Sepsis in Children

Sepsis is defined as a life-threatening systemic response syndrome caused by viruses, bacteria, fungi, and parasites, or toxins released from these organisms. Neonates and children are particularly prone to sepsis owing to their immature immune systems. Affected individuals may present with localizing symptoms specific to a source of infection but may often complain of nonspecific systemic symptoms. Diagnosis is based on history, exam, laboratory testing, and imaging studies. A high index of suspicion, rapid diagnosis, and clinical intervention with appropriate therapy are mandatory to achieve favorable outcomes.

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Overview

Definition

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated response to a host infection.

Systematic inflammatory response syndrome criteria

Sepsis:

  • 2 of the SIRS criteria:
    • Tachycardia: HR > 90/minute
    • Tachypnea: RR > 20 breaths/minute
    • Fever or hypothermia: temperature > 38°C or < 36°C (> 100.4°F or < 95.0°F)
    • Leukocytosis, leukopenia, or bandemia: WBCs > 1,200/mm3, < 4,000/mm3, or bandemia ≥ 10%
  • Plus, a suspected or confirmed infectious source

Severe sepsis:

  • Must meet the criteria for sepsis
  • Plus, 1 of the following:
    • Hypotension (systolic blood pressure < 90 mm Hg)
    • Organ dysfunction:
      • Cardiovascular dysfunction
      • ARDS
      • Renal failure
      • Altered mental status
    • Lactic acid > 4 mmol

Septic shock is severe sepsis that is unresponsive to fluid resuscitation.

Mortality-rates-in-shock

Mortality rates in sepsis, severe sepsis, and septic shock:
SIRS: systemic inflammatory response syndrome
ARDS: acute respiratory distress syndrome

Image by Lecturio.

Other sepsis-scoring criteria

  • The sequential organ failure assessment (SOFA) score and the abbreviated version (qSOFA) are a newer set of criteria.
  • SOFA and qSOFA help predict mortality associated with sepsis.
  • Can be used as an alternative to SIRS
  • Sepsis is suspected when 2 of the qSOFA criteria are met.
  • The 3 criteria for the qSOFA score include:
    • RR > 22 breaths/min
    • Systolic blood pressure < 100 mm Hg
    • Altered mental status

Epidemiology and Etiology

Epidemiology

  • The incidence of sepsis is inversely related to age in children.
  • Neonatal:
    • Up to 10% of newborns have an infection within the 1st month of life.
    • More common in children with birth weight < 1,500 grams
    • The most common mode of pathogen transmission is intrapartum or through an infected birth canal.
    • Vertical transmission has ↓ due to early detection and the treatment of group B strep during pregnancy
  • Infants and children:
    • In the USA, 75,000 children are hospitalized annually for severe sepsis.
    • 65% of cases are associated with respiratory or bloodstream infections.
    • Immunizations against Streptococcus pneumoniae and Haemophilus influenzae have ↓ the incidence

Risk factors

  • Neonatal:
    • Immunological immaturity
    • Exposure to maternal genital tract pathogens
    • Trauma to the scalp during childbirth
    • Invasive procedures (e.g., prolonged endotracheal intubation, parenteral feeding)
    • Poor mechanical defenses (e.g., easily erodible skin)
    • Resistant microorganisms
  • Infants and children:
    • Age < 1 month
    • Serious injury (e.g., penetrating trauma)
    • Chronic and debilitating conditions
    • Immunosuppression (e.g., HIV infection)
    • Large surgical incisions
    • Indwelling or invasive devices (e.g., chest tube)
    • Frequent urinary tract infections

