ALL ABOUT ANA AND PHARMA OF PAEDIATRIC AGE GROUP

1. Pediatric anatomy and
pharmacology
Presenter – Dr. aparna (pg 2nd yr)
Moderator –Dr. A.K. sinha (asso. prof.)
GMC HALDWANI (UTTARAKHAND)

2. DEVELOPMENTAL CONSIDERATIONS
• within 8 weeks of conception- Organogenesis
• second trimester -organ function develops
• third trimester -the infant gains weight, primarily muscle and fat
Any insult in
• 1st trimester-abnormal organogenesis
• 2nd trimester-functional development of organs may be abnormal;
• 3rd trimester-, organs may be smaller or muscle and fat mass may be reduced
Insult can be
• congenital viral infections, exposure to drugs (therapeutic or recreational),
nutritional insufficiency (caloric or vascular) , or maternal illness. A genetic
predisposition to developmental malformations can also produce adverse
effects.
Outcome may range from simple preterm birth to a constellation of congenital
malformations.

5. Ductus botalli
Arantius duct

6. Transition
• placenta is removed from the circulation; portal blood pressure falls,
which causes the ductus venosus to close;
• blood becomes oxygenated through the lungs. Exposure of the ductus
arteriosus to oxygenated blood induces ductal closure.
• pulmonary vascular resistance decreases while peripheral vascular
resistance rapidly rises which causes increase in pressure on the left side
of the heart leading to mechanical closure of the foramen ovale.

7. • True mechanical closure of ductus arteries by fibrosis does
not occur until 2 to 3 weeks of age.
• During this critical period, the infant readily reverts from the
adult type of circulation to a fetal type of circulation; this state
is called transitional circulation. Many factors (e.g., hypoxia,
hypercapnia, anesthesia-induced changes in peripheral or
pulmonary vascular tone) can affect this precarious balance
and result in a sudden return to the fetal circulation.
• ANATOMICAL DIFFERENCES-The myocardial structure of the
heart, is significantly less developed in neonates than in
adults.

8. • This developmental immaturity of myocardial structures accounts for the
tendency toward biventricular failure, sensitivity to volume loading, poor
tolerance of increased afterload and heart rate–dependent cardiac
output.
• Another issue is that cardiac calcium stores are reduced because of the
immaturity of the sarcoplasmic reticulum; consequently, neonates have a
greater dependence on exogenous (blood-ionized) calcium and probably
increased susceptibility to myocardial depression by volatile anesthetics
that have calcium channel– blocking activity.

9. Respiratory system
Typically, the airway of infants differs from adults in five ways:
(1) The relatively large size of the infant’s tongue, in relation to the
oropharynx, increases the likelihood of airway obstruction and
technical difficulties during laryngoscopy.
(2) The larynx is located higher (more cephalic) in the neck, thus
making straight blades more useful than curved blades.
(3) The epiglottis is shaped differently, being short, stubby, omega
shaped, and angled over the laryngeal inlet. Control with the
laryngoscope blade is therefore more difficult.
(4) The vocal cords are angled; consequently, a blindly passed tracheal
tube may easily lodge in the anterior commissure rather than slide
into the trachea.
(5) Finally, the infant larynx is funnel shaped, the narrowest portion
occurring at the cricoid cartilage

12. Classic teaching has been that the adult larynx is cylindrical and the infant
larynx is funnel shaped. However, it is now known that the narrowest portion
in approximately 70% of adults is also in the subglottic region at the level of
the cricoid cartilage. The opening is so large
in adults that commonly used tracheal tubes are usually
easy to advance past the glottic opening.

13. In infants or young children, a tracheal tube that easily passes the vocal cords may be tight in the subglottic
region because of the relatively greater proportional narrowing at the level of the cricoid cartilage. Thus
uncuffed tracheal tubes were in the past preferred for children younger than 6 years of age. However, the
development of better tracheal tube design and several prospective studies have combined to allow the more
common use of cuffed tracheal tubes, even in infants.8,9 Nonetheless, a leak should be maintained around the
cuff (with or without inflation) because injury to the tracheal mucosa is still possible.

