Treatment: Severe Sepsis and

Septic Shock
Patients in whom sepsis is suspected must be managed
expeditiously.

This task is best accomplished by personnel who are

experienced in the care of the critically ill.

Successful Management requires urgent measures

1. To treat the infection,
2. To provide hemodynamic and respiratory support, and
3. To eliminate the offending microorganisms.
These measures should be initiated within 1 h of the patient's
presentation with severe sepsis or septic shock.

Rapid assessment and diagnosis are therefore essential.

1. Antimicrobial Agents
 Antimicrobial chemotherapy should be started as soon as samples
of blood and other relevant sites have been obtained for culture.

 A large retrospective review of patients who developed septic

shock found that the interval between the onset of hypotension and
the administration of appropriate antimicrobial chemotherapy was
the major determinant of outcome;
 A delay of as little as 1 h was associated with lower survival
rates.
Use of inappropriate antibiotics, defined on the basis of local
microbial susceptibilities and published guidelines for empirical
therapy, was associated with fivefold lower survival rates, even
among patients with negative cultures.
It is therefore very important to promptly initiate Empirical
Antimicrobial Therapy that is effective against both gram-positive
and gram-negative bacteria (Table 271-3).

Maximal recommended doses of antimicrobial drugs should be

given intravenously, with adjustment for impaired renal
function when necessary.

Available information about patterns of antimicrobial

susceptibility among bacterial isolates from the community, the
hospital, and the patient should be taken into account.
When culture results become available, the regimen can often be
simplified, as a single antimicrobial agent is usually adequate for
the treatment of a known pathogen.

Meta-analyses have concluded that, with one exception,

combination antimicrobial therapy is not superior to monotherapy
for treating Gram-negative Bacteremia;
The exception is that aminoglycoside monotherapy for P.
aeruginosa bacteremia is less effective than the combination of
an aminoglycoside with an antipseudomonal B-lactam agent.
Empirical antifungal therapy should be strongly considered if
The septic patient is already receiving broad-spectrum
antibiotics or parenteral nutrition,
1. Has been neutropenic for >5 days,
2. Has had a long-term central venous catheter, or
3. Has been hospitalized in an ICU for a prolonged period.

The chosen antimicrobial regimen should be reconsidered daily in

order to provide maximal efficacy with minimal resistance,
toxicity, and cost.
Most patients require antimicrobial therapy for at least 1 week.

The duration of treatment is typically influenced by factors such as

1. The site of tissue infection,
2. The adequacy of surgical drainage,
3. The patient's underlying disease, and
4. The antimicrobial susceptibility of the microbial isolate(s).
The absence of an identified microbial pathogen is not necessarily
an indication for discontinuing antimicrobial therapy,
Since "appropriate" antimicrobial regimens seem to be
beneficial in both culture-negative and culture-positive cases.
2. Removal of the Source of Infection
 Removal or drainage of a focal source of infection is essential.

 In one series, a focus of ongoing infection was found in 80% of

surgical intensive care patients who died of severe sepsis or septic
shock.

 Sites of occult infection should be sought carefully, particularly

in the Lungs, Abdomen, and Urinary Tract.
Indwelling IV or arterial catheters should be removed and the tip
rolled over a blood agar plate for quantitative culture;
After antibiotic therapy has been initiated, a new catheter
should be inserted at a different site.

Foley and drainage catheters should be replaced.

The possibility of Paranasal Sinusitis (often caused by gram-

negative bacteria) should be considered if the patient has
undergone nasal intubation.
Even in patients without abnormalities on chest radiographs, CT of
the chest may identify unsuspected parenchymal, mediastinal, or
pleural disease.

In the neutropenic patient, cutaneous sites of tenderness and

erythema, particularly in the perianal region, must be carefully
sought.

In patients with sacral or ischial decubitus ulcers, it is important to

exclude pelvic or other soft tissue pus collections with CT or MRI.
In patients with severe sepsis arising from the urinary tract,
sonography or CT should be used to rule out Ureteral Obstruction,
Perinephric Abscess, and Renal Abscess.

Sonographic or CT imaging of the upper abdomen may disclose

evidence of Cholecystitis, Bile Duct Dilatation, and pus
collections in the liver, subphrenic space, or spleen.
3. Hemodynamic, Respiratory, and Metabolic
Support
 The primary goals are to restore adequate oxygen and substrate
delivery to the tissues as quickly as possible and to improve tissue
oxygen utilization and cellular metabolism.

