Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosisAuthorsWendy J Pomerantz, MD, MSScott L Weiss, MDSection EditorsSusan B Torrey, MDSheldon L Kaplan, MDAdrienne G Randolph, MD, MScDeputy EditorJames F Wiley, II, MD, MPHDisclosures: 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 policyAll 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. INTRODUCTIONSepsis 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".)DEFINITIONSDefinitions 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.InfectionInfection 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 syndromeThe 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 1 to 5 yearsSchool age child: >5 to 12 yearsAdolescent and young adult: >12 to 50 percent FiO2 to maintain oxygen saturation 92 percent, or need for nonelective mechanical ventilationNeurologic Glasgow coma score 11 (table 2), or acute change in mental statusHematologic Platelet count 2 times upper limit of normal for ageEPIDEMIOLOGYThe overall burden of illness from pediatric sepsis is high globally with important regional differences. As an example, in a prospective cross-sectional 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 [15-17,20,21] 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 factorsAmong 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 monthSerious 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 incisionsIn-dwelling vascular catheters or other invasive devices (eg, endotracheal tube, Foley catheter, chest tube)Urinary tract abnormalities with frequent infectionIn 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'.)PATHOGENSSepsis can be caused by bacterial, viral, fungal, parasitic, and rickettsial infections. Bacteria and viruses are the most frequently identified pathogens.BacteriaAlthough 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 in-dwelling vascular cathetersStreptococcus pneumoniaeStreptococcus pyogenesGroup B streptococcus in the neonatePseudomonas aeruginosa including carbapenem-resistant strainsEscherichia coli, including those with extended spectrum beta-lactamase activity (ESBL)Enterococcus species, including vancomycin-resistant speciesKlebsiella species, including those with ESBL activityAlpha streptococcus in children with acute myelogenous leukemia with mucositis and neutropeniaAlthough 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 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.VirusesViral 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 coagulationCentral nervous system disease Seizures, lethargy, irritability, and bulging fontanelleFungiFungal 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 conditionsIndwelling vascular cathetersProlonged neutropenia (>4 to 7 days)Recent broad-spectrum antibiotic useOther pathogensParasitic (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 sepsisBetween 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 MANIFESTATIONSChildren 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 findingsInfectionInfection 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 syndromeAs 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].ShockEvidence 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 (2 seconds)Diminished pulsesMottled or cool extremitiesOther physical findingsAdditional 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 appearanceSigns 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)RigorsAltered mental status (eg, irritability, anxiety, confusion, lethargy, somnolence)Decreased tone in neonates and infantsSeizuresMeningismusRespiratory depression or failurePulmonary rales or decreased breath sounds caused by bronchopneumoniaDistended, 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 leakPetechiae 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 studiesChildren 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 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'.)ImagingChildren 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.DIAGNOSISThe 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 DIAGNOSISAll 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)HypoglycemiaEnvironmental hyperthermiaSeizuresCongenital heart disease, particularly left-sided obstructive lesions (eg, aortic coarctation, hypoplastic left heart syndrome) presenting in patients less than two weeks of ageCardiac arrhythmias (primarily supraventricular tachycardia)Myocarditis or primary cardiomyopathyInborn errors of metabolismCongenital adrenal hyperplasiaMalrotation with volvulus IntussusceptionPyloric stenosisPosterior urethral valvesNecrotizing enterocolitisGastroenteritis with dehydrationWater intoxicationToxic exposures (eg, methemoglobinemia or carbon monoxide poisoning)Acute bilirubin encephalopathyDetailed 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.SUMMARYThe 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".)Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES1. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348:138.2. Hall MW, Knatz NL, Vetterly C, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med 2011; 37:525.3. Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis. 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