Sepsis: Immune Response MeltdownPage 9 of 14

7. Treatment of Sepsis

Treatment ensues with resuscitating the patient, followed by a search for the infection, empirical administration of broad-spectrum antibiotics, control of the septic cause if possible, and a turn to sepsis-specific medications following blood cultures.

Resuscitate the Patient

Once septic patients develop macrovascular shock (refractory hypotension) or microvascular shock (elevated lactate), they are on the steep part of the mortality curve and immediate identification and intervention is critical to avert rapid deterioration and death.

Sweet et al., 2012

The first six hours are the critical period in the treatment of sepsis. Clinical studies have demonstrated that during this initial phase the use of a standardized protocol leads to reduced mortalities and ICU stays. The EGDT protocol sets specific target values of critical physiologic parameters toward which the treatment procedures aim (Gutovitz et al., 2011). The sepsis guidelines assume that all recommendations will be overseen and tailored to the individual patient by experienced emergency and critical care physicians.

Two treatment bundles are recommended by the Surviving Sepsis Campaign to accomplish the following goals during the first 6 hours of resuscitation of sepsis-induced hypoperfusion (Dellinger et al., 2013b; Buckman, 2013):

  • Central venous pressure (CVP) = 8–12 mm Hg
  • Mean arterial pressure (MAP) = ≥ 65 mm Hg
  • Urine output ≥ 0.5 ml/kg/hr
  • Superior vena cava oxygenation saturation (ScvO2) or mixed venous oxygen saturation (SvO2) 70% or 65%, respectively
  • Normalization of lactate in patients with elevated lactates

Time Zero and Sepsis Bundles

Patients with septic shock require early and vigorous resuscitation with an integrated approach directed to rapid restoration of systemic oxygen delivery and improvement of tissue oxygenation. The first priority is stabilization of the airway and breathing with supplemental oxygen and, if necessary, institution of mechanical ventilation. Once hypoperfusion is recognized, early restoration of perfusion is necessary to limit secondary organ dysfunction and reduce mortality (Boodoosingh et al., 2013).

The 2012 Surviving Sepsis Guidelines include recommendations for a bundle to be completed within the first 3 hours and a bundle to be completed within the first 6 hours of recognition of severe sepsis or septic shock.

Since treatment for the septic patient needs to be started immediately upon recognition, and because many tasks must be done within certain time frames, time zero is when the clock begins after diagnosing the patient with sepsis.

Although time zero may be defined differently in individual hospitals, according to the Surviving Sepsis Campaign performance improvement initiative:

  • Time of triage in the ED should be used as time zero in order to maximize the bundle’s effectiveness for diagnosis as well as treatment.
  • The campaign acknowledges “that a percentage of patients may not meet criteria for severe sepsis or septic shock at ED triage” and that “100% compliance for some indicators is not always possible” (Dellinger et al., 2013a).

Test Your Knowledge

In general, time zero for treatment is understood to have begun when the patient first complained of feeling ill.

  1. True
  2. False

Answer: B

The bundle to be completed within 3 hours of time zero is:

  1. Lactate levels should be drawn.
  2. Blood cultures should be drawn before antibiotics are given.
    • Do not delay administration of broad-spectrum antibiotics more than 45 minutes for blood culture draw.
  3. Broad-spectrum antimicrobial agents should then be administered (within the first hour) that target likely pathogens (bacterial, fungal, or viral).
    • Antimicrobial therapy should be reassessed daily for possible de-escalation.
  4. A minimum initial fluid challenge of 30 ml/kg bolus of crystalloid (normal saline) should be given for hypotension or a lactate of 4 mmol/l.
    • More rapid administration and greater amounts of fluid may be needed in some patients.
    • Colloids may be given as part of the fluid challenge if large amounts of crystalloids are required.
    • Avoid hetastarch. (Dellinger et al., 2013a; Buckman, 2013)

The 2012 guidelines recommend further resuscitation of patients with hypotension that persists after the initial fluid challenge or who have blood lactates ≥ 4 mmol/l. This protocol should be started upon recognition of severe sepsis or septic shock. A central venous catheter (CVC) should be placed for central venous pressure (CVP), central venous oxygen saturation readings (ScvO2) and for administration of vasopressors (if needed). A CVC can also be used to infuse IV fluids, medications, blood products, and to draw blood (Schmidt & Mandel, 2016).

