Perinatal physiology Neonatal physiology and pharmacology

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Perinatal physiology Neonatal physiology and
pharmacology

• Dr. Poonam Patel

University College of Medical Sciences GTB
Hospital, Delhi
www.anaesthesia.co.in
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Definitions

• Perinatal period The perinatal period commences
  at 22 completed weeks (154 days) of gestation
  (the time when birth weight is normally 500 g),
  and ends seven completed days after birth. (WHO -
  World Health Organization).
• Neonate 1-30 days old

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Perinatal physiology

• The circulatory system is the first to achieve a
  functional state in early gestation
• The developing fetus outgrows its ability to
  obtain distribute nutrients and O2 by diffusion
  from the placenta
• The functioning heart grows develops at the
  same time it is working to serve the growing
  fetus
• At 2 months gestation the development of the
  heart and blood vessels is complete
• In comparison, the development of the lung begins
  later is not complete until the fetus is near
  term

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Fetal Circulation

• Placenta
• Gas exchange
• Waste elimination
• O2 saturation of 65 in maternal blood, but 80
  in the fetal umbilical vein (UV)
• Low affinity of fetal Hb for 2,3-DPG as compared
  with adult hemoglobin
• Low concentration of 2,3-DPG in fetal blood
• O2 2,3-DPG compete with HbF for binding, the
  reduced affinity of HbF for 2,3-DPG causes the
  HbF to bind to O2 tighter
• Higher fetal O2 saturation

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Fetal Circulation

• P50 is 27mmHg for adult Hb, but only 20mmHg for
  fetal Hb
• This causes a left shift in the O2 dissociation
  curve

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Fetal Circulation
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Fetal Circulatory Flow

• Starts at the placenta with the umbilical vein
• Carries essential nutrients O2 from the
  placenta to the fetus (towards the fetal heart,
  but with O2 saturated blood)
• The liver is the first major organ to receive
  blood from the UV
• Essential substrates such as O2, glucose amino
  acids are present for protein synthesis
• 40-60 of the UV flow enters the hepatic
  microcirculation where it mixes with blood
  draining from the GI tract via the portal vein
• The remaining 40-60 bypasses the liver and flows
  through the ductus venosus into the upper IVC to
  the right atrium (RA)

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Fetal Circulatory Flow

• The fetal heart does not distribute O2 uniformly
• Essential organs receive blood that contains more
  oxygen than nonessential organs
• This is accomplished by routing blood through
  preferred pathways
• From the RA the blood is distributed in two
  directions
• 1. To the right ventricle (RV)
• 2. To the left atrium (LA)
• Approximately 1/3 of IVC flow deflects off the
  crista dividens passes through the foramen
  ovale of the intraatrial septum to the LA

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• Flow then enters the LV ascending aorta
• This is where blood perfuses the coronary and
  cerebral arteries
• The remaining 2/3 of the IVC flow joins the
  desaturated SVC (returning from the upper body)
  mixes in the RA and travels to the RV main
  pulmonary artery
• Blood then preferentially shunts from the right
  to the left across the ductus arteriosus from the
  main pulmonary artery to the descending aorta
  rather than traversing the pulmonary vascular bed
• The ductus enters the descending aorta distal to
  the innominate and left carotid artery
• It joins the small amount of LV blood that did
  not perfuse the heart, brain or upper extremities

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• The remaining blood (with the lowest sat of 55)
  perfuses the abdominal viscera
• The blood then returns to the placenta via the
  paired umbilical arteries that arise from the
  internal iliac arteries
• Carries unsaturated blood from the fetal heart
• The fetal heart is considered a Parallel
  circulation with each chamber contributing
  separately, but additively to the total
  ventricular output
• Right side contributing 67
• Left side contributing 33
• The adult heart is considered Serial

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Transitional Neonatal Circulation

• Successful transition from fetal to neonatal
  circulation requires
• 1. Foramen Ovale, ductus arteriosus ductus
  venosus close to establish a heart whose chambers
  pump in series rather than parallel
• 2. Removal of placenta
• 3. Decrease in PVR The principal force causing a
  change in the direction path of blood flow in
  the newborn

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Transitional Neonatal Circulation

• Changes that establish the newborn
  circulation are an orchestrated series of
  interrelated events
• As soon as the infant is separated from the low
  resistance placenta takes the initial breath
  creating a negative pressure (40-60cm H2O),
  expanding the lungs, a dramatic decrease in PVR
  occurs
• Exposure of the vessels to alveolar O2 increases
  the pulmonary blood flow dramatically
  oxygenation improves

