Systemic inflammatory response syndrome (SIRS) and sepsis in children:

Definitions, epidemiology, clinical manifestations, and diagnosis

Authors
Wendy J Pomerantz, MD, MS
Scott L Weiss, MD
Section Editors
Susan B Torrey, MD
Sheldon L Kaplan, MD
Adrienne G Randolph, MD, MSc
Deputy Editor
James F Wiley, II, MD, MPH
Disclosures: Wendy J Pomerantz, MD, MS Nothing to disclose. Scott L Weiss,
MD Nothing to disclose. Susan B Torrey, MD Nothing to disclose. Sheldon L
Kaplan, MD Grant/Research/Clinical Trial Support: Pfizer [vaccine (PCV13)];
Forest Lab [antibiotic (Ceftaroline)]; Optimer [antibiotic (fidaxomicin)].
Consultant/Advisory Boards: Pfizer [vaccine (PCV13)]. Adrienne G Randolph,
MD, MSc Consultant/Advisory Boards: Asahi Kasei Pharma [sepsis with
coagulopathy (ART-13)]; Ferring, Inc [septic shock (terlipressin)]. James F Wiley,
II, MD, MPH Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group.
When found, these are addressed by vetting through a multi-level review process,
and through requirements for references to be provided to support the content.
Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Jul 2015. | This topic last updated: Jul 28, 2015.
INTRODUCTION Sepsis is a clinical syndrome that complicates severe infection
and is characterized by the systemic inflammatory response syndrome (SIRS),
immune dysregulation, microcirculatory derangements, and end-organ dysfunction.
In this syndrome, tissues remote from the original insult display the cardinal signs of
inflammation, including vasodilation, increased microvascular permeability, and
leukocyte accumulation.
Although inflammation is an essential host response, the onset and progression of
sepsis center upon a "dysregulation" of the normal response, usually with an increase
in both proinflammatory and antiinflammatory mediators, initiating a chain of events
that leads to widespread tissue injury. Evidence supports a state of acquired immune
suppression or immunoparalysis in some patients, which may occur simultaneously
with or following the initial proinflammatory response [1,2]. It is this dysregulated

host response rather than the primary infectious microorganism that is typically
responsible for multiple organ failure and adverse outcomes in sepsis. (See
"Pathophysiology of sepsis".)
Early recognition of sepsis is crucial to ensuring the best outcomes in children and is
aided by a working knowledge of the children at particular risk, the common
pathogens, and the clinical manifestations. The definition, epidemiology, clinical
manifestations, and diagnosis of the systematic inflammatory response syndrome and
sepsis in children are discussed here.
The rapid recognition, resuscitation, and initial management of pediatric septic shock
and the evaluation and management of undifferentiated shock in children are
discussed separately:
(See "Septic shock: Rapid recognition and initial resuscitation in children".)
(See "Septic shock: Ongoing management after resuscitation in children".)
(See "Initial evaluation of shock in children".)
(See "Initial management of shock in children".)
DEFINITIONS Definitions for sepsis and organ dysfunction for children have
been developed by the International Consensus Conference on Pediatric Sepsis [3].
These definitions are important for the standardization of observational studies and in
the evaluation of therapeutic interventions in clinical trials. They may also be useful
in helping clinicians determine the severity of a child's illness and in monitoring
clinical progression and response to therapy. However, it should be noted that clinical
concern for sepsis should not be limited to pre-defined cut-points for physiologic or
laboratory abnormalities [4]. As an example, in an observational study of 1729
children younger than 18 years of age who were admitted to an intensive care unit
(ICU), only two-thirds of children treated for severe sepsis or septic shock also met
consensus criteria at the time of clinical diagnosis [5]. Thus, clinical suspicion for
sepsis often occurs even though all components of the consensus criteria are not
present.
Infection Infection is defined as a suspected or proven infection caused by any
pathogen. Infections can be proven by positive culture, tissue stain, or polymerase
chain reaction test. The definition also includes clinical syndromes associated with a
high probability of infection, such as petechiae and purpura in a child with
hemodynamic instability, or fever, cough, and hypoxemia in a patient with
leukocytosis and pulmonary infiltrates on chest radiograph.
Systemic inflammatory response syndrome The systemic inflammatory response
syndrome (SIRS) is a widespread inflammatory response that may or may not be