Etiology

  • Neonates:
    • Most common bacteria:
      • Group B Streptococcus (in neonates)
      • S. agalactiae
      • MRSA
      • Escherichia coli
      • Enterococcus faecalis
    • Uncommon bacteria:
      • S. pneumoniae
      • Pseudomonas aeruginosa
      • Listeria monocytogenes
      • Klebsiella
      • H. influenzae
      • Mycoplasma hominis
    • Viruses:
      • Adenovirus
      • CMV
      • Enteroviruses
      • Parechoviruses
      • Hepatitis B and C viruses
      • HSV
      • Human immunodeficiency virus (HIV)
      • Parvovirus
      • Rubella virus
      • Varicella-zoster virus (VZV)
      • EBV (in immunocompromised individuals)
    • Fungi:
      • Candida spp.
      • Malassezia spp.
      • Protozoa
    • Plasmodia:
      • Toxoplasma gondii
      • Trypanosoma cruz
  • Infants and children:
    • E. coli
    • S. aureus
    • S. pneumoniae
    • H. Influenzae type b
    • Neisseria meningitidis
    • Salmonella spp.
    • Viruses

Pathophysiology

The host’s ability to resist direct damage by the pathogen and immune system response determines if an infection can be controlled or will result in sepsis.

  • Antigen recognition → initiates the innate immune response → secretion of cytokines → activation of the complement system, platelet-activation-factor, arachidonic acid, and inflammatory pathways, and NO release
  • Activated coagulation factors and fibrinolysis → DIC
  • System-wide inflammation → generalized vasodilation and poor organ perfusion anaerobic metabolism → lactic acidosis
  • ↓ Perfusion → multiorgan dysfunction syndrome
  • Generalized vasodilation → relative hypovolemia and, eventually, distributive shock

Clinical Presentation

Nonspecific

  • Poor feeding
  • Change in behavior
  • Lethargy
  • Altered mental status
  • ↑/↓ HR
  • Hypotension
  • Temperature instability

System specific

  • Circulatory
    • Poor perfusion:
      • Pallor and cyanosis
      • ↑ Capillary refill
      • Edema
      • Dehydration
    • Septic shock:
      •  “Warm” shock:
        • Instant capillary refill
        • Bounding pulses (wide pulse pressure)
        • Warm extremities
      •  “Cold” shock:
        • ↓ Capillary refill (> 2 seconds)
        • ↓ Pulse
        • Cold extremities
        • Most common in pediatrics
  • Digestive:
    • Vomiting/diarrhea
    • Abdominal distention
    • Hepatomegaly
  • Respiratory:
    • ↑/↓ RR
    • Retractions
    • Grunting
    • Nasal flaring
    • Dyspnea
    • Cyanosis
    • Hypoxia (< 90% saturation)
  • Urologic:
    • Oliguria
    • Anuria
  • Neurologic:
    • Seizures or tremors
    • Apathy
    • Irritability
    • Lethargy
    • Hypotonia/hypertonia
    • Hyperreflexia
    • Full fontanelle
    • Abnormal Moro reflex
    • Irregular breathing
    • High-pitched crying
  • Hematologic:
    • Jaundice
    • Hepatosplenomegaly
    • Bleeding
  • Dermatologic:
    • Mottling
    • Petechiae
    • Purpura

Clinical progression in neonatal sepsis

Table: Clinical progression in neonatal sepsis
Initial phaseSeptic phaseLate phase
  • The child appears ill.
  • Poor feeding
  • Lethargy
  • Unexplained tachycardia
  • GI symptoms
  • Respiratory symptoms
  • Neurologic signs
  • Urologic symptoms
  • Circulatory collapse
  • Hematologic signs

Diagnosis

Laboratory analysis

  • CBC:
    • ↑/↓ WBC count
    • ↓ Platelet count
    • ↑ Blasts
  • Electrolytes:
    • ↓ Na
    • ↓/↑ K
    • ↓ Phosphorus
    • ↓ Glucose due to ↑ metabolic demand and ↓ caloric intake
    • Serum creatinine and BUN: prerenal azotemia due to AKI
  • Blood gas:
    • Metabolic acidosis
    • ↑ Lactic acid: strong predictor of mortality
    • Hypoxemia
  • Total bilirubin:
    • ↑ (> 4 mg/dL) ALT
    • ↑ Transaminases may indicate liver dysfunction, HSV, or enterovirus infection
  • Blood cultures x 2 to identify the causative agent
  • PT, PTT, and INR due to coagulation disorder
  • ↓ Fibrinogen
  • ↑ D-dimer: DIC
  • Urinalysis and culture

