Adam J. Schwarz, M.D.
Assistant Professor of Pediatrics
Medical Director, PICU
University of Kansas Medical Center
Sepsis is a syndrome of systemic toxicity that results from the presence of infectious agents or
their products in the blood. A patient may be bacteremic and not be septic. A bacteremic patient
has circulating bacteria in the blood, and blood cultures may be positive, but if they do not have
signs of systemic inflammation, than we do not technically say they are septic. It is estimated that
everyone sustains some degree of bacteremia fairly frequently, such as after brushing our teeth.
Thus we all are frequently “bacteremic” for a short period of time, but our body deals with the
bacteria swiftly without an inflammatory cascade inducing a state of systemic toxicity.
Sepsis, on the other hand, results from the body’s inflammatory response to components of
infectious agents such as bacteria, viruses, or fungi, as well as to various toxins that these
organisms may release. The Septic Inflammatory Response State, or SIRS, is the term used to
describe the body’s response to the presence of infectious inducers of inflammation (Table 1).
The body responds to the presence of these infectious agents or their products by releasing
mediators of inflammation called cytokines. If the body’s inflammatory response is extremely
profound, then the patient may present with the signs and symptoms we know of as
overwhelming sepsis. Thus it is the body’s own response to these agents that results in the
morbidity and mortality of sepsis.
Table 1: Findings of the Systemic Inflammatory Response Syndrome
Table 1: Findings of the systemic Inflammatory Response Syndrome
Fever or hypothermia (with evidence of infection)
Hyperdynamic cardiac output in association with hypoperfusion
Other organ system dysfunction
Table 2: Sepsis definitions
As far as specific causative agents go, these will vary with age and circumstance, and a detailed
discussion of each organism is beyond the scope of this review. In short, however, any infectious
agent that provokes a vigorous inflammatory response may induce sepsis. These may be gram
(-) bacteria, such as the meningococcus or E. coli, or gram (+) organisms such as
pneumococcus, Staph., group B strep (especially neonates), group A strep., etc… These agents
1. SIRS. 2 or more of the following: a) temperature >38.3°C or<36°C; b) tachycadia;
c) tachypnea, d) WBC count >12,000/mm3
or < 4000/mm3
or >10% immature
2. Sepsis is defined as SIRS associated with suspected or confirmed infection.
Positive blood cultures are not necessary.
3. Septic shock is cardiovascular collapse related to severe sepsis despite adequate
4. Organ dysfunction criteria are a) hypoxemia (PaO2/FiO2 ratio<300); b) acute
oliguria c) coagulopathy (plt count<100,000, INR>1.5 or PTT>60s d) ileus e)
release cellular components or toxins that stimulate the inflammatory host response. Gram (-)
organisms, for example, have a cell wall that is composed of lipopolysaccharides (LPS),
collectively called endotoxins, which are highly inflammatory. However, gram (+) organisms,
which do not possess LPS (endotoxin) may also be extremely inflammatory and release other
inducers of inflammation (such as peptidoglycans, teichoic acids, toxins such as toxic-shock
stimulating toxin (TSST-1), etc…) that can result in sepsis. In addition, viruses and fungi can also
cause sepsis. As long as a vigorous inflammatory state results, we say that there is sepsis. If
this inflammation gets out of control, the patient will be very sick and may even die. Mortality
from different studies of sepsis across all ages varies from 10-80%, depending on the study,
organisms, and enrollment criteria.
II. Physiology of Sepsis
The SIRS can affect virtually any and all organ systems in the body.
The first major system we generally recognize as significantly affected by SIRS is the CV
system. Sepsis leads to a decrease in tissue oxygen delivery. This is a critical concept,
because sepsis MAY lead to INCREASED CARDIAC OUTPUT, or a clinical picture of
BRISK CAPILLARY REFILL, WARM EXTREMITIES, and BOUNDING PULSES, and still
be consistant with poor tissue oxygen delivery. The blood simply is not going where it
is supposed to go. Thus a patient in septic shock may present with the clinical picture of
cold extremities, weak pulses, and delayed capillary refill (“cold shock”), or they may have the
aforementioned brisk capillary refill and warm extremities with bounding pulses associated
with overvigorous vasodilation (“warm shock”).
