Pediatric Critical Care Medicine

Emory University
Childrens Healthcare of Atlanta
CNS Bacterial Infections
Introduction
Infections of the CNS are among the most devastating
infectious diseases
Cause death and disability worldwide
Often present as medical emergencies
Early, appropriate care is critical to reducing morbidity and mortality
CNS Development
CNS Development
2 wks: Neural plate forms from ectoderm
Neural tube completed by day 26-28
3-4 wks: Hemispheres form
Pons/medulla develop at 3-7.5 wks
8-18 wks: Neuronal proliferation
Up to 200,000 new neurons per minute
> 25 wks: Arborization, synaptogenesis, apoptosis, neural
connectivity
30 wks - adolescence: Continuing myelination
CNS Development
The mature human brain will have 10 billion neurons
Most are formed during the period of rapid proliferation (8-18 wks)
Very little neurogenesis after birth
70% of developing neurons will die by apoptosis during
development
Bcl-2, Apaf1, cystein-protease caspase
Pathways are upregulated during development
Newborn brain more prone to injury-related PCD
Blood-Brain Barrier
Blood-Brain Barrier
There is debate over whether the infant BBB is leaky
Tight junctions in mature BBB form a true zona occludens
Agree that permeability of macromolecules in the same as in adults
BBB has both static and dynamic properties
Astrocyte feet have lots of control
Impermeable to ions, proteins, osmolar agents
Osmotic (not oncotic) gradients are critical to water movement through
aquaporin channels


Pathogenesis
Pathogens must first gain access to CNS to cause disease
Subarachnoid space (meningitis)
CNS parenchyma (encephalitis, myelitis, abscess)
Most are spread through the bloodstream
May also occur through direct spread
Adjacent structures (otitis, sinusitis, dental abscess)
Shunt infections
Skull fractures
Clinical Syndromes
Syndrome Signs and Symptoms Pathogen
Acute Meningitis Acute onset of fever, HA, vomiting,
meningismus, AMS
Progression over hours to days
Bacteria, viruses
Subacute or Chronic
Meningitis
Gradual onset, lower fever,
progression over weeks
Tuberculous, fungal
Acute Encephalitis

Diffuse: AMS and seizures
Focal: tropism of virus for specific
CNS location (HSV)
Viruses
Encephalopathy w/
Systemic Infection
Symptoms vary, often AMS.
Chorea?
Shigella, typhoid,
malaria, Rickettsia,
endocarditis
Postinfectious Various, depending on lesion
ADEM, transverse myelitis, optic
neuritis, MS
Viruses, vaccines
Diagnosis
Thorough history and physical exam are very important!
Note chronicity of symptoms, comorbid conditions, preceding illnesses,
VP shunt
Travel, surgery, trauma, sick contacts, insect bites, animal contact,
sexual activity
Lab evaluation: CBC, CMP, CPR, UA, blood culture
CSF: opening pressure, cultures, cytology
Fungal, AFB, mycobacterial cx if appropriate
CSF gram stain, PCR, antigen testing, serology
Other studies: Imaging, EEG, biopsy, I&D

CSF Findings
Characteristics Viral Bacterial Tubercular
WBC/mm
3
Normal (<5) or
raised (10-100)
Raised 100
>1000
Raised 100
1000
Cell type Lymphocytes Neutrophils Lymphocytes
Glucose
(CSF: serum)
Normal (<0.6) or
decreased (<0.4)
Decreased <0.4
(or much lower)
Decreased <0.4
Protein Normal (<50) or
up to 100
Raised 100
>500
Raised 100-500
General Management
Neurologic evaluation
Meningeal signs
Severity of coma
Neuro exam (focal deficits, cranial nerves, bulbar tone)
Increased ICP
Other sites of infection or injury
Otitis, sinusitis, PNA
Rashes or skin lesions
Trauma
General Management
Consider intubation if GCS <8 or bulbar hypotonia
Take care to minimize ICP spikes
Consider thiopental, propofol, ketamine (becoming more accepted for
high ICP), lidocaine
Modified RSI, avoid overventilation
Get antibiotics going early and at high doses!
Cardiovascular support as needed
General Management
Consider ICP monitoring for moderate to severe ICP elevation
Level of consciousness correlates well with decreased cerebral
perfusion
M&M are inversely related to CPP
Control seizures with benzodiazepenes
About 50% of patients with seizures progress to status
Status is hard to treat and has poor outcome