Diagnostic imaging

  • Chest X-ray: if suspected pneumonia or fluid overload
  • Ultrasound or CT scan of the abdomen: +/- if etiology not apparent
  • Head CT: warranted in individuals with coagulopathy and altered mental status

Management and Prevention

Management

  • Begins with stabilizing the affected individual
  • Goal-directed therapy:
    • IV access within 5 minutes
    • Fluid resuscitation within 30 minutes
    • Broad-spectrum antibiotic therapy within 60 minutes
    • Inotropic infusion within 60 minutes (in fluid-refractory shock)
    • Periodic reevaluation of:
      • Central and peripheral pulses
      • Skin perfusion (capillary refill and skin temperature)
      • Fluid status
      • Urine output (> 1 mL/kg/hour)
      • Systolic blood pressure
      • Mental status
      • Serum lactate levels
      • Central venous oxygen saturation (ScvO₂)
  • Resuscitation goals:
    • Mean arterial pressure > 65 mm Hg
    • Urine output > 0.5 mL/kg/hour
    • Central venous pressure (CVP) 8–10 mm Hg
    • ScvO₂ > 70% or SvO₂ > 65%
  • Therapies:
    • Crystalloid solutions: starting bolus of 20 cc/kg
    • Vasopressors (e.g., norepinephrine, epinephrine)
    • Inotropic therapy (e.g., epinephrine, dopamine)
    • Calculation of the rate of infusion: dose/volume of dilution / child’s weight/time of infusion

Antibiotic therapy

  • Ideally, start as soon as possible.
    • Within the 1st hour of presentation (golden hour)
    • After obtaining culture samples
  • Empirical broad-spread antibiotics at 1st; then, tailor to cultures and antibiograms
  • Factors to consider:
    • Age
    • History
    • Comorbidities
    • Clinical situation
    • Type of infection
    • Gram staining results
  • Antibiotic therapy options:
    • < 28-weeks old: ampicillin (50 mg/kg) or vancomycin (15 mg/kg) + cefotaxime (100 mg/kg) + gentamicin (2.5 mg/kg) and acyclovir (20 mg/kg) if suspecting HSV
    • > 28-weeks old:
      • Vancomycin (15 mg/kg) + ceftriaxone (75 mg/kg) or cefotaxime (100 mg/kg)
      • In immunosuppresion: vancomycin (15 mg/kg) + cefepime (75 mg/kg) or meropenem (20 mg/kg
    • In children who cannot receive penicillin: vancomycin (15 mg/kg) + meropenem (20 mg/kg) or aztreonam (90–120 mg/kg/day) + clindamycin (40 mg/kg)
    • In children with fungal infections: amphotericin B + caspofungin

Prevention

  • Follow vaccination schedule to prevent infections.
  • Limit the use of indwelling catheters.
  • Screening for potential pathogens during pregnancy, and management prior to birth.
  • Rectovaginal swab for group B Streptococcus colonization at 35–37-weeks gestation, serum testing for:
    • HIV
    • Syphilis
    • Hepatitis B surface antigen testing
    • C. trachomatis
    • N. gonorrhea
    • Screening for hepatitis C antibodies in high-risk women