The release of septic inflammatory mediators leads to the induction of the enzymes that
synthesize nitric oxide (inducible nitric oxide synthase). Nitric oxide is a potent vasodilator.
The result is inappropriate and often massive peripheral vasodilation. This reduces venous
return to the heart (preload), as well as causing inappropriate distribution of blood flow to
end-organs like the gut, the liver, the kidney, and the skin. Arterio-venous shunts that are
normally closed may open that permit blood to bypass the capillaries and tissue beds, so the
tissues never see oxygen-rich blood. In addition, the resulting vasodilation creates a much
larger potential space for blood to run off into, reduces peripheral vascular resistance, and
leads to a drop in diastolic blood pressure, a widened pulse pressure, or a fall on overall
The heart will try to compensate by increasing cardiac output, leading to what is referred to
as a hyperdynamic state. Heart rate is increased, afterload is reduced, and preload (left-
ventricular end-diastolic filling volume (LVEDV)) will also be reduced due to massive
peripheral vasodilation. Cytokines can also directly depress myocardial contractility. Some
authors refer to the presence of a “myocardial depressant factor” that is released in up to
50% of cases of septic shock, but we really aren’t sure what this MDF is. Speculation
regarding TNF abounds, but it may be some other cytokine or combination of cytokines.
Regardless of the cause, cardiac contractility can also be depressed during sepsis.
The end result of all of these effects on the cardiovascular system is poor end-organ tissue
oxygen delivery. The patient is tachycardic. He/she will have a widened pulse pressure (the
difference between the systolic and diastolic blood pressure) and may be overall hypotensive.
The signs of peripheral perfusion may be that of classic compensated shock, with cold
extremities, weak pulses, and prolonged capillary refill secondary to the great drop in preload
and relative intravascular volume as the patient is too vasodilated. However, the clinical
picture of perfusion MAY be that of warm extremities with bounding pulses and brisk capillary
refill if there is enough cardiac output to OVERPERFUSE the skin, while the rest of the body,
other end-organs, and overall blood pressure is inadequate. The patient has a significant
metabolic acidosis because of poor tissue oxygen delivery that makes the tissues metabolize
anaerobically with the release of lactic acid.
At the risk of foreshadowing the section on treatment of septic shock, hopefully it will be clear
to you now that a patient in septic shock will need a lot of FLUID, and possibly inotropic
support. Vigorous fluid resuscitation will fill the increased intravascular space created by NO-
induced vasodilatation and improve preload. Inotropes will assist cardiac contractility (β-
effect) and increase peripheral vascular resistance to increase central blood pressure (α-
Finally, poor cardiac perfusion and the need to stimulate contractility with inotropes, as well
as possibly catheters that enter or traverse the right atrium, may precipitate the occurrence of
A patient in septic shock will have a profound metabolic acidosis. In order to compensate
and maintain a normal pH, the patient will attempt to hyperventilate in order to reduce the
pCO2. This can take a lot of metabolic work to fuel the muscles of respiration, especially
when the patient is poorly perfused to begin with. Normally we devote < 1% of our cardiac
output and oxygen to breathe, but a patient in frank septic shock may consume up to 25-30%
of their oxygen simply to fuel the muscles of respiration working hard to compensate for the
profound metabolic lactic acidosis. It is therefore often very appropriate to intubate a patient
in septic shock, even if their SaO2 is adequate with supplemental oxygen and their pCO2 is
actually low due to their tachypnea, in order to REDUCE THE METABOLIC WORK OF
BREATHING. Let the ventilator do the work of breathing for the patient.
In addition, many patients in septic shock develop ARDS and pulmonary edema. The
necessary fluid resuscitation, coupled with the very real possibility that the alveolar-capillary
membrane will be disrupted due to the inflammatory septic response, lead to pulmonary
involvement and very often significant disease and respiratory failure. Thus, intubating early
secures the airway and initiates control of the respiratory system. For ventilator management
of respiratory failure and ARDS see those respective chapters and sections.
