maintain intravascular volume withIV fluids. Initiate treatment with

1–2 L of normal saline administered over 1–2 h, keeping pulmonary

capillary wedge pressure at 12–16 mmHg or central venous pressure

at 8–12 cmH2O, urine output at _0.5 mL/kg per hour, mean arterial

blood pressure at _65 mmHg, and cardiac index at _4 (L/min)/m2.

Add inotropic and vasopressor therapy if needed. Maintain central

venous O2 saturation at _70%, using dobutamine if necessary.

b. Maintain oxygenation withventilator support as indicated.

c. Monitor for adrenal insufficiency or reduced adrenal reserve. Pts

witha plasma cortisol response of _9 _g/dL to an ACTH challenge

may have improved survival if hydrocortisone (50 mg q6h IV) and

9-_-fludrocortisone (50 _g/d via nasogastric tube) are administered

for 7 days.

4. Other treatments (investigational): Antiendotoxin, anti-inflammatory, and

anticoagulant drugs are being studied in severe sepsis treatment. The

anticoagulant recombinant activated protein C (aPC), given as a constant

infusion of 24 _g/kg per hour for 96 h, has been approved for treatment

of severe sepsis or septic shock in pts with APACHE II scores of _25

preceding aPC infusion and low risk of hemorrhagic complications. The

long-term impact of aPC is uncertain, and long-term survival data are not

yet available. Other agents have not improved outcome in clinical trials.

Prognosis

In all, 20–35% of pts withsevere sepsis and 40–60% of pts with septic shock

die within 30 days, and further deaths occur within the first 6 months. The

severity of underlying disease most strongly influences the risk of dying.

Prevention

In the United States, most episodes of severe sepsis and septic shock are complications of nosocomial infections. Thus the incidence of sepsis would be affected by measures to reduce those infections (e.g., limiting the use and duration of indwelling vascular and bladder catheters, aggressively treating localized

infection, avoiding indiscriminate antimicrobial or glucocorticoid use, and instituting optimal infection control measures).