Transcript Nelfinavir - Emory University Department of Pediatrics

Necrotizing Enterocolitis
Ira Adams-Chapman, M.D.
Assistant Professor in Pediatrics
Medical Director, Developmental Progress Clinic
Emory University School of Medicine
Division of Neonatology
NEC Epidemiology
Incidence
• NEC incidence up to 10% in VLBW overall
– Up to 22% in selected centers
• Incidence inversely related to gestational age
– Smaller infants also with higher morbidity and
mortality
• Rare in term infants
– Usually associated with predisposing/underlying
disorders
NEC Epidemiology
Morbidity and Mortality
• Remains a significant cause of morbidity and
mortality in the VLBW population
• Overall mortality rate 15-30%
• 20-40% require surgery
– With up to 50% mortality
• 20% of medically managed NEC patients develop
strictures
• Concern regarding ND outcome of survivors
– poor growth, CP, vision and hearing impairment, low
Bayley scores
Pathophysiology of NEC
Prematurity
Immaturity of intestine
Motility
Circulatory
and digestion regulation
Hypoxic-ischemic
Injury?
NEC
Feeding
Barrier
function
Immune
defense
Abnormal bacterial
colonization
NEC Epidemiology:
Risk Factors
• Prematurity and low BW most consistently
documented risk factors
– Risk inversely related to GA and BW
• 90% are premature
• 90% were feeding
– Breastmilk reduces risk by 3 to 10-fold
How Do We Feed Babies?
• Mature suck swallow develops at
approximately 34 weeks gestation
• Suckling stimulates digestive enzymes and
may enhance feeding tolerance
• Gavage feeds for the immature infants – no
consensus on which regimen is best
• Monitor for tolerance – residuals, serial
abdominal exams
Nutritional Goals
• Provide adequate
calories for growth:
• 120 kcal/kg/day
• 15-30 gm/kg/day of
weight gain
• Head circumference
should increase 1
cm/week
• Linear growth is
important
Advancing feeding volumes
The Big Questions:
• How much?
• How fast to increase?
• Feeding frequency?
• Continuous vs bolus?
• Do feeding practices
impact the risk of
NEC?
Advancing Feeding Volumes
• No clear consensus on best practice
• Judicious advancement with constant
assessment of patient tolerance
• Typically, start with 20 ml/kg/day and then
advance daily by 10 ml/kg/day
• Advantages to bolus vs continuous feeds
• Monitor for signs of NEC
Breastfeeding and Prematurity
• Breastmilk is best!
• Variable nutritional
content of breastmilk
• Content changes over
time
• Unsupplemented BM
may not meet all
nutritional needs of the
growing preemie
• Appears to confer
some protection from
risk of NEC
Minimal Enteral Nutrition
• Trophic feedings/Non-nutritive feedings are
strongly advised
• Prevents atrophy of intestinal enzymes
• Associated with improved feeding tolerance
• May help prevent microinvasion of bacteria
• Animal models supports use of trophic
feedings
Enteral Nutrition
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Start early!!!
Benefits of colostrum
Benefits of breastmilk
Benefits of trophic feedings in the preterm
Pathophysiology of NEC
Prematurity
Immaturity of intestine
Motility
Circulatory
and digestion regulation
Hypoxic-ischemic
Injury?
NEC
Feeding
Barrier
function
Immune
defense
Abnormal bacterial
colonization
Immature Intestinal Motility and
Digestion
• Incompletely digested molecules can cause
intestinal injury
• Delayed transit time can contribute to the problem
• Feeding can mature motility patterns while
hypoxia can worsen it
Pathophysiology of NEC
Prematurity
Immaturity of intestine
Motility
Circulatory
and digestion regulation
Hypoxic-ischemic
Injury?
NEC
Feeding
Barrier
function
Immune
defense
Abnormal bacterial
colonization
Immature Circulatory Regulation
• Hypoxia-ischemia unlikely to be inciting injury
• However, immature intestinal circulatory
regulation could predispose to ischemic injury in
response to feeding or abnormal bacteria
• Reduced endothelial nitric oxide may play a role
Pathophysiology of NEC
Prematurity
Immaturity of intestine
Motility
Circulatory
and digestion regulation
Hypoxic-ischemic
Injury?
