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Flashcards in Neonatal Case Conference Deck (38):
1

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

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

2

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

3

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
Citrobacter
Fungi
Candida albicans

4

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

5

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??

6

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

7

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

8

Enterovirus Neonatal Transmission

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

9

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

10

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

11

when is ECMO more frequently used?

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

12

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

13

Sulfonamide ADA in infants

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

14

Chloramphenicol ADA in infants

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

15

Thalidomide ADA in infants

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

16

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:
Absorption:
Oral
Intramuscular
Transdermal
Rectal

Distribution:
Total body water
Extracellular water
Body fat
Protein binding

Metabolism:
Phase I
Phase II

Elimination:
Glomerular filtration
Tubular secretion


17

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 ↑

18

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

19

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

20

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

21

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***)

22

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
Acetylation

23

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

24

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

25

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

clonidine, digoxin, morphine, fentanyl

26

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
Ethnicity
Male sex
Low Apgar scores

27

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

28

Neonatal Sepsis – Pathogens

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


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


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

EEG showed multifocal epileptic potentials consistent with encephalitis

29

Ampicillin MOA

: inhibits bacterial cell wall synthesis

30

Gentamicin MOA

inhibits bacterial protein synthesis

31

Third Generation Cephalosporin
MOA

Cefotaxime vs. ceftriaxone
MOA: inhibits bacterial cell wall synthesis

32

Acyclovir

MOA: inhibits viral DNA synthesis and viral replication

33

Viral Myocarditis

Incidence – 1:100,000
Implicated in up to 12% of sudden cardiac deaths in adolescents and young adults

Pathophysiology:
Acute phase: inflammatory cell invasion of myocardium and myocardial necrosis and apoptosis
T-cell invasion: most destructive 7-14 days after inoculation
Healing phase: myocardial fibrosis; continued inflammation and persistent viremia may lead to left ventricular dysfunction and dilation

34

Viral Myocarditis – Treatment

Acute phase:

Inotropes
Afterload reduction
Mechanical ventilation
Extracorporeal membrane oxygenation (ECMO)
Immune therapy
Intravenous immunoglobulin (IVIG)
Immunosuppressive agents

35

Extracorporeal Membrane Oxygenation (ECMO)

Prolonged cardio-pulmonary bypass (3-10 days)
Supports patients with life-threatening respiratory or cardiac failure


Neonatal indications:

Primary pulmonary hypertension
Meconium aspiration syndrome
Respiratory distress syndrome
Group B Streptococcal sepsis
Asphyxia
Congenital diaphragmatic hernia

36

ECMO Circuit

Blood siphoned, driven by right arterial pressure
Roller pump draws blood into bladder and pushes it through oxygenators and heat exchanger

37

ECMO Complications

Clots in circuit (19%)
Oxygenator failure
Seizures
Intracranial bleeding
Hemolysis and coagulopathy
Arrhythmias
Oliguria (within 24-48 hours)
Metabolic acidosis

38

Medication Use in ECMO

Site of drug delivery
- Directly into patient? - don't want to mess with IV lines, etc. because of anticoagulation efforts
- Proximal, distal, or directly into venous reservoir? best choice is still proximal to the reservoir in order to limit the risk of air embolism

Hemodilution
- Circulating blood volume will double (blood mixing with priming solution) affecting drugs with small volumes of distribution and those that are highly protein bound

Drug binding interactions with the circuit
- Adsorption and sequestration onto plastic cannula and/or silicone oxygenator

Altered renal, hepatic, and cerebral blood flow
- Non-pulsatile blood flow