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Transitional Neonatal Circulation

• The pulmonary vasculature of the newborn can also
  respond to chemical mediators such as
• Histamine
• Acetylcholine
• Prostaglandins
• All are vasodilators
• Hypoxia and/or acidosis can reverse this causing
  severe pulmonary constriction

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Transitional Neonatal Circulation

• PVR PAP continue to fall at a moderate rate
  throughout the first 5-6 weeks of life then at a
  more gradual rate over the next 2-3 years
• Most of the decrease in PVR (80) occurs in the
  first 24 hours the PAP usually falls below
  systemic pressure in normal infants
• Babies delivered by C-section have a higher PVR
  than those born vaginally it may take them up
  to 3 hours after birth to decrease to the normal
  range

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Closure of the Ductus Arteriosus,Foramen Ovale
Ductus Venosus
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Ductus Arteriosus

• Closure occurs in two stages
• Functional closure occurs 10-15 hours after birth
• This is reversible in the presence of hypoxemia
  or hypovolemia
• Permanent closure occurs in 2-3 weeks
• Fibrous connective tissue forms permanently
  seals the lumen
• This becomes the ligamentum arteriosum

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Foramen Ovale

• Increased pulmonary blood flow left atrial
  distention help to approximate the two margins of
  the foramen ovale
• This is a flap like valve eventually the
  opening seals closed
• This hole also provides a potential right to left
  shunt
• Crying, coughing valsalva maneuver increases
  PVR which increases RA RV pressure
• A right to left atrial shunt may therefore
  readily occur in newborns young infants

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Foramen Ovale

• Probe Patency
• Is present in 50 of children lt 5 years old in
  more than 25 of adults
• Therefore, the possibility of right to left
  atrial shunting exists throughout life there is
  a potential avenue for air emboli to enter the
  systemic circulation
• A patent FO may be beneficial in certain heart
  malformations where mixing of blood is essential
  for oxygenation to occur such as in transposition
  of the great vessels

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Ductus Venosus

• After the placenta is separated , blood passing
  through the ductus venosus is suddenly reduced
  causing passive closure over the next 3-7 days

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Changes in the lung after delivery

• Fluid compressed from fetal lung during vaginal
  delivery establishing lung volume ? first breath
  initiated centrally secondary to arousal from
  sound, temperature changes and touch ?central
  chemoreceptors stimulated by hypoxia and
  hypercarbia further increase respiratory drive ?
  initial respiratory efforts generate large
  negative intrapleural pressure (-70 mm Hg) ?
  recruitment of alveoli with assistance of surface
  tension lowering properties of surfactant
  ?alveolar fluid is cleared through upper airway ?
  residual fluid cleared over 24- 72 hours by
  transcapillary and translymphatic route ?
  initially expiration is active with pressures of
  18-115 cm H2O generated forcing amniotic fluid
  from the bronchi.

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Neonatal Physiology

• Nervous System
• Soft pliable cranium with two open fontanelles
• Structurally complete brain but incompletely
  myelinated (till 2 years of age).
• Predominant brain constituent in neonate is
  water. During infancy myelin and protein content
  increases.
• Spinal cord ends at L4

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• Blood brain barrier is immature in the neonate
  till 6 months of age allowing easy access to
  large lipid soluble molecules like anaesthetic
  drugs and free bilirubin.
• Brain increases in size by 3 times during first
  year of life, producing high metabolic demand. In
  neonate one third of cardiac output perfuses the
  brain as compared to one seventh in adult
• Cerebral blood flow ?
• neonate 30- 40 ml/ 100gm / min
• Adult 55 ml/100 gm / min
• Children 65- 100 ml/ 100gm /min

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• Cerebral blood flow is autoregulated in neonate
  upto mean arterial pressure of 30 mmHg.
• Autonomic responses better developed to protect
  against hypertension as parasympathetic system
  predominates.
• Neonates have neural and neuroendocrine
  mechanisms for perception of noxious stimuli as
  early as 6 weeks after gestation.

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Respiratory physiology

• Respiratory rhythm generated in ventrolateral
  medulla and modulated by central chemoreceptors
  in response to carbon dioxide, ph and oxygen
  content in the blood.
• Peripheral chemoreceptors are located in aortic
  and carotid bodies ? functional at birth ?
  initially silent because of high post delivery
  blood oxygen content ? receptor adaptation occurs
  over 48 hours.