14. • These more expensive tracheal tubes are usually reserved for children
with anticipated prolonged tracheal intubation (reduced ventilator-
associated pneumonia),12 and the lower-cost tracheal tubes are still used
for short-term intraoperative tracheal intubation
• Although infants are obligate nasal breathers, approximately 8% of
preterm neonates (31 to 32 weeks’ postconceptual age [PCA]) and 40% of
term infants can convert to oral breathing if the nasal airway is obstructed.

15. Pulmonary system
• Alveoli increase in number and size until the child is approximately 8 years old.
Further growth is exhibited as an increase in size of the alveoli and airways.
• At term, complete development of surface active proteins helps maintain
patency of the airways. If a child is prematurely born and these proteins are
insufficient, then respiratory failure (e.g., respiratory distress syndrome) may
follow.
• Respiration is less efficient in infants. The small diameter of the airways
increases resistance to airflow; The airway of infants is highly compliant and
poorly supported by the surrounding structures.
• The chest wall is also highly compliant, therefore the ribs provide little support
for the lungs; that is, negative intrathoracic pressure is poorly maintained.
Thus functional airway closure accompanies each breath.
• Another important factor is the composition of the diaphragmatic and
intercostal muscles. These muscles do not achieve the adult configuration of
type I muscle fibers until the child is approximately 2 years old. Because type I
muscle fibers provide the ability to perform repeated exercise, any factor that
increases the work of breathing contributes to early fatigue of the respiratory
muscles of infants; this partially explains why the infant’s respiratory rate and
hemoglobin desaturation is so rapid, and their propensity to develop fatigue
and apnea with airway obstruction.

18. Lower respiratory tract

19. CNS
• The blood brain barrier is poorly formed.
• Drugs such as barbiturates, opioids, antibiotics and
bilirubin cross the blood brain barrier easily causing a
prolonged and variable duration of action
• The cerebral vessels in the preterm infant are thin
walled, fragile. They are prone to intraventricular
haemorrhages. The risk is increased with hypoxia,
hypercarbia, hypernatraemia, low haematocrit, awake
airway manipulations, rapid bicarbonate administration
and fluctuations in blood pressure and cerebral blood
flow. Cerebral autoregulation is present and functional
from birth.

20. THE KIDNEYS
• because of small perfusion pressures and immature glomerular and
tubular function - Renal function is diminished in neonates and even more
in preterm infants
• Nearly complete maturation of glomerular filtration and tubular function
occurs by approximately 20 weeks after birth, although delayed in
preterm infants.
• Complete maturation of renal function occurs at approximately 2 years of
age.
Thus the ability to excrete free water and solute loads may be impaired in
neonates, and the half-life of medications excreted by means of
glomerular filtration will be prolonged (e.g., antibiotics, hence the longer
intervals between doses in neonates).

22. Pharmacology of anaesthetics in
pediatric population

23. DEVELOPMENTAL PHARMACOLOGY
The response of infants and children (particularly neonates) to
medications is modified by many factors:
• Body composition,
• protein binding,
• body temperature,
• distribution of cardiac output,
• functional organ (heart, liver,kidneys) maturity,
• maturation of the blood-brain barrier,
• the relative size of the liver and kidneys
• and the presence or absence of elevated intraabdominal
pressure(gastroschisis or omphalocele closure)
• or congenitalmalformations

24. • Total body water content is significantly higher in preterm infants than in
term infants and in term infants than in 2 year olds. Fat and muscle
content increases with age. CLINICAL IMPLICATIONS:
(1) a drug that is water soluble has a large volume of distribution and usually
requires a large initial dose (mg/kg) to achieve the desired blood level
(e.g.,most antibiotics, succinylcholine);
(2) because the neonate has less fat, a drug that depends on the
redistribution into fat for the termination of its action will have a long
clinical effect; and
(3) a drug that redistributes into muscle may have a long clinical effect (e.g.,
fentanyl, for which, however, saturation of muscle tissue has not been
demonstrated).

