Neonatal Sepsis

See Also

Definitions

Neonatal Sepsis
1. Invasive infection in first 30 days of life
Early onset Sepsis
1. Intrapartum infection within first 72 hours of life
2. Neonatal Sepsis within the first week of life
Late onset Sepsis
1. Neonatal Sepsis onset at 7 to 30 days of life
2. Some studies define late onset as everything after the first 72 hours
3. Results from postnatal infections

Epidemiology

Incidence: 1-2 cases per 1000 live births
Meningitis occurs in one third of Sepsis cases

Risk Factors
Early onset Sepsis

Major
1. Maternal prolonged Rupture of Membranes >18-24 hours
2. Intrapartum Maternal Fever >38 C (>100.4 F)
3. Chorioamnionitis
4. Sustained Fetal Tachycardia >160 beats per minute
Minor
1. Intrapartum Maternal Fever >37.5 C (>99.5 F)
2. Twin Gestation (or other Multiple Gestation)
3. Premature Infant (<37 weeks)
4. Maternal Leukocytosis (White Blood Cell Count >15,000)
5. Maternal Urinary Tract Infection
6. Prolonged Rupture of Membranes > 12 hours
7. Tachypnea (<1 hour)
8. Maternal Group B Streptococcus Colonization
9. Low APGAR (<5 at 1 minute)
10. Low birth weight (<1500 grams)
11. Foul lochia
Risk Calculator (Kaiser Permanente Neonatal Early Onset Sepsis Calculator)
1. https://neonatalsepsiscalculator.kaiserpermanente.org/

Risk Factors
Late onset Sepsis

Skin or mucosal injury
Invasive procedures (e.g. Endotracheal Intubation)
Necrotizing Enterocolitis (esp. prematurity)
1. May present with feeding problems, Hematochezia, Vomiting
Prolonged Antibiotics
Antacid agents (H2-receptor blockers, Proton Pump Inhibitors)

Causes
Early onset Sepsis (0-7 days of life)

Common
1. Group B Streptococcal Sepsis
  1. Most common Neonatal Sepsis cause in term infants
  2. Incidence reduced 80% since Universal GBS Culture and GBS Prophylaxis in U.S.
2. Escherichia coli (esp. ECK1)
  1. Most common Neonatal Sepsis cause in Preterm Infants (<2.5 kg)
Other causes
1. Listeria monocytogenes
  1. Rare in the United States (predominant in Spain)
2. Streptococcus (other species)
3. Enterococcus
4. Haemophilus Influenzae (non-typable)
5. Neonatal Herpes Simplex Virus

Causes
Late onset Sepsis (7-30 days of life)

Coagulase-negative staphylococci (Nosocomial)
Staphylococcus aureus
Enterococci
Multi-drug-resistant Gram Negative Rods
Candida
Late-onset Group B Streptococcal Sepsis
Neonatal Herpes Simplex Virus (esp. in first 14 days of life)

History

See Newborn History

Exam

See Newborn Exam
See Pediatric Vital Signs

Signs

Respiratory distress (90%)
1. Tachypnea
2. Apnea
3. Hypoxia
4. Flaring or grunting
5. Irregular respirations
Temperature instability sustained over 1 hour (30%)
1. Newborn Temperature < 97 F (36 C)
2. Newborn Temperature > 99.6 F (37 C)
Gastrointestinal symptoms
1. Vomiting
2. Diarrhea
3. Abdominal Distention
4. Ileus
5. Dehydration signs with poor feeding
6. Splenomegaly
Neurologic
1. Activity decreased or lethargy
2. Irritability
3. Tremor, jitteriness or Seizure
4. Hyporeflexia or hypotonia
5. High pitched cry
6. Swelling of Fontanel
Cardiovascular
Skin
1. Pallor or skin mottling
2. Petechiae or Purpura
3. Cold or clammy skin
4. Cyanosis
5. Jaundice