associated with infection. The presence of two or more of the following criteria (one
of which must be abnormal temperature or leukocyte count) defines SIRS [3]:
Core temperature (measured by rectal, bladder, oral, or central probe) of >38.5C or
<36C
Tachycardia, defined as a mean heart rate more than two standard deviations above
normal for age, or for children younger than one year of age, bradycardia defined as
a mean heart rate <10th percentile for age (table 1)
Mean respiratory rate more than two standard deviations above normal for age or
mechanical ventilation for an acute pulmonary process (table 1)
Leukocyte count elevated or depressed for age, or >10 percent immature
neutrophils
These original cutpoints that define age-specific SIRS criteria were chosen to be
sensitive to physiological parameters indicative of a systemic inflammatory state,
allowing for the maximum number of potential patients with sepsis to be identified
for observational and clinical trials.
While several studies have demonstrated value and reproducibility of these SIRS
criteria in the clinical trial setting [5-7], other vital sign ranges (such as those used in
the Pediatric Advanced Life Support [PALS] septic shock guidelines [8]) may be
more informative to guide diagnostic and therapeutic decisions outside of the
research setting and other cutoff values have been proposed for respiratory rates [9].
Age groups The consensus panel used age-related physiologic and laboratory
values to modify definitions that had been developed for adult patients [10]. Six age
groups for age-specific vital signs (heart rate, respiratory rate, and blood pressure)
and laboratory variables (leukocyte count) are identified (table 1):
Newborn: 0 days to 1 week
Neonate: 1 week to 1 month
Infant: 1 month to 1 year
Toddler and preschool: >1 to 5 years
School age child: >5 to 12 years
Adolescent and young adult: >12 to <18 years

Sepsis The systemic inflammatory response syndrome in the presence of

suspected or proven infection constitutes sepsis. Several definitions further describe
sepsis in terms of severity and response to therapy.
Severity
Severe sepsis Sepsis is considered severe when it is associated with
cardiovascular dysfunction, acute respiratory distress syndrome (ARDS), or
dysfunction in two or more other organ systems as defined in the section on multiple
organ failure below. The diagnostic criteria for ARDS are discussed elsewhere. (See
"Acute respiratory distress syndrome: Clinical features and diagnosis in adults",
section on 'Diagnostic criteria'.)
Septic shock Septic shock refers to sepsis with cardiovascular dysfunction (as
described in the section on multiple organ failure below) that persists despite the
administration of 40 mL/kg of isotonic fluid in one hour [3].
Refractory septic shock There are two types of refractory septic shock: fluidrefractory septic shock exists when cardiovascular dysfunction persists despite at
least 60 mL/kg of fluid resuscitation; and catecholamine-resistant septic shock exists
when shock persists despite therapy with dopamine 10 mcg/kg per min and/or
direct-acting catecholamines (epinephrine, norepinephrine) [3].
Multiple organ failure Reliably identifying and quantifying organ dysfunction is
useful for tracking clinical changes and the response to therapy in children with
septic shock. The International Consensus on Pediatric Sepsis [3] developed criteria
for organ dysfunction based upon several scoring systems [11-13], taking into
account a balance of specificity, sensitivity, and widespread availability of laboratory
tests.
Cardiovascular Hypotension, or reliance on a vasoactive drug to maintain blood
pressure, or two of the following: metabolic acidosis, elevated arterial lactate,
oliguria, or prolonged capillary refill
Respiratory Arterial oxygen tension/fraction of inspired oxygen (PaO2/FiO2)
<300, arterial carbon dioxide tension (PaCO2) >65 torr or 20 mmHg over baseline
PaCO2, need for >50 percent FiO2 to maintain oxygen saturation 92 percent, or need
for nonelective mechanical ventilation
Neurologic Glasgow coma score 11 (table 2), or acute change in mental status
Hematologic Platelet count <80,000/microL or a decline of 50 percent from
highest value recorded over the past three days or disseminated intravascular
coagulation (DIC), a consumptive coagulopathy diagnosed by clinical findings of
hemorrhage and microthrombi and laboratory abnormalities including
thrombocytopenia, prolongation of clotting times (PT and aPTT), and evidence of

fibrinolysis (low fibrinogen with elevated fibrin degradation products), which is a