General Management
Electrolyte and fluid derangements are common
At risk for diabetes insipidus
Do not fluid restrict empirically
Prospective RCT by Singhi et al found no outcome improvement with
fluid restriction vs. maintenance
Correct hyponatremia slowly over 36-48 hrs
3% if necessary for seizures
Also at risk for hypokalemia
GI losses, hemodilution, osmotherapy, diuretics, sepsis
BACTERIAL MENINGITIS
Etiology, Pathophysiology, Diagnosis, Treatment, Outcome
Bacterial Meningitis: Etiology
*There are 3 main bacterial meningeal
pathogens:
1. Haemophilus influenzae
2. Neisseria meningitidis
3. Streptococcus pneumoniae
*Incidence varies by region and age.
Haemophilus influenzae
Small GN, pleomorphic,
coccobacilli
H. flu type B causes almost
ALL invasive disease
Nontypeable Hib can rarely
cause meningitis.
Incidence of Hib decreased
by 97% after vaccine
Neisseria meningitidis
- GN diplococci
- Serotypes A,B,C,Y, and
W135 cause most invasive
disease.
- Virulence depends on:
1. Capsular polysaccharide
2. LPS(endotoxin)
3. Pili
4. IgA protease
5. ompS gene


Streptococcus pneumoniae
* Small, non-motile GPC in
pairs or chains.
* 8 serotypes cause 90% of
invasive disease.
1, 4, 6, 9, 14, 18, 19 & 23
* Virulence depends on
capsular polysaccharides
* Associated with CSF leak
(skull fractures), asplenia,
HIV, cochlear implants
Other Pathogens: GN bacilli
Neonatal GN sepsis/meningitis is most commonly due to
E.coli
K1 capsular polysaccharide antigen is a marker of neurovirulence
Outside of neonates, GN meningitis is often nosocomial
Associated with GI infections, head trauma, NS procedures, immune
deficiency
Klebsiella, Salmonella, Enterobacter, and Pseudomonas
Klebsiella Ventriculitis/Abscess
Other Pathogens: GBS
Still a common cause of invasive neonatal disease
Six main serotypes: Type III causes most neonatal meningitis
Incidence is down in developed countries due to screening and
treatment of pregnant women
GBS Meningitis with Infarcts
Other Pathogens: Listeria
Listeria monocytogenes is a Gram positive rod and still an
important cause of neonatal sepsis
Can also be seen in older children with cellular immune
deficiencies
Associated with maternal consumption of unpasteurized
cheese or contaminated meats
Other Pathogens: Anaerobes
* Anaerobic meningitis occurs in only in certain conditions
Rupture of brain abscess
Chronic otitis, mastoiditis, sinusitis
Head trauma, NS procedures
Congenital dural defects
GI infections, suppurative pharyngitis
CSF shunts
Immune suppression
* Includes Bacteroides fragilis, Fusobacterium spp.,
Clostridum spp
Pathogenesis
Pathophysiology
* With acute CNS infection there is loss of autoregulation:
Early increase in CBF, followed later by a decrease
At risk for global cerebral hypoperfusion
* Focal hypoperfusion can result from vasculitis leading to
ischemia
Can occlude large vessels: carotid, MCA, ACA
* Cerebral edema can be vasogenic, cytotoxic, or interstitial
Interstitial edema is the main cause of obstructive hydrocephalous
in meningitis



Cerebral Edema
Clinical Presentation
Depends on the age of the patient and the offending organism
Generally more abrupt onset than viral
Infants have a variable presentation
Fever, poor feeding, lethargy, irritability, high-pitched cry, full
fontanelle
Older children may have acute onset of fever, HA, vomiting,
photophobia, and altered mental status
+/- Kernig or Brudzinski sign