25. Anesthetic requirement is smaller for preterm than for term neonates and smaller for
term neonates than for 3 month olds. This fact, combined with the need for deeper
planes of anesthesia to achieve satisfactory conditions for tracheal intubation, places
the infant in a precarious position because the safety margin between anesthetic
overdose (from a cardiovascular standpoint) and inadequate depth of anesthesia (for
tracheal intubation) is small.

26. • Avoiding controlled respirations until an intravenous line is
inserted,rapidly reducing the delivery of inspired anesthetic
drug,especially with the initiation of controlled respirations after the
administration of a muscle relaxant, and, in some cases, substituting
opioids for an inhaled anesthetics are practices that may improve safety.
Uptake of volatile anesthetics is more rapid in children
• an increased respiratory rate and cardiac index
• and a greater proportional distribution of cardiac output to vessel-rich
organs.
• This rapid rise in blood anesthetic levels, combined with functional
immaturity of cardiac development,-- delivering an inhaled anesthetic
overdose to infants and toddlers is so easy

27. • more rapid rise in alveolar concentration in infants.
• Age-related differences in blood-gas partition coefficients
• state of hydration (e.g., excessive fasting would make a small infant relatively
dehydrated) and
• the type of anesthesia circuit used. For example, a Mapleson D has a smaller
volume than a circle system; therefore less volume is needed to achieve
equilibration when the concentration of anesthetic agent exiting the vaporizer
increases.
• With a Mapleson D circuit (rarely used in modern anesthetic practices), the
fresh gas flow is introduced into the system at the airway and directly enters
the child’s lungs.
• Perhaps the most important factor influencing the potential for anesthetic
overdose in neonates is the number of MAC multiples that can be delivered by
the vaporizer; for example, a halothane vaporizer can deliver up to 5.75 MAC
multiples versus 2.42 MAC multiples for a sevoflurane vaporizer

28. • Chidren are not small adults.
• From route of adminstration to effect of drugs every
step is different from adults.

29. • Dose of drug administred
drug in tissue distribution
Drug conc in systemic circulation
metabolism and excretion
Drug conc at site of action
effect
dual processes of pharmacokinetics and pharmacodynamics of drugs administered to
patients in general is illustrated in the next figure-

30. ABSORPTION
• extravascular routes preoperatively and post operative.
• intravenously in the operation theatre or ICU.
ROUTE
• Oral :
• The gastric pH, which is 6 to 8 at birth, decreases to 1 to
2 within 24 hours and finally reaches adult levels between
6 months and 3 years of age.
•Decreased basal acid output and total volume of gastric
secretions is seen in the neonate.
•Bile acid secretion being less in the neonate may reduce
the absorption of lipid soluble drugs.
•The rate of gastric emptying varies during the neonatal
period, but can be markedly increased in the first week of
life.

31. • Long chain fatty acids (as found in certain neonatal
formulae) can delay gastric emptying, and this must be
remembered while determining the fasting status of
neonates appearing for surgery.
•Processes of both passive and active transport are fully
mature in infants by approximately 4 months of age.
•Intestinal enzymatic changes in the neonate such as low
activity levels of cytochrome P-450 1A1 (CYP1A1) can
alter the bioavailability of drugs.
Disadvantages of the oral route include emesis, destruction of
the drug by digestive enzymes or their metabolism prior to
absorption, presence of food or other drugs, which cause
irregularities in absorption and first pass hepatic effect

32. Oral transmucosal drug /nasal administration :
This route of administration of drugs bypasses the first pass
hepatic effect and causes a rapid onset of drug action eg.
sublingual nitroglycerine and nasal midazolam and ketamine.