common hematologic manifestation in sepsis. (See "Disseminated intravascular
coagulation in infants and children", section on 'Diagnosis'.)
Renal Serum creatinine 2 times upper limit of normal for age or twofold increase
in baseline creatinine
Hepatic Total bilirubin 4 mg/dL (not applicable to newborn) or alanine
aminotransferase (ALT) >2 times upper limit of normal for age
EPIDEMIOLOGY The overall burden of illness from pediatric sepsis is high
globally with important regional differences. As an example, in a prospective crosssectional study at 128 sites in 26 countries, the prevalence of severe sepsis in
children admitted to pediatric intensive care units was as follows [14]:
Approximately 6 to 8 percent of patients were treated in pediatric intensive care
units (PICUs) in North America, Europe, Australia, and New Zealand with PICU
mortality ranging from 21 to 32 percent.
An estimated 15 to 16 percent of patients were treated in 10 PICUs across Asia and
10 PICUs across South America with mortalities of 40 and 11 percent, respectively.
Almost 25 percent of patients were treated in the three South African PICUs with a
mortality rate of 40 percent mortality.
The incidence of sepsis also varies by region. For example, in the United States
approximately 75,000 children are hospitalized for severe sepsis each year with an
annual incidence of about 1 case per 1000 population [15]. The occurrence of
pediatric severe sepsis has been steadily rising since the mid-1990's and now
accounts for 4.4 percent of admissions to children's hospitals and 7 percent of
patients treated in PICUs in the United States [15-17]. In China, the incidence of
sepsis is estimated at 1.8 cases per 1000 population or more than 360,000 cases
annually [18].
Respiratory infection and bloodstream infections are found in almost two-thirds of
cases of severe sepsis worldwide [14-16]. Many of these illnesses are caused by
vaccine-preventable pathogens [19]. Since 1960, mortality from pediatric severe
sepsis among patients managed in resource-rich regions has decreased from 97
percent to approximately 4 to 10 percent in patients treated with severe sepsis [1517,20,21] and 13 to 34 percent in patients with septic shock [5,15-24]. (See
"Pneumonia in children: Epidemiology, pathogenesis, and etiology", section on
'Epidemiology' and "Septic shock: Ongoing management after resuscitation in
children", section on 'Overview'.)

Risk factors Among infected children, septic shock, including refractory septic
shock or multiple system organ failure, is the most severe form. (See 'Severity'
above.)
The following factors have been associated with an increased risk for septic shock
[25,26]:
Age younger than one month
Serious injury (eg, major trauma, burns, or penetrating wounds)
Chronic debilitating medical condition (eg, static encephalopathy with quadriplegia
and frequent aspiration pneumonia, uncorrected congenital heart disease, short gut
syndrome)
Host immunosuppression (malignancy, human immunodeficiency virus infection,
severe malnutrition, congenital immunodeficiency, sickle cell disease and other
disease with splenic dysfunction, or immunomodulating medications [eg,
chemotherapy]) (see "Approach to the child with recurrent infections")
Large surgical incisions
In-dwelling vascular catheters or other invasive devices (eg, endotracheal tube,
Foley catheter, chest tube)
Urinary tract abnormalities with frequent infection
In contrast, routine immunization of infants against Haemophilus influenzae type b
and Streptococcus pneumoniae has resulted in a dramatic decrease in the incidence of
invasive disease in young children due to these organisms. (See "Pneumococcal
(Streptococcus pneumoniae) conjugate vaccines in children", section on 'Invasive
disease' and "Prevention of Haemophilus influenzae infection", section on
'Efficacy/effectiveness'.)
PATHOGENS Sepsis can be caused by bacterial, viral, fungal, parasitic, and
rickettsial infections. Bacteria and viruses are the most frequently identified
pathogens.
Bacteria Although the frequency of specific pathogenic organisms varies from
institution to institution, the most common bacterial pathogens isolated from children
with severe sepsis include [20,27-32]:
Staphylococcus aureus including methicillin-resistant strains (MRSA)
Coagulase-negative Staphylococcus especially in neonates or young infants with indwelling vascular catheters

Streptococcus pneumoniae
Streptococcus pyogenes
Group B streptococcus in the neonate
Pseudomonas aeruginosa including carbapenem-resistant strains
Escherichia coli, including those with extended spectrum beta-lactamase activity
(ESBL)
Enterococcus species, including vancomycin-resistant species
Klebsiella species, including those with ESBL activity
Alpha streptococcus in children with acute myelogenous leukemia with mucositis
and neutropenia
Although less common, meningococcal infections, especially in unimmunized
populations, and the toxic shock syndrome caused by toxin-producing strains of
Staphylococcus aureus and Streptococcus pyogenes, remain important additional
causes of sepsis in children. (See "Clinical manifestations of meningococcal
infection" and "Staphylococcal toxic shock syndrome" and "Epidemiology, clinical
manifestations, and diagnosis of streptococcal toxic shock syndrome".)
Factors that alter the prevalence of causative pathogens include age,
immunocompromise, and the presence of an in-dwelling vascular catheter:
In young infants three months of age or younger, gram-negative organisms,
particularly Escherichia coli, and Group B streptococcus are most frequently
isolated. Staphylococcus aureus is also a frequent pathogen. (See "Definition and
etiology of fever in neonates and infants (less than three months of age)", section on
'Bacterial pathogens'.)
In patients with sepsis and febrile neutropenia, both gram-positive (eg, coagulasenegative Staphylococcus, Staphylococcus aureus, Streptococcus pneumoniae,
Streptococcus viridians) and gram-negative organisms (eg, Pseudomonas
aeruginosa, Escherichia coli, Klebsiella species) are common. Other gram-negative
organisms, including Enterobacter, Citrobacter, and Acinetobacter species and
Stenotrophomonas maltophilia, also occur though less frequently. MRSA and
multidrug-resistant gram-negative bacteria, such as certain strains of Pseudomonas
aeruginosa and ESBL-producing organisms, are frequently isolated. (See "Fever in
children with chemotherapy-induced neutropenia", section on 'Etiology of fever'.)