NEC
Feeding
Barrier
function
Immune
defense
Abnormal bacterial
colonization
Immature Intestinal Barrier Function
• Intestinal barrier has structural and biochemical
component
• Structural barrier (tight junctions formed by 10
weeks).
– Structural epithelial barrier regulates
absorption/secretion
• Amniotic fluid matures these functions from 26 weeks to term
– Goblet cells produce mucins adding to structural barrier
• Expression mimics adult pattern between 23 and 27 weeks
• Paneth cells important to biochemical barrier
– Secrete antimicrobial peptides (defensins)
• Contribute to antimicrobial, inflammatory, & secretory
defenses
• Paneth cells and defensin expression reduced in preterm
infants
Immature Intestinal Barrier Function
Immature intestinal barrier function
Immature secretion
and absorption
Immature secretory
diarrhea
Inability to rid intestine
of pathogens/toxins?
Decreased Paneth cell
number
Immature mucin
expression by Goblet cells
Increased intestinal
permeability
Enhanced bacterial
adherence
Reduced defensin
expression
Reduced
antimicrobial
activity?
Reduced
secretory
diarrhea?
Reduced
proinflammatory
activity?
Pathophysiology of NEC
Prematurity
Immaturity of intestine
Motility
Circulatory
and digestion regulation
Hypoxic-ischemic
Injury?
NEC
Feeding
Barrier
function
Immune
defense
Abnormal bacterial
colonization
Immature Immune Defense
• Many inflammatory mediators implicated in the
pathogenesis of NEC
• Inflammation key defense mechanism especially
in microbe rich intestine
– Inflammatory pathways also activate anti-apoptotic/
cytoprotective mediators
• But can cause harmful collateral damage
– Barrier damage can cause opportunistic infection
• Excessive or hypoactive inflammation may play a
role
Immature Immune Defense
Immature intestinal innate immunity
Exaggeration
Inflammation
Opportunistic
infection?
VS.
Increased
intestinal injury?
Intestinal barrier
damage?
Poor inflammatory
response
Increased
apoptosis?
Bacterial
overgrowth?
Pathophysiology of NEC
Prematurity
Immaturity of intestine
Motility
Circulatory
and digestion regulation
Hypoxic-ischemic
Injury?
NEC
Feeding
Barrier
function
Immune
defense
Abnormal bacterial
colonization
Abnormal Bacterial Colonization
• Commensal bacteria regulate genes important for
barrier function, digestion and angiogenesis
• Commensals also inhibit inflammatory signalling
• NEC does not develop in sterile in utero
environment
• Abnormal Clostridium colonization in VLBW has
been implicated in NEC
Hooper LV, et al., Science, 2001
Collier-Hyams LS, et al., Cell Mol Life Sci, 2005
de la Cochietiere MF, Ped Res, 2004
Pathophysiology of NEC
• Etiology is unknown; multifactorial
• Contributing risk factors:
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Ischemia
Feedings
Breast milk protective
Bacterial invasion
Immature mucosal immune system
Clinical Presentation
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Feeding intolerance and residuals
Abdominal distension
Visable loops of bowel
Hypoactive bowel sounds
Bloody stools
Tenderness
Systemic symptoms (↓BP, ↓PLT, ↓WBC, DIC,
RDS, acidosis)
NEC: Clinical Presentation
Bell’s Stages
I. Suspected disease
Mild systemic signs (apnea, bradycardia, temperature instability)
Mild intestinal signs (abdominal distention, gastric residuals, bloody stools)
Nonspecific or normal radiological signs
II. Definite disease
Mild to moderate systemic illness
Additional intestinal signs (absent bowel sounds, abdominal tenderness)
Specific radiologic signs (pneumatosis intestinalis or portal venous air)
Laboratory changes (metabolic acidosis, thrombocytopenia)
III. Advanced disease
Severe systemic illness (hypotension)
Additional intestinal signs (marked abdominal distention, peritonitis)
Severe radiologic signs (pneumoperitoneum)
Additional laboratory changes (metabolic and respiratory acidosis, DIC)
Radiographic Findings in NEC
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Dilated loops of bowel
Thickened loops of bowel
Pneumatosis intestinalis
Pneumoperitoneum
Portal venous air
Normal Bowel Gas Pattern
Nonspecific but Abnormal Bowel
Gas Pattern
Nonspecific but Abnormal Bowel
Gas Pattern
Pneumatosis Intestinalis
Pneumoperitoneum
Pneumoperitoneum
Cross Table Image
Pneumoperitoneum
Left Lateral Decubitus View
Pneumoperitoneum
Outline of Falciform Ligament
NEC: Diagnosis and Management
Clinical concern for NEC
NPO
Low-intermittent orogastric suction
Obtain cultures
Antibiotics
Serial x-rays
Hematologic studies, blood chemistries
Support clinically as indicated
I. Suspected disease
Medical treatment
(Course determined
by
clinical judgement)
III. Advanced disease
Intensive cardiovascular and
respiratory support
Consider surgical intervention
II. Definite disease
Medical treatment 7-14d
NEC: Diagnosis and Management
Surgical indications
Radiologic signs:
Pneumoperitoneum
Persistent fixed loop
Portal venous air
Ascites
Laboratory signs:
Severe thrombocytopenia
Severe neutropenia
Severe acidosis
Management of NEC
• Exploratory laparotomy
• Perintoneal drainage with Penrose
• Medical Management
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Antibiotics
Vasopressors
Coagulopathy/DIC
Decompression
Management of NEC
• Lap vs drain??
