Sepsis and Septic Shock

Most cases of septic shock are caused by hospital-acquired gram-negative bacilli or gram-positive cocci and often occur in patients who are immunocompromised and in patients with chronic and debilitating diseases (1). Rarely, it is caused by Candida or other fungi. A postoperative infection should be suspected as the cause of septic shock in patients who have recently had surgery. A unique, uncommon form of shock caused by staphylococcal and streptococcal toxins is called toxic shock syndrome.

Septic shock occurs more often in neonates (see Neonatal Sepsis), older adults, and pregnant people. Predisposing factors include

• Diabetes mellitus

• Cirrhosis

• Leukopenia (especially that associated with cancer or treatment with cytotoxic medications)

• Invasive devices (including endotracheal tubes, vascular or urinary catheters, drainage tubes, and other foreign materials)

• Prior treatment with antibiotics or corticosteroids

• Recent hospitalization (especially in an intensive care unit)

Common causative sites of infection include the lungs and the urinary, biliary, and gastrointestinal tracts.

The pathogenesis of septic shock is not completely understood. An inflammatory stimulus (eg, a bacterial toxin) triggers production of pro-inflammatory mediators, including tumor necrosis factor (TNF) and interleukin (IL)-1. These cytokines cause neutrophil–endothelial cell adhesion, activate the clotting mechanism, and generate microthrombi. They also release numerous other mediators, including leukotrienes, lipoxygenase, histamine, bradykinin, serotonin, and IL-2. They are opposed by anti-inflammatory mediators, such as IL-4 and IL-10, resulting in a negative feedback mechanism.

Initially, arteries and arterioles dilate, decreasing peripheral arterial resistance; cardiac output typically increases. This stage has been referred to as warm shock. Later, cardiac output may decrease, blood pressure falls (with or without an increase in peripheral resistance), and typical features of hypoperfusion appear.

Even in the stage of increased cardiac output, vasoactive mediators cause blood flow to bypass capillary exchange vessels (a distributive defect). Poor capillary flow resulting from this shunting, along with capillary obstruction by microthrombi, decreases delivery of oxygen and impairs removal of carbon dioxide and waste products. Decreased perfusion causes dysfunction and sometimes failure of ≥ 1 organs, including the kidneys, lungs, liver, brain, and heart.

Coagulopathy may develop because of intravascular coagulation with consumption of major clotting factors, excessive fibrinolysis in reaction thereto, and more often a combination of both.

With sepsis (without septic shock), patients typically have fever, tachycardia, diaphoresis, and tachypnea; blood pressure remains normal. Other signs of the causative infection may be present.

Symptoms and signs of sepsis can be subtle and often easily mistaken for manifestations of other disorders (eg, primary cardiac dysfunction, pulmonary embolism, delirium, or infectious gastroenteritis). It can be particularly difficult to recognize clinical manifestations of sepsis in patients with immunosupression or in postoperative patients.

As sepsis worsens or septic shock develops, an early sign, particularly in older adults or the very young, may be confusion or decreased alertness. Blood pressure decreases, yet the skin is paradoxically warm. Later, extremities become cool and pale, with peripheral cyanosis and mottling. Organ dysfunction causes additional symptoms and signs specific to the organ involved (eg, oliguria, dyspnea).

• History and physical examination

• Blood pressure (BP), heart rate, and oxygen monitoring

• Complete blood count (CBC) with differential, electrolyte panel, creatinine, and lactate

• Invasive central venous pressure (CVP), partial pressure of arterial oxygen (PaO2), and central venous oxygen saturation (ScvO2) readings

• Cultures of blood, urine, and other potential sites of infection, including wounds in surgical patients

Sepsis is suspected when a patient with a known infection develops systemic signs of inflammation or organ dysfunction (1). Similarly, a patient with otherwise unexplained signs of systemic inflammation should be evaluated for infection by history, physical examination, and imaging or laboratory testing. Tests include urinalysis and urine culture (particularly in patients who have indwelling catheters), blood cultures, and cultures of other suspect body fluids. Blood levels of C-reactive protein and procalcitonin are often elevated in severe sepsis and may facilitate diagnosis, but they are not specific. In patients with a suspected surgical or occult cause of sepsis, ultrasonography (eg, Rapid Ultrasound for Shock and Hypotension (RUSH) Examination), CT, or MRI may be required, depending on the suspected source. Ultimately, the diagnosis is clinical.

Other causes of shock (eg, hypovolemia, myocardial infarction [MI]) should be ruled out via history, physical examination, ECG, and serum cardiac biomarker measurement as clinically indicated. Even in the absence of MI, hypoperfusion caused by sepsis may result in ECG findings of cardiac ischemia including nonspecific ST-T wave abnormalities, T-wave inversions, and supraventricular and ventricular arrhythmias.

It is important to detect organ dysfunction as early as possible. A number of scoring systems have been devised for early detection of sepsis, but the sequential organ failure assessment score (SOFA score) and the quick SOFA score (qSOFA) have been validated with respect to mortality risk and are relatively simple to use. The qSOFA score is based on the blood pressure, respiratory rate, and the Glasgow Coma Scale and does not require waiting for lab results.