C. Infectious Disease
Obviously sepsis is, by definition, caused by the presence of some infectious agent. The
presence of these infectious agents, or toxins produced by these organisms, are recognized
by the body as a foreign invading substance and triggers a dynamic inflammatory response
via the release of inflammatory mediators called cytokines. We therefore want to eliminate
the source of the infection. Generally antibiotics are used to treat bacterial infections, which
are the most common infectious class of organism. However, fungal infections would be
treated by anti-fungal agents, and a few viral infections are treatable with certain specific anti-
viral agents. The important point to recognize, however, is that EVEN WITH TREATMENT
WITH ANTIBIOTICS, the inflammatory pathways triggered by bacterial components may still
be activated or augmented. In fact, it is possible that in some infections the act of suddenly
killing all of the organisms with antibiotics may lead to massive release of bacterial
byproducts and components that cause an increase in the septic inflammatory response
state, resulting in acute and possibly irreversible decompensation of the patient and death.
D. Disseminated Intravascular Coagulation (D.I.C.)
DIC is a syndrome in which there is massive coagulation that occurs diffusely throughout the
systemic circulatory system. As fibrin clots are deposited throughout the microvasculature,
platelets are attracted, trapped, and damaged leading to thrombocytopenia. Red blood cells
that pass through vessels laced with strands of fibrin or narrowed by coagulation are
damaged and hemolyzed, leading to a microangiopathic hemolytic anemia. Coagulation
factors are consumed, resulting in an increased PT and PTT. As the body’s compensatory
fibrinolytic system frantically tries to keep up with the diffuse coagulation, fibrin is split into
fragments (labeled X,Y,D, and E) collectively called fibrin degradation products (FDP’s),
which are themselves inhibitors of platelet aggregation. Thus DIC is a state of both rampant
coagulation as well as fibrinolysis and inhibition of appropriate platelet function. The result is
microvascular occlusion and tissue ischemia, as well as a bleeding diathesis resulting from
the consumption of coagulation factors. Bleeding into the skin causes purpura. Poor
perfusion to end-organs can result in skin mottling, cold or even black extremities, kidney
failure, liver failure, CNS damage, gut injury, etc…
DIC results from the effect of microorganisms on the endothelial lining of blood vessels and
components of the clotting cascade. For example, endotoxin can directly damage the vessel
endothelial wall, exposing the very thrombogenic subendothelium and initiating the clotting
cascade diffusely. Endotoxin can also directly activate factor XII, one of the initiators of
coagulation, and it can bind a specific platelet receptor that furthers both thrombosis and
platelet consumption. Other infectious agents can also trigger the coagulation cascade. SIRS
associated shock from general cardiovascular compromise furthers microvascular ischemia
and worsens DIC. Additionally, antigen-antibody complexes and the release of various
inflammatory cytokines all can damage vascular endothelium, interfere with coagulation
factors, decrease platelet function, and contribute to DIC.
Laboratory findings generally reveal a prolonged PT and PTT in 50-75% of patients, but can
be normal. Fibrinogen levels are usually depleted due to consumption, but the laboratory test
may count fibrinogen fragments in total fibrinogen levels and inaccurately report a normal
level. Thrombocytopenia is common, as is increased FDP and D-dimer. FDP, however, may
be increased in patients with liver dysfunction (since they are cleared by the liver) and not
necessarily indicate DIC. Some patients will have fragmented RBC’s on the peripheral smear
(~50%), but the absence of schistocytes does not exclude the diagnosis. In short, an entire
DIC profile needs to be interpreted in the patient known to be at risk for DIC. Evaluation of
the PT, PTT, fibrinogen level, FDP’s and D-dimer, CBC, and LFT’s in association with the
clinical condition of the patient should enable the diagnosis of DIC to be made.
Finally, other clinical conditions can trigger DIC. These include any shock state, surgery,
neonatal illness, obstetric accidents, head injury, and tumors.
Both shock and DIC affect the renal vasculature, reducing renal perfusion and causing tubule
injury that results in both pre-renal and intrinsic renal failure, also know as acute tubular
necrosis. This may lead to normovolemic, oliguric, or even anuric renal failure. Renal failure
is defined by the inability to eliminate metabolic waste products and is indicated by the rise in
BUN and creatine. So long as the patient maintains urine output, the potassium is generally
adequately managed. In frank anuric renal failure hyperkalemia may complicate the clinical
picture necessitating dialysis.