The bundle to be completed within 6 hours of time zero is (Buckman, 2013):

  1. Vasopressors should be given for hypotension that does not respond to initial fluid boluses to maintain mean arterial pressure (MAP) of 65 mm Hg.
    • Norepinephrine is recommended as the first-choice vasopressor.
    • Epinephrine is recommended when norepinephrine does not maintain adequate blood pressure.
    • Dopamine is recommended only in selected cases with low risk of tachyarrhythmias.
  2. For persistent hypotension despite fluid resuscitation or initial lactate ≥ 4 mmol/l:
    • Measure CVP—resuscitation target is 8–12 mm Hg.
    • Give fluid boluses of 500 ml every 30 min to achieve this goal.
    • Measure ScvO2 (central venous oxygen saturation): resuscitation target is ≥ 70%.
      • Once CVP and MAP are at goal, the clinician’s attention should then turn to the central venous oxygen saturation, ScvO2. The clinician must decide between the addition of dobutamine and transfusing blood if the ScvO2 is less than 70%. For a hematocrit less than 30%, blood is transfused. (Boodoosingh et al., 2013)
  3. Re-measure lactate if initial lactate is elevated (>2 mmol/l); goal is normalization of lactate. (Buckman, 2013)

Test Your Knowledge

The Surviving Sepsis Campaign guidelines recommend “bundles” of measures that must be completed in:

  1. Three and six seconds from time zero.
  2. Three and six minutes following time zero.
  3. Three and six hours from time zero.
  4. Three and six shifts following time zero.

Apply Your Knowledge

What is your facility doing to increase awareness of the bundles for sepsis? How can you being an advocate to improve compliance?

Answer: C

Recommendations During Resuscitation

Attention is directed to respiration, blood volume, blood pressure, cardiac output, and septic shock.


The first priority when treating a critical illness is to ensure a patent airway and adequate ventilation. If the venous oxygen saturation target is not met, provide supplemental oxygen or begin mechanical ventilation. There are many reasons that a septic patient might need mechanical ventilation. A patient who is in shock may be obtunded (have less than full mental capacity) or unconscious and need to be intubated. A septic patient may have pneumonia or ARDS—or, lactic acidosis or pulmonary edema may have significantly increased the work required by the respiratory muscles.

Blood Volume

Typically, a septic patient is hypovolemic. Therefore, with any signs of poor tissue perfusion, intravenous fluids are begun and crystalloids are the initial fluids of choice. Severe sepsis or shock may require large volumes of fluid infusion. One study found that an average of 5 liters of crystalloid was necessary in the first 6 hours. Colloids may be added when large amounts of fluids are needed. Hetastarch is no longer recommended (Buckman, 2013).

Fluid is given rapidly in boluses of 500 ml of normal saline to achieve a minimum of 30 ml/kg, with blood pressure, tissue perfusion, and pulmonary edema assessed before and after each bolus. Fluids are administered as long as there is hemodynamic improvement and until the target values are met, initially aiming for a central venous pressure of 8 mm Hg (12 mm Hg in mechanically ventilated patients). Patients with severe sepsis or septic shock should have a central venous catheter placed for these readings. Fluids are stopped if pulmonary edema develops or when no improvement in the target values is seen.

Test Your Knowledge

Initial fluid resuscitation for sepsis:

  1. Attempts to improve tissue perfusion with large volumes of intravenous crystalloids.
  2. Provides electrolyte-rich fluid by mouth to counteract severe dehydration.
  3. Should be delayed until 6 hours after the administration of antibiotics because it dilutes their concentration in the circulation.
  4. Has been superseded by the early administration of corticosteroids.

Answer: A

Blood Pressure

The resuscitation goal is a mean arterial pressure >65 mm Hg. In about one-third of septic patients with hypotension, the blood pressure will rise sufficiently after intravenous fluids have been given. If adequate fluid administration does not improve the low tissue perfusion, then it is likely that the patient is in shock and vasopressors are needed. Norepinephrine is the recommended first-line vasopressor. Epinephrine can be used when an additional agent is needed to maintain blood pressure. Dopamine should only be used in highly selected patients with a low risk of tachyarrhythmias (Buckman, 2013). Vasopressors are typically given through a central venous catheter (Shapiro et al., 2010).

Did You Know. . .

Mean arterial pressure reflects a patient’s overall tissue perfusion pressure, and it is frequently monitored when treating sepsis. The normal range of MAP is 70–110 mm Hg. Ischemia is likely if MAP is <60 mm Hg.