Clinical Presentation
*Seizures may be the
presenting feature in nearly 1 in
6 children
Have a low index of suspicion
with seizures + fever
*Papilledema is uncommon at
presentation
*Focal signs can be found in
14% of cases
Sudural epyema, cortical
infarction, cerebritis
*Rashes are not uncommon
Petechial or purpuric rash highly
suggests meningococcemia
Diagnosis
* Definitive diagnosis is by analysis and culture of the CSF
LP should be done at earliest opportunity
Do not delay antibiotics may alter culture and gram stain but chemistry
or cells
* WAIT on the LP if:
Evidence of raised ICP (pupil changes, cushings, kussmaul pattern,
deep coma), focal neuro exam, resp/CV instability, coagulopathy
Get a head CT if there is focality or question about diagnosis
Diagnosis
CSF findings include high opening pressure, pleocytosis, low
glucose, and high protein
Cloudy CSF with high opening pressure is diagnostic
Glucose ratio of 0.4 is 80% sensitive and 98% specific
CSF WBC (predicted) = CSF RBC x (blood WBC/blood
RBC)
Observed CSF WBC/ predicted <0.01 and WBC/RBC ratio of <0.01
are 100% reliable in ruling out bacterial meningitis
Diagnosis
Gram stains are quick, cheap, and accurate
90% strep, 86% H. flu, 75% neisseria, 30% Listeria
CSF culture will be positive in the majority of untreated cases
Empiric diagnosis can be made if:
CSF WBC > 300, with >60% polys
Glucose < 50% of serum
Absolute glucose < 30
Diagnosis: Viral vs. Bacterial
* Latex agglutination
Helpful in partially treated meningitis
Specific but not that sensitive
Strep pneumo 96% specific, 70 -100 % sensitive
* PCRs are available for neisseria and pneumococcus
Both are sensitive and specific
DNA load correlates with mortality for neisseria
Very expensive
* CRP may be helpful but only if very high or very low
* Peripheral WBC, CSF lactate, limulus amebocyte lysate,
procalcitonin, and various cytokines are up in the air
Complications
Raised ICP
Seizures
Subdural empyema
Infarcts
Cerebritis
Brain abscess
Hydrocephalous, ventriculitis
Cranial nerve involvement
Sensorineural hearing loss
Treatment: By Age
Age Common pathogens Antimicrobial Therapy
< 1 month GBS, E. coli, Listeria,
Klebsiella
Amp + cefotaxime or an
aminoglycoside
1-23 months S.pneumoniae, N.
meningitidis, GBS, H.flu,
E.coli
Vanc + 3
rd
gen
cephalosporin
2-50 years N. meningitidis, S.
pneumoniae
Vanc + 3
rd
gen
cephalosporin
> 50 years S. pneumoniae, N.
meningitidis, Listeria, GN
bacilli
Vanc + amp + 3
rd
gen
ceph
Treatment: Head Trauma
Type of Trauma Pathogens Antimicrobial Therapy
Basilar skull fracture S.pneumo, H.flu, group A
strep
Vanc + 3
rd
gen ceph
Penetrating trauma S.aureus, coag-neg staph,
GN bacilli (Pseudomonas)
Vanc + cefepime, ceftaz,
or meropenem
Post-neurosurgery GN bacilli, S. aureus, coag-
neg staph
Vanc + cefepime, ceftaz,
or meropenem

CSF shunt Coag-neg staph, GN bacilli,
propionibacterium acnes
Vanc + cefepime, ceftaz,
or meropenem

Duration of Therapy
Organism Length of Treatment
Neisseria meningitidis 7 days
Strep pneumoniae 10-14 days
GBS, Listeria, GNs 3 weeks minimum
Other Considerations
In developing countries, ampicillin and chloramphenicol are
sometimes used due to the high cost of cephalosporins
Increasing resistance of H.flu to ampicillin, but it is via B-lactamase
production
Remember that strep and meningococcus resistance is by alteration of
penicillin binding proteins
Meropenem and newer fluoroquinolones are as effective as
cephalosporins, but still are not 1
st
line
Meropenem is good for ESBLs
Other Considerations
With treatment CSF culture and Gram stain will become
negative in 24-48 hours
Glucose will normalize in 72 hours
Cells and protein take days
Fever may persist for 7-10 days (H.flu), but beyond this
consider other factors
Thrombophlebitis, spread of infection, empyema, drug fever
A recurrence of fever may also indicate a complication or a secondary
nosocomial infection
Do we need a repeat LP?
Repeat LPs are not routinely necessary if the patient gets
better and is afebrile
EXCEPT for neonatal GN meningitis
Consider repeat LP in these situations:
No clinical improvement after 3-4 days of abx
NEW focal neuro signs, AMS, or increased ICP
Initial culture had resistant/weird bugs and no improvement after 24-48
hrs of appropriate therapy

Should we give steroids?
* Inflammatory cascade in bacterial meningitis leads to tissue
damage and can worsen neurologic sequelae
Antibiotics make this worse
* Steroids can decrease inflammation, ICP, cerebral edema, and CSF
outflow obstruction
* Dexamethasone given to patients with H.flu or pneumococcal
meningitis has shown benefit
* The AAP recommends its use in H.flu meningitis
0.4 mg/kg q12h x 2 days
* Adult guys give it when strep pneumo is suspected
Consider adding rifampin?
* The benefits of steroids have NOT been established in neonatal
meningitis
Prognosis
Mortality continues to be as high as 15-20%
Coma, raised ICP, seizures, and shock are significant
predictors of morbidity and mortality
Neurologic sequelae are common
Hydrocephalous, spasticity, vision/hearing loss, cognitive defects,
developmental delay

Prevention
Isolation is necessary for H.flu and Neisseria for the first 24
hours of treament
Rifampin prophylaxis is indicated for household contacts of
H.flu if any of them is unvaccinated and <4yrs old
Rifampin is also recommended for household and daycare
contacts of Neisseria
Single oral dose of cipro or azithro is ok for adults
Prevention
H.flu vaccine is awesome and has virtually eliminated H.flu
meningitis in developed countries
Heptavalent pneumococcus vaccine is good too
Dont forget kids with asplenia, nephrotic syndome, sickle cell, and
cochlear implants need 23-valent
Quadrivalent meningococcal vaccine (A, C, Y, W135) is
recommended for high risk kids > 2 yrs and college
students/military

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