The shock associated with sepsis, as well as with maldistribution of blood flow from
microvascular occlusion with DIC or shunts leads to poor gut perfusion and ischemia. This
may result in GI bleeding, gastritis, translocation of bacteria from within the gut to the
bloodstream, and ileus.
Poor perfusion from shock can lead to CNS injury.
The bleeding diathesis that results from DIC can lead to hemorrhagic stroke or localized
In addition, the general septic state may result from or also be associated with meningitis that
may result in localized infarcts, thrombosis, or hemorrhage
Severe cases of septic shock, notoriously meningococcemia, may result in infarction of the
adrenal glands and a state of adrenal insufficiency. Controversy remains about the
appropriate level of stress hormones such as cortisol in cases of severe sepsis.
III. Treatment of Sepsis
A. Infectious Disease
Eliminate the source of infection. If there is a wound it may need to be drained. If there is
another route of infection, such as a central line, that line should be removed and replaced.
Antibiotics are the mainstay of therapy. If the organism is known along with its sensitivities,
then antibiotics can be tailored to that bacteria or fungus. If the source of the sepsis remains
unknown, than broad spectrum antibiotics are initiated. Antifungals may be needed if fungal
infection is suspected or documented. Certain viruses might be treatable with antiviral
Common broad spectrum antibiotics include third-generation cephalosporins such as
cefotaxime, ceftriaxone, and ceftazidime. Imipenem or meropenem are sometimes used.
Double-coverage for gram (-) organisms may be effected by adding gentamycin, and
occasionally broad-spectrum penicillins such as piperacillin or ticarcillin. Gram (+) organisms
such as S. aureus,
S. epidermidis, and PCN-resistant pneumococcus may be covered by vancomycin. Fungal
sepsis should be treated with amphotericin. Viral sepsis with a member of the herpes family
such as varicella or herpes can be treated with acyclovir.
As noted above, simply killing the organism may not eliminate the problem once the septic
inflammatory state has commenced The release of components of bacteria as they are killed
may further stimulate the inflammatory septic reaction. A natural question would therefore be
whether we could manipulate the body’s inflammatory response with anti-inflammatory
agents such as steroids or specific anti-cytokine therapies such as anti-TNF antibodies or IL-
1 receptor antagonists etc… The short answer to this important question is that, while animal
studies of multiple anti-cytokine and anti-inflammatory agents have looked very promising,
NO LARGE SCALE CONTROLLED TRIAL OF STEROIDS OR OTHER
IMMUNOMODULATORY THERAPY IN HUMAN CLINICAL TRIALS HAS HAD A POSITIVE
EFFECT ON RECOVERY AND SURVIVAL IN SEPSIS TO DATE. The same thing is true
with respect to modulators of hypotension such as anti-N.O. agents. Thus we are left with
simply attempting to eradicate the infection and its source, and support the disturbances in
physiology that results from S.I.R.S.
The ability to adequately restore and provide oxygen delivery to the end-organ tissues is the
critical goal in the treatment of sepsis. Recall that oxygen delivery is dependant upon cardiac
output and arterial oxygen content. The formula for this is:
DO2 = CO x CaO2
Cardiac output is the product of heart rate (HR) and stroke volume (SV).
CO = HR x SV
Stroke volume is dependant upon LVEDV (preload), contractility, and afterload.
Arterial oxygen content is dependant upon the amount of hemoglobin available for oxygen
transport as well as by how much of that hemoglobin actually is saturated with oxygen
(SaO2). Thus CaO2 is described by the formula:
CaO2 = (Hb x SaO2 x 1.34 ml O2/gm Hb) + (PaO2 x 0.0031)
Therefore, septic shock results, to a large extent, from disturbances in these variables that
affect oxygen delivery. Since sepsis induces the production of N.O. resulting in massive
vasodilation, both LVEDV (preload) and afterload are greatly reduced. Thus the patient in
septic shock will need a lot of FLUID RESUSCITATION. Multiple 20cc/kg boluses of fluid,
given as fast as possible, with reassessment of the patient at the end of the bolus and
repeating as often as necessary, are required. For regular fluid boluses alone the initial fluid
should be a crystalloid such as NS. It is tempting to give colloid boluses such as 5% albumin
on the assumption that the colloid stays in the intravascular space better than crystalloid.