 Adequate organ perfusion is thus essential.

Circulatory adequacy is assessed by
1. Measurement of Arterial Blood Pressure and
2. Monitoring of parameters such as Mentation, Urine Output,
and Skin Perfusion.

Indirect indices of oxygen delivery and consumption, such as

Central Venous Oxygen Saturation, may also be useful.
Initial management of hypotension should include the
administration of IV fluids, typically beginning with 1–2 L of
normal saline over 1–2 h.

To avoid Pulmonary Edema, the Central Venous Pressure

should be maintained at 8–12 cmH2O.

The urine output rate should be kept at >0.5 mL/kg per hour by
continuing fluid administration;
A diuretic such as Furosemide may be used if needed.
In about one-third of patients, hypotension and organ
hypoperfusion respond to fluid resuscitation;
A reasonable goal is to maintain a Mean Arterial Blood
Pressure of >65 mmHg (systolic pressure >90 mmHg).

If these guidelines cannot be met by volume infusion,

Vasopressor Therapy is indicated.

Titrated doses of Norepinephrine or Dopamine should be

administered through a central catheter.
If myocardial dysfunction produces elevated cardiac filling
pressures and low cardiac output, Inotropic Therapy with
Dobutamine is recommended.

In patients with septic shock, plasma vasopressin levels

increase transiently but then decrease dramatically.

Early studies found that vasopressin infusion can reverse septic

shock in some patients, reducing or eliminating the need for
catecholamine pressors.
More recently, a randomized clinical trial that compared
vasopressin plus norepinephrine with norepinephrine alone in 776
patients with pressor-dependent septic shock found no difference
between treatment groups in the primary study outcome, 28-day
mortality.

Although vasopressin may have benefited patients who

required less norepinephrine, its role in the treatment of septic
shock seems to be a minor one overall.
CIRCI should be strongly considered in patients who develop
hypotension that does not respond to fluid replacement therapy.

Hydrocortisone (50 mg IV every 6 h) should be given;

If clinical improvement occurs over 24–48 h, most experts
would continue hydrocortisone therapy for 5–7 days before
slowly tapering and discontinuing it.

Meta-analyses of recent clinical trials have concluded that

hydrocortisone therapy hastens recovery from septic shock
without increasing long-term survival.
Ventilator therapy is indicated for progressive hypoxemia,
hypercapnia, neurologic deterioration, or respiratory muscle
failure.

Sustained Tachypnea (respiratory rate, >30 breaths/min) is

frequently a harbinger of impending respiratory collapse;
Mechanical Ventilation is often initiated
1. To ensure adequate oxygenation,
2. To divert blood from the muscles of respiration,
3. To prevent aspiration of oropharyngeal contents, and
4. To reduce the cardiac afterload.
The results of recent studies favor the use of low tidal volumes (6
mL/kg of ideal body weight, or as low as 4 mL/kg if the plateau
pressure exceeds 30 cmH2O).

Patients undergoing mechanical ventilation require careful

sedation, with daily interruptions; elevation of the head of the
bed helps to prevent nosocomial pneumonia.

Stress-Ulcer Prophylaxis with a histamine H2-receptor

antagonist may decrease the risk of gastrointestinal hemorrhage
in ventilated patients.
Erythrocyte transfusion is generally recommended when the
blood hemoglobin level decreases to 7 g/dL, with a target level of
9 g/dL in adults.

Erythropoietin is not used to treat sepsis-related anemia.

Bicarbonate is sometimes administered for severe metabolic

acidosis (arterial pH <7.2),
But there is little evidence that it improves either hemodynamics
or the response to vasopressor hormones.
DIC, if complicated by major bleeding, should be treated with
transfusion of Fresh-frozen Plasma and Platelets.

Successful treatment of the underlying infection is essential to

reverse both acidosis and DIC.

