Pediatric anatomy and pharmacology

Presenter – Dr. aparna (pg 2nd yr) Moderator –Dr. A.K. sinha (asso. prof.)

GMC HALDWANI (UTTARAKHAND)

DEVELOPMENTAL CONSIDERATIONS

• within 8 weeks of conception- Organogenesis • second trimester -organ function develops• third trimester -the infant gains weight, primarily muscle and fatAny 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 reducedInsult 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.

Ductus botalli

Arantius duct

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.

• 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.

• 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.

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

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 largein adults that commonly used tracheal tubes are usually

easy to advance past the glottic opening.

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.

• 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.

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.

Lower respiratory tract

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.

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).

Pharmacology of anaesthetics in pediatric population

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

• 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).

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.

• 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

• 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

• Chidren are not small adults.• From route of adminstration to effect of drugs every

step is different from adults.

• Dose of drug administred drug in tissue distribution Drug conc in systemic circulation metabolism and excretionDrug 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-

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.

• 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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

• 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.

• 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.

• 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.

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.

• 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.• .

In children induction with sevoflurane done by two methods1)the inspired conc of sevoflurane inceased upto 8%and controlled

ventilation 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.

• 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.

• Isoflurane-• Noxious smell• Associated with airway incidents.• Stimulate pulmonary irritant receptor and

increase sympathatic activity and stimulation of RAAS.

• 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.

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.

• 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.

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.

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.

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 .

• 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.

• 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.

• 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. .