However, there is often capillary leak that may result in the colloid leading out of the vessels
into the tissue space. This may result in increasing tissue oncotic pressure, drawing fluid out
of the intravascular space, and causing retention of such fluid in the extravascular space.
Thus there should be a defensible reason why a colloid is chosen over crystalloid as a fluid
bolus (significant hypoalbuminemia, for example).
How much fluid to give or keep giving is often very difficult to determine. Unless the patient
clearly improves and reverses the clinical state of shock immediately with fluid early on, it is
often necessary to have an objective indicator of intravascular volume in order to help gauge
the effectiveness of the fluid resuscitation. Patients in septic shock, should therefore have a
central venous line with more than one lumen placed in order to administer the multiple fluid
boluses and inotropes required, as well as to measure the pressure within the venous system
returning to the heart in the form a CVP. Similar data can be obtained via a pulmonary artery
catheter (Swan-Ganz catheter) via measurement of the wedge pressure (PCWP). Typically a
normal CVP measures 5-10 cm H2O. In the septic patient, fluid expansion to a “generous “
CVP, generally > 12 cm H2O and often 15-18cm H2O, would suggest adequate expansion of
intravascular volume. Similarly, if a PCWP is followed, fluid expansion to a wedge pressure
of 18 cm H2O generally suggests appropriate fluid expansion. If the patient remains in shock
once these parameters are met then further resuscitation is generally attempted by
increasing inotropic support.
The DO2 equation reveals how critical it is to avoid anemia and assure adequate oxygen
carrying capacity. PRBC’s should be administered in order to maintain the Hb above 10 (i.e.
hematocrit >30). There is no data, however, that suggests that increasing the hemoglobin
above 10-12 leads to any further increase in tissue oxygen utilization, and some concern that
overtransfusion might increase blood viscosity that ultimately reduces oxygen delivery at
hematocrits above 40.
Arrhythmias are treated by either correcting any underlying cause of cardiac irritability such
as catheter placement or reducing (if possible) IV inotrope dosages. Otherwise lidocaine can
be used. Starting doses are a loading dose of 1-2 mg/kg followed by an infusion at a rate of
10-50 µg/kg/min. Lidocaine, however, is a myocardial depressant so the lowest effective rate
should be used.
Since sepsis causes inappropriate peripheral vasodilation as well as depressing myocardial
contractility, inotropes are generally required. There are several inotropic agents that may be
useful in the treatment of septic shock. A detailed discussion of each of these may be found
in the chapter on inotropes. Inotropes can both increase myocardial contractility and have
variable effects on peripheral vascular resistance. Some inotropes are potent
vasoconstrictors (i.e. epinephrine, norepinephrine), whereas others are mild (dobutamine) or
potent (milrinone) vasodilators. Which inotropic combinations will be effective depends upon
the clinical volume and contractile state of the patient’s cardiac system. For instance,
increasing peripheral vasoconstriction in order to raise central blood pressure might result in
furthering microvascular ischemia. However, if the patient has refractory hypotension and
cannot even maintain the central blood pressure that perfuses the heart and the brain, the
patient will not ultimately survive neurologically intact anyway. Thus, sometimes the risk of
compromising end-organ perfusion must be assumed in order to restore perfusion to the
most critical organs first, the brain and the heart, and accept and treat the consequences of
renal, hepatic, skin ischemia, etc. later.
Dopamine is often used in patients with septic shock, either alone or in combination with
other inotropes. Dopamine is generally useful for its mixed effect on end-organ perfusion
such as renal and splanchnic vasculature at low doses (2-5 µg/kg/min). At intermediate
doses the β-1 effect assists myocardial contractility, and at higher doses the α-effect may
increase peripheral vasoconstriction and central blood pressure.
Epinephrine is often considered the mainstay of inotropic support in the pediatric patient with
septic shock. Epinephrine stimulates both α- and β- receptors so that there is both increased
myocardial contractility and increased peripheral vasoconstriction. The peripheral
vasoconstriction brings blood back into the central circulation but at the expense of peripheral
end-organ perfusion. At high enough doses extremities will become severely ischemic and
even turn dark and ultimately necrotic. Doses typically begin at 0.1 µg/kg/min and are titrated
up to effect and side-effects. In severe cases patients may be on doses of 2-3 µg/kg/min or
Dobutamine is almost a pure inotrope, with primarily β1 effects which effect cardiac
contractility, and a little bit of β2 mediated peripheral vasodilation which might improve tissue
perfusion. There is no α-effect. Typical doses begin at 5 µg/kg/min and are increased
generally to 20 µg/kg/min.