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Ventilatory response to carbon dioxide

• CO2 levels ? ? alveolar ventilation ? response
  increases with gestational age and postnatal age.
  
• Resting CO2 levels are lower than in adult
• Ventilatory response to CO2 reaches adult value
  by 2 years

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Ventilatory response to hypoxemia

• During first 3 weeks ? temperature dependant.
• Hypothermia ? hypoxemia decreases ventilation
• normothermia ? hypoxemia causes transient
  hyperventilation via peripheral chemoreceptors
  that is followed by a decrease in ventilation
• At the end of first month ? response is
  independent of temperature ? hypoxemia increases
  alveolar ventilation

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• Breathing Patterns of Infants
• Less than 6 months of age
• Predominantly abdominal (diaphragmatic) and the
  rib cage (intercostal muscles) contribution to
  tidal volume is relatively small (20-40)
• In preterm neonate ? periodic breathing pattern
  with occasional episodes of apnea (5-15 secs) ?
  prolonged apneic episodes cause bradycardia and
  hypoxemia

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Anatomic Differences in the Respiratory System

• Upper Airway the nasal airway is the primary
  pathway for normal breathing
• During quiet breathing the resistance through the
  nasal passages accounts for more than 50 of the
  total airway resistance (twice that of mouth
  breathing)
• Except when crying, the newborns are considered
  obligate nose breathers
• This is because the epiglottis is positioned high
  in the pharynx and almost meets the soft palate,
  making oral ventilation difficult
• If the nasal airway becomes occluded the infant
  may not rapidly or effectively convert to oral
  ventilation
• Nasal obstruction usually can be relieved by
  causing the infant to cry

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• The Tongue is large occupies most of the
  cavity of the mouth oropharynx
• Pharyngeal Airway is not supported by a rigid
  bony or cartilaginous structure
• Is easily collapsed by
• The posterior displacement of the mandible during
  sleep
• Flexion of the neck
• Compression over the hyoid bone

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• Laryngeal Airway this maintains the airway
  functions as a valve to occlude protect the
  lower airway
• In the infant the larynx is located high
  (anterior cephalad) opposite C-4 (adults is
  C-6)
• The body of the hyoid bone is between C2-3 in
  the adult is at C-4
• The high position of the epiglottis larynx
  allows the infant to breathe swallow
  simultaneously
• The larynx descends with growth
• Most of this descent occurs in the 1st year but
  the adult position is not reached until the 4th
  year
• The vocal cords of the neonate are slanted so
  that the anterior portion is more cephalad
  anteriorly and rostral posteriorly

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• Narrowest area of the airway
• Adult is between the vocal cords
• Infant is in the cricoid region of the larynx
  (3-5mm diameter)
• The cricoid is circular cartilaginous and
  consequently not expansible
• An endotracheal tube may pass easily through an
  infants vocal cords but be tight at the cricoid
  area.
• This is also frequently the site of trauma during
  intubation
• 1mm of edema on the cross sectional area at the
  level of the cricoid ring in a pediatric airway
  can decrease the opening 75 vs. 19 in an adult

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• Trachea
• Infant the alignment is directed caudally
  posteriorly
• Adult it is directed caudally
• Cricoid pressure is more effective in
  facilitating passage of the endotracheal tube in
  the infant
• Newborn Trachea
• Distance between the bifurcation of the trachea
  the vocal cords is 4-5cm
• Endotracheal tube (ETT) must be carefully
  positioned fixed
• Because of the large size of the infants head
  the tip of the tube can move about 2cm during
  flexion extension of the head
• It is extremely important to check the ETT
  placement every time the babys head is moved

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• Anatomical differences of chest and lower
  airway
• ribs are horizontal , soft, non calcified do
  not rise as much as an adults during inspiration
• Intercostal muscles are poorly developed with
  fewer type1 oxidative fibers
• The diaphragm is more important in ventilation
  the consequences of abdominal distention are much
  greater
• As the child grows (learns to stand) gravity
  pulls on the abdominal contents encouraging the
  chest wall to lengthen

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• Diaphragmatic intercostal muscles of infants
  are more liable to fatigue than those of adults
• This is due to a difference in muscle fiber type
• -Adult diaphragm has 60 of type I slow twitch,
  high oxidative, fatigue resistant
• -Newborns diaphragm has 75 of type II fast
  twitch, low oxidative, less energy efficient
• -The same pattern is seen in intercostal muscles
• The newborn is more prone to respiratory fatigue
  may not be able to cope when suffering from
  conditions that result in reduced lung compliance
  (RDS)

