ARTICULO MEDICO:Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis

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

All topics are updated as new evidence becomes available and our peer review process is

complete.

Literature review current through: Jan 2013. | This topic last updated: dic 11, 2012.

INTRODUCTION — Sepsis is a clinical syndrome that complicates severe infection and is

characterized by the systemic inflammatory response syndrome, 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, 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 (table 1) [3]:

· Core temperature (measured by rectal, bladder, oral, or central probe) of >38.5ºC or <36 div="">

· 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 age="" div="" for="" percentile="">

· Mean respiratory rate more than two standard deviations above normal for age or

mechanical ventilation for an acute pulmonary process

· Leukocyte count elevated or depressed for age, or >10 percent immature neutrophils

Age groups — The consensus panel used age-related physiologic and laboratory values to modify

definitions that had been developed for adult patients [6]. 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 div="" 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", 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: fluid-refractory

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 [7-9], 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 aco2="" arterial="" carbon="" dioxide="" tension="">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 50="" a="" decline="" div="" from="" microl="" of="" or="" percent="">

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 — Among resource-rich countries the best estimates regarding the incidence of

severe sepsis come from the United States where approximately 40,000 children develop severe

sepsis each year, an estimated annual incidence of 0.6 cases per 1000 population [10]. Respiratory

infection and primary bacteremia are found in almost two-thirds of cases of severe sepsis in this

population. Since 1960, mortality from pediatric severe sepsis has decreased from 97 percent to

approximately 4 to 10 percent in patients with severe sepsis [10,11] and 13 to 34 percent in patients

with septic shock [5,10-14]. (See "Septic shock: Ongoing management after resuscitation in

children", section on 'Overview'.)

Although worldwide estimates for severe sepsis are lacking, infectious diseases account for almost

60 percent of the 7.6 million annual deaths in children younger than five years of age [15]. The

majority of these deaths occur in developing countries in Asia and sub-Saharan Africa.

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 [16,17]:

· 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])

· 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

[10,18-23]:

· 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, coagulase-negative

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 andStenotrophomonas 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 methicillinresistant

Staphylococcus aureus, should be suspected in patients with severe sepsis or septic

shock. In immunocompromised patients, EBV, CMV, and adenovirus may also cause sepsis.

(See "Clinical presentation and diagnosis of dengue virus infections", section on 'Clinical

presentation' 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 [10]. Fungal sepsis is more common in

children with certain risk factors including [24]:

· 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 [5,17,18]. 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) [25].

CLINICAL MANIFESTATIONS — 

Children with sepsis have significant alterations in vital signs and

white blood cell count indicating a systemic inflammatory response (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

[26].

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 div="" 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 [27]:

· 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 [28].

· 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 [29,30].

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 [31]. 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="" affect="" div="" may="" mmol="" 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, 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. The user is referred to 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 [32,33]. For example, procalcitonin and Creactive

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 [34,35]. It

may also be useful in predicting bacterial infection in patients with fever and neutropenia [36,37].

(See "Evaluation and management of fever in the neonate and young infant (less 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 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 goaldirected

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 (≥40ºC [104ºF]) 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 41°C (105.8°C) 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

(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 [38]. (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 [39]. 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

[39,40].

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 [39,41,42]. These manifestations may be confused with other diseases

including sepsis, serotonin syndrome, or neuroleptic malignant syndrome [39,42,43].

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

[39,42]. 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.)

· The systemic inflammatory response syndrome 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, particularlyStaphylococcus 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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REFERENCES