For patients in shock, blood pressure cuffs do not always give accurate blood pressure measurements. When vasopressors are being given, it is best to measure blood pressures with an indwelling arterial cannula (Dellinger et al., 2013b; Morrell et al., 2009).

Once a staple of critical care monitoring, pulmonary artery catheters (Swan-Ganz catheters) are being used less often and more cautiously (Weinhouse, 2013). Some clinicians recommend against the routine use of pulmonary artery catheters for sepsis, severe sepsis, or septic shock (Schmidt & Mandel, 2013).

Test Your Knowledge

Swan Ganz catheters are no longer a staple of critical care monitoring.

  1. True
  2. False

Apply Your Knowledge

Q: Why are pulmonary artery catheters (Swan Ganz catheters) being used less often?

A: Once popular and widely used in the 1970s to 1990s, studies show many complications (eg, pulmonary bleeding), questionable benefits, and unreliable measurements from using pulmonary artery catheters. What have you seen in your ICU? The transesophageal echography can show more reliable results of heart function.

Answer: A

Cardiac Output

If the oxygenation saturation remains low and if it appears that cardiac output is reduced, consider using dobutamine (an ionotrope) to increase the cardiac output. If it is not clear whether the cardiac output is below normal, a vasopressor (norepinephrine or dopamine) is typically combined with the dobutamine (Dellinger et al., 2013b; Schmidt & Mandel, 2013).It is recommended that cardiac output not be pushed above normal levels.

Septic Shock

Septic shock can be recognized by its refractory hypotension, which means that despite aggressive fluid resuscitation the patient’s blood pressure remains hypotensive. The resuscitation of patients in septic shock should continue until all target values are met (eg, lactate and pH and oxygenation), not just the blood pressure target. For shock, resuscitation should start immediately and not be delayed by the collection of culture samples. Likewise, delays in admitting a patient to the ICU should not slow the initiation of the patient’s resuscitation (Dellinger et al., 2013b; Gaieski, 2013).

Search for the Infection

Targets during the initial search for an infection include:

  • Two or more blood culture samples:
    • One percutaneous
    • One from each vascular access device that has been in place >48 hr
  • Culture samples from other potentially infected sites (Dellinger et al., 2013b)

Identify the Microbes

Beginning antibiotic therapy is a high priority: delays increase the risk of mortality. Antibiotics or other anti-infectives should be given within 1 hour of recognition of sepsis (Buckman, 2013; Morrell et al., 2009).

Briefly Search for the Source

A quick, wide-ranging physical examination is the best way to begin the search for an infection. The source is sought and diagnosed or excluded as rapidly as possible. Intervention for source control should be done within 12 hours when the patient is able to tolerate it (Buckman, 2013).

Surgical sites are tested for warmth, redness, swelling, induration, or tenderness. Lungs should be auscultated, the abdomen palpated, the mouth, throat, nose, and ears looked at, and the head and extremities examined and palpated.

Any potential sites of infection should be cultured. If necessary, urine, cerebrospinal fluid, or respiratory secretions should also be cultured. All samples should be immediately transported to a microbiology laboratory (Dellinger et al., 2013b).

Give Antibiotics Empirically

Recommendations for the initial administration of antibiotics are:

  • Begin intravenous antibiotics quickly; if there is severe sepsis or septic shock, begin antibiotics within 1 hour.
  • Characteristics of an acceptable empiric antibiotic:
    • Broad-spectrum, covering all likely bacteria
    • Good tissue penetration into the probable site of the infection
  • Use a combination of antibiotics for:
    • Pseudomonas
    • Neutropenic patients
  • Antifungals or antivirals should be used if fungal or viral source is suspected
  • Reassess the antibiotic regimen daily (Dellinger et al., 2013b)

Test Your Knowledge

Antibiotics are a key tool in treating sepsis. They should be given:

  1. As soon as sepsis is suspected and before any other treatment begins.
  2. As soon as a patent airway and appropriate ventilation are ensured.
  3. Along with intravenous fluids during the initial resuscitation.
  4. As soon as basic patient data are collected and preferably right after blood cultures have been drawn.

Answer: D

Initial Drugs

It is recommended that initial empiric anti-infective therapy include one or more drugs that have activity against all likely pathogens—bacterial and/or fungal or viral (Dellinger et al., 2013b).