Differential Diagnosis

  • Pediatric meningitis: inflammation of the meninges, which can be life threatening. Multiple microorganisms are responsible for meningitis. Symptoms vary according to age and range from bulging fontanelles in infants to nuchal rigidity in older children. Fever, headache, lethargy, and vomiting may also be present. A lumbar puncture is used for diagnosis. Management is using antibiotics.
  • Pediatric adrenal insufficiency: characterized as primary (affecting the adrenal gland) and central (hypothalamic-pituitary dysfunction), and may be congenital or acquired. Affected individuals present with hypovolemia, hypoglycemia, hyponatremia, and hyperkalemia. Laboratory tests are used to confirm the diagnosis. Management is using saline and dextrose to regulate electrolytes.
  • Necrotizing enterocolitis: a GI disease characterized by the intestinal necrosis of a part of the intestine. Common in preterm infants and newborns who are ill. Infants present with poor feeding, abdominal distension, and signs of sepsis. Necrotizing enterocolitis is diagnosed using abdominal X-ray. Early diagnosis and antibiotics can improve outcomes. Surgical intervention may be needed.
  • Cardiogenic shock: a condition that occurs when there is circulatory collapse secondary to cardiac insult. Affected individuals present with tachycardia, hepatomegaly, cardiac gallops, murmurs, precordial heaves, and jugular venous distension. Laboratory tests aid in the diagnosis. Chest X-ray and cardiac output monitoring are useful. Management involves maintaining the airway, oxygenation, ventilation, and circulation.
  • Pediatric infective pericarditis: an infection of the pericardium by bacteria, viruses, or fungi. Affected individuals present with fever and chest pain that worsen with palmar pressure to the sternum and may have prodromal syndrome. Pediatric infective pericarditis may cause pericardial effusion or cardiac tamponade and death. Laboratory tests and cardiac imaging aid in the diagnosis. Management involves pain control and antibiotic therapy or pericardiocentesis.
  • Pediatric metabolic acidosis: an acid-base disorder that results from low serum HCO3 or high hydrogen ion concentrations. Various etiologies including hypovolemia, toxic ingestion, inborn errors of metabolism, cardiac failure, diabetic ketoacidosis, chronic renal failure, and sepsis result in metabolic acidosis. Identifying and treating the underlying etiology is important in management.

References

  1. Butt, W. (2001). Septic shock. Pediatric Clinics of North America, 48(3), 601.
  2. Haslam, D.B. (2020). Epidemiology of infections. In R.M. Kliegman MD, J.W. St Geme MD, N.J. Blum MD, Shah, Samir S., MD, MSCE, Tasker, Robert C., MBBS, MD, Wilson, Karen M., MD, MPH (Eds.), Nelson Textbook of Pediatrics (pp. 99–1005.e1)
  3. Mathias, B., Mira, J.C., Larson, S.D. (2016). Pediatric sepsis. Current Opinion in Pediatrics, 28(3), 380–387.
  4. Pasman, E.A. (2021). Shock in Pediatrics Treatment & Management: Approach Considerations, Initial Resuscitation, Glucose and Calcium Stabilization. Medscape. Retrieved August 8, 2021, from https://emedicine.medscape.com/article/1833578-treatment
  5. Rhodes, A., Evans, L.E., Alhazzani, W., Levy, M.M., Antonelli, M., Ferrer, R., Dellinger, R.P. (2017). Surviving sepsis campaign: international guidelines for the management of sepsis and septic shock. Intensive Care Medicine, 43(3), 304–377.
  6. Santhanam, S. (2021). Pediatric Sepsis: Practice Essentials, Background, Pathophysiology. Medscape. Retrieved August 8, 2021, from https://emedicine.medscape.com/article/972559-overview
  7. Sarmin, M., Afroze, F., Sharifuzzaman, Alam, T., Shaly, N.J., Ahmed, T., Chisti, M.J. (2019). Predictor of death in diarrheal children under 5 years of age having severe sepsis in an urban critical care ward in Bangladesh. Global Pediatric Health, 6, 2333794X19862716.
  8. Mathias, B., Mira, J.C., Larson, S.D. (2016). Pediatric sepsis. Current Opinion in Pediatrics, 28(3), 380–387.
  9. Wood, B.P. (2020). Necrotizing Enterocolitis Imaging: Practice Essentials, Radiography, Ultrasonography. Medscape. Retrieved August 8, 2021, from https://emedicine.medscape.com/article/411616-overview

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