– Clinical trials in progress
– Is one more appropriate depending on the
diagnosis?
– Small percentage will ultimately require
surgery
Spontaneous Bowel Perforation
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Different disease than NEC
Infants typically have never been fed
Occurs within the 1st week of life
Typically isolated perforation in small
bowel
• Overall prognosis better than NEC
Short Bowel Syndrome
How short is too short????
• The answer keeps changing!!
Present IC valve - >25 cm
Absent IC valve - >40 cm
• At risk for TPN induced cholestasis
• Malabsorption syndrome
• Bowel transplantation
Short Bowel Syndrome
• Bowel adaptation occurs after bowel resection
• Characterized by epithelial hyperplasia
• Mucosal atrophy occurs if unable to establish
enteral feedings
• Monitor stool pH, fat absorption and volume and
consistency of output
• Risk for bacterial overgrowth – esp if IC valve
removed
Short Bowel Syndrome
• Nutritional deficiency
– Fat soluable vitamins (Vit A, D, E)
– Minerals (Fe, Zn, Ca, Mg)
– Bowel lengthening procedure
– Transplantation
Short Bowel Syndrome
• Incidence varies between sites
• Recent report of 15 centers across US
reported rates from 0.1% to 1.6%
• Site specific outcomes
• Variable patient populations
FIGURE 2 Types of food consumed by ELBW infants at 18 to 22 months' corrected age (n
= 2159)
Cole, C. R. et al. Pediatrics 2008;122:e573-e582
Copyright ©2008 American Academy of Pediatrics
FIGURE 1 Estimated time to in-hospital death for infants 401 to 1500 g birth weight
Cole, C. R. et al. Pediatrics 2008;122:e573-e582
Copyright ©2008 American Academy of Pediatrics
Why Does It Matter??
Everyone
wants a
honey pot to
take home!
Neurodevelopmental Outcome
Association with NEC
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Serious complication of prematurity
Affects 10% of ELBW infants
Often associated with severe SIRS
Various cytokines are elevated in patients
with NEC – TNF-α, PAF, IL-6, IL-8, NO
• Cytokine response has not been well
correlated to disease severity
Neurodevelopmental Outcome
Association with NEC
• Recent evidence that the inflammatory
response associated with NEC may be a
mediator for brain injury
• NICHD outcome study showed 2-fold
increased risk for abnormal motor outcome.
• Recent abstracts suggest increased
incidence of abnormal CUS and mental
delay
Neurodevelopmental Outcome
Association with NEC
• Recent review by Hintz, et al, Pediatrics
• Infants with surgical NEC were more likely
to have growth impairment, MDI <70, PDI
< 70 and overall neurodevelopmental
impairment at 18-22 months AA, compared
to infants with medically managed NEC or
no NEC
ND Outcome and NEC
NEC: Potential Preventive Strategies
•Common practice
Human milk feedings
Conservative feeding
Trophic feeding
•Research ongoing
Antenatal steroids
IgA supplementation
Arginine supplementation
Erythropoietin
Oral antibiotics
Probiotics
Thank You!