33. Parenteral :
 The rate of systemic absorption of drugs after IM administration
is more rapid and predictable than after oral or rectal
administration due to high density of skeletal muscle capillaries in
infants than older children.
 Reduced skeletal muscle blood flow and inefficient muscular
contractions (responsible for drug dispersion) can theoretically
reduce the rate of IM absorption of drugs in neonates.
Drugs injected intravenously act almost immediately.

34. Transdermal :
 it provides sustained therapeutic plasma drug
concentrations eg fentanyl, clonidine, nitroglycerine and EMLA.
 Enhanced percutaneous absorption of drugs in infancy is
due to the presence of a thinner stratum corneum in the preterm
neonate and greater extent of cutaneous perfusion and hydration
of the epidermis throughout childhood.
 Neonates have a large ratio of body surface area to body
mass. There is a potential for drug overdose in neonates by this
route.

35. Rectal :
Drugs administered in the anal canal
below the ano-rectal or dentate line bypass the liver after
absorption
 above this line by absorption via the superior rectal vein
undergo first pass hepatic metabolism.
 Absorption of rectally administered drugs is thus slow and
erratic and also depends on whether the drugs are given in the
form of suppositories, rectal capsules or enemas.
drugs used per rectum include thiopentone, methohexital,
diazepam, atropine, and acetaminophen.

36. Intrapulmonary :
This mode of administration is increasingly being used in
infants and children eg. surfactant and adrenaline.
 Though the goal is to achieve a predominantly local effect
systemic exposure does occur.

37. Uptake and Distribution-
depends on
 cardiac output,
 tissue perfusion and
 blood tissue partition co-efficient of the drug.
volume of distribution (Vd)
The relatively larger extracellular and total body water spaces
in neonates and infants compared to adults, coupled with adipose tissue
that has a higher ratio of water to lipid, result in lower plasma
concentrations of these drugs.

38. Fetal albumin has a lower binding affinity and capacity for
drugs like weak acids (salicylates). Substances like free fatty
acids, bilirubin, sulfa and maternal steroids can displace a drug
from albumin binding sites and increase the free fraction of the
drug in the neonate.
 1 acid - glycoprotein, reduced amounts of which is probably
responsible for a significant proportion of unbound drug in
infants. Drugs like diazepam, propranalol and lignocaine are less
highly bound to a1 acid - glycoprotein in children than in adults.

39. Metabolism
Development of phase I and phase II enzymes :
Phase I reactions -
oxidation, reduction and hydrolysis are cytochrome p-450
dependent.
The clearance of intravenously administered midazolam from
plasma is primarily a function of hepatic CYP3A4 and CYP3A5
activity and the level of activity increases during the first 3
months of life.
 Most phase I enzymes function at adult levels by 6 months of
life.. All phase II enzymes mature by 1 year of age.

40. Phase II reactions -
involve conjugation with acetate, glycine, sulfate and
glucuronic acid.
 Individual isoforms of glucuronosyl transferase (UGT) have
unique maturational profiles.
 Glucuronidation of acetaminophen (a substrate for
UGT1A6) and salicylates is decreased in newborns.
A compensatory pathway (glycine pathway) for metabolism
of salicylates makes their elimination half life only slightly
longer in neonates.

41.  Both phase I and phase II reactions can be induced by
barbiturates. The rate of drug metabolism is also determined
by other factors such as intrinsic rate of the process, hepatic
blood flow etc

42. Excretion
 The neonatal kidney receives only 5-6% of cardiac output
compared to adults who receive 20-25% of cardiac output.
Term neonates have a full complement of glomeruli while
preterm neonates do not have a full number of glomeruli.
The glomerular filtration rate (GFR) is approximately 2-4 ml
per minute per 1.73 m2 in term neonates. This increases
rapidly over the first 2 weeks of life and reaches adult values
by 8-12 months of age.
 Tubular secretion is immature at birth and reaches adult
values during the first year of life.
A slightly acidic urine at birth (pH 6-6.5) decreases the
elimination of weak acids. If the kidney is the primary route
of drug elimination, the neonate’s reduced renal function can
delay the drug elimination.