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Differences in Lung volumes in neonate

• Lung volumes in neonate are lesser than adult
  when adjusted for weight and even smaller when
  adjusted for metabolic differences
• Total alveolar surface area for gas exchange in
  neonates is 50 times less than in adults even
  though metabolic rate in neonate is twice than
  that in adult.
• FRC, TV and dead space is similar to adults when
  normalised for body weight

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Pulmonary Function Values

• Neonate Adult
• Tidal volume (ml/kg) 6 7
• Respiratory rate 35 15
• Vital capacity (ml/kg) 35 70
• Functional residual
• capacity (ml/kg) 30 35
• Closing capacity (ml/kg) 35
  23
• Total lung capacity (ml/kg) 63
  86
• Alveolar ventilation (ml/kg/min) 130
  60

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Gas Exchange Values

• Neonate (3kg) Adult (70kg)
• O2 consumption 7 3.5
• (ml/kg/min)
• CO2 production 6 3
• (ml/kg/min)

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Cardiovascular physiology

• There are gross structural differences
  changes in the heart during infancy
• At birth the right left ventricles are
  essentially the same in size wall thickness
• During the 1st month volume load afterload of
  the LV increases whereas there is minimal
  increase in volume load decrease in afterload
  on the RV
• By four weeks the LV weighs more than the RV
• This continues through infancy early childhood
  until the LV is twice as heavy as the RV as it is
  in the adult

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Myocardial cell in neonate

• The myocardial tissues contain a large number of
  nuclei mitochondria with an extensive
  endoplasmic reticulum to support cell growth
  protein synthesis during infancy
• The amount of cellular mass dedicated to
  contractile protein in the neonate infant is
  less than the adult
• 30 vs. 60
• These differences in the organization, structure
  contractile mass are partly responsible for the
  decreased functional capacity of the young heart
• Both ventricles are relatively noncompliant

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Circulation

• The vasomotor reflex arcs are functional in the
  newborn as they are in adults
• Baroreceptors of the carotid sinus lead to
  parasympathetic stimulation sympathetic
  inhibition
• There are less catecholamine stores a blunted
  response to catecholamines. Therefore neonates
  infants can show vascular volume depletion by
  hypotension without tachycardia

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Cardiovascular Parameters

• Parameters are much different for the infant than
  for the adult
• Heart rate higher
• Decreasing to adult levels at 5 years old
• Cardiac output higher (200ml/kg/min)
• Especially when calculated according to body
  weight it parallels O2 consumption
• Cardiac index constant
• Because of the infants high ratio of surface area
  to body weight
• O2 consumption depends heavily on temperature
• There is a 10-13 increase in O2 consumption for
  each degree rise in core temperature

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Circulation Variables in Infants

• Age (months) Sys/Dias mean
• 1 85/65 50
• 3 90/65 50
• 6 90/65 50
• 9 90/65 55
• 12 90/65 55

Age (months) Sys/Dias mean 1 85/65
50 3 90/65 50 6 90/65
50 9 90/65 55 12 90/65
55
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Autonomic Control of the Heart

• Sympathetic innervation of the heart is
  incomplete at birth with decreased cardiac
  catecholamine stores it has an increased
  sensitivity to exogenous norepinephrine
• It does not mature until 4-6 months of age

• Parasympathetic innervation has been shown to be
  complete at birth therefore we see an increased
  sensitivity to vagal stimulation

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Autonomic Control of the Heart

• The imbalance between sympathetic
  parasympathetic tone predisposes the infant to
  bradycardia
• Anything that activates the parasympathetic
  nervous system such as anesthetic overdose,
  hypoxia can lead to bradycardia

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Body fluid composition
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Changes in body fluid composition

• First 12-24 hours of life ?urine output is
  limited to 0.5 ml/kg/hr due to poor renal
  perfusion (oliguric phase)
• ?
• Natriuresis phase ? isotonic fluid lost from
  extracellular compartment
• ?
• 1-2 weight loss per day for first 5 days
• Extracellular water becomes 30 of total body
  water

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Fluid requirements

• Insensible losses are important ?
• Stools - 5 ml/kg/24 hours
• Transdermal 12 ml/ kg/ 24 hours
• Sodium containing fluids not given in the first
  few days of life until physiological diuresis is
  established
• 10 dextrose is used as maintenance fluid which
  is gradually increased over first few days of
  life
• Initial fluid requirements are 60-80 ml/kg/day
  increasing to 150 ml/ kg/day over the first week.