As soon as all culture samples have been taken, patients should be started on an intravenous antibiotic regimen. Anti-infective administration should not be delayed more than 45 minutes to collect the cultures and should be started within 1 hour of recognition of sepsis. Rapid administration of appropriate anti-infective agents has been shown to reduce mortality by 10% to 15% in patients with severe sepsis, whereas a delay of only 1 hour is enough to raise mortality rates (Shapiro et al., 2010).

The choice of anti-infectives should take into account the:

  • Immune competency of the patient
  • Renal functioning of the patient
  • Likely tissue of the primary infection
  • Common pathogens of the hospital and the community

Unless the causative microbe is known, the empiric antibiotics or other anti-infectives should be effective against Gram-positive bacteria, Gram-negative bacteria, and likely fungi and viruses. Methicillin-resistant Staphylococcus aureus (MRSA) is a growing cause of sepsis in the community as well as among hospitalized patients. For sepsis of unknown origin, vancomycin is recommended until MRSA is excluded as the cause of the sepsis (Schmidt & Mandel, 2013).

If pseudomonas is unlikely, then vancomycin should be combined with a third-generation cephalosporin, carbapenem, or extended-spectrum carboxypenicillin.

Test Your Knowledge

Empiric antibiotics are:

  1. Also known as fourth-generation antibiotics.
  2. Given before the exact microbes causing sepsis are identified to at least begin fighting the infection.
  3. Coated antibiotic tablets to prevent irritation of the stomach.
  4. Administered to SIRS patients as a prophylaxis.

Answer: B

Subsequent Drugs

Usually antibiotics are given for 7 to 10 days, although the detailed plan for any individual patient varies (Schmidt & Mandel, 2013). The effectiveness of the patient’s antibiotic regimen should be reassessed daily. If microbiology lab results identify the infecting microbe, the antibiotic regimen is tailored for that organism and its particular drug.

In many cases of sepsis, microbiologic analyses can identify no infectious cause. For example, half of the cases of severe sepsis or septic shock will have negative blood cultures. In such cases, other evidence and clinical experience must be used to separate the patients with sepsis from the patients with noninfectious SIRS. If it is decided that the cause of a patient’s septic-like syndrome is noninfectious, antibiotics should be stopped (Dellinger et al., 2013b).

Test Your Knowledge

Once a septic patient has been started on a particular empiric antibiotic regimen:

  1. It is critical to give the full 7 to 10 days of treatment before making any change.
  2. New antibiotics should be added if the patient’s initial fever persists.
  3. New antibiotics should be added if the patient’s white blood cell count continues to rise.
  4. The need for and the choice of antibiotic should be reassessed daily.

Answer: D

Control the Septic Source

Identifying the source of sepsis, called source control, is the rapid diagnosis of the specific body site of infection amenable to control measures such as abscess drainage, debridement of infected necrotic tissue, and removal of a potentially infected device. Possible infectious causes include: intra-abdominal abscess, intestinal infarction and/or gastrointestinal perforation, cholangitis, pyelonephritis, empyema, and septic arthritis (Boodoosingh et al., 2012).

When source control is required, minimally invasive interventions are employed—for example, performing percutaneous rather than surgical drainage of an abscess. If less invasive approaches are inadequate or there is uncertainty about the diagnosis, then more aggressive measures should be considered (Boodoosingh et al., 2012; Dellinger et al., 2013b).

When an intravascular access device has been identified as the possible cause of severe sepsis, removal of the device is done only after other vascular access has been established. Even with appropriate antibiotics, many infections can only be fully controlled when the source is removed, drained, or cleaned. Sometimes, the infection is clinically obvious or it can be clearly inferred from the medical history. The 2012 Guidelines recommend that source control be accomplished within 12 hours of diagnosis (Dellinger et al., 2013b).

At other times, however, it is necessary to conduct a quick but thorough search. Here are some search suggestions:

  • Catheters. All indwelling cannulas, lines, and catheters are potential sources of the infection. Wherever possible, remove indwelling tubes, roll each tip in a culture plate and, after antibiotic therapy is initiated, insert a replacement catheter in a new site. Replace Foley and other drainage catheters (Glickman et al., 2010).
  • Wounds. Inspect surgical and traumatic wound sites by removing their dressings. Look for signs of infection, such as swelling, purulent discharge, erythema, increased warmth, tenderness, or crepitus. An x-ray of suspicious areas can show gas from necrotizing tissues.
  • Lungs. The respiratory system is the most common site of the infection causing an episode of sepsis. Ask a septic patient about chest pain, dyspnea, and productive cough. Be alert to tachypnea. Carefully auscultate the chests of ill patients who have a high respiratory rate because tachypnea can be the first sign of a developing pneumonia (Shapiro et al., 2010).
  • Heart. Fever with a heart murmur, a history of intravenous drug use, prosthetic heart valves, or mitral valve prolapse suggests the possibility of endocarditis. Look for skin signs of endocarditis, which will support the diagnosis. In patients with endocarditis, a transesophageal echocardiogram will sometimes show valve problems (Shapiro et al., 2010).
  • Abdomen. Assess the patient for abdominal pain, nausea, vomiting, and diarrhea. Then, look for signs of cholecystitis, appendicitis, or diverticulitis. In your search, remember that noninfectious acute pancreatitis can trigger SIRS (Jui, 2010). An abdominal x-ray is useful because it can show a paralytic ileus, signs of stomach or bowel perforation, or an abscess. An abdominal ultrasound can reveal a number of gallbladder and liver problems, as well as fluid pockets and abscesses. An uncertain diagnosis can often be confirmed by a CT scan.
  • Genitourinary tract. Ask a septic patient about flank or pelvic pain, dysuria, and genital or urinary discharge. Consider acute pyelonephritis. Find out whether there is a recent history of genitourinary procedures and, in women, whether there has been a recent pregnancy, birth, or abortion (Jui, 2010). Check for anogenital lesions and rectal tenderness. Asses women for adnexal tenderness and for evidence of cervical or uterine infection. Ultrasound or CT can be used to search for pelvic abscesses.
  • Head. Look for evidence of sinusitis: orbital pain, tender sinuses, or edema. Ask whether the patient has had any recent nasotracheal or nasogastric intubations. Check for ear, pharyngeal, or tonsil infections. An uncertain diagnosis can often be confirmed using a CT scan.
  • Central nervous system. Meningitis can trigger sepsis. Ask a septic patient about headache, vomiting, stiff neck, and photophobia, and look for nuchal rigidity, fever, altered mental state, papilledema, or petechial skin rashes.
  • Skin. Look for ulcers or cellulitis. Also, look for lesions, petechiae, or rashes that may be clues to the underlying infection.
  • Blood. When the physical examination cannot find a source for severe sepsis or septic shock, consider the possibility of a primary bacteremia or endocarditis (Jui, 2010).

Test Your Knowledge

In sepsis, “source control” means:

  1. Reduction of nosocomial infections.
  2. Preventing access to Schedule II-controlled substances used for patients with sepsis.
  3. Identification and removal of the source of the infection.
  4. Isolation of patients with sepsis.

Answer: C

Sepsis-Specific Medications

Unfortunately, there are few medications available to patients already exhibiting sepsis. Corticosteroids are anti-inflammatories that may be useful in the septic patient.

Limited Options

Even after aggressive treatment, the septic patient continues to have an elevated chance of mortality. Scientists have worked with minimal success to find drugs that will reduce the sepsis-specific risks of dying. At this time, a single cure for sepsis does not seem likely. “A deeper understanding of the processes leading to sepsis is necessary before we can design an effective suite of interventions” (Lancet Infectious Diseases, 2012).

According to Lee & Slutsky (2010):

Despite intensive research over decades, few new therapies have been developed, and the mainstay of treatment remains nonspecific supportive care. Indeed, sepsis has been described as the “graveyard” of pharmaceutical discovery because most drugs that appeared promising based on in vitro and animal models have proved to be ineffective in humans.

Corticosteroids and Sepsis

The concept that sepsis is an out-of-control inflammatory response has long suggested that anti-inflammatory drugs may help septic patients to recover. However, clinical trials of corticosteroids have given inconclusive results, and the use of corticosteroids for sepsis is controversial (Shapiro et al., 2010).

The Guidelines suggest using intravenous hydrocortisone as a treatment for adult septic shock only if adequate fluid resuscitation and vasopressor therapy are unable to restore hemodynamic stability. If this is not achievable, the Guidelines suggest intravenous hydrocortisone alone at a dose of 200 mg/dl (Buckman, 2013).

Test Your Knowledge

Because sepsis is an out-of-control inflammatory reaction, corticosteroids:

  1. Have proved an ideal addition to the treatment of mild forms of sepsis.
  2. Would seem to be helpful, but have not proven so in most patients with sepsis.
  3. Are currently used as drugs to prevent sepsis, especially in immune-compromised patients.
  4. Are typically given as an adjunct or booster with empiric antibiotics.

Answer: B