Patients who are hypercatabolic and have acute renal failure

may benefit greatly from Intermittent Hemodialysis or Continuous
Veno-venous Hemofiltration.
4. General Support
 In patients with prolonged severe sepsis (i.e., > 2 or 3 days),
nutritional supplementation may reduce the impact of protein
hypercatabolism; the available evidence, which is not strong,
favors the enteral delivery route.
Prophylactic heparinization to prevent deep venous thrombosis
is indicated for patients who do not have active bleeding or
coagulopathy;
When heparin is contraindicated, compression stockings or an
intermittent compression device should be used.

Recovery is also assisted by prevention of skin breakdown,

nosocomial infections, and stress ulcers.
The role of tight control of the blood glucose concentration in
recovery from critical illness has been addressed in numerous
controlled trials.

Meta-analyses of these trials have concluded that use of insulin

to lower blood glucose levels to 100–120 mg/dL is potentially
harmful and does not improve survival rates.
Most experts now recommend using insulin only if it is needed to
maintain the blood glucose concentration below 150 mg/dL.

Patients receiving intravenous insulin must be monitored

frequently (every 1–2 h) for hypoglycemia.
5. Other Measures
 Despite aggressive management, many patients with severe
sepsis or septic shock die.

 Numerous interventions have been tested for their ability to

improve survival rates among patients with severe sepsis.
The list includes
1. Endotoxin-neutralizing Proteins,
2. Inhibitors of cyclooxygenase or nitric oxide synthase,
3. Anticoagulants,
4. Polyclonal Immunoglobulins,
5. Glucocorticoids,
6. A Phospholipid Emulsion, and
7. Antagonists to TNF-a, IL-1, Platelet-activating Factor, and
Bradykinin.
Unfortunately, none of these agents has improved rates of
survival among patients with severe sepsis/septic shock in more
than one large-scale, randomized, placebo-controlled clinical
trial.

Many factors have contributed to this lack of reproducibility,

including
1. Heterogeneity in the patient populations studied, the primary
infection sites, the preexisting illnesses, and the inciting
microbes; and
2. The nature of the "standard" therapy also used.

A dramatic example of this problem was seen in a trial of Tissue

Factor Pathway Inhibitor (Fig. 271-1).
Whereas the drug appeared to improve survival rates after 722
patients had been studied (p = .006), it did not do so in the next
1032 patients, and the overall result was negative.

This inconsistency argues that the results of a clinical trial may

not apply to individual patients, even within a carefully selected
patient population.

It also suggests that, at a minimum, a sepsis intervention should

show a significant survival benefit in more than one placebo-
controlled, randomized clinical trial before it is accepted as
routine clinical practice.
In one prominent attempt to reduce patient heterogeneity in
clinical trials, experts have called for changes that would restrict
these trials to patients who have similar underlying diseases (e.g.,
major trauma) and inciting infections (e.g., pneumonia).

The goal of the Predisposition–infection–response–organ

Dysfunction (PIRO) grading system for classification of septic
patients (Table 271-1) is similar.
Other investigators have used specific biomarkers, such as IL-6
levels in blood or the expression of HLA-DR on peripheral-blood
monocytes, to identify the patients most likely to benefit from
certain interventions.

Multivariate risk stratification based on easily measurable

clinical variables should be used with each of these approaches.
Mortality rates among patients who
received tissue factor pathway
inhibitor (TFPI) or placebo, shown
as the running average over the course
of the clinical trial. The drug seemed
highly efficacious at the interim
analysis in December 2000, but this
trend reversed later in the trial.
Demonstrating that therapeutic agents
for sepsis have consistent,
reproducible efficacy has been
extremely difficult, even within well-
defined patient populations.
Recombinant Activated Protein C (aPC) was the first drug to be
approved by the U.S. Food and Drug Administration for the
treatment of patients with severe sepsis or septic shock.

Approval was based on the results of a single randomized

controlled trial in which the drug was given within 24 h of the
patient's first sepsis-related organ dysfunction;
The 28-day survival rate was significantly higher among aPC
recipients who were very sick (APACHE II score, >25) before
infusion of the protein than among placebo-treated controls.
Subsequent trials failed to show a benefit of aPC treatment in
patients who were less sick (APACHE II score, <25) or in
children.

A 2nd trial of aPC in high-risk patients is now under way in

Europe.