43. Individual drugs
Intravenous induction agents
Thiopentone –
intravenous bolus administration of 2.5% thipoentone is
sufficent to induce children.
Termination of effect occurs through redistribution into muscle
and fat so it should be used in reduced doses in children with low
fat stores.

44. • Propfol-
• it is highly lipophillic.
• Promptly distributed in vessel rich organs ,rapid redistribution ,high
renal clearence account for short duration of action.
• So induction dose is higher in younger children(2.9mg/kg).
• Major draw back –painful injection
• Which can be eliminated by mixture of .2mg/kg lidocaine in
propofol or mini-bier block.
• It should be use with caution in children with egg/soy allergies.
• Major concern-in chidren with known defect in lipid metabolism as
it can cause propofol infusion syndrome.

45. • Ketamine-
• causes central dissociation of cerebral cortex and
provides amnesia and analgesia.
Routes of administration can be-
intramuscular/intravenous/rectal(10mg/kg)/orally(6-
10mg/kg),/intanasally(3-6mg/kg).
Intravenous .25-.5mg/kg may be used to provide sedation
and analgesia for painful procedures.
Contraindications-active URTI,increased ICT,open globe
injury,seizure disorders.
Only preservative free ketamine should be used for
epidural analgesia because risk of neurotoxicity.

46. • Etomidate-
• extremely useful in children with head
injury and those with unstable cardiovascular
status eg cardiomyopathy.
• Major concerns regarding allergic reactions
and adrenal supression.so should not be used
in critically ill children.

47. Inhaled anesthetics
• The expired minimum alevolar concentration of
an inhalational anesthetic required in children
changes with age.
• Infants have a higher MAC than that of older
children or adults the reasons for age related
diffrences in MAC are not known.
• Uptake of volatile anesthetics is more rapid in
children because of increased respiratory rate
and cardiac index and a greater proportional
distribution of cardiac outputto vessel rich
organs.

48. • Sevoflurane-
• Sevoflurane is less pungent then iso and desflurane.
• Mac is highest for neonates.
• In comparision to halothane ,halothane produces decrease
in tidal volume,and increase in respi rate wheras
sevoflurane decrease both of them.
• Children older then 3yrs experienced increase in HR and no
change in SBP with sevoflurane,whereas with halothane
,HR not change but SBP decreases.
• Sevoflurane causes less myocardial depression then
halothane.
• .

49. In children induction with sevoflurane done by two methods
1)the inspired conc of sevoflurane inceased upto 8%and controlled
ntilation is instituted.when spontenous respiration stops then propofol
1mg/kg administred ,the vaporizer shut off and ETT inserted.
• 2)if muscle relaxation is required then sevoflurane
administred with conc 3.5%-4% and muscle relaxant
administred ,then ETT inserted.
• Sevoflurane and baralyme can associated with fires and
expolsion d/t exothermic reaction (esp with dry desiccant)
• Major concern in children with sevoflurane induction is high
rate of emergence agitation which can be reduced by
midazolam,fentanyl,ketorolac.

50. • Halothnae-
• rapidity of awakening(3-5min)
• Airway realated problems are less with halothane
then iso/desflurane.
• Risk of halothane hEpatitis is less in children.
• Risk of arrhythmias are more in children which is
usually caused by hypercapnia and inadeqate
dept of anaesthesia and hypovolemia.
• Myocardial depression which is profound in
children with CHD.

51. • Isoflurane-
• Noxious smell
• Associated with airway incidents.
• Stimulate pulmonary irritant receptor and
increase sympathatic activity and stimulation
of RAAS.