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Metabolism in neonate

• High energy requirements in neonate ?128
  kcal/kg/day
• Increased oxygen requirements are seen after
  birth ? 5 ml/kg/min on day 1 and 7 ml/kg/min on
  day 7 ? persists during infancy and reaches adult
  value in late childhood.
• Main source of energy for brain and myocardium is
  glucose
• Circulating catecholamines at birth ? energy
  generated by glycogenolysis, lipolysis,
  gluconeogenesis ? physiological drop in blood
  glucose seen 2 hours post delivery
• Glycogen stores depleted by 12 hours ? after this
  energy supplied by fat oxidation till enteral
  feeding established

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• Hypoglcemia defined as blood glucose
• ? ?
• lt 30 mg/dl lt 20 mg/dl
• (term neonate) (preterm neonate)
• (during first 3 days of life)
• After first 3 days of life ? hypoglycemia defined
  as blood glucose lt40 mg/dl

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Hepatic physiology

• Glucose from the mother is the main source of
  energy for the fetus
• Stored as fat glycogen with storage occurring
  mostly in last trimester
• At 28 weeks gestation the fetus has practically
  no fat stored, but by term 16 of the body is fat
  35gms of glycogen is stored
• In utero liver function is essential for fetal
  survival
• Maintains glucose regulation, protein / lipid
  synthesis drug metabolism
• The excretory products go across the placenta
  are excreted by the maternal liver
• Liver volume represents 4 of the total body
  weight in the neonate (2 in adult)
• However, the enzyme concentration activity are
  lower in the neonatal liver

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• Glucose is the infants main source of energy
• In the 1st few hours following delivery there is
  a rapid drop in plasma glucose levels
• Hepatic glycogen stores are rapidly depleted
  with fat becoming the principle source of energy
• The newborn should not be deprived for a long
  period of time from enteral or IV nutrition
• The lower limit of normal for glucose is 30mg/dl
  in the term infant
• Infants do not usually show neurological signs
  symptoms, but may develop sweating , pallor or
  tachycardia
• A glucose level lt 20mg/dl usually precipitates
  neurological signs such as apnea or convulsions
• Premature infants may have a tendency for
  hypoglycemia for weeks

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• Coagulation
• At birth, Vit K dependent factors (II, VII, IX
  X) are at a level of 20-60 of the adult value.
  This results in prolonged prothrombin time.
• Synthesis of Vit K dependent factors occurs in
  the liver which being immature leads to
  relatively lower levels of these factors.
• It takes several weeks for the levels of
  coagulation factors to reach adult values
• Administration of Vit K immediately after birth
  is important to prevent hemorrhagic disease

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Renal physiology

• The healthy newborn has a complete set of
  nephrons at birth (1 million)
• The glomeruli are smaller than adults
• The filtration surface related to body weight is
  similar
• Glomerular Filtration Rate (GFR)
• At birth is 1.5ml/kg/min. It increases quickly
  during the first two weeks, but then is
  relatively slow to approach the adult level (2
  ml/kg/min) by 2 years of age
• Low GFR in the full term infant affects the
  babys ability to excrete saline water loads as
  well as drugs
• Glomerular function
• Factors that contribute to the increase in GFR
• Increase in CO
• Changes in renovascular resistance
• Altered regional blood flow
• Changes in the glomeruli

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• Tubular Function Permeability
• Not fully mature in the term neonate even less
  in the premature infant
• Maturation of the tubules is behind that of the
  glomeruli
• Lack of renal medullary osmotic gradient and
  absence of medullary tubules limit urinary
  concentrating ability
• Concentrating ability of neonatal kidney
  (600mosm/kg) is half that of the adult (1200
  1400 mosm/kg)
• The kidney does show some response to
  antidiuretic hormone (ADH), but is less sensitive
  to ADH than the cells of mature nephrons
• Tubular reabsorption reaches adult value by 1
  year of age.
• Peak renal capacity is reached at 2-3 years after
  which it decreases at a rate of 2.5 per year
• Glycosuria and aminoaciduria due to immature
  active transport in the proximal tubules

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• Diluting Capacity
• Matures by 3-5 weeks postnatal age
• The ability to handle a water load is reduced
  the neonate may be unable to increase water
  excretion to compensate for excessive water
  intake. They are very sensitive to over hydration
• In infants children, hyponatremia occurs more
  frequently than hypernatremia

