Neonatal Case Conference Flashcards
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
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 Citrobacter Fungi 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
kernicterus
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: 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
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
Acetylation
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
Ethnicity
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%) 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
Ampicillin MOA
: inhibits bacterial cell wall synthesis
Gentamicin MOA
inhibits bacterial protein synthesis
Third Generation Cephalosporin
MOA
Cefotaxime vs. ceftriaxone
MOA: inhibits bacterial cell wall synthesis
Acyclovir
MOA: inhibits viral DNA synthesis and viral replication
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
Viral Myocarditis – Treatment
Acute phase:
Inotropes Afterload reduction Mechanical ventilation Extracorporeal membrane oxygenation (ECMO) Immune therapy Intravenous immunoglobulin (IVIG) Immunosuppressive agents
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
ECMO Circuit
Blood siphoned, driven by right arterial pressure
Roller pump draws blood into bladder and pushes it through oxygenators and heat exchanger
ECMO Complications
Clots in circuit (19%) Oxygenator failure Seizures Intracranial bleeding Hemolysis and coagulopathy Arrhythmias Oliguria (within 24-48 hours) Metabolic acidosis
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