For patients with a suspected infection who are not in the intensive care unit (ICU), the qSOFA score is a better predictor of inpatient mortality than the SIRS criteria and SOFA score. For patients with a suspected infection who are in the ICU, the SOFA score is a better predictor of in-patient mortality than the SIRS criteria and qSOFA score (2).

Patients with ≥ 2 of the following criteria meet criteria for SIRS and should have further clinical investigation:

• Temperature > 38° C (100.4° F) or < 36° C (96.8° F)

• Heart rate > 90 beats per minute

• Respiratory rate > 20 breaths per minute or partial pressure of arterial carbon dioxide (PaCO2) < 32 mm Hg

• White blood cell (WBC) count > 12,000/mcL (12 × 10⁹/L), < 4,000/mcL (4 × 10⁹/L), or > 10% immature (band) forms

Patients with ≥ 2 of the following qSOFA criteria should have further clinical and laboratory investigation:

• Respiratory rate ≥ 22 breaths per minute

• Altered mentation

• Systolic blood pressure ≤ 100 mm Hg

The SOFA score is somewhat more robust when patients are treated in the ICU), but this score requires laboratory testing (see table Sequential Organ Failure Assessment Score). There are other scoring systems in clinical use (3).

CBC, arterial blood gases (ABGs), chest x-ray, serum electrolytes, BUN (blood urea nitrogen), creatinine, partial pressure of carbon dioxide (PCO2), and liver function are monitored. Serum lactate levels, ScvO2, or both can be determined to help guide treatment. WBC count may be decreased (< 4,000/mcL [< 4 × 10⁹/L]) or increased (> 15,000/mcL [> 15 × 10⁹/L]), and polymorphonuclear leukocytes may be as low as 20%. During the course of sepsis, the WBC count may fluctuate, depending on the severity of sepsis or shock, the patient's immunologic status, and the etiology of the infection. Concurrent corticosteroid use may elevate WBC count and thus mask WBC changes due to trends in the illness.

Hyperventilation with respiratory alkalosis (low PaCO2 and increased arterial pH) occurs early, in part as compensation for lactic acidemia. Serum bicarbonate is usually low, and serum and blood lactate levels increase. As shock progresses, metabolic acidosis worsens, and blood pH decreases. Early hypoxemic respiratory failure leads to a decreased PaO2/fraction of inspired oxygen (FIO2) ratio and sometimes overt hypoxemia with PaO2 < 70 mm Hg. Diffuse infiltrates may appear on the chest x-ray due to acute respiratory distress syndrome (ARDS). BUN and creatinine usually increase progressively as a result of renal insufficiency. Bilirubin and transaminases may rise, although overt hepatic failure is uncommon in patients with normal baseline liver function.

Hemodynamic measurements with a central venous or pulmonary artery catheter can be used when the specific type of shock is unclear or when large fluid volumes (eg, > 4 to 5 L balanced crystalloid within 6 to 8 hours) are needed.

Bedside echocardiography in the ICU is a practical and noninvasive alternative method of hemodynamic monitoring. In septic shock, cardiac output is increased and peripheral vascular resistance is decreased, whereas in other forms of shock, cardiac output is typically decreased and peripheral resistance is increased.

Neither CVP nor pulmonary artery occlusive pressure (PAOP) is likely to be abnormal in septic shock, unlike in hypovolemic, obstructive, or cardiogenic shock.

Many patients with severe sepsis develop relative adrenal insufficiency (ie, normal or slightly elevated baseline cortisol levels that do not increase significantly in response to further stress or exogenous adrenocorticotropic hormone [ACTH]). Adrenal function may be tested by measuring serum cortisol at 8 AM; a level < 5 mcg/dL (< 138 nmol/L) is inadequate. Alternatively, cortisol can be measured before and after injection of 250 mcg of synthetic ACTH; a rise of < 9 mcg/dL (< 248 nmol/L) is considered insufficient.

Rapid Ultrasound for Shock and...

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• Perfusion restored with IV fluids and sometimes vasopressors

• Oxygen support

• Broad-spectrum antibiotics

• Source control

Patients with septic shock should be treated in an ICU. The following should be monitored frequently (as often as hourly):

• Volume status using CVP, PAOP, serial ultrasonography, and/or ScvO2

• ABGs

• Blood glucose, lactate, and electrolyte levels

• Renal function

Arterial oxygen saturation should be measured continuously via pulse oximetry. Urine output, a good indicator of renal perfusion, should be measured (in general, indwelling urinary catheters should be avoided unless they are essential). The onset of oliguria (eg, < approximately 0.5 mL/kg/hour) or anuria, or rising creatinine may signal impending renal failure.

Following evidence-based guidelines and formal protocols for timely diagnosis and treatment of sepsis has been shown to decrease mortality and length of stay in the hospital (1, 2).

Overall mortality in patients with septic shock is decreasing and is about 20% (with a wide range, depending on patient characteristics) (1). Poor outcomes often follow failure to institute early aggressive therapy (eg, within 6 hours of suspected diagnosis). Once severe lactic acidosis with decompensated metabolic acidosis becomes established, especially in conjunction with multiorgan failure, septic shock is likely to be irreversible and fatal. Mortality can be estimated with different scores, including the mortality in emergency department sepsis (MEDS) score. The multiple organ dysfunction score (MODS) measures dysfunction of 6 organ systems and correlates strongly with risk of mortality.