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• Creatinine
• Normal value is lower in infants than in adults
• This is due to the anabolic state of the newborn
  the small muscle mass relative to body weight
  (0.4mg/dl vs. 1mg/dl in the adult)
• At birth plasma creatinine levels mirror maternal
  values but fall to neonatal values by 2 weeks of
  age.
• Bicarbonate (NaHCO3)
• Renal tubular threshold is also lower in the
  newborn (20mmol/L vs. 25mmol/L in the adult)
• Therefore, the infant has a lower pH, of about
  7.34
• BUN
• The infants urea production is reduced as a
  result of growth so the immature kidney is
  able to maintain a normal BUN

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Temperature Regulation

• Body Temperature
• Is a result of the balance between the factors
  leading to heat loss gain and the distribution
  of heat within the body
• The potential exists for unstable conditions to
  progress to a positive feedback cycle
• The decrease in body temperature will lead to a
  decrease in the metabolic rate, leading to
  further heat loss diminished metabolic rate
• The body normally safeguards against this
  unstable state by increasing BMR during the
  initial exposure to cold or by reducing heat loss
  through vasoconstriction

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Temperature Regulation
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Temperature Regulation

• Central Temperature Control Mechanism
• This is intact in the newborn
• Is only able to maintain a constant body
  temperature within a narrow range of
  environmental conditions
• O2 consumption is at a minimum when the
  environmental temp is within 3-5 (1-2C) of body
  temp (an abdominal skin temp of 36C)
• This is known as the neutral thermal environment
  (NTE)
• A deviation in either direction from the NTE will
  increase O2 consumption
• An adult can sustain body temperature in an
  environment as cold as 0C where as a full term
  infant starts developing hypothermia at about
  22C

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• Generation of Heat
• Depends mostly on body mass
• Heat loss to the environment is mainly due to
  surface area
• Neonates have a ratio of surface area to mass
  about 3Xs higher than that of adult
• Premature Infants Temperature Control
• Are more susceptible to environmental changes in
  temperature
• The premature neonate has skin only 2-3 cells
  thick has a lack of keratin
• This allows for a marked increase in evaporative
  water loss (in extremes this can be in excess of
  heat production)

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• Important Mechanisms for Heat Production
• Metabolic activity
• Shivering
• Non-shivering thermogenesis
• Newborns usually do not shiver
• Heat is produced primarily by non-shivering
  thermogenesis
• Shivering does not occur until about 3 months of
  age

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• Non-shivering Thermogenesis
• Exposure to cold leads to production of
  Norepinephrine
• This in turn increases the metabolic activity of
  brown fat
• Brown fat is highly specialized tissue with a
  great number of mitochondrial cytochromes (these
  are what provide the brown color)
• The cells have small vacuoles of fat are rich
  in sympathetic nerve endings
• They are mostly in the nape between the
  scapulae but some are found in the mediastinal
  (around the internal mammary arteries) the
  perirenal regions (around the kidneys adrenals)

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• Once released Norepinephrine acts on the alpha
  beta adrenergic receptors on the brown adipocytes
• This stimulates the release of lipase, which in
  turn splits triglycerides into glycerol fatty
  acids, thus increasing heat production
• The increase in brown fat metabolism raises the
  proportion of CO diverted through the brown fat
  (sometimes as much as 25), which in turn
  facilitates the direct warming of blood
• The increased levels of Norepinephrine also
  causes peripheral vasoconstriction mottling of
  the skin

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l
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• Heat Loss
• The major source of heat loss in the infant is
  through the respiratory system
• A 3kg infant with a MV of 500ml spends 3.5cal/min
  to raise the temperature of inspired gases
• To saturate the gases with water vapor takes an
  additional 12cal/min
• The total represents about 10-20 of the total
  oxygen consumption of an infant
• The sweating mechanism is present in the neonate,
  but is less effective than in adults
• Possibly because of the immaturity of the
  cholinergic receptors in the sweat glands
• Full term infants display structurally well
  developed sweat glands, but these do not function
  appropriately
• Sweating during the first day of life is actually
  confined mostly to the head

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• Heat Exchange mechanims
• 1. Conduction
• Use warm blankets, Bair huggers warmed gel pads
  
• 2. Convection
• Increase OR temp, radiant warmers
• 3. Radiatian
• Radiation is the major mechanism of heat loss
  under normal conditions (same techniques to
  prevent as used in Convection)
• 4. Evaporation
• Under normal conditions 20 of the total body
  heat loss is due to evaporation
• This occurs both at the skin lungs
• Since the infants skin is thinner more
  permeable than the older childs or adults
  evaporative heat loss from the skin is greater
• In the anesthetized infant the MV (relative to
  body weight) is high thus increasing evaporative
  heat loss through the respiratory system