Norepinephrine (Levophed®) is predominantly an α-agonist that results in increased
peripheral vasoconstriction and thus increase peripheral vascular resistance. Its role is as a
pressor agent to increase blood pressure in the face of shock that persists after adequate
fluid replacement. Some practitioners will provide the α-effect with norepinephrine and
inotropic effect with dobutamine. Others will rely on epinephrine. Typical doses of
norepinephrine are similar to epinephrine and begin at 0.1 µg/kg/min and are titrated upward
to effect and side-effects.
Milrinone is a phosphodiesterase inhibitor that works via a different mechanism than the
catecholamines. It results in an increase in intracellular cAMP levels that results in increased
cardiac inotropy as well as potent peripheral vasodilation. It may be useful in the treatment of
shock in patients who have adequate intravascular volume but need increased cardiac
contractility and better peripheral perfusion.
See respective chapters on mechanical ventilation and ARDS (if present).
The therapy for DIC in sepsis is very controversial. On the one hand there is consumption of
the factors of coagulation, leading to a prolonged PT and PTT and consumption of platelets
and fibrinogen which predisposes the patient to bleeding. Clinically this can be treated with
FFP (clotting factors), platelets, and cryoprecipitate (fibrinogen). However, rampant
coagulation in the microvasculature is what causes end-organ tissue ischemia. Adding more
of the components of coagulation may be like adding “fuel to the fire”, worsening the
maldistribution of tissue perfusion, and adversely affecting outcome.
Thus it is generally agreed that, with ACTIVE BLEEDING, platelets, FFP, and
cryoprecipitate should be given. Without active bleeding we may be hesitant to give
these therapies despite a prolonged INR, PT, PTT, and low platelets and fibrinogen.
Some clinicians advocate giving heparin therapy, or low-molecular weight heparin to slow
down the coagulopathy. There are no studies to support demonstrate efficacy of heparin
Similarly, there are some investigators looking at the use of antithrombin III (ATIII), which can
be quite variable and low in sepsis. ATIII is an inhibitor of the coagulation cascade at many
levels. However, despite some early suggestion in limited trials that it may have some use in
treating DIC, there have been NO PLACEBO CONTROLLED TRIALS of ATIII replacement
therapy that demonstrate a statistically significant improvement on outcome in adults or
children in septic shock and DIC.
As mentioned above, there is some question whether patients in severe septic shock or
pupura fulminans have adequate levels of circulating glucocorticoids to support their
physiology when so severely stressed. Some clinicians might give a dose of 50-100
mg/m2/day of hydrocortisone and draw a serum cortisol level. If low than they might continue
with replacement doses. Recently, a study of adult patients with septic shock who had
survived 48 hours and were inotropic dependant showed some benefit when treated with
supraphysiologic doses of hydrocortisone compared with controls(CCM 1998, 26(4) 645-
650). Treatment patients received 100 mg hydrocortisone IV tid for five days compared with
placebo controls. At the end of 7 days, 68% of the steroid group had reversal of shock
compared with 21% of controls, a difference of 47% (p<0.007). In addition, mortality was
“only” 32% in the steroid group compared with 65% in the controls (NS). Thus there may yet
be a role for the selected use of glucocorticoids in the treatment of certain patients with septic
Gastritis or peptic ulceration should be prevented with the use of H-2 blockers such as
ranitidine or pepcid, or coating the gastic mucosa with sucralfate. Nutrition may need to be
supported with adequate TPN.
Renal support by reversing shock and restoring perfusion to the kidneys will hopefully prevent
frank anuric renal failure. Improving perfusion via the use of dopaminergic doses of low-dose
dopamine (0.5-4 µg/kg/min) may improve renal blood flow and maintain diuresis. It is
controversial whether the use of such therapy actually staves off or reverses renal failure.
However, dopamine may convert anuric or severely oliguric renal failure to oliguric or
normovolemic renal failure, allow maintainance of potassium homeostasis, and permit more