In hospital-acquired bacterial infections, such as catheter-associated bloodstream

infections, coagulase-negative Staphylococcus is the most commonly isolated
organism, followed by gram-negative organisms.
Viruses Viral pathogens can mimic bacterial sepsis. Etiologies include respiratory
viruses (eg, influenza, parainfluenza, adenovirus, respiratory syncytial virus (RSV),
and human metapneumovirus) and Dengue virus, a mosquito-borne pathogen that
can cause Dengue shock syndrome. While these viruses, especially pandemic H1N1
influenza strain, may cause the sepsis syndrome in isolation, the presence of bacterial
co-infections, particularly methicillin-resistant Staphylococcus aureus, should be
suspected in patients with severe sepsis or septic shock. In immunocompromised
patients, Epstein-Barr virus, cytomegalovirus, and adenovirus may also cause sepsis.
(See "Clinical manifestations and diagnosis of dengue virus infection", section on
'Clinical manifestations' and "Clinical manifestations and diagnosis of pandemic
H1N1 influenza ('swine influenza')", section on 'Bacterial superinfection'.)
Herpes simplex virus (HSV), enterovirus and adenovirus infection in neonates and
young infants can be indistinguishable from bacterial sepsis. Characteristic vesicular
lesions (skin, eye, or mucus membrane) suggesting the diagnosis of herpes simplex
may be absent in 30 to 40 percent of infected infants. Most neonates become
symptomatic with the first three weeks of life. Nonspecific clinical manifestations
include (see "Neonatal herpes simplex virus infection: Clinical features and
diagnosis", section on 'Clinical manifestations'):
Disseminated disease Respiratory collapse, liver failure, and disseminated
intravascular coagulation
Central nervous system disease Seizures, lethargy, irritability, and bulging
fontanelle
Fungi Fungal infections, especially candida species, have been reported in 10
percent of pediatric patients with severe sepsis and septic shock [15,16,20]. Fungal
sepsis is more common in children with certain risk factors including [33]:
Malignancy or other immunocompromising medical conditions
Indwelling vascular catheters
Prolonged neutropenia (>4 to 7 days)
Recent broad-spectrum antibiotic use
Other pathogens Parasitic (eg, malaria) and Rickettsial infections (eg, Rocky
Mountain spotted fever) may present with sepsis and should be suspected based upon
the local prevalence of disease and travel history. (See "Clinical manifestations of

malaria", section on 'Clinical manifestations' and "Clinical manifestations and

diagnosis of Rocky Mountain spotted fever", section on 'Clinical manifestations'.)
Culture-negative sepsis Between approximately 30 and 75 percent of children
with sepsis have no infectious etiology identified [5,26,27]. This "culture-negative"
sepsis may indicate host response to bacterial components, such as endotoxin, in the
circulatory system or result from antibiotic treatment prior to obtaining bacterial
cultures.
Alternatively, current diagnostic tests may not be sufficiently sensitive to detect the
inciting pathogen in all cases. Newer molecular diagnostic techniques, such as
multiplex polymerase chain reaction (PCR), have the potential to improve the rate of
organism identification. As an example, in a study comparing multiplex PCR to
routine blood culture in 1673 samples obtained from 803 children with suspected
sepsis, the rate of positive results was significantly higher with PCR than blood
culture (15 versus 10 percent, respectively) with significantly fewer contaminants (2
versus 6 percent, respectively) [34].
CLINICAL MANIFESTATIONS Children with sepsis have significant alterations
in vital signs and white blood cell count indicating a systemic inflammatory response
syndrome (SIRS) in the presence of clinical or laboratory findings of infection.
Shock and other organ dysfunction often accompany signs of sepsis.
Physical findings
Infection Infection is typically suggested by physical findings such as petechiae
and purpura in a child with shock, or fever, cough, and hypoxemia in a patient with
leukocytosis and pulmonary infiltrates on chest radiograph (table 3). Infections can
also be proven by positive culture, tissue stain, or polymerase chain reaction test.
However, these results are frequently not available during the initial phase of
treatment. Furthermore, in up to 60 percent of patients with sepsis, no pathogen is
identified. (See 'Pathogens' above and 'Laboratory studies' below.)
Systemic inflammatory response syndrome As defined above, the systemic
inflammatory response syndrome (SIRS) is present when a child has an abnormality
of temperature (fever or hypothermia) or age-specific abnormality of the white blood
cell count and one of the following: tachycardia, bradycardia, respiratory distress, or
pulmonary condition requiring mechanical ventilation (table 1). (See 'Systemic
inflammatory response syndrome' above.)
Among these criteria for SIRS, the presence of fever and tachypnea or fever and
abnormal white blood cell count are most common. In an observational study of 92
hospitalized children with SIRS, these two presentations were found in
approximately 75 and 50 percent of patients, respectively [6].