52. • Desflurane-
• high incidence of laryngospasm in children.
• But can be use for maintenance.
• Advantage is rapid awakening.
• Potential risk of CO poisioning d/t dry carbon
dioxide absorbant.

53. Anxiolytics and sedatives
• Diazepam-
• oral absorption is more rapid then adults.
• Intravenous injection is painful so rectal and
oral route is prefered.
• Extremely long half life in neonates(80 hrs)so
not indicated in infants under 6mnt of age d/t
immature hepatic metabolism.

54. • Midazolam-
• water soluble so no pain on injection.
• Shorter elimination half life-( 2hrs)is advantage over
diazepam.
• Severe hypotension has occurred after iv bolus injection in
neonates.
• Routes-
• IM(.1-.15mg/kg)/oral(.25-1.0mg/kg)/rectal(.75-
1.0mg/kg)nasal(.2mg/kg) sublingual(.2mg/kg)
• Nasal route may increase risk of CNS toxicity.

55. Narcotics
Morphine –
• morphine depresses the respiratory centre of
newborns more than does pethidine.
• When the brain uptake index (BUI) for morphine was
determined in developing rats, it was higher in the younger than
the older rats.
• infants less than 1 week of age demonstrate longer elimination
half life compared to older infants.

56. Pethidine –
• Though pethidine is more lipid soluble than morphine
there is reduced CNS uptake and sensitivity to pethidine
• It produces only 1/10 the respiratory depression and less
sedation than morphine.
• The activity of pethidine may be less because the opioid
receptors of the brain are more primitive and do not recognize
structural analogues.
Fentanyl –
In the neonate, fentanyl clearance seems comparable to
that of the older child or the adult, while in the premature infant
fentanyl clearance is markedly reduced.

57. Neuromuscular blocking drugs (NMBD)
Infants have a much greater potentiation and reduction in dose
requirements than older children.
Depolarizing muscle relaxants –
•On a weight basis more succinylcholine is needed in infants than in
older children or adults.
• Succinylcholine is rapidly distributed throughout the ECF because
of its relatively small molecular size. Therefore, the recommended
dose is twice that of adults (2 mgkg-1).
• The rate of succinylcholine hydrolysis may be slower in the
preterm infant than in the older child due to their immature liver.
•Intramuscular injection dose is-5mg/kg for infants
• 4mg/kg for children older then 6mt
•Effect of im injection may last upto 20min
•In emergency scoline may be administred via submental approch .

58. • Cardiac arrythmias are very frequent even in teenagers.
• Vagolytic should be administred before first dose of scoline
in all children including teenagers unless contraindication
to tachycardia is not present.
• High potential for rhabdomyolysis and hyperkalemia esp
inyounger age group <8yrs who have unrecognized
muscular dystrophy.
• Masseter tetany usually associated with malignant
hyperthermia.
• Safer alternative of scoline for RSI and t/t of laryngospasm
is rocuronium(1.2mg/kg) only if antagonist is available.

59. • Nondepolarizing muscle relaxants-
• Infants are more sensitive to these drugs.
• Increase volume of distribution and reduced hepatic and renal
clerance prolonges the effect.
• So NM blockade occurs at low dose.
• The choice of NDMR depends on S/E and duration of desired
muscle relaxation.
• Eg if tachycardia is required in fentanyl sedation then
pancuronium is relaxant of choice.
• Atracurium and cis atracurium undergoes hoffman elimination
and ester hydrolysis.so useful in newborn and children.
• Only injection rocuronium can be administred intamuscular.
• Dose 1mg/kg in infants
• Dose 1.8mg/kg in children >1yr
• Duration of action is 1hr.

60. • Anticholinesterases –
• Neuromuscular blockade in children is antagonized much
faster and by much smaller doses of anticholinesterases as
compared to adults.
• Both cholinesterase and pseudocholinesterase levels are
reduced in premature and term newborns.
• Adult levels are not reached until one year of age.
.