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A 8 day old female infant born at 36 weeks gestation presented to the ED with feeding difficulties, intermittent cyanosis and apneic spells.

First Impressions?

Initial Differential Diagnosis

Inborn error of metabolism (IEM)
TORCH infections
Congenital heart disease
Hypoxic ischemic encephalopathy
Intracranial bleed


Neonatal Sepsis

Definition- a clinical syndrome in the neonate characterized by systemic signs of infection with bacteremia in the first month of life
Meningitis is usually a sequela of bacteremia and usually shares a common cause and pathogenesis
Typical organisms include both gram (-) and gram (+) organisms
Two patterns of disease- early and late onset


Organisms Associated with Bacterial Sepsis

Gram Positive organisms
Group B strep (GBS) (EOS and LOS)
Staphylococci aureus (LOC)
Coagulase negative staphylococcus (CoNS) (LOS)
Listeria monocytongenes

Gram Negative organisms
E. coli (EOS and LOS)
Haemophilus influenza
Candida albicans


Diagnosis of Neonatal Sepsis

Blood culture remains the gold standard
Serum biomarkers can serve as an adjunct to culture based diagnosis
The ideal marker
- Elevates early in the infectious process
- Stays elevated to allow appropriate sampling
- Have well defined values that differentiate infection from other entities
- A very high sensitivity and negative predictive value


C-Reactive Protein (CRP)

Most commonly used biomarker
Synthesized within 6 hours of exposure to an infectious process
But takes up to 24 hours after onset of infection to become abnormal
Is also elevated with trauma and ischemia
A good indicator of neonatal sepsis??
CRP does have high specificity between 93-100% meaning what??


our patient's initial positive results:

CSF showed mononuclear pleocytosis of 330 cells/µL
EEG showed multifocal epileptic potentials consistent with encephalitis
CRP 5 mg/L (Normal is less than 10)

Empirical treatment with amoxicillin, gentamicin and acyclovir were started. A loading dose of phenobarbital was given.
Despite antibiotic therapy the baby continues to deteriorate with tachycardia and increasing respiratory distress requiring intubation.

EKG showed ST depressions

Final diagnosis: Coxsackie B3 Myocarditis


Enteroviral Infections in the Newborn

Among the most common viruses causing disease in humans with approximately 10-15 million symptomatic infections yearly in the USA
Infections tend to have a seasonal pattern during summer and fall
Illnesses range from a nonspecific febrile illness, mild URIs, self limiting gastroenteritis to myocarditis, hepatitis and encephalopathy


Enterovirus Neonatal Transmission

Can be acquired antenatally, intrapartum and postnatally
In-utero transmission can be by transplacentally or by ascending infection


Clinical Features of Enterovirus Infection

Associated with wide spectrum of signs and symptoms ranging from nonspecific febrile illness to fatal multisystem disease which is frequently called “Neonatal Enterovirus Sepsis”
Most common presenting features include fever, irritability, poor feeding and lethargy
A nonspecific rash is seen in approximately half of infants infected
Approximately half have evidence of hepatitis or jaundice. Hepatomegaly may be present but splenomegaly is rare


How did we deal with our patient?

IV immunoglobulin was given
Because of the decreased cardiac output and developing arrhythmias dopamine and milrinone were started
Over the next 48 hours the infant became refractory to amiodarone and electroconversion for tachyarrhythmia
ECMO (Extracorporeal Membrane Oxygenation) was started

ECMO was continued for 3 weeks with adequately decompressed heart chambers and without major bleeds or infection, however, left ventricular function did not improve and ECMO was withdrawn


when is ECMO more frequently used?

diaphragmatic hernia, at least that's where it started to be used.


birth weight classifications

ELBW less than 1 kg

VLBW less than 1.5 kg

SGA less than 10th percentile

AGA 10th-90th percentile

LGA more than 90th percentile


Sulfonamide ADA in infants

Displaces bilirubin from protein-binding sites, bilirubin deposits in the brain, results in encephalopathy


Chloramphenicol ADA in infants

gray baby syndrome
Abdominal distension, vomiting, diarrhea, characteristic gray color, respiratory distress, hypotension, progressive shock


Thalidomide ADA in infants

Congenital abnormalities; also: polyneuritis, nerve damage, mental retardation


overriding principles in pediatric pharmacology

Children are NOT just “little adults”
Cannot extrapolate dose from adult data based simply on body weight or surface area

Must understand pediatric pharmacokinetic concepts:

Total body water
Extracellular water
Body fat
Protein binding

Phase I
Phase II

Glomerular filtration
Tubular secretion


Pediatric Pharmacokinetics of Oral drug absorption

Gastric volume ↓
Gastric acid ↓ (gastric pH ↑)
Increased absorption of acid labile drugs *** (penicillin G, erythromycin)
Decreased absorption of weakly acidic drugs ***(phenobarbital, phenytoin)
Extrauterine factors (nutrition) most likely responsible for initiating acid production
Transport of bile acids ↓
Gastric emptying ↓, intestinal transit time ↑


Pediatric Pharmacokinetics of Intramuscular Drug Absorption

Absorption inconsistent due to differences in:
- Muscle mass
- Poor perfusion (erratic blood flow)
- Peripheral vasomotor instability
- Insufficient muscle contractions

Sick, immobile neonates or those receiving paralytics may show reduced absorption rates

IM dosing reserved for emergencies or when IV sites inaccessible

Exception: *** phytonadione IM given at birth --> slow release until dietary intake adequate


Pediatric Pharmacokinetics: Transdermal Drug Absorption

Directly related to:
- Degree of skin hydration
- Relative absorptive area

Inversely related to:
- Thickness of stratum corneum

Substantially increased percutaneous absorption:
- Underdeveloped epidermal barrier
- Compromised skin integrity
- Increased skin hydration
- Ratio of BSA to total body weight highest in youngest
---- Relative systemic exposure higher


Pediatric Pharmacokinetics: Rectal Drug Absorption

May be important alternative site when oral agents cannot be used:
- Nausea
- Vomiting
- Seizure activity
- Preparation for surgery

Erratic absorption depending on formulation and retention time


Gentamicin pediatric pharmacokinetics

hydrophilic drug

in the premature neonate-- .5-.7 L/ kg
at one year- .4
in adulthood- .2-.3 L/kg

Body Fat
Total body water varies inversely with fat tissue

Protein Binding ↓
Due to: reduced levels of albumin and α1-acid glycoprotein (+ decreased affinity)
Bilirubin non-covalently bound to albumin with lower affinity in newborn than adult (displaced by ceftriaxone***)


Sample drugs that are metabolized in the infant (phase 1 and 2) and when the CYP is developed in the infant

Phase 1 CYPS:

develop early: erythromycin, alprazolam, simvastatin

within 2 weeks: codeine

throughout childhood: warfarin, phenytoin

within 3 months: acetominophen

negligible in those not exposed: caffeine

alcohol dehydrogenase- at 5 years: chloramphenicol

Phase II:

Glucuronidation undeveloped
Sulfation well-developed


Pediatric drug elimination

Glomerular Filtration
- Ability to filter, excrete, reabsorb not maximized until 1 year
- Rapid rise in GFR:
--- Increased renal blood flow
--- Increased function of nephrons
--- Appearance of additional nephrons

Tubular Secretion
-- Reduced immediately after birth, increases over 1st year

Closely monitor renal function
-- Urine output often used  diaper weights


Medication Dosing in Children

Weight chosen as best estimate of growth
References provide doses in units per weight:
- mg/kg/day
- mcg/kg/dose
- Exception: chemotherapeutic agents (BSA)

Doses outside of reference ranges should always be questioned

Older children/adolescents transition to adult dosing when calculated weight-based dose exceeds adult doses


Ten-fold overdose of narrow therapeutic window drug can be fatal

clonidine, digoxin, morphine, fentanyl


Neonatal Sepsis incidence and risk factors

Incidence inversely proportional to birth weight and GA
Mortality 30-50% (highest observed in neonates 18 hours
Maternal signs/symptoms of intra-amniotic infection
Male sex
Low Apgar scores


Neonatal Sepsis – Pathogenesis

Organisms ascend birth canal

Organisms can also enter amniotic fluid via occult tears

Chorioamnionitis: intra-amniotic infection
- Clinical diagnosis – maternal fever (≥ 38 ˚C; 100.4 ˚ F)
- Other criteria used in clinical trials (2 of the following):
--- Maternal leukocytosis > 15,000 cells/mm3
--- Maternal tachycardia > 100 bpm
--- Fetal tachycardia > 160 bpm
--- Uterine tenderness
--- Foul odor of amniotic fluid


Neonatal Sepsis – Pathogens

Early Onset (within 5-7 days)
GBS (50%)
E. coli (20%)
Listeria monocytogenes
Gram-negative bacilli

Antimicrobial agents:
Third generation cephalosporin
Acyclovir (not routinely used)

Late Onset (after 5-7 days’ PNA)
CONS (68%)
S. aureus

EEG showed multifocal epileptic potentials consistent with encephalitis


Ampicillin MOA

: inhibits bacterial cell wall synthesis


Gentamicin MOA

inhibits bacterial protein synthesis