Shock Evidence of inadequate tissue perfusion and oxygen delivery with or

without hypotension often accompanies sepsis in children. In infants and children,
tachycardia is a sensitive, though non-specific, indicator often seen in early stages of
shock. Hypotension is a late sign of shock in infants and children who are better able
to maintain blood pressure than adults through an increase in heart rate, systemic
vascular resistance, and venous tone. (See "Physiology and classification of shock in
children", section on 'Common features'.)
Other clinical findings of shock vary depending upon whether the patient has
distributive ("warm") shock or "cold" shock (see "Physiology and classification of
shock in children", section on 'Common features'):
Distributive ("warm") shock Distributive shock is characterized by
hyperdynamic (or high output) physiology with decreased systemic vascular
resistance and elevated cardiac output as manifested by the following findings (see
"Physiology and classification of shock in children", section on 'Distributive shock'):
Flash capillary refill (<1 second)
Bounding pulses
Warm, dry extremities
Wide pulse pressure (typically greater than 40 mmHg in older children and adults;
lower pulse pressures may reflect widening in infants and neonates)
Cold shock "Cold" shock reflects increased systemic vascular resistance and
decreased cardiac output as indicated by the following signs (see "Physiology and
classification of shock in children", section on 'Hypovolemic shock'):
Delayed capillary refill (>2 seconds)
Diminished pulses
Mottled or cool extremities
Other physical findings Additional clinical findings in infants and children with
sepsis may indicate a primary site of infection or arise from organ dysfunction
caused by inadequate perfusion and include [35]:
Toxic or ill appearance
Signs of dehydration (eg, dry mucus membranes, sunken eyes, decreased urine
output, prolonged capillary refill time, decreased skin turgor, and, in infants, a
sunken fontanelle) (table 4)

Rigors
Altered mental status (eg, irritability, anxiety, confusion, lethargy, somnolence)
Decreased tone in neonates and infants
Seizures
Meningismus
Respiratory depression or failure
Pulmonary rales or decreased breath sounds caused by bronchopneumonia
Distended, tender abdomen (eg, perforated viscus or intraabdominal abscess)
Costovertebral angle tenderness (eg, pyelonephritis)
Macular erythema (toxic shock syndrome) (picture 1 and picture 2)
Skin cellulitis or abscess (picture 3)
Peripheral edema caused by capillary leak
Petechiae or purpura suggesting either a specific infectious source (eg,
meningococcemia, rickettsial infection) or disseminated intravascular coagulopathy
(picture 4 and picture 5)
Multiple nodules which can be seen with disseminated S.aureus or fungal infections
(picture 6)
Laboratory studies Children with suspected sepsis should undergo the following
laboratory studies:
Rapid blood glucose Hypoglycemia may accompany the metabolic demands and
decreased oral intake associated with sepsis in children, especially in neonates and
infants. Stress hyperglycemia may be noted initially and has been most carefully
studied in meningococcemia in children [36].
Arterial blood gas or venous blood gas and pulse oximetry Patients with sepsis
frequently have inadequate tissue perfusion with lactic acidosis. Hypoxemia from
bronchopneumonia or pulmonary edema may also occur.
Complete blood count with differential (including platelet count) Age-specific
leukocytosis or leukopenia are a criteria for pediatric SIRS (table 1). In addition,

neutrophilia, neutropenia, or thrombocytopenia may indicate acute infection. (See