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Hematology in neonate

• 70- 80 of Hb in newborn is HbF
• HbF is replaced with HbA at 6 months of age
• Site of haematopoiesis in utero liver
• After delivery bone marrow
• Blood volume (ml/kg)
• Prematures 105
• Term newborn 85
• Adult 65

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Blood Cell Count

• Age Hb(g/dl) Hct() WBC(c/mm3)
• 1 day 19 61 18,000
• 1 month 14 43 12,000
• 1 year 12 35 10,000
• 10 years 13 39 8,000

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Neuro muscular junction physiology

• Development of neuromuscular system
• Skeletal muscle develop in a particular sequence
• ?
• Muscle fibers differentiate into type 1
  (oxidative, red muscles) and
  type 2 fibers ( glycolytic , white contracting)
• ?
• Initially type 2 fibers at 20 weeks gestation
• ?
• From 26- 30 weeks increase in type 1 fibers
• By 30 weeks type 1 and type 2 fibres are equal in
  number
• ?
• Diaphragm at full term has only 25 type 1 fibres
• Becomes 50 by age of 8 months.
• ?
• Hence ensure complete reversal of relaxant in
  this age group.

74
Neuromuscular junction development physiology

• At 8 weeks of gestation , AChRs occupy entire
  surface of myotubes( primitive muscle fibers)
• ?
• Onset of innervation at 9 weeks, AChR reactive
  areas contract to form primitive motor end plates
  on one side of muscle fibres.
• ?
• From 9 to 16 weeks polyneural innervation present
• ?
• By 25 weeks transition from polyneural to
  mononeral
• ?
• From 25 to 31 weeks motor end plate attains
  mature appearance, although continues to grow in
  size until the end of first year of life.

75
Acetylcholine receptor

• Fetal (2a, ß, d, ? subunits ) and adult forms of
  receptor (2a, ß, d, e subunits)
• before innervation fetal receptor predominates
• During synapse formation two receptor classes
  coexist
• at later stages of synapse formation fetal
  receptors are fully replaced by adult type. Fetal
  receptors not detected after 31 weeks of
  gestation
• May reappear at extrajunctional sites in
  pathological states

76

• 2 molecules of ACh combine with a subunit
• ?
• Central pore opens (duration in fetal receptor 6
  ms and in adult receptor 1.5 ms)
• ?
• Allows sodium ions to enter cell
• ?
• Depolarisation leading to muscle contraction
• Fetal receptor sensitive to agonist like ACh and
  resistant to antagonist like NDMR

77
Maturation of neuro muscular junction

• Maturation incomplete at birth
• Main deficiency is reduced availability of Ach in
  motor nerves
• Hence 3 times more sensitive to NDMR and normal
  response to succinylcholine in neonate

78
Neonatal pharmacology

• Factors affecting drug absorption in neonates
• 1. Physicochemical factors
• Drug formulation
• Molecular weight
• Proportion of drug in ionized/ non ionized form
• Lipid solubility

79

• 2. Patient factors-
• general- surface area available for absorption
• Gastrointestinal-
• -Gastric content and gastric emptying
• -Gastric and duodenal ph
• -Bile salt pool
• -Bacterial colonization of lower gut
• -Disease states (short gut syndrome, biliary
  atresia)

80

• Muscle-
• -Increased capillary density in neonatal muscle
  increases absorption from muscles
• -Reduced cardiac output states reduce absorption
• Skin-
• -Blood supply
• -Peripheral vaodilation
• -Thickness of skin/ stratum corneum
• -Surface area
• Rectal-
• -Depth of insertion
• -Lower gut motility

81
Drug distribution in neonate

• Fluid distribution volume of distribution for
  water soluble drugs is increased
• Body tissue composition due to less fat and
  muscle, drug redistribution is reduced
• Protein binding lower albumin and total protein
  concentrations resulting in greater free drug
  levels.
• Drug competing with bilirubin for protein
  binding
• Blood brain barrier less lipid soluble drugs
  also enter brain easily

82
Hepatic metabolism of drug

• Depends on enzyme maturity and hepatic blood flow
• Phase 1 reactions (oxidation, reduction and
  hydrolysis) mature to adult value by 6 months
  of age
• Phase 2 reactions sulfation is mature at birth
• Glucoronidation , acetylation , glycination
  mature by 1 year of age

83
Renal excretion

• Glomerular and tubular function immaturity can
  prolong elimination half life of many drugs
• With low renal blood flow at birth, the fine
  balance between vasoconstrictor and vasodilator
  renal forces are important.