Labs

Bedside Glucose
1. Treat Hypoglycemia (Glucose < 40 mg/dl) with D10W 2-4 ml/kg IV
Complete Blood Count (findings suggestive of Sepsis)
1. White Blood Cell Count
  1. Decreased below 5000 /mm3
  2. Increased above 25000 /mm3
2. Absolute Neutrophil Count (ANC) < 1000 /mm3
3. Immature (bands) to total Neutrophil Count ratio > 0.2
C-Reactive Protein
1. Reassuring if negative (<10 mg/L) when measured serially in first 24-48 hours (94% NPV)
2. Only one elevated C-RP alone is not specific for Neonatal Sepsis
Basic metabolic panel
1. Includes Blood Urea Nitrogen (BUN) and Creatinine
Blood Culture (positive in 5-10% of Neonatal Sepsis)
1. Most important lab to obtain with suspected Neonatal Sepsis
Lactic Acid
Arterial Blood Gas (or Venous Blood Gas)
1. Indicated for signs or symptoms of Hypoxia
Lumbar Puncture
1. Indications (most cases of suspected Newborn Sepsis)
  1. Sepsis is considered primary diagnosis
  2. Blood Culture positive
  3. Neurologic signs or symptoms
2. Specific Tests
  1. CSF Examination
  2. CSF Culture
  3. CSF Antigens
  4. HSV PCR
  5. Enterovirus PCR
Urinalysis and Urine Culture
1. Indicated for late-onset Neonatal Sepsis
2. Not useful in perinatal period (age <3 days old)
Consider Urine Antigens
1. Escherichia coli
2. Neisseria Meningitis
3. Streptococcal Pneumoniae
4. Group B Streptococcus
Neonatal HSV Testing (if suspected)
1. Liver Function Tests
2. Coagulation tests such as INR, PTT
3. CSF HSV PCR
4. Surface culture for HSV (Conjunctiva, mouth, anus, skin lesions)
Respiratory symptoms during seasonal outbreak times
1. Rapid Influenza Test
2. Respiratory Syncytial Virus (RSV)

Differential Diagnosis

See Neonatal Distress Causes

Diagnostics
Electrocardiogram (EKG)

Indications
1. Tachycardia
2. Cardiac ausultation findings (e.g. cardiac murmur, gallup, rub)
3. Hepatosplenomegaly
Technique
1. Consider obtaing EKG at half speed for easier interpretation
2. Expect T Wave Inversion in leads V1 and V2

Imaging

Chest XRay
1. Indicated in all cases
2. Evaluate for Pneumonia, cardiomegaly, Pneumothorax
Other imaging indicated in specific scenarios
1. CT Head
  1. Indicated for suspected Head Trauma
  2. Subdural Hematoma may present with findings suggestive of Neonatal Sepsis
    1. Low grade fever
    2. Irritability, decreased activity and poor feeding

Evaluation

Neonatal Sepsis Calculator (Kaiser)
1. https://neonatalsepsiscalculator.kaiserpermanente.org/
2. Calculates likelihood of Neonatal Sepsis based on local early onset sepsis Incidence (e.g. 0.7 per 1000 live births)

Management
Stabilization in a septic newborn

See Newborn Resuscitation
Endotracheal Intubation
1. Indicated in critically ill newborns (RSI not required)
Oxygenation
1. Treat Hypoxia but avoid hyperoxia
2. Hyperoxia risks lung and vascular tissue injury due to oxidative stress
Immediate Intravenous Access
1. Umbilical Vein Catheter
2. Peripheral IV at scalp vein
3. Intraosseous Access
  1. Indicated for no access after 2 attempts
Intravenous Fluids
1. Initial: 10 ml/kg Normal Saline bolus
2. Repeat in 10 ml/kg boluses as needed
  1. Maximum 20 ml/kg in Preterm Infants (risk of Intracranial Hemorrhage with over-hydration)
  2. Maximum 40 ml/kg in term infants
Body Temperature
1. Infant should be kept under radiant warmer with abdominal skin probe at 36.5 C (97.7 F)
2. Avoid extreme Temperature changes
  1. Risk of encephalopathic changes, apnea and Temperature dysregulation
3. Rewarm hypothermic infants
  1. Warm blankets
  2. Warm fluids
4. Lower fever
  1. Antipyretics
Blood Glucose
1. Treat Hypoglycemia (Glucose < 40 mg/dl) with D10W 2-4 ml/kg IV
Antimicrobials
1. Do not delay Antibiotics after blood and Urine Cultures to wait for other labs (e.g. Lumbar Puncture)
2. Antibiotic selection is described below
3. Neonatal HSV management may be indicated (see below)
Vasopressors
1. Dopamine has been first-line Vasopressor for infants with fluid-refractory Septic Shock
2. Some expert opinions are to use Norepinephrine (and possibly Epinephrine) instead
Glucocorticoids
1. Indications
  1. Critically ill newborns (esp. preterm) with fluid/vascopressor refractory hemodynamic instability
  2. Postulated to treat underlying relative Adrenal Insufficiency
2. Dosing
  1. Hydrocortisone 2 mg/kg
Seizure management
1. Correct Electrolyte abnormalities
2. Endotracheal Intubation
  1. Indicated for airway management (esp. if Phenobarbital administered)
3. Phenobarbital 20 mg/kg IV
  1. Indicated in intractable Seizures
Other measures
1. Sodium Bicarbonate in Severe Metabolic Acidosis is not typically recommended