"Causes of neutrophilia", section on 'Acute infection'.)
Blood lactate Elevation of blood lactate (>3.5 mmol/L) obtained by arterial
puncture or from an indwelling vascular cannula may help identify the presence and
severity of septic shock at presentation. Although evidence is limited in children,
reduction in serum or blood lactate levels have been associated with improved
survival in adults with shock [37,38]. Preliminary results in an observational study of
blood lactate levels in 239 children with SIRS also suggest that venous blood lactate
>4 mmol/L at initial presentation is associated with progression to organ dysfunction
at 24 hours [39]. Rapid determination of blood lactate may be obtained at the
bedside. (See "Initial management of shock in children", section on 'Physiologic
indicators and target goals'.)
Serum electrolytes Electrolyte disturbances (eg, hyponatremia, hyperkalemia,
hypokalemia, and hypophosphatemia) may accompany disease processes associated
with sepsis and septic shock, such as syndrome of inappropriate anti-diuretic
hormone secretion, gastroenteritis, and capillary leak.
Blood urea nitrogen and serum creatinine Elevation in blood urea nitrogen
may indicate dehydration. Elevation in creatinine may reflect prerenal azotemia.
Serum creatinine 2 times upper limit of normal for age or twofold increase in
baseline creatinine defines renal dysfunction in the setting of sepsis. (See 'Sepsis'
above.)
Serum calcium Hypocalcemia (ionized calcium <1.1 mmol/L) may affect
myocardial function and vascular tone and should be corrected if present. If serum
calcium is abnormal, serum phosphorus and magnesium should also be measured.
Serum total bilirubin and alanine aminotransferase Total bilirubin 4 mg/dL
(not applicable to newborn) or alanine aminotransferase (ALT) >2 times upper limit
of normal for age indicates liver dysfunction in the setting of sepsis. (See 'Sepsis'
above.)
Prothrombin time (PT), partial thromboplastin time (aPTT), international
normalized ratio (INR) Elevation in PT and aPTT or INR suggests disseminated
intravascular coagulopathy (DIC).
Fibrinogen and D-dimer Decreased fibrinogen and increased D-dimer support
the presence of a consumptive coagulopathy and DIC.
Blood culture Given the high prevalence of bacterial bloodstream infections in
children with sepsis, blood cultures should be obtained in all patients, preferably
before antibiotics are administered.

Urinalysis The presence of bacteria, nitrites, or pyuria suggests a urinary tract

infection.
Urine culture Urinary tract infection is a common source of infection in children
with sepsis and catheterized urine cultures should be obtained in all patients,
preferably before antibiotic administration.
Other cultures Other cultures (eg, cerebrospinal fluid [CSF], wound culture,
aspirated fluid from an abscess collection) should be obtained as indicated by clinical
findings.
Diagnostic serologic testing For some infections (eg, herpes simplex virus,
enterovirus, influenza), other diagnostic testing (eg, viral culture, polymerase chain
reaction, rapid immunoassay antigen test, or direct and immunofluorescent antibody
staining) may be helpful to establish the source of infection. See UpToDate topics on
clinical manifestations and diagnosis of the specific infection suspected for guidance
on diagnostic testing.
Inflammatory biomarkers, such as C-reactive protein and procalcitonin, may be
useful in select cases, but routine testing is not currently recommended [40,41]. For
example, procalcitonin and C-reactive protein may be useful in predicting serious
bacterial infection infants and young children who present to an emergency
department with fever with no apparent source of infection [42,43]. It may also be
useful in predicting bacterial infection in patients with fever and neutropenia [44,45].
(See "Evaluation and management of fever in the neonate and young infant (younger
than three months of age)", section on 'Inflammatory mediators'.)
Imaging Children with tachypnea, rales, wheezing, hypoxemia, or white blood
cell count greater than 20,000/mm3 warrant a chest radiograph to assess for
bronchopneumonia, pulmonary edema, and heart size. Cardiomegaly suggests fluid
overload or congenital heart disease.
Other imaging may be appropriate depending upon clinical findings. For example,
computed tomography (CT) of the head may be necessary in the patient with
evidence of coagulopathy and altered mental status to evaluate for intracranial
hemorrhage; ultrasound or computed tomography of the abdomen may be indicated
to evaluate for intra-abdominal abscess.
DIAGNOSIS The diagnosis of sepsis is made in children with suspected or
proven infection who meet two or more criteria for SIRS (table 1). Pneumonia,
bloodstream, skin, or urinary tract infections, and, less commonly, meningitis
comprise the most common infections in children with sepsis. (See 'Systemic
inflammatory response syndrome' above and 'Clinical manifestations' above.)
Sepsis is primarily a clinical diagnosis. Clinical manifestations typically progress
along a continuum of severity from sepsis to severe sepsis (sepsis plus cardiac,