Given the drug's known toxicity (increased risk of severe bleeding)

and uncertain performance in clinical practice, many experts are
awaiting the results of the European trial before recommending
further use of aPC.
Other agents in ongoing or planned clinical trials include
Intravenous immunoglobulin,
A small-molecule endotoxin antagonist (eritoran), and
Granulocyte-macrophage colony-stimulating factor that was
recently reported to restore monocyte immunocompetence in
patients with sepsis-associated immunosuppression.
A careful retrospective analysis found that the apparent efficacy of
all sepsis therapeutics studied to date has been greatest among the
patients at greatest risk of dying before treatment;
Conversely, use of many of these drugs has been associated
with increased mortality rates among patients who are less ill.

The authors proposed that neutralizing one of many different

mediators may help patients who are very sick, whereas
disrupting the mediator balance may be harmful to patients whose
adaptive defense mechanisms are working well.
This analysis suggests that if more aggressive early resuscitation
improves survival rates among sicker patients, it will become more
difficult to obtain additional benefit from other therapies;
That is, if an intervention improves patients' risk status, moving
them into a "less severe illness" category, it will be harder to
show that adding another agent to the therapeutic regimen is
beneficial.
The Surviving Sepsis Campaign
 An international consortium has advocated "bundling" multiple
therapeutic maneuvers into a unified algorithmic approach that
will become the standard of care for severe sepsis.
In theory, such a strategy could improve care by mandating
measures that seem to bring maximal benefit, such as the rapid
administration of appropriate antimicrobial therapy;
On the other hand, this approach would deemphasize
physicians' experience and judgment and minimize the
consideration of potentially important differences between
patients.
Bundling multiple therapies into a single package also obscures
the efficacy and toxicity of the individual measures.

Caution should be engendered by the fact that two of the key

elements of the initial algorithm have now been withdrawn for
lack of evidence, while a third remains unproven and
controversial.
Prognosis
Approximately 20–35% of patients with severe sepsis and 40–
60% of patients with septic shock die within 30 days.

Others die within the ensuing 6 months.

Late deaths often result from

1. Poorly Controlled Infection,
2. Immunosuppression,
3. Complications of intensive care,
4. Failure of multiple organs, or
5. The patient's underlying disease.
Case-fatality rates are similar for culture-positive and culture-
negative severe sepsis.

Prognostic stratification systems such as APACHE II indicate

that factoring in the patient's age, underlying condition, and
various physiologic variables can yield estimates of the risk of
dying of severe sepsis.

Age and Prior Health Status are probably the most important risk
factors (Fig. 271-2).
In patients with no known preexisting morbidity, the case-fatality
rate remains below 10% until the fourth decade of life, after which
it gradually increases to exceed 35% in the very elderly.

Death is significantly more likely in severely septic patients

with preexisting illness, especially during the third to fifth
decades.

Septic shock is also a strong predictor of short- and long-term

mortality.
Influence of Age and Prior Health Status on outcome from severe sepsis.

With modern therapy, fewer than 10% of previously healthy young individuals (below 35
years of age) die with severe sepsis; the case-fatality rate then increases slowly through
middle and old age. The most commonly identified etiologic agents in patients who die are
Staphylococcus aureus, Streptococcus pyogenes, S. pneumoniae, and Neisseria meningitidis.
Individuals with preexisting comorbidities are at greater risk of dying of severe sepsis at any
age. The etiologic agents in these cases are likely to be S. aureus, Pseudomonas aeruginosa,
various Enterobacteriaceae, enterococci, or fungi.
Prevention
Prevention offers the best opportunity to reduce morbidity and
mortality from severe sepsis.

In developed countries, most episodes of severe sepsis and

septic shock are complications of nosocomial infections.

These cases might be prevented by reducing the number of

invasive procedures undertaken,
1. By limiting the use (and duration of use) of indwelling vascular and
bladder catheters,
2. By reducing the incidence and duration of profound neutropenia (<500
neutrophils/L), and
3. By more aggressively treating localized nosocomial infections.
Indiscriminate use of antimicrobial agents and glucocorticoids
should be avoided, and optimal infection-control measures should
be used.

Studies indicate that 50–70% of patients who develop

nosocomial severe sepsis or septic shock have experienced a
less severe stage of the septic response (e.g., SIRS, sepsis) on at
least one previous day in the hospital.

Research is needed to identify patients at increased risk and to

develop adjunctive agents that can modulate the septic response
before organ dysfunction or hypotension occurs.