Management
General

Continue monitoring and Antibiotics for 48 to 72 hours
1. Indications to continue Antibiotics 14 to 21 days
  1. Symptomatic newborn
  2. Blood Culture positive
2. Discontinue Antibiotics and monitoring if
  1. Blood Cultures negative at 48 to 72 hours and
  2. No signs of Sepsis on examination
Signs of Sepsis with negative culture
1. Consider Neonatal HSV infection
Well appearing newborn with isolated fever
1. Monitor infant for signs of Sepsis
2. Antibiotic indications (contrast with observation only)
  1. Symptomatic infants
  2. Asymptomatic infants with >2 risk factors (see above)

Management
Antibiotics for Early Onset (age <1 week)

Bacterial spectrum
1. Group B Streptococcus
2. Escherichia coli
3. Klebsiella
4. Enterobacter
5. Staphylococcus aureus (not common)
6. Listeria (rare in United States)
Protocol: Ampicillin AND Cefotaxime AND Consider Gentamicin
1. Antibiotic 1: Ampicillin (Meningitis dose often used empirically)
  1. Sepsis: 25 mg/kg IV/IM every 8 hours (37 mg/kg every 12 hours if <2 kg)
  2. Meningitis: 37 mg/kg IV/IM every 8 hours (50 mg/kg every 12 hours if <2 kg)
2. Antibiotic 2: Cefotaxime
  1. Dose: 50 mg/kg/dose IV or IM every 12 hours
  2. Indicated in Meningitis
  3. Increased Antibiotic Resistance in Escherichia coli (esp. Preterm Infants)
3. Antibiotic 3: Gentamicin (consider)
  1. Ask pharmacy to assist on dosing and monitoring
  2. Gestation <30 weeks: 2.5 mg/kg/dose IV/IM q24 hours
  3. Gestation 30-34 weeks: 2.5 mg/kg/dose IV/IM q18 hours
  4. Gestation 34-37 weeks: 2.5 mg/kg/dose IV/IM q12 hours
  5. Gestation >37 weeks: 2.5 mg/kg/dose IV/IM every 8 hours

Management
Antibiotics for Late Onset (age 1-4 weeks)

Coverage broadened over early onset Sepsis
1. Haemophilus Influenzae
2. Staphylococcus epidermidis
Antibiotic Dosing for infant over 7 days old
1. Ampicillin (the higher dose in possible Meningitis)
  1. Weight <2 kg: 25-50 mg/kg/dose IV or IM q8 hours
  2. Weight >2 kg: 25-50 mg/kg/dose IV or IM q6 hours
2. Gentamicin
  1. Ask pharmacy to assist on dosing and monitoring
  2. Gestation <37 weeks: 2.5 mg/kg/dose IV/IM q12 hours
  3. Gestation >37 weeks: 2.5 mg/kg/dose IV/IM q8 hours
Primary Protocol 1
1. Ampicillin (dosed as above)
2. Cefotaxime 50 mg/kg/dose IV or IM q8 hours
Primary Protocol 2
1. Ampicillin (dosed as above)
2. Ceftriaxone 75-100 mg/kg/dose IV or IM q24 hours
Alternative Protocol
1. Ampicillin (dosed as above)
2. Gentamicin (dosed as above)
Additional considerations
1. Add Vancomycin if MRSA suspected
  1. Dose: 15 mg/kg IV q12 hours
  2. Ask pharmacy to assist on dosing and monitoring
2. Add Acyclovir if Neonatal HSV suspected (esp. in first 21 days of life)
  1. Dose: 30 mg/kg/day IV divided every 8 hours
  2. Consider for vesicular rash, Seizure, encephalopathy, Transaminitis, DIC
3. GBS coverage in severe beta-lactam allergy (Ampicillin allergy)
  1. Clindamycin (38% GBS resistance)
  2. Erythromycin (51% GBS resistance)
  3. Back (2012) Antimicrob Agents Chemother 56(2): 739-42 [PubMed]

Prevention

Prolonged Rupture of Membranes GBS Prophylaxis
Routine Group B Strep Screening in pregnancy (36 weeks)
1. NNT 5701 with GBS screening to prevent 1 GBS Sepsis case
2. NNT 1191 with GBS treatment to prevent 1 GBS Sepsis case

References

Joseph and Webb (2015) Crit Dec Emerg Med 29(1): 10-8
Behrman (2000) Nelson Pediatrics, Saunders, p. 550
Cloherty (1991) Neonatal Care, Little Brown, P. 146-58
Gilbert (2015) Sanford Guide, ATI, accessed IOS App 4/20/2016
Biondi (2015) Infect Dis Clin North Am 29(3): 575-85 [PubMed]
Hermansen (2015) Am Fam Physician 92(11): 994-1002 [PubMed]