respiratory, or dysfunction in two or more other organ systems), septic shock

(persistent hemodynamic instability despite initial fluid therapy), and multiple organ
failure. (See 'Severity' above.)
When suspected, the clinician must rapidly respond to signs of hemodynamic
instability, organ dysfunction, and administer antibiotics to ensure optimal outcomes.
(See "Septic shock: Rapid recognition and initial resuscitation in children", section
on 'Resuscitation'.)
DIFFERENTIAL DIAGNOSIS All children with findings consistent with sepsis
warrant goal-directed therapy and antibiotic administration pending documentation
of an infectious etiology. However, several conditions may have similar clinical
manifestations, and, once clinical stabilization has occurred, an alternative etiology
to sepsis may be evident based upon careful review of clinical findings.
In neonates and young infants, alternative diagnoses include:
Child abuse (eg, abusive head trauma)
Hypoglycemia
Environmental hyperthermia
Seizures
Congenital heart disease, particularly left-sided obstructive lesions (eg, aortic
coarctation, hypoplastic left heart syndrome) presenting in patients less than two
weeks of age
Cardiac arrhythmias (primarily supraventricular tachycardia)
Myocarditis or primary cardiomyopathy
Inborn errors of metabolism
Congenital adrenal hyperplasia
Malrotation with volvulus
Intussusception
Pyloric stenosis
Posterior urethral valves
Necrotizing enterocolitis

Gastroenteritis with dehydration

Water intoxication
Toxic exposures (eg, methemoglobinemia or carbon monoxide poisoning)
Acute bilirubin encephalopathy
Detailed history, physical examination, and selected diagnostic studies frequently can
differentiate these conditions from sepsis. The approach to the septic-appearing
infant is discussed separately. (See "Approach to the septic-appearing infant".)
Among older children and adolescents the following conditions can cause elevated
temperature with tachycardia or hemodynamic instability:
Heat stroke The diagnostic criteria for patients with heatstroke are elevated core
temperature (40C [104F]) and central nervous system (CNS) abnormalities
following environmental heat exposure. Other typical clinical manifestations include
tachycardia, tachypnea, flushed and warm skin, diaphoresis, and coagulopathy.
Exposure to excessive ambient heat is present on history. The height of the fever may
exceed 41C (105.8C) and an infectious prodrome or source of infection is absent.
(See "Heat stroke in children", section on 'Clinical features' and "Heat stroke in
children", section on 'Differential diagnosis'.)
Serotonin syndrome Hyperthermia commonly occurs in patients with serotonin
syndrome, a potentially life-threatening condition associated with increased
serotonergic activity in the central nervous system (CNS). Serotonin syndrome
encompasses a spectrum of disease where the intensity of clinical findings is thought
to reflect the degree of serotonergic activity. Mental status changes can include
anxiety, agitated delirium, restlessness, and disorientation. Patients may startle easily.
Autonomic manifestations can include diaphoresis, tachycardia, hyperthermia,
hypertension, vomiting, and diarrhea. Neuromuscular hyperactivity can manifest as
tremor, muscle rigidity, myoclonus, hyperreflexia, and bilateral Babinski sign.
Hyperreflexia and clonus are particularly common; these findings, as well as rigidity,
are more often pronounced in the lower extremities.
The recognition that the patient has been exposed to a serotonergic drug is essential
to the diagnosis. (See "Serotonin syndrome".)
Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is an
idiosyncratic reaction to antipsychotic agents. In addition to hyperthermia, NMS is
also characterized by "lead pipe" muscle rigidity, altered mental status,
choreoathetosis, tremors, and evidence of autonomic dysfunction, such as
diaphoresis, labile blood pressure, and arrhythmias. The history of antipsychotic drug
exposure is a key component of the diagnosis. (See "Neuroleptic malignant
syndrome".)