84
morphine Hepatic conjugation and renal clearance is reduced. More CNS penetration. Adult values of clearance reached by 6-12 months. Initial dose in neonates is .025mg/kg
fentanyl Clearance is 70 80 of the mature value due to immature enzyme systems, reduced hepatic blood flow. Raised intra abdominal pressures reduce hepatic blood flow. Dose in infants is 1-3 µg/kg, in neonates the initial dose is lower.


85
Paracetamol Hepatic metabolism of PCM reaches adult value by 4 months. Hence reduced formation of hepatotoxic metabolites. Rectal administration slow and variable absorption due to lower gut motility, drug formulation, depth of drug insertion Oral loading dose in a neonate is 15mg/kg, then 10-15mg/kg. maximum dose of 60 mg/kg/day Rectal loading dose 20mg/kg. then 15mg/kg.
NSAIDs NSAIDs in neonate can reduce GFR by counteracting vasodilatory prostaglandin E Safe in infants gt 3 months.
86
SUCCINYLCHOLINE larger volume of distribution. low levels of butyrylcholinesterase activity Children are more susceptible than adults to bradycardia, masseter spasm and malignant hyperthermia. Neonates require higher dose of succinylcholine (3mg/kg) Atropine must always be administered prior to succinylcholine in children. Less development of muscle fasciculations and post operative myalgia

87
NDMR

• Response of neonates to non depolarising
  relaxants is variable because of
• Immaturity of neuromuscular junction ?Ach release
  from motor nerves ? increased sensitivity to
  NDMR.
• Large volume of distribution requiring large doses

88
Atracurium preferred agent in young infants. Dose 0.5mg/kg
Pancuronium preferred in neonates where bradycardia undesirable Dose .05mg/kg
Vecuronium behaves like long acting relaxant in neonates due to liver immaturity. Dose .08mg/kg
Rocuronium has longer duration of action in neonates. Dose- 0.6 mg/kg
89
Thiopentone neonates are more sensitive due to lesser fat, less protein binding, impaired clearance. 2-4 mg/kg
Propofol is not licensed for use as an inducing agent in neonates.
90
Diazepam reduced hepatic blood flow and immature hepatic excretory mechanism can prolong the elimination half life up to 100 hours in the neonate Intravenous solution contains preservative benzyl alcohol, avoided in neonates because of the risk of metabolic acidosis and kernicterus
Midazolam Clearance depends on hepatic blood flow and enzyme activity. Active metabolite of midazolam has minimal activity. More suited for use in neonates. Dose - .05-.1 mg/kg
91
INHALATIONAL ANESTHETICS

• Rapid inhalational induction is seen in neonates
  and infants ?
• 1)higher alveolar ventilation and lower FRC
• 2) relatively higher blood flow to vessel rich
  organs
• 3) lower blood gas partition coefficients of
  inhalational agents.
• MAC for inhalational agents is maximum between
  1-6 months of age and decreased in neonates.

92
MAC VALUES

age halothane isoflurane sevoflurane
0-1 mth 0.87 1.60 3.3
1-6 mth 1.20 1.87 3.2
6-12 mth 1.20 1.80 2.5
1-3 yrs 0.97 1.60 2.6
3-5 yrs 0.91 - 2.5
5-12 yrs 0.87 - 2.5
25 yrs 0.73 1.28 2.6
93
Local anesthetics

• Due to lower levels of a1 acid glycoprotein in
  neonates, higher concentration of drug is in free
  form
• Local anesthetics are metabolised in liver and
  clearance is low in neonates
• Neonates and infants are more sensitive to heart
  block induced by local anesthetics due to faster
  heart rates.

94
References

• Millers text book of anaesthesia, 6th edition
• A practice of anaesthesia, wylie, 7th edition.
• Clinical anesthesiology, Morgan, Mikhail, Murray,
  
• 4th edition
• Adaptation for life a review of neonatal
  physiology. Anaesthesia and intensive care
  medicine 93
• Obstetric anaesthesia, Chestnut.
• Textbook of paediatric anaesthesia, 3rd edition,
  Hatch and Sumners
• Clinical anaesthesia, 5th edition, Barash
• Pediatric anesthesia, 2nd edition, Gregory

95

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