Malignant hyperthermia Malignant hyperthermia is a rare genetic disorder that

manifests following exposure to certain agents, most commonly succinylcholine and
halothane. Other potent inhalational anesthetics (eg, sevoflurane, desflurane,
isoflurane) can also cause malignant hyperthermia. The onset of malignant
hyperthermia is usually within one hour of the administration of general anesthesia,
but rarely, may be delayed up to 10 hours after induction. Clinical manifestations
include hypercapnia, hyperthermia, tachycardia, masseter muscle rigidity, and
rhabdomyolysis. (See "Malignant hyperthermia: Clinical diagnosis and management
of acute crisis".)
Toxic overdose Drug-related causes of hyperthermia, tachycardia, shock, and
multiple organ dysfunctions include overdose of cocaine, methamphetamine or
related compounds (eg, bath salts), amphetamine, MDMA [ecstasy], salicylates,
anticholinergic agents and withdrawal from opioid or benzodiazepine medications. A
history of drug exposure, an elevated salicylate level, or a positive toxicology screen
for drugs of abuse may be present. (See "Cocaine: Acute intoxication" and "MDMA
(ecstasy) intoxication" and "Methamphetamine intoxication" and "Anticholinergic
poisoning" and "Salicylate poisoning in children and adolescents".)
Kawasaki disease Kawasaki disease is a clinical syndrome consisting of fever
for 5 days and four of five physical findings (bilateral bulbar conjunctival injection,
oral mucous membrane changes [eg, injected lips or strawberry tongue], peripheral
extremity changes [eg, erythema of palms or soles, edema of hands or feet, and
eventual periungual desquamation], rash, or cervical lymphadenopathy). Tachycardia
is frequently present and poor peripheral perfusion may occur, especially in infants.
However, shock is unusual in patients with Kawasaki disease. Shock may be present
in up to 7 percent of children with Kawasaki disease [46]. (See "Kawasaki disease:
Clinical features and diagnosis", section on 'Clinical manifestations'.)
Baclofen withdrawal syndrome Baclofen is chemically derived from the natural
inhibitory neurotransmitter gamma aminobutyric acid (GABA) and binds to GABAb
receptors that inhibit neuronal excitation in the spinal cord [47]. Intrathecal baclofen
has become an established therapy for spasticity in children with cerebral palsy. The
medication is delivered by a programmable pump that is implanted in the
subcutaneous layer of the abdomen. Baclofen withdrawal may occur if the pump
fails, the delivery catheter becomes occluded, the medication runs out, or the amount
of baclofen in the pump reservoir falls below 2 mL [47,48].
One to three days after abrupt withdrawal of baclofen, the patient can develop
marked spasticity, muscle rigidity, seizures, hyperthermia, hypertension, pruritis and,
in advanced cases, rhabdomyolysis with multiple system organ failure and
disseminated intravascular coagulopathy [47,49,50]. These manifestations may be
confused with other diseases including sepsis, serotonin syndrome, or neuroleptic
malignant syndrome [47,50,51].

The diagnosis of baclofen withdrawal is made when evaluation of the pump

identifies an empty or low drug reservoir or an unexpectedly full reservoir indicating
tubing failure [47,50]. Resumption of intrathecal baclofen delivery is the definitive
treatment. Benzodiazepine administration (eg, lorazepam) may temporarily control
spasticity and seizures until intrathecal baclofen can be reestablished. High-dose oral
baclofen may also be attempted but is frequently not effective.
SUMMARY
The systemic inflammatory response syndrome (SIRS) is present when a child has
an abnormality of temperature (fever or hypothermia) or age-specific abnormality of
the white blood cell count and one of the following: tachycardia, bradycardia,
respiratory distress, or pulmonary condition requiring mechanical ventilation (table
1). (See 'Systemic inflammatory response syndrome' above.)
SIRS in the presence of suspected or proven infection constitutes sepsis. Clinical
manifestations typically progress along a continuum of severity from sepsis to severe
sepsis, septic shock, and multiple organ failure. (See 'Sepsis' above and 'Severity'
above.)
Infection is typically suggested by physical findings, such as petechiae and purpura
in a child with shock, or fever, cough, and hypoxemia in a patient with leukocytosis
and pulmonary infiltrates on chest radiograph (table 3). Infections can also be proven
by positive culture, tissue stain, or polymerase chain reaction test. However, these
results are frequently not available during the initial phase of treatment. Furthermore,
in up to 60 percent of patients with sepsis, no pathogen is identified. (See 'Pathogens'
above and 'Laboratory studies' above.)
Bacterial, viral, fungal, parasitic, and rickettsial infections can all cause sepsis.
Common bacteria that cause severe sepsis include Staphylococcus aureus,
Streptococcus pneumoniae, and gram-negative organisms. Viral pathogens can mimic
bacterial sepsis, especially herpes simplex virus infection and enterovirus in neonates
(28 days of age). However, the presence of bacterial co-infections, particularly
Staphylococcus aureus, should be suspected in patients with severe sepsis or septic
shock. (See 'Pathogens' above.)
Clinical findings of septic shock may include fever, a toxic or ill appearance, edema
(as the result of capillary leak), respiratory distress, altered mental status, and
inadequate tissue perfusion. Patients may have "warm shock" with decreased
systemic vascular resistance (SVR, bounding pulses and normal or flash capillary
refill) or "cold shock" with poor peripheral perfusion due to increased SVR
(decreased capillary refill, decreased peripheral pulses as compared with central
pulses). (See 'Clinical manifestations' above.)
All children with findings consistent with sepsis warrant timely antibiotic
administration and prompt initiation of goal-directed therapy pending documentation

of an infectious etiology. However, several conditions may have similar clinical

manifestations, and, once clinical stabilization has occurred, an alternative etiology
to sepsis may be evident based upon careful review of clinical findings. (See
'Differential diagnosis' above.)
The management of septic shock is discussed separately. (See "Septic shock: Rapid
recognition and initial resuscitation in children" and "Septic shock: Ongoing
management after resuscitation in children".)
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